tag:blogger.com,1999:blog-70843517694080804862024-03-13T19:49:00.572-07:00NeuropharmaA blog on neuropharmacologyCarlos Vázquezhttp://www.blogger.com/profile/09266699098392968330noreply@blogger.comBlogger15125tag:blogger.com,1999:blog-7084351769408080486.post-3387501527070859982015-11-14T04:09:00.003-08:002015-11-14T04:09:47.756-08:00Oral Steroids Not Inferior to Intravenous Steroids in Multiple Sclerosis Relapses<header class="entry-header" style="background-color: white; box-sizing: border-box; font-family: Georgia, Times, serif; line-height: 22.4px;"><blockquote class="tr_bq" style="border-image-outset: initial; border-image-repeat: initial; border-image-slice: initial; border-image-source: initial; border-image-width: initial; border: none; box-sizing: border-box; color: #999999; margin-bottom: 6px; padding: 0px;">
<span style="box-sizing: border-box; font-size: 16px; font-weight: 700; line-height: 22.4px;">Clinical question:</span><span style="font-size: 16px; line-height: 22.4px;"> </span><span style="font-size: 16px; line-height: 22.4px;">Is there any difference between oral and intravenous methylprednisolone for multiple sclerosis relapses?</span></blockquote>
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<span style="box-sizing: border-box; font-weight: 700;">Background:</span> When relapses of multiple sclerosis occur, studies have shown that intravenous steroids are the treatment of choice. Prior Cochrane meta-analyses have not found any significant difference between intravenous and oral treatments; however, the studies all have had limitations. This study was designed to provide a statistically significant answer.</div>
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<span style="box-sizing: border-box; font-weight: 700;">Study design:</span> Randomized, double-blinded, noninferiority trial.</div>
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<span style="box-sizing: border-box; font-weight: 700;">Setting:</span> Thirteen multiple sclerosis centers in France.</div>
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<span style="box-sizing: border-box; font-weight: 700;">Synopsis:</span> Patients were selected if they had had a relapse within the previous 15 days; the mean time was seven days. One hundred patients were in the oral steroid group, and 99 were in the intravenous steroid group. Each group received 1 g of methylprednisolone daily for three days. In addition, each group received saline infusions or placebo capsules to keep the study blind.</div>
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After 28 days, 81% of the oral group and 80% of the intravenous group had improvements of their symptoms. Side effects from the medications were similar as well.</div>
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The study was limited by the fixed dosing (1 g daily) that was not bioequivalent. Also, MRIs, although not always used in relapses, could have added more objective information, as everyone was followed clinically using the Kurtzke Functional System Scale.</div>
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<span style="box-sizing: border-box; font-weight: 700;">Bottom line:</span> Consider using oral instead of IV steroids in patients with relapsing multiple sclerosis.</div>
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<span style="box-sizing: border-box; font-weight: 700;">Citation:</span> Le Page E, Veillard D, Laplaud DA, et al. <a href="http://www.ncbi.nlm.nih.gov/pubmed?term=Oral+versus+intravenous+high-dose+methylprednisolone+for+treatment+of+relapses+in+patients+with+multiple+sclerosis+%28COPOUSEP%29%3A+a+randomised%2C+controlled%2C+double-blind%2C+non-inferiority+trial&TransSchema=title&cmd=detailssearch" style="box-sizing: border-box; color: #0e66a9; text-decoration: none; transition: all 0.1s ease-in-out;" target="_blank">Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial</a>. <em style="box-sizing: border-box;">Lancet</em>. 2015;386(9997):974-981.</div>
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Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-7084351769408080486.post-90950702576272751412015-09-22T11:57:00.002-07:002015-09-22T11:57:28.862-07:00Clinical Trial on the Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia<div class="contentSection" style="border: 0px; font-family: inherit; font-size: inherit; font-stretch: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 10px 0px 0px; vertical-align: baseline;">
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<strong style="border: 0px; font-family: inherit; font-size: 14px; font-stretch: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">Objective</strong><span style="font-family: Georgia, Cambria, Times, 'Times New Roman', serif; font-size: 1em; font-style: inherit; font-variant: inherit; line-height: 1.5;"> </span><span style="border: 0px; font-family: Georgia, Cambria, Times, 'Times New Roman', serif; font-size: inherit; font-stretch: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">To assess the efficacy, safety, and tolerability of dextromethorphan hydrobromide–quinidine sulfate for Alzheimer disease–related agitation.</span></div>
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<span class="Abstract 0" id="scm6MainContent_ucArticleContent_rptSections_lblSection_0" style="border: 0px; font-family: inherit; font-size: inherit; font-stretch: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">
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<strong style="border: 0px; font-family: inherit; font-size: 14px; font-stretch: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">Design, Setting, and Participants</strong> <span style="border: 0px; font-family: inherit; font-size: inherit; font-stretch: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">Phase 2 randomized, multicenter, double-blind, placebo-controlled trial using a sequential parallel comparison design with 2 consecutive 5-week treatment stages conducted August 2012–August 2014. Patients with probable Alzheimer disease, clinically significant agitation (Clinical Global Impressions–Severity agitation score ≥4), and a Mini-Mental State Examination score of 8 to 28 participated at 42 US study sites. Stable dosages of antidepressants, antipsychotics, hypnotics, and antidementia medications were allowed.</span></div>
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<strong style="border: 0px; font-family: inherit; font-size: 14px; font-stretch: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">Interventions</strong> <span style="border: 0px; font-family: inherit; font-size: inherit; font-stretch: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">In stage 1, 220 patients were randomized in a 3:4 ratio to receive dextromethorphan-quinidine (n = 93) or placebo (n = 127). In stage 2, patients receiving dextromethorphan-quinidine continued; those receiving placebo were stratified by response and rerandomized in a 1:1 ratio to dextromethorphan-quinidine (n = 59) or placebo (n = 60).</span></div>
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<strong style="border: 0px; font-family: inherit; font-size: 14px; font-stretch: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">Main Outcomes and Measures</strong> <span style="border: 0px; font-family: inherit; font-size: inherit; font-stretch: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">The primary end point was change from baseline on the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (scale range, 0 [absence of symptoms] to 12 [symptoms occur daily and with marked severity]).</span></div>
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<div style="border: 0px; font-family: Georgia, Cambria, Times, 'Times New Roman', serif; font-size: 1em; font-stretch: inherit; font-style: inherit; font-variant: inherit; line-height: 1.5; margin-bottom: 10px; padding: 0px; vertical-align: baseline;">
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<strong style="border: 0px; font-family: inherit; font-size: 14px; font-stretch: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">Results</strong> <span style="border: 0px; font-family: inherit; font-size: inherit; font-stretch: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">A total of 194 patients (88.2%) completed the study. With the sequential parallel comparison design, 152 patients received dextromethorphan-quinidine and 127 received placebo during the study. Analysis combining stages 1 (all patients) and 2 (rerandomized placebo nonresponders) showed significantly reduced NPI Agitation/Aggression scores for dextromethorphan-quinidine vs placebo (ordinary least squares <i style="border: 0px; font-family: inherit; font-size: inherit; font-stretch: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">z</i> statistic, −3.95; <i style="border: 0px; font-family: inherit; font-size: inherit; font-stretch: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">P</i> < .001). In stage 1, mean NPI Agitation/Aggression scores were reduced from 7.1 to 3.8 with dextromethorphan-quinidine and from 7.0 to 5.3 with placebo. Between-group treatment differences were significant in stage 1 (least squares mean, −1.5; 95% CI, −2.3 to −0.7; <i style="border: 0px; font-family: inherit; font-size: inherit; font-stretch: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">P</i><.001). In stage 2, NPI Agitation/Aggression scores were reduced from 5.8 to 3.8 with dextromethorphan-quinidine and from 6.7 to 5.8 with placebo. Between-group treatment differences were also significant in stage 2 (least squares mean, −1.6; 95% CI, −2.9 to −0.3; <i style="border: 0px; font-family: inherit; font-size: inherit; font-stretch: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">P</i>=.02). Adverse events included falls (8.6% for dextromethorphan-quinidine vs 3.9% for placebo), diarrhea (5.9% vs 3.1% respectively), and urinary tract infection (5.3% vs 3.9% respectively). Serious adverse events occurred in 7.9% with dextromethorphan-quinidine vs 4.7% with placebo. Dextromethorphan-quinidine was not associated with cognitive impairment, sedation, or clinically significant QTc prolongation.</span></div>
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<strong style="border: 0px; font-family: inherit; font-size: 14px; font-stretch: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">Conclusions and Relevance</strong> <span style="border: 0px; font-family: inherit; font-size: inherit; font-stretch: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">In this preliminary 10-week phase 2 randomized clinical trial of patients with probable Alzheimer disease, combination dextromethorphan-quinidine demonstrated clinically relevant efficacy for agitation and was generally well tolerated.</span></div>
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<span style="border: 0px; font-family: inherit; font-size: inherit; font-stretch: inherit; font-style: inherit; font-variant: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;"><a href="http://jama.jamanetwork.com/article.aspx?articleid=2442936" target="_blank">Full text</a></span></div>
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Carlos Vázquezhttp://www.blogger.com/profile/09266699098392968330noreply@blogger.com0tag:blogger.com,1999:blog-7084351769408080486.post-7611113803122454112012-11-23T10:52:00.000-08:002012-11-23T10:52:05.159-08:00Pharmacogenomic update on multiple sclerosis: a focus on actual and new therapeutic strategies<table cellpadding="0" cellspacing="0" class="tr-caption-container" style="float: left; margin-right: 1em; text-align: left;"><tbody>
<tr><td style="text-align: center;"><a href="http://www.nature.com/tpj/journal/v12/n6/images/tpj201241f1.jpg" imageanchor="1" style="clear: left; margin-bottom: 1em; margin-left: auto; margin-right: auto;"><img border="0" height="292" src="http://www.nature.com/tpj/journal/v12/n6/images/tpj201241f1.jpg" width="320" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Action mechanism of IFN-<span class="mb">α</span><span class="mb">/</span>β. (<b>a</b>) The interaction between IFNAR receptor, composed of two subunits IFNAR1 and IFNAR2, and IFN-<span class="mb">α</span><span class="mb">/</span>β induces an immediate transcriptional response through JAK–STAT signal transduction pathway. (<b>b</b>)
The JAK–STAT system involves a cascade of molecular effectors that
includes the membrane receptor, the cytoplasmic JAK and the
transcription factors STATs. After signal, JAK autophosporylates itself,
then activating STAT proteins. (<b>c</b>) STATs pass from the cytoplasm to the nucleus, promoting transcription of genes responsive to STAT. AAF, IFN-<span class="mb">α</span>-activated factor; IFN, interferon; ISRE, IFN-stimulated response elements; JAK, Janus kinase; GAS, IFN-<span class="mb">γ</span>-activated
sequence; ISGF3, interferon-stimulated gene factor 3; IRF9, interferon
regulatory factor 9; STAT, signal transducers and activators of
transcription; TYK2, tyrosine kinase 2.</td></tr>
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Multiple sclerosis (MS) is an inflammatory and demyelinating disease of
central nervous system comprising several subtypes. Pharmacological
treatment involves only few drugs. Among these, interferon beta (IFN-β)
and glatiramer acetate were the most used. Although evidence supports
the efficacy of these agents in treating MS symptoms, actual studies
allowed to introduce new innovative drugs in clinical practice. Applying
pharmacogenetic approach to MS, IFN-β and several other immune pathways
were abundantly investigated. Numerous reports identified some
promising therapy markers but only few markers have emerged as
clinically useful. This may be partially due to differences in clinical
and methodological criteria in the studies. Indeed, responder and
non-responder definitions lack standardized clinical definition. The
goal of this review is to treat advances in research on the
pharmacogenetic markers of MS drugs and to highlight possible
correlations between type of responses and genetic profile, with regard
to clinical and methodological discrepancies in the studies (<a href="http://www.nature.com/tpj/journal/v12/n6/pdf/tpj201241a.pdf" target="_blank">Full text</a>).</div>
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Carlos Vázquezhttp://www.blogger.com/profile/09266699098392968330noreply@blogger.com0tag:blogger.com,1999:blog-7084351769408080486.post-31389908417447348892012-02-14T08:46:00.001-08:002012-11-23T10:53:11.233-08:00Do Antidepressants Really Work?<span id="ctl00_cColumn_NewsArticle1_lblDetail">Three recent books and a series of commentaries and reviews in the press raise the question whether widely used antidepressants are really effective in most of the individuals who take them. In an especially high-profile article, Marcia Angell, former editor in chief of <i>The New England Journal of Medicine</i> provided a stinging rebuke of psychiatric drugs in general and of course the drug companies that manufacture them. Writing in <i>The New York Review of Books</i> Angell seemed to seriously consider the possibility that “psychoactive drugs are useless”. There were also highly visible pieces in <i>USA Today</i> and <i>Newsweek</i>, the first on a study done by the psychologist Robert DeRubeis headlined “Antidepressant lift may be all in your head,” and the other a cover article on a retrospective “meta-analysis” by the psychologist Irving Kirsch and colleagues of clinical trial data provided to the FDA by pharmaceutical companies and interpreted as evidence that antidepressants were no more effective than <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2253608/?tool=pubmed">placebo</a> in most patients. </span><br />
Mainstream scientists, however, have and continue to understand the same data as showing that antidepressants work well for at least 20 percent of patients on an initial trial. The scientific dilemma is to separate patients who really need a drug from those who will respond to placebo. In the future this should be possible as the field develops better laboratory tests for measuring relevant brain function. In the meantime, the challenge for doctor and patient is the same as for the scientist – to make as good a decision as possible about whether or not to use an antidepressant in each situation without a laboratory test for guidance.<br />
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Simply stated, clinical trial data on antidepressants, similar to that for many other classes of drugs, including most cancer and anti-inflammatory drugs, have never shown that more than 60 to 70 percent of patients in any given study improve. And, in many studies, improvement on a placebo (so-called sugar pill with no active drug) is observed in 30 to 50 percent of patients during the average six week trial period. This could be taken to mean that only about 20 percent of depressed patients truly benefit from their antidepressant medication (i.e. beyond those patients who would benefit from just a placebo), with 30 to 40 percent of patients failing to improve on either drug or placebo.<br />
Why, then are drugs with such limitations widely used as antidepressants by the medical profession? To start with, the <a href="http://www.webmd.com/depression/guide/depression-diagnosis">diagnosis of depression</a> based on various reported emotional and physical complaints does not often point to a specific cause, as for example might be revealed by a throat culture for strep throat or an X-ray of a hairline fracture causing pain. Some depressions are caused by specific physical or organic disease (e.g. hypothyroidism) but most have no (as yet) known physical etiology. Given the indisputable complexity of the brain and the myriad biochemical processes involved in normal brain function, any one of which if dysfunctional could contribute to the clinical syndrome we call depression, it would be unrealistic to expect that a single and relatively simple pharmacological intervention would work for all or even most patients. The same is true for many common non-psychiatric disorders, especially cancers, which are due to a vast array of acquired and inherited genetic mutations and environmental insults. Most cancer drugs, for example, are only partially effective in treating a small subgroup of patients with any given tumor type, and unfortunately not for very long. Moreover, we have no blood or brain imaging tests that can reliably diagnose depression or ascertain its severity.<br />
Antidepressant drugs that work only for some patients were <a href="http://www.psychiatrist.com/pcc/pccpdf/v05s07/v05s0702.pdf">discovered serendipitously</a> in the 1950’s; they were being tested for other purposes and used inadvertently in depressed patients who subsequently reported feeling “better”. It was only later that the reported improvement in mood following treatment with these drugs was coupled to a formal diagnosis of depression and the drugs subsequently tested in controlled clinical trials.<br />
The most widely prescribed class of antidepressants (so-called SSRIs) that has attracted so much recent attention has a specific biochemical action in the brain. SSRIs selectively inhibit the uptake of the neurotransmitter, serotonin, at the neuronal synapse, effectively enhancing the activity of serotonin at only those synapses and in key brain regions. Modern SSRIs evolved from basic brain research to understand how the earlier, serendipitously discovered class of drugs (called tricyclic antidepressants) worked and to synthesize compounds that were free of the tricyclics’ toxic side effects (the most serious of which is death with even moderate overdoses).<br />
Given the relative safety of SSRIs it is now common for someone with the symptoms of depression to be prescribed one by their physician, generally a primary care doctor, even though the clinical trial data tell us that only about 1 in 5 such patients will respond better to the drug than placebo over the ensuing four to six weeks. The doctor, however, has no way of selecting only those patients who will benefit from these SSRIs and, therefore, given the extremely low risk of serious side effects, prescribes the drug and follows the patient to see if he or she is among the 60 to 70 percent who will improve. It is almost impossible however to know in such a real-life setting how many patients would have responded to just placebo.<br />
In some forms of depression an individual is so severely impaired that he or she requires hospitalization. Studies done decades ago in hospitalized depressed patients receiving tricyclic antidepressants showed a 60 to 70 percent improvement or response rate but a much lower (20 to 30 percent) improvement rate on placebo, suggesting that for every three such patients treated two are true drug responders. Today, however, such patients are no longer enrolled in placebo controlled clinical trials unless they fall into the 30 to 40 percent who fail to respond to a standard treatment. If a new agent held the promise of a special property such as very rapid response, a short placebo controlled trial could be justified.<br />
Instead, the vast majority of studies are done in outpatients with depression, a clinically diverse group who complain of some symptoms of depression but also include individuals who are able to carry out most everyday activities of daily living, including work. It is in this patient population that high placebo response rates are often observed. Furthermore, to qualify for an outpatient trial of a new antidepressant, a person need have only five out of ten possible symptoms of depression and thus individuals are enrolled in these studies who have virtually no symptoms in common. Given such mixed groups of patients, it is not surprising that both drug and placebo response rates are highly variable.<br />
Interestingly, some of the articles questioning the general effectiveness of antidepressants over placebo interpret the data as indicating that their real use should be for more serious depression. But the very nature of outpatient clinical trials excludes the most seriously affected individuals who might require hospitalization or pose an acute suicide risk. The measure of “severity” in clinical trials is based on highly subjective responses to questions about feelings, appetite, sleep patterns, etc. At the extremes, individuals who tend to complain about their symptoms can score much higher on such scales than much more impaired stoic, non-complaining persons who deny their real suicidal thoughts. We know that subjective reports about sleep are often very different from the objective laboratory documentation of sleep with EEG. In the not-too-distant future using the tools of functional brain imaging we should be able to objectively document and quantify the abnormal brain “physiology” that underlies depression. We will then have objective and standardized measures of “depression”, understood as degree of altered brain function, which are not dependent on subjective or cultural factors influencing how depressed patients rate themselves or are rated by others.<br />
The subjectivity of ratings produces problems in the <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181766/?tool=pubmed">interpretation of the data from trials</a>. For example, pressures from both patients and investigators to meet entry criteria for trials leads to inflated scores and entry of individuals who would not be expected to need or benefit from a drug. Conversely, patients who tend to minimize symptoms can have a relatively low score but actually be in greater need of the drug than others with higher scores. We know such patients exist because when all patients who improve on drug are subsequently randomized to continue on active drug or be switched to placebo, we observe a 25 to 35 percent difference in relapse rates between the conditions even among patients without an initially high score. This shows that across the range of entry scores, there are individuals who really do need the medication. Such benefit only becomes clear when one winnows out those who initially improve on placebo which, as noted earlier, can be as high as 50 percent. In fact, the ability of antidepressants to prevent the relapse of depression over many months provides clearer support for their effectiveness than do shorter-term studies of acutely ill patients. The consistent finding of a higher relapse rate into depression of patients switched to placebo who initially improve on an antidepressant also supports the current practice of placing patients with an uncertain degree of depression on medication, since it especially benefits those who require medication not only to improve but also to stay well.<br />
Thus, antidepressants do work better than sugar pills in difficult to define subgroups of depressed individuals and therefore their overall effectiveness (vs. placebo) in large clinical trials conducted in diverse populations is very modest at best. Scientists, physicians and patients cannot be satisfied with this state of affairs. For decades we have been seeking ways of selecting the right patients for a particular antidepressant medication so as to ideally prescribe one only to someone who will really benefit from it.<br />
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Studies to better identify individuals <a href="http://dana.org/uploadedFiles/News_and_Publications/Insel_ArchGenPsy.pdf" title="Translating Scientific Opportunity Into Public Health Impact">who respond well to specific medications</a> are underway in depression and other disorders using the tools of modern genetics and brain imaging. For instance, genetics already provides a means of identifying people in whom the liver breaks down drugs in such a way that the average dose would be ineffective or toxic. There are promising hints that genetic subtypes may help identify individuals who are more likely to respond to placebo. Most neuroscientists have even greater hope that sophisticated measures of brain function both with surface electrophysiological measures (related to the traditional EEGs used for years in neurology) and more complex <i>functional</i> MRI (same instruments used to look at structures deep inside the brain or other body organ systems) will be able to predict both drug and placebo responders. Emerging data indicates that such measures, when coupled with those from genetics, should allow for likely drug and placebo responders to be reliably identified. Identifying who will respond best to which drug should also be possible with the same laboratory tests but will have its greatest value when we find effective medications for the 30 to 40 percent of depressed patients who fail to respond to either drug or placebo<br />
In reality the current generation of antidepressants, including the SSRIs, are arguably really no more effective than the oldest generation of antidepressants discovered by serendipity over a half century ago. As we underscore, despite their usefulness for many depressed patients, there should be little debate about their limitations. Currently used antidepressants do not work particularly well for the majority of patients (as complete remission rates are still relatively low) and they can take weeks to be fully effective. Antidepressants do work however for many patients and like many cancer drugs they can literally save lives. Still it is also true that the considerable advances in neuroscience and our understanding of both normal and abnormal brain function over the past 20 to 30 years have yet to fully translate into more effective approaches to treating depression. We believe given the recent research advances in genetics and imaging however that this rather depressing state of affairs is about to change and that more effective and even rapidly-acting antidepressant drugs as well as non-pharmacological interventions may well be on the horizon. We look forward to that future of more effective treatments and the means of matchi ng the best treatment, including some placebo equivalent, to anyone with depression.<br />
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<br />
Further Reading:</i></b><br />
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1. “<a href="http://www.ncbi.nlm.nih.gov/pubmed/18303940">Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration.</a>” Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. <span class="jrnl">PLoS Med</span>. 2008 Feb;5(2):e45.</div>
2. “<a href="http://www.psychiatrist.com/pcc/pccpdf/v05s07/v05s0702.pdf">History of the Use of Antidepressants in Primary Care</a>.” Joseph A. Lieberman III, M.D.,<i> (Primary Care Companion J Clin Psychiatry 2003;5[suppl 7]:6–10)</i><br />
3. “<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181766/?tool=pubmed">Rating Scales in Depression: Limitations and Pitfalls</a>.” Per Bech, M.D. ; Dialogues Clin Neurosci. <span lang="FR">2006 June; 8(2): 207–215.</span><br />
4. <a href="http://dana.org/uploadedFiles/News_and_Publications/Insel_ArchGenPsy.pdf" title="Translating Scientific Opportunity Into Public Health Impact">Translating scientific opportunity into public health impact: a strategic plan for research on mental illness</a>. Insel TR Arch Gen Psychiatry. 2009 Feb; 66(2):128-33.Carlos Vázquezhttp://www.blogger.com/profile/09266699098392968330noreply@blogger.com0tag:blogger.com,1999:blog-7084351769408080486.post-63079182907841304842012-02-14T08:45:00.001-08:002012-11-23T10:53:31.973-08:00Off-the-Shelf Drug Rapidly Clears Alzheimer’s Protein in Mice<br />
A drug that is already approved by the FDA for treating a rare skin cancer greatly reduces brain levels of Alzheimer’s-associated amyloid beta (A-beta) protein in mouse models. The drug, bexarotene, works in the mice by boosting the activity of apolipoprotein E, a fat-carrying molecule that normally helps to clear A-beta from the brain (see “<a href="http://dana.org/news/features/detail.aspx?id=33588">Why Does apoE4 Make Alzheimer’s More Likely?</a>”). If bexarotene’s A-beta clearance effect in mice translates to humans, then it may prove useful against Alzheimer’s—though perhaps more as a preventive than as a treatment for established Alzheimer’s dementia.<br />
“This is quite an exciting paper; the effect on A-beta clearance is dramatic and rapid,” says <a href="http://www.mountsinai.org/profiles/samuel-e-gandy">Sam Gandy</a>, who chairs the Alzheimer’s research program at Mount Sinai School of Medicine.<br />
“The drug reduces the soluble forms of A-beta within hours,” says Paige Cramer, the PhD student who was first author of the paper. Cramer works in the laboratory of <a href="http://gel-server1.cwru.edu/pages/gary.html">Gary Landreth</a>, director of the Alzheimer’s Research Laboratory at Case Western Reserve University School of Medicine in Cleveland, Ohio, and principal investigator for the study, which <a href="http://www.sciencemag.org/content/early/2012/02/08/science.1217697" title="appears today in Science Express">appears today in <i>Science Express</i></a>.<br />
The study is based on observations, going back to the early 1990s, of a strong connection between Alzheimer’s and apolipoprotein-E (apoE). <a href="http://www.ncbi.nlm.nih.gov/pubmed/8446617">Researchers</a> have found that apoE proteins normally bind strongly to A-beta, and that apoE4, one of the normal variants of apoE in the population, is linked to a much higher and earlier risk of Alzheimer’s.<br />
Recently scientists have determined the likely reason for the connection: <a href="http://www.ncbi.nlm.nih.gov/pubmed/21715678">A-beta</a> aggregates, which have a high affinity for fat molecules, normally cling to the fats carried by apo-E molecules, and in this way are brought into, and disposed within, immune-type cells in the brain called microglial cells. ApoE4 is comparatively inefficient at handling fat molecules, and so it does a poorer job of removing A-beta aggregates. Regardless of which apoE variants a person has, boosting apoE production should enhance the clearance of A-beta from the brain—mainly because more apoE means more A-beta-carrying capacity. ApoE production also <a href="http://www.ncbi.nlm.nih.gov/pubmed/21718217">seems</a> to stimulate the readiness of microglial cells to digest A-beta aggregates.<br />
Bexarotene, a drug approved by the FDA in 2000 for cutaneous T-cell lymphoma, binds and activates the retinoid X receptor, a protein that in brain cells happens to be involved in promoting apoE production. Since bexarotene can cross from the bloodstream into the brain, Landreth reasoned that it might work as an apoE-boosting, A-beta-clearing drug.<br />
In the new study, he and Cramer and their colleagues tested it on “Alzheimer’s mice” that had been genetically engineered to overproduce aggregates of A-beta. Such mice, as they age, show subtle cognitive deficits – which are presumed to be caused by small, soluble “oligomer” aggregates of A-beta. The team found that within only a few days, a modest daily dose of the drug reduced soluble forms of A-beta in the mouse brains by about one-third, compared to control mice, and reduced insoluble A-beta deposits, or “plaques,” by about half. They observed microglial cells stuffed with A-beta, as well as increases in the levels of proteins that normally work with apoE. In mice that lacked apoE, these A-beta clearing effects did not occur. The treated mice showed immediate improvements in standard memory tests, suggesting that the drug quickly reduced brain levels of toxic A-beta oligomers.<br />
Because the drug is already FDA-approved, its safety is already mostly known. “For skin cancer treatment, patients are often on bexarotene doses that are far higher than [the human equivalent of] the dose that we used in mice, and for long periods,” says Cramer. Long-term use of bexarotene can raise triglyceride levels and have other potentially dangerous side-effects, but Cramer says that such side-effects are generally treatable with other drugs, and bexarotene is tolerated by most cancer patients.<br />
Cramer says that she and Landreth are forming a company and hope to set up clinical trials of bexarotene against Alzheimer’s. Even without such trials, neurologists in the U.S. could legally prescribe the drug “off-label” to people with Alzheimer’s, since bexarotine is already approved by the FDA.<br />
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However, the drug may not work well in those who already have Alzheimer’s dementia. The current thinking about Alzheimer’s is that most of the dementia is caused by the spread of neuron-killing aggregates of tau protein in the brain. This “tauopathy” process seems to be triggered by the initial, slow spread of harmful A-beta aggregates, but, once started, it probably can proceed on its own even if the A-beta aggregates are removed by bexarotene or other treatments.<br />
“You would want to intervene [with a drug such as bexarotene] before the tauopathy phase begins,” says Gandy, although he adds, “I don’t think we can assume that it would only help presymptomatic patients until we actually do a trial.”<br />
Finding people who are still a few years away from developing tauopathy and dementia would mean, in effect, diagnosing them using PET brain scans of A-beta deposits, and cerebrospinal fluid tests for A-beta and tau aggregates, or other “biomarkers.” A shift towards early diagnosis is already a major priority for the research community (see “<a href="http://dana.org/news/features/detail.aspx?id=33152">Alzheimer's Prevention Trials Set to Start in 2012</a>”) and could be accelerated by the availability of such a promising drug. Cramer and Landreth want to use early-diagnostic biomarkers in any initial clinical trial of bexarotene. “Obviously the earlier [the treatment] the better,” she says.<br />
In principle, a drug that strongly clears harmful forms of A-beta could give clinicians a several year window to treat patients newly diagnosed as high risk — “during which we might be able to clear away amyloid completely,” says Gandy—and thus delay dementia indefinitely. The approach might turn out to be particularly useful for people who have the apoE4 variant or a strong family history of Alzheimer’s. On the other hand, many other laboratories and companies are developing Alzheimer’s drugs, and by the time pre-dementia diagnosis of the disease becomes widely used, there may be safer, cheaper, and more effective options than bexarotene.<br />
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<span id="ctl00_cColumn_NewsArticle1_Comments_repComments_ctl01_lblTitle">Off-the -shelf Drug Rapidly clears Alzheimer's protein in mice</span></h3>
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</span> <span id="ctl00_cColumn_NewsArticle1_Comments_repComments_ctl01_lblHTML">The evidence and arguement that b-amyloid is the root cause that riggers the aggregation of tau leading to AD is not convincing.Most scientists accepted this position citing paper published by JosephPrice et al.The authors presented two key points : 1.The authors found that there were tau tangles in hippocampus of healthy aging people,but with the dementing rating getting worse,there were increased tau tangles and also b-amyloid in this area.They therefore concluded that b-amyloid triggers the increase of tau leading to dementia.The data showed a correlation between increased tau tangle and b-amyloid ,but causative relation cannot be concluded from correlation.It is equally plausible that as the tau tangles increases,the dementia became clinically observable.At the same time this increased level of tau tangles also triggers the formation of b-amyloid because the lysosomal resource is limited. If b-amyloids cause the formation of tau tangles then the genetically modified b-amyloid mouse would have developed tau tangles in these area which has not been observed.There was also pathologically no difference between the tangles of healthy and demented candidates.To argue that the first was naturally cummulated and the second was triggered by b-amyloid is not convincing. 2. The authors cited familial AD as evidence that b-amyloid has a critical role and use this to support the first arguement.It is a known fact that mutated b-amyloid genes (APP & presenilin)lead to AD ,but the causative link between the mutated gene with excessive b-amyloid which in turns leads to AD has never been proven.If at all, the evidence concluded otherwise.Scientists had found that the mutated presenilin gene did not produce more b-amyloid as previously thought but instead the gene impaired the lysosome which is the garbage clearing systems that clears both b-amyloid and tau tangles resulting in net increase in both.If tau aggregation is the driver ,then it is tau that is responsible for the familial AD. b-amyloid is either irrelevent or just an accomplice in taking away some lysosomal resources.</span> </div>
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Carlos Vázquezhttp://www.blogger.com/profile/09266699098392968330noreply@blogger.com0tag:blogger.com,1999:blog-7084351769408080486.post-48544461512310410652011-12-28T10:07:00.000-08:002012-11-23T10:52:48.357-08:00IVIg therapy: neurologic indications, contraindications, precautions, and complications<span style="background-color: white;">Intravenous immune globulin (IVIg) is a purified preparation of gamma globulin, comprised of 4 subclasses of antibodies (ie, IgG, IgM, IgA, and IgE), approximating the distribution in human serum. IVIg is derived from large pools of human plasma (ie, greater than 1000 donors per lot) and purified to remove infective agents, vasoactive substances, and aggregated proteins.</span><br />
<span style="background-color: white;">IVIg is at least 90% intact IgG, the half-life of which is generally from 18 to 32 days in healthy adults, although it varies depending upon patient factors and which specific product is used. IgG is comprised of 4 subclasses of which IgG1 is the major component in normal serum and in IVIg. IgG1 is involved in tissue protection, complement activation, and virus inactivation. Peak serum levels of IgG are attained immediately after IVIg administration, but drop about half during the first week postinfusion, even though the reported half-life of IgG is somewhat longer. IVIg in immune deficient states simply replaces missing antibodies, whereas immunomodulatory doses of IVIg for autoimmune conditions are considerably larger. Various mechanisms have been proposed for immunomodulatatory actions of IVIg, including promoting blockade of Fc receptors in macrophages (thereby preventing phagocytosis of circulating opsonized platelets or cells tagged with autoantibodies), providing anti-idiotypic antibodies to neutralize pathogenic auto-antibodies, absorbing complement, down regulating immunoglobulin production, neutralizing viruses, enhancing suppression cells, inhibiting lymphocyte proliferation, and reducing interleukin (IL-1) production or activity.</span><br />
<span style="background-color: white;">IndicationsIVIg therapy is used either for immunomodulation of autoimmune conditions or for antibody replacement. Neurologic indications are genrally associated with an immunomodulatory role, and include Guillain-Barre syndrome and chronic inflammatory demyelinating neuropathy. Other nonneurologic indications associated with an immunomodulatory role include idiopathic thrombocytopenic purpura, Kawasaki syndrome, and acquired hemophilia. Indications suitable for treatment by IgG replacement include general or specific immunodeficiency states, hepatitis A or rubella prophylaxis, chronic lymphocytic leukemia with hypogammaglobulinemia, multiple myeloma with specific antibody deficiency, low birth weight babies at risk for infection, and infants or children with HIV.</span><br />
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<a name='more'></a><span style="background-color: white;"><br style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; background-color: #f6f6f6; color: #804000; font-family: 'Trebuchet MS', Trebuchet, Verdana, sans-serif; font-size: 13px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; orphans: 2; text-align: -webkit-auto; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px;" /></span><br />
<b style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; background-color: #f6f6f6; color: #804000; font-family: 'Trebuchet MS', Trebuchet, Verdana, sans-serif; font-size: 13px; font-style: normal; font-variant: normal; font-weight: bold; letter-spacing: normal; line-height: normal; orphans: 2; text-align: -webkit-auto; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px;"><i><span style="background-color: white;">"Off-Label" Neurologic Indications for IVIg</span><span class="Apple-converted-space"><span style="background-color: white;"> </span></span></i></b><span style="background-color: white;">(Ratko et al 1995; Dalakas 1999; Bjornson and Grabbenstein 2003).</span><br />
<i style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; background-color: #f6f6f6; color: #804000; font-family: 'Trebuchet MS', Trebuchet, Verdana, sans-serif; font-size: 13px; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; orphans: 2; text-align: -webkit-auto; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px;"><span style="background-color: white;">Evidence supports routine use</span></i><br />
<span style="background-color: white;">(1) Chronic inflammatory demyelinating polyneuropathy: excellent evidence of efficacy. Equivalent to plasma exchange in children and adults.</span><br />
<span style="background-color: white;">(2) Guillaine-Barre syndrome: excellent evidence of efficacy. Equivalent to plasma exchange in children and adults.</span><br />
<span style="background-color: white;">(3) Multifocal motor neuropathy: good evidence of efficacy in adults, with documented improved strength and reduced conduction block.</span><br />
<i style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; background-color: #f6f6f6; color: #804000; font-family: 'Trebuchet MS', Trebuchet, Verdana, sans-serif; font-size: 13px; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; orphans: 2; text-align: -webkit-auto; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px;"><span style="background-color: white;">Evidence does not support routine use</span></i><br />
<span style="background-color: white;">(1) Dermatomyositis/polymyositis: may be used in severe illness when other therapies have failed or are contraindicated. Fair evidence of possible efficacy in adults.</span><br />
<span style="background-color: white;">(2) Diabetic amyotrophy: anecdotal evidence of possible efficacy in an adult.</span><br />
<span style="background-color: white;">(3) Epstein-Barr-virus-induced cerebellar ataxia: anecdotal evidence of efficacy in an adult.</span><br />
<span style="background-color: white;">(4) Intractable pediatric epilepsy: may be used as a last resort in intractable pediatric epilepsy (eg, West syndrome or Lennox-Gastaut syndrome), especially in patients who may be candidates for surgical resection.</span><br />
<span style="background-color: white;">(5) Lambert-Eaton myasthenic syndrome: possible efficacy.</span><br />
<span style="background-color: white;">(6) Multiple sclerosis: possible effectiveness in a small number of adult patients.</span><br />
<span style="background-color: white;">(7) Myasthenia gravis: may be used in severe cases to treat acute decompensation, when other therapies have failed or are contraindicated. Fair evidence of possible efficacy in adults.</span><br />
<span style="background-color: white;">(8) Stiff man syndrome: anecdotal evidence of possible efficacy in adults.</span><br />
<span style="background-color: white;">(9) Systemic vasculitic syndromes: may be used in severe illness when other therapies have failed or are contraindicated.</span><br />
<span style="background-color: white;"><br style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; background-color: #f6f6f6; color: #804000; font-family: 'Trebuchet MS', Trebuchet, Verdana, sans-serif; font-size: 13px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; orphans: 2; text-align: -webkit-auto; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px;" /></span>
<b style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; background-color: #f6f6f6; color: #804000; font-family: 'Trebuchet MS', Trebuchet, Verdana, sans-serif; font-size: 13px; font-style: normal; font-variant: normal; font-weight: bold; letter-spacing: normal; line-height: normal; orphans: 2; text-align: -webkit-auto; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px;"><span style="background-color: white;">Contraindications</span></b><br />
<span style="background-color: white;">(1) IVIg is contraindicated in patients who have had an anaphylactic or severe systemic reaction following previous administration of gamma globulin, anti-immunoglobulin A antibodies, or thimerosal.</span><br />
<span style="background-color: white;">(2) IVIg is relatively contraindicated in patients with isolated IgA deficiency. If IVIg treatment is deemed necessary, such patients should receive products containing the lowest IgA concentration possible and should be monitored closely for anaphylaxis.</span><br />
<span style="background-color: white;"><br style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; background-color: #f6f6f6; color: #804000; font-family: 'Trebuchet MS', Trebuchet, Verdana, sans-serif; font-size: 13px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; orphans: 2; text-align: -webkit-auto; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px;" /></span>
<span style="background-color: white;">P</span><b style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; background-color: #f6f6f6; color: #804000; font-family: 'Trebuchet MS', Trebuchet, Verdana, sans-serif; font-size: 13px; font-style: normal; font-variant: normal; font-weight: bold; letter-spacing: normal; line-height: normal; orphans: 2; text-align: -webkit-auto; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px;"><span style="background-color: white;">recautions</span></b><br />
<span style="background-color: white;">(1) Pre-existing atherosclerotic disease or vascular risk factors (eg, coronary artery disease, hypertension, cerebrovascular disease, diabetes mellitus).</span><br />
<span style="background-color: white;">(2) Sucrose containing products more commonly cause renal dysfunction compared to nonsucrose containing products.</span><br />
<span style="background-color: white;">(3) Patients predisposed to acute renal failure, including patients with pre-existing renal insufficiency, diabetes mellitus, older age (greater than 65 years), volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. For such patients administer IVIg at minimum concentration and slowest infusion rate.</span><br />
<span style="background-color: white;">(4) Patients with agammaglobulinemia or extreme hypogammaglobulinemia who have never received immunoglobulin substitution therapy, or have not received it within the preceding 8 weeks, may be at risk of developing inflammatory reactions.</span><br />
<span style="background-color: white;"><br style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; background-color: #f6f6f6; color: #804000; font-family: 'Trebuchet MS', Trebuchet, Verdana, sans-serif; font-size: 13px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; orphans: 2; text-align: -webkit-auto; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px;" /></span>
<b style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; background-color: #f6f6f6; color: #804000; font-family: 'Trebuchet MS', Trebuchet, Verdana, sans-serif; font-size: 13px; font-style: normal; font-variant: normal; font-weight: bold; letter-spacing: normal; line-height: normal; orphans: 2; text-align: -webkit-auto; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px;"><span style="background-color: white;">Complications</span></b><br />
<i style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; background-color: #f6f6f6; color: #804000; font-family: 'Trebuchet MS', Trebuchet, Verdana, sans-serif; font-size: 13px; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; orphans: 2; text-align: -webkit-auto; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px;"><span style="background-color: white;">General:</span></i><br />
<span style="background-color: white;">Side effects with IVIg occur in approximately 2% to 6% of patients, usually with the first or second infusion; hence, prophylactic hydrocortisone and antihistamine may be used prior to these infusions (Misbahand Chapel 1993). If an early adverse reaction occurs, it will generally become apparent 30 to 60 minutes after beginning the infusion. Early reactions include muscle pain, malaise, headache, chills, flushing, low back pain, joint pain, fever, tightness of the chest, and nausea. Patients with immediate, infusion-related symptoms should have the infusion slowed or interrupted, and should be pretreated with a nonsteroidal anti-inflammatory agent and antihistamine for subsequent doses. The risk of reactions is significantly higher when active infection is present. Epinephrine should be available for possible anaphylaxis.</span><br />
<span style="background-color: white;">To decrease the risk of delayed reactions, reduced doses and rates of infusion should be considered for elderly patients and those with a history of migraine (ie, because of an increase risk of aseptic meningitis), or cardiovascular or cerebrovascular disease (ie, because of an increased risk of stroke or myocardial infarction). Renal complications occur more often in those with pre-existing renal impairment.</span><br />
<span style="background-color: white;">Late adverse effects include transmission of infections, including previous transmission of hepatitis C in hundreds of cases. Current IVIg products are considered safe in terms of viral transmission.</span><br />
<i style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; background-color: #f6f6f6; color: #804000; font-family: 'Trebuchet MS', Trebuchet, Verdana, sans-serif; font-size: 13px; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; orphans: 2; text-align: -webkit-auto; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px;"><span style="background-color: white;">Thrombotic events:</span></i><br />
<span style="background-color: white;">High dose or rapid infusion of IVIg is a putative risk factor for thrombotic complications (Frame and Crawford 1986; Sztajzel et al 1999; Elkayam et al 2000; Go and Call 2000; Turner and Wills 2000; Alliot et al 2001; Grillo et al 2001; Emerson et al 2002; Stubleand Dice 2002; Caress et al 2003; Dalakas and Clark 2003; Okuda et al 2003; Zaidan et al 2003). High-dose IVIg may increase blood viscosity and secondarily impair blood flow (Reinhart and Berchtold 1992; Dalakas 1994; Dalakas and Clark 2003). Some preparations also include activated coagulation factor XI as a contaminant in IVIg preparations, which can lead to significant thrombin production and contribute to an increased risk of thrombotic complications after IVIg therapy (Wolberg et al 2000). Other putative mechanisms of increasing thrombotic risk with IVIg are unconfirmed, and include passive infusion of antiphospholipid antibodies with IVIg, activation of platelets, and development of cerebral vasospasm (Frame et al 1986; Sztajzel et al 1999; Sherer et al 2001).</span><br />
<span style="background-color: white;">In 1 fatal case of stroke following IVIg therapy, autopsy showed intravascular aggregates of fibrin-IgG, as well as platelets and a necrotizing microangiopathy in the infarcts (Byrne et al 2002).</span><br />
<span style="background-color: white;">IVIg should be administered with caution to those at particular risk for thromboembolic events, including elderly patients, patients with pre-existing vascular disease, patients with hyperviscosity states (eg, cryoglobulinemia, monoclonal gammopathies, hypergammaglobulinemia, hyperfibrinogenemia, high lipoproteins, and hypercholesterolemia), and children with HIV infection (Woodruff et al 1986; Hague et al 1990; Reinhart and Berchtold 1992; Misbah and Chapel, 1993; Dalakas 1994; Elkayam et al 2000; Grillo et al 2001; Byrne et al 2002; Caress et al 2003; Dalakas and Clark 2003; Okuda et al 2003).</span><br />
<span style="background-color: white;">In patients with atherosclerotic disease or vascular risk factors (eg, cerebrovascular disease, coronary artery disease, hypertension, or diabetes mellitus), the concentration of infused IVIg should be no more than 5%, and infusion rates should be no faster than 0.5 mL/kg per hour increased slowly to a maximum rate of 4 mL/kg per hour if well tolerated (Elkayam et al 2000; Bjornson et al 2003).</span><br />
<span style="background-color: white;">There is no consensus on treatment of IVIg-related strokes. Intravascular thrombolysis has been demonstrated with strokes using tPA (Okuda et al 2003), and with inominate vein thrombosis using urokinase (Go and Call 2000). Anticoagulants have been used in some patients (Dalakas and Clark 2003). Patients who develop cerebral vasospasm may benefit from nimodipine (Sztajzel et al 1999).</span><br />
<span style="background-color: white;">Rapid infusion of IVIg may also cause flushing and changes in pulse rate or blood pressure, which usually resolve promptly with slowing or temporarily stopping the infusion.</span><br />
<span style="background-color: white;">Aseptic meningitis: Aseptic meningitis may occur from 1 hour to 7 days after infusion of IVIg. Symptoms can include fever, headache, nuchal rigidity, nausea, and vomiting. CSF analysis generally shows a neutrophilic pleocytosis with mildly increased protein level and a modestly depressed glucose level, but no bacteria (Kato et al 1988; Casteels-Van Daele et al 1990; Watson et al 1990; Kressebuch et al 1992; Rao et al 1992; Ozsoylu et al 1993; De Vlieghere et al 1994). All reported patients have recovered, although some individuals needed short-term treatment with steroids to alleviate symptoms. In a prospective cohort study of 54 patients treated with high-dose (2 g/kg) IVIg treatment, 6 (11%) developed aseptic meningitis within 24 hours (Sekul et al 1994). Patients with a history of migraine are apparently more likely to develop symptoms of aseptic meningitis.</span><br />
<i style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; background-color: #f6f6f6; color: #804000; font-family: 'Trebuchet MS', Trebuchet, Verdana, sans-serif; font-size: 13px; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; orphans: 2; text-align: -webkit-auto; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px;"><span style="background-color: white;">Encephalopathy:</span></i><br />
<span style="background-color: white;">A small number of cases of transient acute encephalopathy or reversible leukoencephalopathy have been reported (Mathy et al 1998; Lewis et al 2000).</span><br />
<span style="background-color: white;">Acquired infections: In 1994, Baxter Healthcare Corporation instituted a worldwide recall of Gammagard® and Polygam® because of reports of 68 cases of possible transmission of hepatitis C occurring between October 1993 and June 1994 related to IVIg administration. Laboratory findings indicate that immunoglobulins screened negative for anti-hepatitis C virus can nevertheless remain infectious, and therefore virus-inactivation procedures during manufacturing are necessary to produce safe IVIg preparations. All IVIg formulations licensed in the United States now include a virucidal step.</span><br />
<span style="background-color: white;">There is no evidence that AIDS has been transmitted by IVIg. Since 1985, all blood plasma used for manufacture of IVIg in the United States has been nonreactive in screening for HIV antibody.</span><br />
<span style="background-color: white;">Acute renal failure: Acute renal failure has been associated with administration of IVIg. The majority of cases of acute renal failure have been successfully managed, but some deaths have been reported. IVIg products containing sucrose may present a greater risk for acute renal failure. Therapy requiring higher and consecutive doses of IVIg with resulting hyperosmolality may have contributed to renal dysfunction in some cases. Renal histopathologic examination of some of the IVIg-associated acute renal failure cases suggests osmotic injury to the proximal renal tubules, including acute tubular necrosis, vacuolar degeneration, and osmotic nephrosis. Patients at increased risk include those with pre-existing renal dysfunction, diabetes, volume depletion, sepsis, paraproteinemia, older age (greater than 65 years), and those receiving concomitant nephrotoxic drugs. The recommended dose of IVIg should not be exceeded, and the dose or administration rate should be decreased in those at risk for acute renal failure. Renal function tests, including BUN, serum creatinine, and urine output, should be assessed prior to the initial infusion and monitored at periodic intervals thereafter. Patients should report symptoms such as decreased urine output, sudden weight gain, fluid retention or edema, or shortness of breath.</span><br />
<i style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; background-color: #f6f6f6; color: #804000; font-family: 'Trebuchet MS', Trebuchet, Verdana, sans-serif; font-size: 13px; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; orphans: 2; text-align: -webkit-auto; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px;"><span style="background-color: white;">Anaphylaxis:</span></i><br />
<span style="background-color: white;">Anaphylactic reactions are rare with IVIg. They have been reported to occur following intravenous administration of intramuscular preparations. Patients with an absolute absence of IgA and pre-existing anti-IgA antibodies of either IgG or IgE isotypes are at greatest risk of anaphylaxis, and an IgA-depleted IVIg preparation should be used in patients with high titers of IgA antibodies.</span><br />
<span style="background-color: white;"><br style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; background-color: #f6f6f6; color: #804000; font-family: 'Trebuchet MS', Trebuchet, Verdana, sans-serif; font-size: 13px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: normal; orphans: 2; text-align: -webkit-auto; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px;" /></span>
<b style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; background-color: #f6f6f6; color: #804000; font-family: 'Trebuchet MS', Trebuchet, Verdana, sans-serif; font-size: 13px; font-style: normal; font-variant: normal; font-weight: bold; letter-spacing: normal; line-height: normal; orphans: 2; text-align: -webkit-auto; text-indent: 0px; text-transform: none; white-space: normal; widows: 2; word-spacing: 0px;"><span style="background-color: white;">References:</span></b><br />
<span style="background-color: white;">Bjornson DC, Grabenstein JD. Immune globulin. In: Hutchison TA, Shahan DR, editors. DRUGDEX® System, MICROMEDEX®: Greenwood Village, Colorado, 2003.</span><br />
<span style="background-color: white;">Dalakas MC. Intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: present status and practical therapeutic guidelines. Muscle Nerve 1999;22:1479-97.</span><br />
<span style="background-color: white;">Dalakas MC. Mechanisms of action of IVIg and therapeutic considerations in the treatment of acute and chronic demyelinating neuropathies. Neurology 2002;59:s13-21.</span><br />
<span style="background-color: white;">Grillo JA, Gorson KC, Ropper AH, Lewis J, Weinstein R. Rapid infusion of intravenous immune globulin in patients with neuromuscular disorders. Neurology 2001;57:1699-1701.</span><br />
<span style="background-color: white;">NIH Consensus Conference. Intravenous immunoglobulin. Prevention and treatment of disease. JAMA 1990;3189-93.</span><br />
<span style="background-color: white;">Sorensen PS. Intravenous immunoglobulin treatment in neurologic disorders: yes. Arch Neurol 1999;56:1025-7.</span><br />
<span style="background-color: white;">Wiles CM, Brown P, Chapel H, et al. Intravenous immunoglobulin in neurological disease: a specialist review. J Neurol Neurosurg Psychiatry 2002;72:440-8.</span><br />
<span style="background-color: white;">Chronic inflammatory demyelinating polyneuropathyBenatar M. Randomized controlled trial of IVIg in untreated chronic inflammatorydemyelinating polyradiculoneuropathy. Neurology 2001;57:938.</span><br />
<span style="background-color: white;">Bjornson DC, Grabenstein JD. Immune globulin. In: Hutchison TA, Shahan DR, editors. DRUGDEX® System, MICROMEDEX®: Greenwood Village, Colorado, 2003.</span><br />
<span style="background-color: white;">Brannagan TH 3rd. Intravenous gammaglobulin (IVIg) for treatment of CIDP and related immune-mediated neuropathies. Neurology 2002;59(12 Suppl 6):S33-40.</span><br />
<span style="background-color: white;">Cocito D, Ciaramitaro P, Isoardo G, et al. Intravenous immunoglobulin as first treatment in diabetics with concomitant distal symmetric axonal polyneuropathy and CIDP. J Neurol 2002;249:719-22.</span><br />
<span style="background-color: white;">Cornblath DR, Chaudhry V, Griffin JW. Treatment of chronic inflammatory demyelinating polyneuropathy with intravenous immunoglobulin. Ann Neurol 1991;30:104-6.</span><br />
<span style="background-color: white;">Dalakas MC. Mechanisms of action of IVIg and therapeutic considerations in the treatment of acute and chronic demyelinating neuropathies. Neurology 2002;59:s13-21.</span><br />
<span style="background-color: white;">Donaghy M, Mills KR, Boniface SJ, et al. Pure motor demyelinating neuropathy: deterioration after steroid treatment and improvement with intravenous immunoglobulin. J Neurol Neurosurg Psychiatry 1994;57:778-83.</span><br />
<span style="background-color: white;">Faed JM, Day B, Pollock M, et al. High-dose intravenous human immunoglobulin in chronic inflammatory demyelinating polyneuropathy. Neurology 1989;39:422-5.</span><br />
<span style="background-color: white;">Hahn AF, Bolton CF, Zochodne D, et al. Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy: a double-blind, placebo-controlled, cross-over study. Brain 1996;119:1067-77.</span><br />
<span style="background-color: white;">Hughes R, Bensa S, Willison H, et al. Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 2001;50:195-201.</span><br />
<span style="background-color: white;">Mendell JR, Barohn RJ, Freimer ML, et al. Randomized controlled trial if IVIg in untreated chronic inflammatory demyelinating polyradiculoneuropathy. Neurology 2001;56:445-9.</span><br />
<span style="background-color: white;">Ochi K, Kohriyama T, Higaki M, Ikeda J, Harada A, Nakamura S. Changes in serum macrophage-related factors in patients with chronic inflammatory demyelinating polyneuropathy caused by intravenous immunoglobulin therapy. J Neurol Sci 2003;208:43-50.</span><br />
<span style="background-color: white;">Van den Bergh PY. Intravenous immunoglobulin (IVIG) in the treatment of chronic demyelinating polyradiculoneuropathy. Acta Neurol Belg 2001;101:147-51.</span><br />
<span style="background-color: white;">van Doorn PA, Vermeulen M, Brand A, et al. Intravenous immunoglobulin treatment in patients with chronic inflammatory demyelinating polyneuropathy: clinical and laboratory characteristics associated with improvement. Arch Neurol 1991;48:217-20.</span><br />
<span style="background-color: white;">Vermeulen M, van Doorn PA, Brand A, et al. Intravenous immunoglobulin treatment in patients with chronic inflammatory demyelinating polyneuropathy: a double blind, placebo controlled study. J Neurol Neurosurg Psychiatry 1993;56:36-9.</span><br />
<span style="background-color: white;">Dermatomyositis/polymyositisAl-Mayouf SM, Laxer RM, Schneider R, Silverman ED, Feldman BM. Intravenous immunoglobulin therapy for juvenile dermatomyositis: efficacy and safety. J Rheumatol 2000;27:2498-2503.</span><br />
<span style="background-color: white;">Bjornson DC, Grabenstein JD. Immune globulin. In: Hutchison TA, Shahan DR, editors. DRUGDEX® System, MICROMEDEX®: Greenwood Village, Colorado, 2003.</span><br />
<span style="background-color: white;">Brownell AK. Intravenous immune globulin for dermatomyositis (letter). N Engl J Med 1994;330:1392.</span><br />
<span style="background-color: white;">Carmeli Y, Mevorach D, Kaminski N, et al. Regression of Kaposi's sarcoma after intravenous immunoglobulin treatment for polymyositis. Cancer 1994;73:2859-61.</span><br />
<span style="background-color: white;">Cherin P, Pelletier S, Teixeira A, et al. Results and long-term followup of intravenous immunoglobulin infusions in chronic, refractory polymyositis: an open study with thirty-five adult patients. Arthritis Rheum 2002;46:467-74.</span><br />
<span style="background-color: white;">Cherin P, Piette JC, Wechsler B, et al. Intravenous gamma globulin as first line therapy in polymyositis and dermatomyositis: an open study in 11 adult patients. J Rheumatol 1994;21:1092-7.</span><br />
<span style="background-color: white;">Gottfried I, Seeber A, Anegg B, Rieger A, Stingl G, Volc-Platzer B. High dose intravenous immunoglobulin (IVIG) in dermatomyositis: clinical responses and effect on sIL-2R levels. Eur J Dermatol 2000;10:29-35.</span><br />
<span style="background-color: white;">Hanslik T, Jaccard A, Guillon JM, et al. Polymyositis and chronic graft-versus-host disease: efficacy of intravenous gammaglobulin. J Am Acad Dermatol 1993;28:492-3.</span><br />
<span style="background-color: white;">Lang BA, Laxer RM, Murphy G, et al. Treatment of dermatomyositis with intravenous gammaglobulin. Am J Med 1991;91:169-72.</span><br />
<span style="background-color: white;">Marie I, Hachulla E, Levesque H, et al. Intravenous immunoglobulins as treatment of life threatening esophageal involvement in polymyositis and dermatomyositis. J Rheumatol 1999;26:2706-9.</span><br />
<span style="background-color: white;">Mastaglia FL, Phillips BA, Zilko PJ. Immunoglobulin therapy in inflammatory myopathies. J Neurol Neurosurg Psychiatry 1998;65:107-10.</span><br />
<span style="background-color: white;">Mendell JR, Barohn RJ, Freimer ML, et al. Randomized controlled trial of IVIg in untreated chronic inflammatory demyelinating polyradiculoneuropathy. Neurology 2001;56:445-9.</span><br />
<span style="background-color: white;">Roifman CM, Schaffer FM, Wachsmuth SE, et al. Reversal of chronic polymyositis following intravenous immune serum globulin therapy. JAMA 1987;258:513-5.</span><br />
<span style="background-color: white;">Epilepsy and anticonvulsant-related complicationsAriizumi M, Baba K, Shiihara H, et al. High dose gammaglobulin for intractable childhood epilepsy. Lancet 1983;2:162-3.</span><br />
<span style="background-color: white;">Bjornson DC, Grabenstein JD. Immune globulin. In: Hutchison TA, Shahan DR, editors. DRUGDEX® System, MICROMEDEX®: Greenwood Village, Colorado, 2003.</span><br />
<span style="background-color: white;">Gross-Tsur V, Shalev RS, Kazir E, et al. Intravenous high-dose gammaglobulins for intractable childhood epilepsy. Acta Neurol Scand 1993;88:204-9.</span><br />
<span style="background-color: white;">Howrie DL, Schwinghammer TL, Wollman M. Use of IV immune globulin for treatment of phenytoin-induced thrombocytopenia. Clin Pharmacokinet 1989;8:734-7.</span><br />
<span style="background-color: white;">Mikati MA, Saab R. Successful use of intravenous immunoglobulin as initial monotherapy in Landau-Kleffner syndrome. Epilepsia 2000;41:880-6.</span><br />
<span style="background-color: white;">Mikati MA, Saab R, Fayad MN, Choueiri RN. Efficacy of intravenous immunoglobulin in Landau-Kleffner syndrome. Pediatr Neurol 2002;26:298-300.</span><br />
<span style="background-color: white;">Straussberg R, Harel L, Ben-Amitai D, Cohen D, Amir J. Carbamazepine-induced Stevens-Johnson syndrome treated with IV steroids and IVIG. Pediatr Neurol 2000;22:231-3.</span><br />
<span style="background-color: white;">Villani F, Avanzini G. The use of immunoglobulins in the treatment of human epilepsy.Neurol Sci 2002;23(Suppl 1):S33-7.</span><br />
<span style="background-color: white;">Wise MS, Rutledge SL, Kuzniecky RI. Rasmussen syndrome and long-term response to gamma globulin. Pediatr Neurol 1996;14:149-52.</span><br />
<span style="background-color: white;">Guillain-Barre syndromeAbd-Allah SA, Jansen PW, Ashwal S, et al. Intravenous immunoglobulin as therapy for pediatric Guillain-Barre syndrome. J Child Neurol 1997;12:376-80.</span><br />
<span style="background-color: white;">Anonymous. Treatment of Guillain-Barre syndrome with high-dose immune globulins combined with methylprednisolone: a pilot study. Ann Neurol 1994;35:749-52.</span><br />
<span style="background-color: white;">Bjornson DC, Grabenstein JD. Immune globulin. In: Hutchison TA, Shahan DR, editors. DRUGDEX® System, MICROMEDEX®: Greenwood Village, Colorado, 2003.</span><br />
<span style="background-color: white;">Bouza-Pineiro P, Pego R, Alonso A, et al. Guillain-Barre syndrome after renal transplantation: a case of clinical success with intravenous immunoglobulin therapy (letter). Nephron 1996;74:223-4.</span><br />
<span style="background-color: white;">Bril V, Ilse WK, Pearce R, et al. Pilot trial of immunoglobulin versus plasma exchange in patients with Guillain-Barre syndrome. Neurology 1996;46:100-3.</span><br />
<span style="background-color: white;">Buchwald B, Ahangari R, Weishaupt A, Toyka KV. Intravenous immunoglobulins neutralize blocking antibodies in Guillain-Barre syndrome. Ann Neurol 2002;5:673-80.</span><br />
<span style="background-color: white;">Chamouni P, Tamion F, Gueit I, et al. Adverse effect of polyvalent immunoglobulin in the treatment of Guillain-Barre syndrome. Transfus Apheresis Sci 2003;28:117-24.</span><br />
<span style="background-color: white;">Dalakas MC. Mechanisms of action of IVIg and therapeutic considerations in the treatment of acute and chronic demyelinating neuropathies. Neurology 2002;59:s13-21.</span><br />
<span style="background-color: white;">Kanra G, Ozon A, Vajsar J, Castagna L, Secmeer G, Topaloglu H. Intravenous immunoglobulin treatment in children with Guillain-Barre syndrome. Eur J Paediatr Neurol 1997;1:7-12.</span><br />
<span style="background-color: white;">Kuwabara S, Mori M, Ogawara K, Hattori T, Oda S, Koga M, Yuki N. Intravenous immunoglobulin therapy for Guillain-Barre syndrome with IgG anti-GM1 antibody. Muscle Nerve 2001;24:54-8.</span><br />
<span style="background-color: white;">McGhee B, Jarjour IT. Single-dose intravenous immune globulin for treatment of Guillain-Barre syndrome. Am J Hosp Pharm 1994;51:97-9.</span><br />
<span style="background-color: white;">Nagpal S, Benstead T, Shumak K, et al. Treatment of Guillain-Barre syndrome: a cost-effectiveness analysis. J Clin Apheresis 1999;14:107-13.</span><br />
<span style="background-color: white;">Plasma Exchange/Sandoglobulin® Guillain-Barre Syndrome Trial Group. Randomised trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barre syndrome. Lancet 1997;349:225-30.</span><br />
<span style="background-color: white;">Raphael JC, Chastang C, Chevret S, et al. Intravenous immune globulin versus plasma exchange in Guillain-Barre syndrome (letter). N Engl J Med 1992;327:816-7.</span><br />
<span style="background-color: white;">Raphael JC, Chevret S, Harboun M, Jars-Guincestre MC; French Guillain-Barre Syndrome Cooperative Group. Intravenous immune globulins in patients with Guillain-Barre syndrome and contraindications to plasma exchange: 3 days versus 6 days. J Neurol Neurosurg Psychiatry 2001;71:235-8.</span><br />
<span style="background-color: white;">Shahar E, Leiderman M. Outcome of severe Guillain-Barre syndrome in children: comparison between untreated cases versus gamma-globulin therapy. Clin Neuropharmacol 2003;26:84-7.</span><br />
<span style="background-color: white;">Shanbag P, Amirtharaj C, Pathak A. Intravenous immunoglobulins in severe Guillian-Barre syndrome in childhood. Indian J Pediatr 2003;70:541-3.</span><br />
<span style="background-color: white;">Sharshar T, Kaveri S, Kazatchkine M. Mechanisms of action of intravenous immunoglobulin (IVIg) in autoimmune and neuromuscular diseases. Electroencephalogr Clin Neurophysiol Suppl 1999;50:486-92.</span><br />
<span style="background-color: white;">Singhi SC, Jayshree M, Singhi P, Banerjee S, Prabhakar S. Intravenous immunoglobulin in very severe childhood Guillain-Barre syndrome. Ann Trop Paediatr 1999;19:167-74.</span><br />
<span style="background-color: white;">Steinberger B, Coleman TA. Multiple complications of IVIG therapy in a patient with Guillain-Barre syndrome. Am J Hematol 2001;67:59.</span><br />
<span style="background-color: white;">Urtasun M, Lopez de Munain A, Carrera N, et al. High-dose intravenous immune globulin in the management of severe Guillain-Barre syndrome. Ann Pharmacother 1992;26:32-3.</span><br />
<span style="background-color: white;">van der Meche FG. Intravenous immune globulin in the Guillain-Barre syndrome. Clin Exp Immunol 1994;97(suppl 1):43-7.</span><br />
<span style="background-color: white;">van der Meche FG, Kleyweg RP, Meulstee J, et al. High-dose intravenous gammaglobulin in Guillain-Barre syndrome (letter). Ann Neurol 1988;24:588.</span><br />
<span style="background-color: white;">van der Meche FG, Schmitz PI. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barre syndrome. Dutch Guillain-Barre Study Group. N Engl J Med 1992;326:1123-9.</span><br />
<span style="background-color: white;">Inclusion body myositisDalakas MC, Koffman B, Fujii M, Spector S, Svakumar K, Cupler E. A controlled study of intravenous immunoglobulin combined with prednisone in the treatment of IBM. Neurology 2001;56:323-7.</span><br />
<span style="background-color: white;">Walter MC, Lochmuller H, Toepfer M, et al. High-dose immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlled study. J Neurol 2000;247:22-8.</span><br />
<span style="background-color: white;">Multifocal motor neuropathyBjornson DC, Grabenstein JD. Immune globulin. In: Hutchison TA, Shahan DR editors. DRUGDEX® System, MICROMEDEX®: Greenwood Village, Colorado, 2003.</span><br />
<span style="background-color: white;">Federico P, Zochodne DW, Hahn AF, Brown WF, Feasby TE. Multifocal motor neuropathy improved by IVIg: randomized, double-blind, placebo-controlled study. Neurology 2000;55:1256-62.</span><br />
<span style="background-color: white;">Kermode AG, Laing BA, Carroll WM, et al: Intravenous immunoglobulin for multifocal motor neuropathy (letter). Lancet 1992;340:920-1.</span><br />
<span style="background-color: white;">Leger JM, Chassande B, Musset L, Meininger V, Bouche P, Baumann N. Intravenous immunoglobulin therapy in multifocal motor neuropathy: a double-blind, placebo-controlled study. Brain 2001;124:145-53.</span><br />
<span style="background-color: white;">Nobile-Orazio E, Meucci N, Barbieri S, et al. High-dose intravenous immunoglobulin therapy in multifocal motor neuropathy. Neurology 1993;43:537-44.</span><br />
<span style="background-color: white;">Turnbull J. Multifocal motor neuropathy improved by IVIg. Neurology 2001;56:1608.</span><br />
<span style="background-color: white;">Van den Berg-Vos RM, Franssen H, Visser J, et al. Disease severity in multifocal motor neuropathy and its association with the response to immunoglobulin treatment. J Neurol 2002;249:330-6.</span><br />
<span style="background-color: white;">Van den Berg-Vos RM, Franssen H, Wokke JH, Van den Berg LH. Multifocal motor neuropathy: long-term clinical and electrophysiological assessment of intravenous immunoglobulin maintenance treatment. Brain 2002;125:1875-86.</span><br />
<span style="background-color: white;">van Doorn PA, van der Meche FG. IVIg treatment improves multifocal motor neuropathy: easy to start but difficult to stop. Neurology 2000;55:1246-7.</span><br />
<span style="background-color: white;">Multiple sclerosis, acute disseminated encephalopmyelitis, and optic neuritisAchiron A, Barak Y, Sarova-Pinhas I. Use of intravenous immunoglobulin in multiple sclerosis. Biodrugs 1998;9:465-75.</span><br />
<span style="background-color: white;">Achiron A, Pras E, Gilad R, et al. Open controlled therapeutic trial of intravenous immune globulin in relapsing-remitting multiple sclerosis. Arch Neurol 1992;49:1233-6.</span><br />
<span style="background-color: white;">Balestri P, Grosso S, Acquaviva A, Bernini M. Plasmapheresis in a child affected by acute disseminated encephalomyelitis. Brain Dev 2000;22:123-6.</span><br />
<span style="background-color: white;">Bieber A, Asakura K, Warrington A, Kaveri SV, Rodriguez M. Antibody-mediated remyelination: relevance to multiple sclerosis. Mult Scler 2000;6(Suppl 2):S1-5; discussion S33. Bjornson DC, Grabenstein JD. Immune globulin. In: Hutchison TA, Shahan DR, editors. DRUGDEX® System, MICROMEDEX®: Greenwood Village, Colorado, 2003.</span><br />
<span style="background-color: white;">Durelli L, Isoardo G. High-dose intravenous immunoglobulin treatment of multiple sclerosis. Neurol Sci 2002;23(Suppl 1):S39-48.</span><br />
<span style="background-color: white;">Fazekas F, Deisenhammer F, Strasser-Fuchs S, et al. Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Lancet 1997;349:589-93.</span><br />
<span style="background-color: white;">Haas J. High dose IVIG in the post partum period for prevention of exacerbations in MS.Mult Scler 2000;6(Suppl 2):S18-20; discussion S33.</span><br />
<span style="background-color: white;">Hommes OR, Maas-Enriquez M. ESIMS--an ongoing clinical trial in secondary progressive multiple sclerosis. Mult Scler 2000;6(Suppl 2):S27-32.</span><br />
<span style="background-color: white;">Kalanie H, Tabatabai SS. Combined immunoglobulin and azathioprine in multiple sclerosis. Eur Neurol 1998;39:178-81.</span><br />
<span style="background-color: white;">Kazatchkine MD, Bellon B, Kaveri SV. Mechanisms of action of intravenous immunoglobulin (IVIG). Mult Scler 2000;6(Suppl 2):S24-6; discussion S33.</span><br />
<span style="background-color: white;">Lewanska M, Siger-Zajdel M, Selmaj K. No difference in efficacy of two different doses of intravenous immunoglobulins in MS: clinical and MRI assessment. Eur J Neurol 2002;9:565-72. Marchioni E, Marinou-Aktipi K, Uggetti C, et al. Effectiveness of intravenous immunoglobulin treatment in adult patients with steroid-resistant monophasic or recurrent acute disseminated encephalomyelitis. J Neurol 2002;249:100-4.</span><br />
<span style="background-color: white;">Nishikawa M, Ichiyama T, Hayashi T, et al. Intravenous immunoglobulin therapy in acute disseminated encephalomyelitis. Pediatr Neurol 1999;21:583-6.</span><br />
<span style="background-color: white;">Noseworthy JH, O'Brien PC, Petterson TM, et al. A randomized trial of intravenous immunoglobulin in inflammatory demyelinating optic neuritis. Neurology 2001;56:1514-22.</span><br />
<span style="background-color: white;">Noseworthy JH, O'Brien PC, Weinshenker BG, et al. IV immunoglobulin does not reverse established weakness in MS. Neurology 2000;55:1135-43.</span><br />
<span style="background-color: white;">Poehlau D. Treatment of chronic progressive multiple sclerosis with intravenous immunoglobulins--interim results on drug safety of an ongoing study. IVIG study group. Mult Scler 2000;6(Suppl 2):S21-3.</span><br />
<span style="background-color: white;">Sorensen PS. The effect on MRI of gammaglobulin treatment in relapsing multiple sclerosis. Mult Scler 2000;6(Suppl 2):S14-7.</span><br />
<span style="background-color: white;">Sorensen PS. The role of intravenous immunoglobulin in the treatment of multiple sclerosis. J Neurol Sci 2003;206:123-30.</span><br />
<span style="background-color: white;">Sorensen PS, Fazekas F, Lee M. Intravenous immunoglobulin G for the treatment of relapsing-remitting multiple sclerosis: a meta-analysis. Eur J Neurol 2002;9:557-63.</span><br />
<span style="background-color: white;">Stangel M, Boegner F, Klatt CH, Hofmeister C, Seyfert S. Placebo controlled pilot trial to study the remyelinating potential of intravenous immunoglobulins in multiple sclerosis. J Neurol Neurosurg Psychiatry 2000;68:89-92.</span><br />
<span style="background-color: white;">Strasser-Fuchs S, Fazekas F, Deisenhammer F, Nahler G, Mamoli B. The Austrian Immunoglobulin in MS (AIMS) study: final analysis. Mult Scler 2000;6 Suppl 2:S9-13.</span><br />
<span style="background-color: white;">Straussberg R, Schonfeld T, Weitz R, Karmazyn B, Harel L. Improvement of atypical acute disseminated encephalomyelitis with steroids and intravenous immunoglobulins. Pediatr Neurol 2001;24:139-43.</span><br />
<span style="background-color: white;">Tenser RB, Hay KA, Aberg JA. Immunoglobulin G immunosuppression of multiple sclerosis: suppression of all three major lymphocyte subsets. Arch Neurol 1993;50:417-20.</span><br />
<span style="background-color: white;">Myasthenia gravisAchiron A, Barak Y, Miron S, Sarova-Pinhas I. Immunoglobulin treatment in refractory Myasthenia gravis. Muscle Nerve 2000;23:551-5.</span><br />
<span style="background-color: white;">Arsura EL, Bick A, Brunner NG, et al. Effects of repeated doses of intravenous immunoglobulin in myasthenia gravis. Am J Med Sci 1988;295:438-43.</span><br />
<span style="background-color: white;">Bjornson DC, Grabenstein JD. Immune globulin. In: Hutchison TA, Shahan DR, editors. DRUGDEX® System, MICROMEDEX®: Greenwood Village, Colorado, 2003.</span><br />
<span style="background-color: white;">Cosi V, Piccolo G. IVIg in polymyositis and myasthenia gravis. Electroencephalogr Clin Neurophysiol Suppl 1999;50:499-505.</span><br />
<span style="background-color: white;">Ferrero B, Durelli L. High-dose intravenous immunoglobulin G treatment of myasthenia gravis. Neurol Sci 2002;23 Suppl 1:S9-24.</span><br />
<span style="background-color: white;">Ferrero B, Durelli L, Cavallo R, et al. Therapies for exacerbation of myasthenia gravis: the mechanism of action of intravenous high-dose immunoglobulin G. Ann N Y Acad Sci 1993;681:563-6.</span><br />
<span style="background-color: white;">Huang CS, Hsu HS, Kao KP, Huang MH, Huang BS. Intravenous immunoglobulin in the preparation of thymectomy for myasthenia gravis. Acta Neurol Scand 2003;108:136-8.</span><br />
<span style="background-color: white;">Gajdos PH. Intravenous immune globulin in myasthenia gravis. Clin Exp Immunol 1994;97(suppl 1):49-51.</span><br />
<span style="background-color: white;">Ronager J, Ravnborg M, Hermansen I, Vorstrup S. Immunoglobulin treatment versus plasma exchange in patients with chronic moderate to severe myasthenia gravis. Artif Organs 2001;25:967-73.</span><br />
<span style="background-color: white;">Selcen D, Dabrowski ER, Michon AM, Nigro MA. High-dose intravensou immunoglobulin therapy in juvenile myasthenia gravis. Pediatr Neurol 2000;22:40-3.</span><br />
<span style="background-color: white;">Takata T, Koide S, Ogata K, et al. Lambert-Eaton myasthenic syndrome associated with idiopathic thrombocytopenic purpura and diffuse panbronchiolitis: long-term remission after a course of intravenous immunoglobulin combined with low-dose prednisolone. Am J Med Sci 1999;318:353-5.</span><br />
<span style="background-color: white;">Wegner B, Ahmed I. Intravenous immunoglobulin monotherapy in long-term treatment of myasthenia gravis. Clin Neurol Neurosurg 2002;105:3-8.</span><br />
<span style="background-color: white;">Wolfe GI, Barohn RJ, Foster BM, et al. Randomized, controlled trial of intravenous immunoglobulin in myasthenia gravis. Muscle Nerve 2002;26:549-52.</span><br />
<span style="background-color: white;">Neuropathies, general or otherComi G, Roveri L, Swan A, et al. A randomised controlled trial of intravenous immunoglobulin in IgM paraprotein associated demyelinating neuropathy. J Neurol 2002;249:1370-7.</span><br />
<span style="background-color: white;">Creange A, Gregson NA, Hughes RA. Intravenous immunoglobulin modulates lymphocyte CD54 and monocyte FcgammaRII expression in patients with chronic inflammatory neuropathies. J Neuroimmunol 2003;135:91-5.</span><br />
<span style="background-color: white;">Crouch ED, Watson LE. Intravenous immunoglobulin-related acute coronary syndrome and coronary angiography in idiopathic thrombocytopenic purpura--a case report and literature review. Angiology 2002;53:113-7.</span><br />
<span style="background-color: white;">Dalakas MC. Mechanisms of action of IVIg and therapeutic considerations in the treatment ofacute and chronic demyelinating neuropathies. Neurology 2002;59(12 Suppl 6):S13-21.</span><br />
<span style="background-color: white;">Donofrio PD. Immunotherapy of idiopathic inflammatory neuropathies. Muscle Nerve 2003;28:273-92.</span><br />
<span style="background-color: white;">Gorson KC, Ropper AH, Weinberg DH, Weinstein R. Efficacy of intravenous immunoglobulin in patients with IgG monoclonal gammopathy and polyneuropathy. Arch Neurol 2002;59:766-72.</span><br />
<span style="background-color: white;">Hahn AF. Intravenous immunoglobulin treatment in peripheral nerve disorders--indications, mechanisms of action and side-effects. Curr Opin Neurol 2000;13:575-82.</span><br />
<span style="background-color: white;">Ogawa T, Taguchi T, Tanaka Y, Ikeguchi K, Nakano I. Intravenous immunoglobulin therapy for diabetic amyotrophy. Intern Med 2001;40:349-52.</span><br />
<span style="background-color: white;">Sharma KR, Cross J, Ayyar DR, Martinez-Arizala A, Bradley WG. Diabetic demyelinating polyneuropathy responsive to intravenous immunoglobulin therapy. Arch Neurol 2002;59:751-7.</span><br />
<span style="background-color: white;">Takahashi Y, Takata T, Hoshino M, Sakurai M, Kanazawa I. Benefit of IVIG for long-standing ataxic sensory neuronopathy with Sjogren's syndrome. IV immunoglobulin. Neurology 2003;60:503-5.</span><br />
<span style="background-color: white;">Stiff person syndromeGerschlager W, Brown P. Effect of treatment with intravenous immunoglobulin on quality of life in patients with stiff-person syndrome. Mov Disord 2002;17:590-3.</span><br />
<span style="background-color: white;">Khanlou H, Eiger G. Long-term remission of refractory stiff-man syndrome after treatment with intravenous immunoglobulin. Mayo Clin Proc 1999;74:1231-2.</span><br />
<span style="background-color: white;">Other neurologic conditionsBen-Nathan D, Lustig S, Tam G, Robinzon S, Segal S, Rager-Zisman B. Prophylactic and therapeutic efficacy of human intravenous immunoglobulin in treating West Nile virus infection in mice. J Infect Dis 2003;188:5-12.</span><br />
<span style="background-color: white;">Bjornson DC, Grabenstein JD. Immune globulin. In: Hutchison TA, Shahan DR, editors. DRUGDEX® System, MICROMEDEX®: Greenwood Village, Colorado, 2003.</span><br />
<span style="background-color: white;">Cohen HA, Ashkenasi A, Ring H, et al. Poliomyelitis-like syndrome following asthmatic attack (Hopkins' syndrome)--recovery associated with IV gamma globulin treatment. Infection 1998;26:247-9.</span><br />
<span style="background-color: white;">Daaboul Y, Vern BA, Blend MJ. Brain SPECT imaging and treatment with IVIg in acute post-infectious cerebellar ataxia: case report. Neurol Res 1998;20:85-8.</span><br />
<span style="background-color: white;">Finsterer J, Engelmayer E, Trnka E, Stiskal M. Immunoglobulins are effective in pontine myelinolysis. Clin Neuropharmacol 2000;23:110-3.</span><br />
<span style="background-color: white;">Fox RJ, Kasner SE, Galetta SL, Chalela JA. Treatment of Bickerstaff's brainstem encephalitis with immune globulin. J Neurol Sci 2000;178:88-90.</span><br />
<span style="background-color: white;">Ishii A, Hayashi A, Ohkoshi N, et al. Clinical evaluation of plasma exchange and high dose intravenous immunoglobulin in a patient with Isaacs' syndrome. J Neurol Neurosurg Psychiatry 1994;57:840-2.</span><br />
<span style="background-color: white;">Jayne DR, Chapel H, Adu D, et al. Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity. QJM 2000;93:433-9.</span><br />
<span style="background-color: white;">Jayne DR, Davies MJ, Fox CJ, Black CM, Lockwood CM. Treatment of systemic vasculitis with pooled intravenous immunoglobulin. Lancet 1991;337:1137-9.</span><br />
<span style="background-color: white;">Karlson EW, Sudarsky L, Ruderman E, et al. Treatment of stiff-man syndrome with intravenous immune globulin. Arthritis Rheum 1994;37:915-8.</span><br />
<span style="background-color: white;">Keime-Guibert F, Graus F, Fleury A, et al. Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (Anti-Hu, anti-Yo) with a combination of immunoglobulins, cyclophosphamide, and methylprednisolone. J Neurol Neurosurg Psychiatry 2000;68:479-82.</span><br />
<span style="background-color: white;">Latov N, Chaudhry V, Koski CL, et al. Use of intravenous gamma globulins in neuroimmunologic diseases. J Allergy Clin Immunol 2001;108(4 Suppl):S126-32.</span><br />
<span style="background-color: white;">Mease PJ, Ochs HD, Wedgewood RJ. Successful treatment of echovirus meningo-encephalitis and myositis-fasciitis with intravenous immune globulin therapy in a patient with x-linked agammaglobulinemia. N Engl J Med 1981;304:1278-81.</span><br />
<span style="background-color: white;">Ogawa T, Taguchi T, Tanaka Y, et al. Intravenous immunoglobulin therapy for diabetic amyotrophy. Intern Med 2001;40:349-52.</span><br />
<span style="background-color: white;">Perlmutter SJ, Leitman SF, Garvey MA, et al. Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet 1999;354:1153-8.</span><br />
<span style="background-color: white;">Pranzatelli MR, Tate ED, Kinsbourne M, Caviness VS Jr, Mishra B. Forty-one year follow-up of childhood-onset opsoclonus-myoclonus-ataxia: cerebellar atrophy, multiphasic relapses, and response to IVIG. Mov Disord 2002;17:1387-90.</span><br />
<span style="background-color: white;">Ratko TA, Burnett DA, Foulke GE, et al. Recommendations for off-label use of intravenously administered immunoglobulin preparations. JAMA 1995;273:1865-70.</span><br />
<span style="background-color: white;">Verma A, Bradley WG. High-dose intravenous immunoglobulin therapy in chronic progressive lumbosacral plexopathy. Neurology 1994;44:248-50.</span><br />
<span style="background-color: white;">Widdess-Walsh P, Tavee JO, Schuele S, Stevens GH. Response to intravenous immunoglobulin in anti-Yo associated paraneoplastic cerebellar degeneration: case report and review of the literature. J Neurooncol 2003;63:187-90.</span><br />
<span style="background-color: white;">Complications: aseptic meningitisBjornson DC, Grabenstein JD. Immune globulin. In: Hutchison TA, Shahan DR, editors. DRUGDEX® System, MICROMEDEX®: Greenwood Village, Colorado, 2003.</span><br />
<span style="background-color: white;">Casteels-Van Daele M, Wijndaele L, Hunninck K, et al. Intravenous immune globulin and acute aseptic meningitis (letter). N Engl J Med 1990;323:614-5.</span><br />
<span style="background-color: white;">De Vlieghere FC, Peetermans WE, Vermylen J. Aseptic granulocytic meningitis following treatment with intravenous immunoglobulin. Clin Infect Dis 1994;18:1008-10.</span><br />
<span style="background-color: white;">Kato E, Shindo S, Eto Y, et al. Administration of immune globulin associated with aseptic meningitis. JAMA 1988;259:3269-70.</span><br />
<span style="background-color: white;">Kressebuch H, Schaad UB, Hirt A, et al. Cerebrospinal fluid inflammation induced by intravenous immunoglobulins (letter). Pediatr Infect Dis J 1992;11:894-5.</span><br />
<span style="background-color: white;">Ozsoylu S. Aseptic meningitis and intravenous gammaglobulin treatment (letter). Am J Dis Child 1993;147:129.</span><br />
<span style="background-color: white;">Rao SP, Teitlebaum J, Miller ST. Intravenous immune globulin and aseptic meningitis (letter). Am J Dis Child 1992;146:539-40.</span><br />
<span style="background-color: white;">Sekul EA, Cupler EJ, Dalakas MC. Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors. Ann Intern Med 1994;121:259-62.</span><br />
<span style="background-color: white;">Watson JD, Gibson J, Joshua DE, et al. Aseptic meningitis associated with high dose intravenous immunoglobulin therapy. J Neurol Neurosurg Psychiatry 1991;54:275-6.</span><br />
<span style="background-color: white;">Complications: stroke and other thrombotic eventsAlliot C, Rapin JP, Bessonn M, Bedjaoui F, Messouak D. Pulmonary embolism after intravenous immunoglobulin. J R Soc Med 2001;94:187-8.</span><br />
<span style="background-color: white;">Bjornson DC, Grabenstein JD. Immune globulin. In: Hutchison TA, Shahan DR, editors. DRUGDEX® System, MICROMEDEX®, Greenwood Village, Colorado, 3/2003.</span><br />
<span style="background-color: white;">Byrne NP, Henry JC, Herrmann DN, et al. Neuropathologic findings in a Guillain-Barre patient with strokes after IVIg therapy. Neurology 2002;59:458-61.</span><br />
<span style="background-color: white;">Caress JB, Cartwright MS, Donofrio PD, Peacock JR Jr. The clinical features of 16 cases of stroke associated with administration of IVIg. Neurology 2003;60:1822-4.</span><br />
<span style="background-color: white;">Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 1994;44:223-6.</span><br />
<span style="background-color: white;">Dalakas MC, Clark WM. Strokes, thromboembolic events, and IVIg: rare incidents blemish an excellent safety record. Neurology 2003;60:1736-7.</span><br />
<span style="background-color: white;">Elkayam O, Paran D, Milo R, et al. Acute myocardial infarction associated with high dose intravenous immunoglobulin infusion for autoimmune disorders. A study of four cases. Ann Rheum Dis 2000;59:77.</span><br />
<span style="background-color: white;">Emerson GG, Herndon CN, Sreih AG. Thrombotic complications after intravenous immunoglobulin therapy in two patients. Pharmacotherapy 2002;22:1638-41.</span><br />
<span style="background-color: white;">Evangelou N, Littlewood T, Anslow P, Chapel H. Transverse sinus thrombosis and IVIg treatment: a case report and discussion of risk-benefit assessment for immunoglobulin treatment. J Clin Pathol 2003;56:308-9.</span><br />
<span style="background-color: white;">Frame WD, Crawford RJ. Thrombotic events after intravenous immunoglobulin. Lancet 1986;ii:468.</span><br />
<span style="background-color: white;">Go RS, Call TG. Deep venous thrombosis of the arm after intravenous immunoglobulin infusion: case report and literature review of intravenous immunoglobulin-related thrombotic complications. Mayo Clin Proc 2000;75:83-5.</span><br />
<span style="background-color: white;">Okuda D, Flaster M, Frey J, Sivakumar K. Arterial thrombosis induced by IVIg and its treatment with tPA. Neurology 2003;60:1825-6.</span><br />
<span style="background-color: white;">Reinhart WH, Berchtold PE: Effect of high-dose intravenous immunoglobulin therapy on blood rheology. Lancet 1992;339:662-4.</span><br />
<span style="background-color: white;">Sherer Y, Wu R, Krause I, Peter JB, Schoenfeld Y. Antiphospholipid antibody levels in intravenous immunoglobulin (IVIg) preparations. Lupus 2001;10:568-70.</span><br />
<span style="background-color: white;">Struble EJ, Dice YG. Intravenous immune globulin (IVIG) precipitating acute myocardial infarction. J Miss State Med Assoc 2002;43:115.</span><br />
<span style="background-color: white;">Sztajzel R, Floch-Rohr JL, Eggimann P. High-dose intravenous immunoglobulin treatment and cerebral vasospasm: a possible mechanism of ischemic encephalopathy? Eur Neurol 1999;41:153-8.</span><br />
<span style="background-color: white;">Turner B, Wills AJ. Cerebral infarction complicating intravenous immunoglobulin therapy in a patient with Miller Fisher syndrome. J Neurol Neurosurg Psychiatry 2000;68:790-1.</span><br />
<span style="background-color: white;">Wolberg AS, Kon RH, Monroe DM, Hoffman M. Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol 2000;65:30-4.</span><br />
<span style="background-color: white;">Woodruff RK, Grigg AP, Firkin FC, Smith IL. Fatal thrombotic events during treatment of autoimmune thrombocytopenic purpura with intravenous immunoglobulin in elderly patients. Lancet 1986;2:217-8.</span><br />
<span style="background-color: white;">Zaidan R, Al Moallem M, Wani BA, et al. Thrombosis complicating high dose intravenous immunoglobulin: report of three cases and review of the literature. Eur J Neurol 2003;10:367-72.</span><br />
<span style="background-color: white;">Complications: general or otherBallow M. Intravenous immunoglobulins: clinical experience and viral safety. J Am Pharm Assoc 2002;42:449-58, 824.</span><br />
<span style="background-color: white;">Bertorini TE, Nance AM, Horner LH, Greene W, Gelfand MS, Jaster JH. Complications of intravenous gammaglobulin in neuromuscular and other diseases. Muscle Nerve 1996;19:388-91.</span><br />
<span style="background-color: white;">Bjorkander J, Wadsworth C, Hanson LA. 1040 prophylactic infusions with an unmodified intravenous immunoglobulin product causing few side effects in patients with antibody deficiency syndrome. Infection 1985;13:102-10.</span><br />
<span style="background-color: white;">Bjornson DC, Grabenstein JD. Immune globulin. In: Hutchison TA, Shahan DR , editors. DRUGDEX® System, MICROMEDEX®: Greenwood Village, Colorado, 2003.</span><br />
<span style="background-color: white;">Brannagan TH III, Nagle KJ, Lange DJ, Rowland LP. Complications of intravenous immune globulin treatment in neurologic disease. Neurology 1996;47:674-7.</span><br />
<span style="background-color: white;">Grillo JA, Gorson KC, Ropper AH, Lewis J, Weinstein R. Rapid infusion of intravenous immune globulin in patients with neuromuscular disorders. Neurology 20021;57:1699-1701.</span><br />
<span style="background-color: white;">Ippolito C, Williams LA, Huber S. Toxicity of rapidly infused concentrated intravenous immunoglobulin. Clin Pharm 1992;11:1022-6.</span><br />
<span style="background-color: white;">Karussis D, Abramsky O. Is the routine use of intravenous immunoglobulin treatment in neurologic disorders justified?: No. Arch Neurol 1999;56:1028-32.</span><br />
<span style="background-color: white;">Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 2001;345:747-55.</span><br />
<span style="background-color: white;">Levy JB, Pusey CD. Nephrotoxicity of intravenous immunoglobulin. QJM 2000;93:751-5.</span><br />
<span style="background-color: white;">Lewis M, Maddison P, Turner B, Wills AJ. Intravenous immunoglobulin causing reversible posterior leukoencephalopathy syndrome? J Neurol Neurosurg Psychiatry 2000;69:704.</span><br />
<span style="background-color: white;">Mathy I, Gille M, Van Raemdonck F, et al. Neurological complications of intravenous immunoglobulin (IVIg) therapy: an illustrative case of acute encephalopathy following IVIg therapy and a review of the literature. Acta Neurol Belg 1998;98(4):347-51.</span><br />
<span style="background-color: white;">Misbah SA, Chapel HM. Adverse effects of intravenous immunoglobulin. Drug Saf 1993;9:254-62.</span><br />
<span style="background-color: white;">Reichl HE, Foster PR, Welch AG, et al. Studies on the removal of a bovine spongiform encephalopathy-derived agent by processes used in the manufacture of human immunoglobulin. Vox Sang 2002;83:137-45.</span><br />
<span style="background-color: white;">Stangel M, Hartung HP, Marx P, Gold R. Side effects of high-dose intravenous immunoglobulins. Clin Neuropharmacol 1997;20:385-93.</span><br />
<span style="background-color: white;">Stangel M, Kiefer R, Pette M, Smolka MN, Marx P, Gold R. Side effects of intravenous immunoglobulins in neurological autoimmune disorders--a prospective study. J Neurol 2003;250:818-21.</span>Carlos Vázquezhttp://www.blogger.com/profile/09266699098392968330noreply@blogger.com2tag:blogger.com,1999:blog-7084351769408080486.post-24215888746743046452011-12-26T05:24:00.001-08:002012-11-23T10:55:02.920-08:00Antipsychotic medications<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">INTRODUCTION</span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> — Antipsychotic medications were introduced more than 50 years ago. Although initially targeted to the treatment of schizophrenia, these medications are effective against psychosis irrespective of cause. They are also of benefit for manic episodes, agitation, delirium, impulse control, dissociation, and as augmentation therapy in other psychiatric disorders.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">This topic reviews drug selection, treatment protocols, side effects and management of antipsychotic medications. The pharmacological characteristics of these medications in adults is discussed separately, as are identification and treatment of overdose with atypical antipsychotic agents, the target symptoms, the treatment of psychosis in special populations, and the non-pharmacologic treatment of psychosis.</span><br />
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"></span><br />
<a name='more'></a><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br /></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">PHARMACOTHERAPY FOR PSYCHOSIS</span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> — As discussed below, both conventional and atypical antipsychotic medications are associated with significant side effects, including sudden death. While antipsychotics are clearly indicated for patients with schizophrenia and other psychoses, their use in all patients should be limited to situations for which the benefits exceed the risks.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Drug selection</span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> — No one antipsychotic medication has emerged as the preferred choice for first-line treatment [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=1" style="color: #0867ab; text-decoration: none;">1</a>]. They have comparable efficacy for psychosis and manic symptoms, and carry similar side effect burdens in reviews of large clinical trials [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=2-4" style="color: #0867ab; text-decoration: none;">2-4</a>].</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">The most comprehensive of these trials was the National Institute of Mental Health (NIMH)-sponsored CATIE study (Clinical Antipsychotic Trials of Intervention Effectiveness), a double-blind assessment of 1493 patients in the maintenance phase of treatment for chronic schizophrenia [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=5" style="color: #0867ab; text-decoration: none;">5</a>]. Patients were randomly assigned to receive the conventional antipsychotic perphenzazine or one of the newer agents (<a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/185495&drug=true" style="color: #0867ab; text-decoration: none;">olanzapine</a>,<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/14699&drug=true" style="color: #0867ab; text-decoration: none;">quetiapine</a>,<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/223516&drug=true" style="color: #0867ab; text-decoration: none;">risperidone</a> or<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/27784&drug=true" style="color: #0867ab; text-decoration: none;">ziprasidone</a>) [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=5" style="color: #0867ab; text-decoration: none;">5</a>]. The study defined effectiveness as time to discontinuation of treatment for any cause over 18 months. The overall discontinuation rate was 74 percent, with olanzapine having the lowest rate at 64 percent.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/185495&drug=true" style="color: #0867ab; text-decoration: none;">Olanzapine</a> demonstrated a modest advantage in treatment duration in the original data analysis. However, subsequent reanalysis suggested this may have been due to more patients taking olanzapine than other drugs prior to study entry; reanalysis found only a trend toward longer treatment duration for olanzapine [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=6" style="color: #0867ab; text-decoration: none;">6</a>]. This suggests that patients in long-term treatment do better when continued on the same medication than when switched. Thus, dose optimization or addition of psychosocial or behavioral therapy may be preferable to a switch in medication for patients stabilized on one medication.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">In phase 2 of CATIE, patients who did not complete the study were given the choice of<a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/63838&drug=true" style="color: #0867ab; text-decoration: none;">clozapine</a> or randomization to a different atypical drug. Among patients receiving a first-line drug, those given<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/223516&drug=true" style="color: #0867ab; text-decoration: none;">risperidone</a> and<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/185495&drug=true" style="color: #0867ab; text-decoration: none;">olanzapine</a> stayed in treatment longer than those receiving<a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/14699&drug=true" style="color: #0867ab; text-decoration: none;">quetiapine</a> or<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/27784&drug=true" style="color: #0867ab; text-decoration: none;">ziprasidone</a>, although 74 percent of these patients discontinued the medication prior to study completion [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=7" style="color: #0867ab; text-decoration: none;">7</a>]. Only 9 percent of eligible patients chose clozapine, but of this group only 56 percent discontinued the drug prematurely [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=8" style="color: #0867ab; text-decoration: none;">8</a>]. The average duration of treatment with clozapine was 10.5 months versus 2 to 3 months with olanzapine, quetiapine, or risperidone. Clozapine alone demonstrated clearly superior efficacy, a finding already well established in previous studies [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=9-14" style="color: #0867ab; text-decoration: none;">9-14</a>].</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">In general, studies comparing usual doses of<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/120995&drug=true" style="color: #0867ab; text-decoration: none;">haloperidol</a> (5 to 20 mg daily) with atypical antipsychotics have reported higher rates of medication discontinuation and patient relapse for the conventional drug [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=15" style="color: #0867ab; text-decoration: none;">15</a>]. However, it has been argued that these studies used higher doses of haloperidol than necessary, increasing the incidence of side effects. A multicenter non-blinded randomized study conducted in Europe in 500 patients newly diagnosed with schizophrenia compared low dose haloperidol (1 to 4 mg daily) with four atypical antipsychotics (amisulpride,<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/185495&drug=true" style="color: #0867ab; text-decoration: none;">olanzapine</a>,<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/14699&drug=true" style="color: #0867ab; text-decoration: none;">quetiapine</a>, and<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/27784&drug=true" style="color: #0867ab; text-decoration: none;">ziprasidone</a>) [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=16" style="color: #0867ab; text-decoration: none;">16</a>]. At 12 months, patients were more likely to discontinue haloperidol than the atypical drugs (72 percent versus 33 to 53 percent), although, with an unblinded study, this may in part reflect a tendency to switch to a perceived more effective treatment. There were no differences in measured symptom response or hospital admission rates among the five medications.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">A meta-analysis of 150 randomized trials directly comparing antipsychotics in patients with schizophrenia found similar efficacy for atypical and conventional drugs, but heterogeneity among the atypical drugs [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=17" style="color: #0867ab; text-decoration: none;">17</a>]. Four atypical drugs (<a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/63838&drug=true" style="color: #0867ab; text-decoration: none;">clozapine</a>, amisulpride,<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/185495&drug=true" style="color: #0867ab; text-decoration: none;">olanzapine</a>, and<a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/223516&drug=true" style="color: #0867ab; text-decoration: none;">risperidone</a>) had better efficacy than other antipsychotics, with small to medium effect size. Most studies used<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/120995&drug=true" style="color: #0867ab; text-decoration: none;">haloperidol</a> as a comparator, and did not evaluate lower potency conventional agents.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Another meta-analysis evaluated 78 randomized head-to-head trials of nine atypical antipsychotics (including three not available in the US) [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=18" style="color: #0867ab; text-decoration: none;">18</a>]. Better efficacy (primarily improvement in positive symptom scores), with small to moderate effect sizes, was also found for<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/185495&drug=true" style="color: #0867ab; text-decoration: none;">olanzapine</a>,<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/223516&drug=true" style="color: #0867ab; text-decoration: none;">risperidone</a>, and<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/63838&drug=true" style="color: #0867ab; text-decoration: none;">clozapine</a> [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=18" style="color: #0867ab; text-decoration: none;">18</a>]. The authors noted that differences in side effects and costs may outweigh differences in efficacy.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">In contrast to relative modest differences in efficacy, studies consistently show statistically and clinically significant differences among antipsychotics in side effects, including risk of EPS, weight gain, metabolic effects, sedation, hypotension, and GI effects. In the CATIE study,<a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/185495&drug=true" style="color: #0867ab; text-decoration: none;">olanzapine</a> discontinuation was primarily related to weight gain and metabolic side effects (increased blood glucose, hyperlipidemia);<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/14699&drug=true" style="color: #0867ab; text-decoration: none;">quetiapine</a> to sedation; and<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/197338&drug=true" style="color: #0867ab; text-decoration: none;">perphenazine</a> to extrapyramidal effects [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=5" style="color: #0867ab; text-decoration: none;">5</a>]. Additional differences among drugs include routes of administration, pharmacokinetics, and cost. Individual patients may respond preferentially to one of these agents, but there are no indications or biological markers to predict which drug will work for a specific person [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=19" style="color: #0867ab; text-decoration: none;">19</a>].</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">In general, atypical antipsychotic medications have been considered first-line, because of their lower risk for extrapyramidal side effects compared to conventional antipsychotics. However, atypical antipsychotics are more expensive, and several cause more metabolic side effects and weight gain than conventional agents. Additionally, unnecessarily high doses of conventional antipsychotics in earlier studies may have increased the incidence of side effects.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">In practice, patients often have had previous medication exposure, and treatment selection can be based on their prior response. Patients with a history of good response to a drug should be given that medication. Patients who had intolerable side effects to one drug should be treated with a drug with the lowest propensity for that adverse effect. For patients who initially failed to respond to a drug, any of the others may reasonably be selected. Individuals who responded well but were habitually nonadherent to treatment should be considered for depot medication (<a href="http://www.uptodateonline.com/online/content/image.do?imageKey=PC%2F20126" style="color: #0867ab; text-decoration: none;" target="_blank">table 1</a>).</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">For new patients, drug selection may be based on the expectation of a specific side effect, such as weight gain in a patient with obesity or diabetes, or EPS in a patient with parkinsonian symptoms. When no obvious risk exists, factors of cost, convenience, and clinician familiarity with the drug should be considered (<a href="http://www.uptodateonline.com/online/content/image.do?imageKey=PC%2F20176" style="color: #0867ab; text-decoration: none;" target="_blank">table 2</a>). For the practitioner who only occasionally uses these medications, it is reasonable to develop greater experience and comfort with one or two medications and preferentially use those.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Behavioral issues in Alzheimer’s patients</span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> — Another arm of the CATIE trial evaluated use of atypical antipsychotics versus placebo in patients with behavioral issues and Alzheimer disease [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=20" style="color: #0867ab; text-decoration: none;">20</a>]. Adverse effects offset the small efficacy of<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/185495&drug=true" style="color: #0867ab; text-decoration: none;">olanzapine</a> and<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/223516&drug=true" style="color: #0867ab; text-decoration: none;">risperidone</a>, which were both more effective than<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/14699&drug=true" style="color: #0867ab; text-decoration: none;">quetiapine</a> in this population (see<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=nuroegen/6511#H12" style="color: #0867ab; text-decoration: none;">“Treatment of behavioral symptoms related to dementia”, section on ‘Antipsychotic agents’</a>. Mortality issues related to use of antipsychotic medications for patients with dementia are discussed below (see<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=psychiat/#H21" style="color: #0867ab; text-decoration: none;">‘Elderly patients with dementia’</a> below.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Treatment course and duration</span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> — Dosages of the antipsychotic drugs should be titrated into the average therapeutic range as quickly as tolerated. Resolution of psychotic symptoms generally occurs over several days and may take as much as four to six weeks, although there is an immediate calming effect for agitated patients. Clinicians should avoid the impulse to change the medication or dose prematurely.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">The decision to increase the dose beyond the average range should follow at least several days of treatment at moderate doses. Higher dosing should be accompanied by careful observation for side effects, but is usually well tolerated. In most instances, an increase in dose of the current medication is preferable to a switch to an alternative drug.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">The duration of treatment depends on the diagnosis. Patients with delirium, agitation, brief psychotic disorders, or impulsivity may require only a few days or weeks of treatment. Schizophrenic patients, in contrast, benefit from continuous treatment and are at risk for relapse with medication discontinuation or even dose reduction [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=21" style="color: #0867ab; text-decoration: none;">21</a>].</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">The role of antipsychotics in maintenance therapy for bipolar disorder is uncertain; usual practice is to withdraw antipsychotics and continue mood stabilizers after several weeks of mood stability [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=22" style="color: #0867ab; text-decoration: none;">22</a>]. Maintenance treatment may also be considered in patients treated for persistent impulsivity or behavioral problems, but there are limited data.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Medications should be periodically reviewed for patients on long-term medication. Routine dose reduction in stable patients to establish the “lowest effective dose” is associated with high rates of relapse and should be avoided [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=1%2C21" style="color: #0867ab; text-decoration: none;">1,21</a>]. Dose reduction may be justified in patients at risk for side effects and in patients on high doses of medication following an acute episode of illness.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Medication changes</span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> — Two basic strategies have been recommended for switching antipsychotic medications [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=23%2C24" style="color: #0867ab; text-decoration: none;">23,24</a>]. A standard cross-titration involves simultaneous taper of the current medication with titration of the replacement drug in three to four steps over several days to several weeks. For patients at higher risk of relapse, the current medication can be maintained at its full dose as the new medication is titrated. Once the second drug has reached its target dose, the former medication may be tapered and discontinued.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Discontinuation of antipsychotic medications is generally well tolerated, except for<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/63838&drug=true" style="color: #0867ab; text-decoration: none;">clozapine</a>, for which both cholinergic rebound and withdrawal-emergent movement disorders have been reported [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=25-27" style="color: #0867ab; text-decoration: none;">25-27</a>]. A slow taper of clozapine (over one to two weeks) is recommended. No specific recommendations for discontinuation of other antipsychotics have been made.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Treatment-refractory cases</span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> — Up to 30 percent of schizophrenic patients do not respond to first-line antipsychotic treatment. Three basic strategies address resistant cases: use of<a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/63838&drug=true" style="color: #0867ab; text-decoration: none;">clozapine</a>, augmentation, or simultaneous multiple antipsychotics. Of these options, only clozapine treatment is of proven efficacy for treatment-refractory patients [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=27-32" style="color: #0867ab; text-decoration: none;">27-32</a>], a finding confirmed in the CATIE study [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=8" style="color: #0867ab; text-decoration: none;">8</a>].</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Clozapine</span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> — There is no consensus as to how many other antipsychotics should be tried before beginning<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/63838&drug=true" style="color: #0867ab; text-decoration: none;">clozapine</a>; guidelines variously recommend two to four other drugs, and differ as to specific medications.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/63838&drug=true" style="color: #0867ab; text-decoration: none;">Clozapine</a> is effective in 30 to 50 percent of patients with psychosis who have not responded to other antipsychotic drugs. Life-threatening agranulocytosis has been reported in one to two percent of patients during the first six months of treatment. Consequently, a schedule for monitoring has been designed requiring weekly CBC for the first six months, biweekly CBC for the second six months, and subsequent testing every four weeks. We suggest that clozapine be prescribed by a specialist familiar with this medication.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Augmentation</span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> — Augmentation strategies include using anticonvulsants,<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/146048&drug=true" style="color: #0867ab; text-decoration: none;">lithium</a>, benzodiazepines, and electroconvulsive therapy [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=1" style="color: #0867ab; text-decoration: none;">1</a>]. Augmentation may be most helpful if a specific secondary symptom, such as mood instability, irritability, or anxiety is prominent, allowing rational drug selection to target those symptoms.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Combination therapy</span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> — The simultaneous use of two or more antipsychotic drugs is more controversial [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=29" style="color: #0867ab; text-decoration: none;">29</a>]. This is difficult to justify pharmacologically, since the antipsychotic effectiveness appears to be related to the same dopaminergic receptor system for all of these drugs.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Data on combination therapy are unclear. Three randomized trials that combine<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/63838&drug=true" style="color: #0867ab; text-decoration: none;">clozapine</a> with<a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/223516&drug=true" style="color: #0867ab; text-decoration: none;">risperidone</a> for treatment of refractory schizophrenia came to differing conclusions [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=30-32" style="color: #0867ab; text-decoration: none;">30-32</a>]. One industry-sponsored study (n = 40) showed modest benefit when risperidone 6 mg/day was added to clozapine for 12 weeks, compared to placebo plus clozapine [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=30" style="color: #0867ab; text-decoration: none;">30</a>]. A second industry-sponsored study of 30 patients treated for six weeks with risperidone 6 mg/day plus clozapine or placebo plus clozapine showed better symptom response in the placebo/clozapine group [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=31" style="color: #0867ab; text-decoration: none;">31</a>]. A third study (n = 68), not industry-sponsored, compared an eight week course of clozapine plus risperidone at 3 mg/day with clozapine plus placebo and also showed no symptom benefit with the addition of risperidone; there was mild memory impairment in the risperidone-treated group [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=32" style="color: #0867ab; text-decoration: none;">32</a>].</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">ADVERSE EFFECTS AND MANAGEMENT</span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> — Side effects are usually mild and of limited duration (<a href="http://www.uptodateonline.com/online/content/image.do?imageKey=PC%2F20372" style="color: #0867ab; text-decoration: none;" target="_blank">table 3</a>). If side effects do not improve with time, dose reduction is recommended, particularly for higher doses. If dose reduction is ineffective, a switch to another medication may be required. A small number of cases require adjunctive medication. The side effects of greatest concern in long-term treatment are tardive dyskinesia (TD) and weight gain.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Tardive dyskinesia</span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> — Tardive dyskinesia (TD) is the late-onset of choreoathetotic movements associated with prolonged exposure to antipsychotic medications. Major risk factors include the use of conventional antipsychotic medications, older age, and longer duration of treatment [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=33" style="color: #0867ab; text-decoration: none;">33</a>]. (See<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=move_dis/8150" style="color: #0867ab; text-decoration: none;">“Tardive dyskinesia: Etiology and epidemiology”</a>.)</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">The course of TD symptoms is variable. Although older textbooks describe TD as chronic and progressive, more recent studies have emphasized the self-limiting quality of many cases, with the majority of patients showing at least intermittent improvement for both conventional and atypical drugs. (See<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=move_dis/9662" style="color: #0867ab; text-decoration: none;">“Tardive dyskinesia: Clinical features and diagnosis”</a>.)</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Patients on long-term maintenance treatment should be monitored periodically for TD. When clinically appropriate, dose reduction may be considered to reduce symptoms. Patients on conventional antipsychotics should be considered for an atypical agent.<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/63838&drug=true" style="color: #0867ab; text-decoration: none;">Clozapine</a> should be considered for patients with severe or progressing symptoms [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=34" style="color: #0867ab; text-decoration: none;">34</a>]. Numerous other treatments, including<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/280203&drug=true" style="color: #0867ab; text-decoration: none;">vitamin E</a>, dopaminergic agents, benzodiazepines, and branched-chain amino acids, have not been shown to be effective. (See<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=move_dis/9073" style="color: #0867ab; text-decoration: none;">“Tardive dyskinesia: Prevention and treatment”</a>.)</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Weight gain</span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> — Weight gain is a significant issue with several of the atypical antipsychotics and should be monitored carefully (<a href="http://www.uptodateonline.com/online/content/image.do?imageKey=PC%2F21047" style="color: #0867ab; text-decoration: none;" target="_blank">table 4</a>). Clozapine carries the greatest risk, followed by<a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/185495&drug=true" style="color: #0867ab; text-decoration: none;">olanzapine</a> [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=35-37" style="color: #0867ab; text-decoration: none;">35-37</a>]. The CATIE study found that over 18 months, patients taking olanzapine gained an average of two pounds per month and 30 percent gained 7 percent or more of their initial body weight [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=5" style="color: #0867ab; text-decoration: none;">5</a>].</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Studies in mice have demonstrated that weight gain with atypical antipsychotics results from stimulation of AMP-activated protein kinase in the hypothalamus; deletion of the H-1 histamine receptor in knockout mice blocks this effect [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=38" style="color: #0867ab; text-decoration: none;">38</a>]. This suggests the potential to develop new antipsychotic agents with differential activity on dopamine and histamine receptors, to avoid weight gain.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">No adjunctive medication has been shown to neutralize weight gain, although studies of<a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/159390&drug=true" style="color: #0867ab; text-decoration: none;">metformin</a> suggest that it may modulate the effect.</span></div>
<ul style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 2em; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<li style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 5px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">A 12 week study of 80 patients stabilized on<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/185495&drug=true" style="color: #0867ab; text-decoration: none;">olanzapine</a> who were randomly assigned to (850 to 2250 mg daily) or placebo showed modest weight loss (1.4 kg) in the<a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/159390&drug=true" style="color: #0867ab; text-decoration: none;">metformin</a> group, but none with placebo [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=39" style="color: #0867ab; text-decoration: none;">39</a>].</span></li>
<li style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 5px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">A 12 week trial in 128 patients who had gained at least 10 percent of baseline body weight with antipsychotic treatment found<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/159390&drug=true" style="color: #0867ab; text-decoration: none;">metformin</a> (750 mg daily) significantly more effective than placebo plus lifestyle intervention in reducing BMI and waist circumference; metformin plus lifestyle intervention was more effective than metformin alone [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=40" style="color: #0867ab; text-decoration: none;">40</a>].</span></li>
<li style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 5px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/159390&drug=true" style="color: #0867ab; text-decoration: none;">Metformin</a> stabilized weight gain and improved insulin sensitivity in a randomized trial in adolescents (age 10 to 17 years) who had gained significant weight with<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/185495&drug=true" style="color: #0867ab; text-decoration: none;">olanzapine</a>,<a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/223516&drug=true" style="color: #0867ab; text-decoration: none;">risperidone</a> or<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/14699&drug=true" style="color: #0867ab; text-decoration: none;">quetiapine</a> [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=41" style="color: #0867ab; text-decoration: none;">41</a>].</span></li>
<li style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 5px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/159390&drug=true" style="color: #0867ab; text-decoration: none;">Metformin</a> also attenuated weight change in a randomized trial of patients who were receiving initial therapy with<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/185495&drug=true" style="color: #0867ab; text-decoration: none;">olanzapine</a> for first episode schizophrenia, and therefore had not already demonstrated weight gain [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=42" style="color: #0867ab; text-decoration: none;">42</a>].</span></li>
</ul>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Several other agents have been evaluated. Modest weight loss was reported in randomized trials for<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/266083&drug=true" style="color: #0867ab; text-decoration: none;">topiramate</a> [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=43-45" style="color: #0867ab; text-decoration: none;">43-45</a>],<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/11938&drug=true" style="color: #0867ab; text-decoration: none;">amantadine</a> [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=46" style="color: #0867ab; text-decoration: none;">46</a>], or<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/16297&drug=true" style="color: #0867ab; text-decoration: none;">sibutramine</a> [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=47" style="color: #0867ab; text-decoration: none;">47</a>], although sibutramine was not more effective than placebo in a study of<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/63838&drug=true" style="color: #0867ab; text-decoration: none;">clozapine</a>-induced weight gain [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=48" style="color: #0867ab; text-decoration: none;">48</a>]. Amantadine may worsen psychosis and sibutramine led to elevated blood pressure and anticholinergic symptoms.<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/109136&drug=true" style="color: #0867ab; text-decoration: none;">Fluoxetine</a> was not better than placebo in preventing weight gain in patients taking<a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/185495&drug=true" style="color: #0867ab; text-decoration: none;">olanzapine</a> [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=49" style="color: #0867ab; text-decoration: none;">49</a>].</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Although<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/159390&drug=true" style="color: #0867ab; text-decoration: none;">metformin</a> shows promise for patients with significant weight gain, the preponderance of evidence supports switching to a different antipsychotic (especially<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/184853&drug=true" style="color: #0867ab; text-decoration: none;">aripiprazole</a> or<a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/27784&drug=true" style="color: #0867ab; text-decoration: none;">ziprasidone</a>) in preference to the addition of an adjunctive medication.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Diabetes and other metabolic abnormalities</span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> — Antipsychotic medications, and atypical antipsychotics in particular, have been associated with hyperglycemia, dyslipidemia and hypertension [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=50-52" style="color: #0867ab; text-decoration: none;">50-52</a>].</span></div>
<ul style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 2em; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<li style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 5px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">The metabolic syndrome has been reported in over 50 percent of long-term users of<a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/63838&drug=true" style="color: #0867ab; text-decoration: none;">clozapine</a> [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=53" style="color: #0867ab; text-decoration: none;">53</a>]. (See<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=diabetes/21989" style="color: #0867ab; text-decoration: none;">“The metabolic syndrome (insulin resistance syndrome or syndrome X)”</a>.)</span></li>
</ul>
<ul style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 2em; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<li style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 5px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">The risk of new-onset diabetes was equivalent for patients treated for one year with<a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/185495&drug=true" style="color: #0867ab; text-decoration: none;">olanzapine</a>,<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/223516&drug=true" style="color: #0867ab; text-decoration: none;">risperidone</a>, or<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/14699&drug=true" style="color: #0867ab; text-decoration: none;">quetiapine</a>, and significantly greater than in patients treated with<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/120995&drug=true" style="color: #0867ab; text-decoration: none;">haloperidol</a> (HR 1.60 to 1.67) [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=54" style="color: #0867ab; text-decoration: none;">54</a>]. One-third of new cases of diabetes could be attributed to use of atypical antipsychotics in the VA patients treated with these drugs.</span></li>
<li style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 5px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">In the CATIE study, at three months, waist circumference was most increased by<a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/185495&drug=true" style="color: #0867ab; text-decoration: none;">olanzapine</a> and<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/14699&drug=true" style="color: #0867ab; text-decoration: none;">quetiapine</a>, was not changed with<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/27784&drug=true" style="color: #0867ab; text-decoration: none;">ziprasidone</a>, and decreased with<a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/197338&drug=true" style="color: #0867ab; text-decoration: none;">perphenazine</a> [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=55" style="color: #0867ab; text-decoration: none;">55</a>]. Fasting triglyceride levels increased with olanzapine and decreased with ziprasidone.</span></li>
<li style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 5px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Atypical antipsychotic drugs have also been associated with a small increased risk of diabetic ketoacidosis [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=56%2C57" style="color: #0867ab; text-decoration: none;">56,57</a>].</span></li>
<li style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 5px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">In a case control study comparing patients treated with antipsychotic drugs to control patients, the odds ratio for hyperlipidemia ranged from 1.82 for<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/63838&drug=true" style="color: #0867ab; text-decoration: none;">clozapine</a> to 1.26 for first generation antipsychotics;<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/184853&drug=true" style="color: #0867ab; text-decoration: none;">aripiprazole</a> was the only antipsychotic that did not significantly increase the risk for hyperlipidemia [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=58" style="color: #0867ab; text-decoration: none;">58</a>].</span></li>
</ul>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">A consensus statement from the American Psychiatric Association, American Diabetes Association, and others recommends baseline assessment of weight, blood pressure, fasting plasma glucose, and fasting lipid profile, and reassessment after 12 weeks of treatment for patients treated with atypical antipsychotic medications [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=59" style="color: #0867ab; text-decoration: none;">59</a>]. Patients with impaired fasting glucose should be tested for diabetes with a 2 hour oral glucose tolerance test [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=60" style="color: #0867ab; text-decoration: none;">60</a>]. Weight should be followed monthly for the first three months and quarterly thereafter (<a href="http://www.uptodateonline.com/online/content/image.do?imageKey=PC%2F21047" style="color: #0867ab; text-decoration: none;" target="_blank">table 4</a>). Unfortunately, adoption of these guidelines has been limited. Among 17,800 patients initiating treatment with atypical antipsychotics in one study, serum lipids were tested in 10 percent and glucose monitored in 22 percent at baseline and 18 percent at 12 weeks [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=61" style="color: #0867ab; text-decoration: none;">61</a>].</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">No adjunctive medication has been conclusively shown to reduce the metabolic effects. Even for drugs that mitigate weight gain, such as<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/159390&drug=true" style="color: #0867ab; text-decoration: none;">metformin</a>, metabolic effects have been modest [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=40%2C41" style="color: #0867ab; text-decoration: none;">40,41</a>] or absent [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=39" style="color: #0867ab; text-decoration: none;">39</a>]. Patients who develop antipsychotic-induced metabolic disturbance should be switched to an agent with less propensity for this side effect, specifically<a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/184853&drug=true" style="color: #0867ab; text-decoration: none;">aripiprazole</a> or<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/27784&drug=true" style="color: #0867ab; text-decoration: none;">ziprasidone</a>.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Extrapyramidal symptoms</span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> — EPS are common with conventional agents and occasionally encountered at higher doses of the atypical drugs. If dose reduction or change in medication are not effective or not well tolerated, several approaches are recommended. Anticholinergic drugs, such as<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/29043&drug=true" style="color: #0867ab; text-decoration: none;">benztropine</a> 1 to 2 mg twice daily to four times daily or<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/270639&drug=true" style="color: #0867ab; text-decoration: none;">trihexyphenidyl</a> 2 to 5 mg twice daily to four times daily are most commonly used. Other possible agents include<a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/11938&drug=true" style="color: #0867ab; text-decoration: none;">amantadine</a> 100 mg twice daily to four times daily or<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/83117&drug=true" style="color: #0867ab; text-decoration: none;">diphenhydramine</a> 25 to 50 mg twice daily to four times daily.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Akathisia</span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> — Akathisia is a subjective sense of restlessness, often accompanied by voluntary movements of the limbs or trunk. It is among the more common movement disorders associated with antipsychotic medications, and may be mistaken for anxiety or insomnia. It should be suspected in any patient who is unable to sit quietly or who complains of feeling nervous, uncomfortable, or unable to sleep.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Approaches to the treatment of akathisia include antipsychotic dose reduction, change to a different atypical drug, or addition of a beta-blocker [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=62" style="color: #0867ab; text-decoration: none;">62</a>], antihistamine [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=63" style="color: #0867ab; text-decoration: none;">63</a>], benzodiazepine [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=64" style="color: #0867ab; text-decoration: none;">64</a>], anticholinergic [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=65" style="color: #0867ab; text-decoration: none;">65</a>], or serotonin antagonist (eg,<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/169291&drug=true" style="color: #0867ab; text-decoration: none;">mirtazapine</a>) [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=66" style="color: #0867ab; text-decoration: none;">66</a>]. Beta-blockers have been the traditional “gold standard” for akathisia treatment but are not more efficacious than other agents [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=67" style="color: #0867ab; text-decoration: none;">67</a>]. There are no studies demonstrating efficacy for combination therapy. Severe akathisia is an indication for<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/63838&drug=true" style="color: #0867ab; text-decoration: none;">clozapine</a> [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=34" style="color: #0867ab; text-decoration: none;">34</a>].</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Neuroleptic malignant syndrome</span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> — The neuroleptic malignant syndrome (NMS), a tetrad of clinical features (fever, rigidity, mental status changes, and autonomic instability), is associated with medications that block dopamine transmission. NMS is seen with every class of antipsychotic drug, including “atypical” antipsychotics [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=68" style="color: #0867ab; text-decoration: none;">68</a>]. Treatment involves withdrawal of medication, and intensive management for cardiovascular support, control of hyperthermia, and fluid and electrolyte balance. (See<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=medneuro/5946" style="color: #0867ab; text-decoration: none;">“Neuroleptic malignant syndrome”</a>.)</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Stroke risk</span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> — Evidence regarding stroke risk associated with atypical antipsychotic drugs is conflicting [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=28%2C69-72" style="color: #0867ab; text-decoration: none;">28,69-72</a>]. A large cohort study of adults aged<span class="Apple-converted-space"> </span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">≥</span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">65 years found a similar risk of ischemic stroke among users of atypical versus typical antipsychotics [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=73" style="color: #0867ab; text-decoration: none;">73</a>]. A study of the time concurrence of antipsychotic use and stroke in patients who both used antipsychotics and had a stroke found the risk of stroke was greater during the time period an antipsychotic was used, was greater for atypical than typical antipsychotics, and was greatest for patients with dementia [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=74" style="color: #0867ab; text-decoration: none;">74</a>].</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Mortality</span></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Sudden death</span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> — Both conventional and atypical antipsychotics increase risk for sudden death [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=75" style="color: #0867ab; text-decoration: none;">75</a>]. A case-controlled study of 90,000 Medicaid recipients (mean age 45.7) found that, compared to nonuse, current use of antipsychotics doubled the risk of sudden death (incidence rate ratios 1.99, 95% CI 1.68-2.34, and 2.26, 1.88-2.72 for typical and atypical drugs respectively). Risk increased with higher medication dose. The rate of sudden death with antipsychotics (1.8 per 1,000 person years) is almost ten-fold the rate of death related to<a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/63838&drug=true" style="color: #0867ab; text-decoration: none;">clozapine</a>-associated agranulocytosis [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=76" style="color: #0867ab; text-decoration: none;">76</a>].</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">The mechanism underlying sudden death was not determined, but is presumed related to the known effect of antipsychotics on cardiac repolarization and QTc prolongation. It is unclear whether ECG monitoring will identify patients at increased risk for sudden death. Drugs and conditions that prolong the QTc interval should be avoided, when possible, in patients who are treated with antipsychotics (<a href="http://www.uptodateonline.com/online/content/image.do?imageKey=CARD%2F1216" style="color: #0867ab; text-decoration: none;" target="_blank">table 5</a>). (See<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=carrhyth/54644" style="color: #0867ab; text-decoration: none;">“Acquired long QT syndrome”</a>.)</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Elderly patients with dementia</span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> — Both conventional and atypical antipsychotic medications have been shown to be associated with an increased risk of mortality when used to treat elderly patients with psychosis or agitated behavior resulting from dementia [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=77-79" style="color: #0867ab; text-decoration: none;">77-79</a>]. The US Food and Drug Administration (FDA) issued a public health advisory in 2008 highlighting these findings and emphasizing that antipsychotics are not approved for the treatment of dementia-related psychosis [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=80" style="color: #0867ab; text-decoration: none;">80</a>]. They advised that the mortality risk should be discussed with patients, families, and other caregivers if antipsychotics are prescribed.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Major studies informing this determinaton include:</span></div>
<ul style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 2em; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<li style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 5px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">A meta-analysis of 15 studies (nine unpublished) of atypical antipsychotic drug therapy for dementia found that mortality was increased in treated patients compared with controls (3.5 versus 2.3 percent, OR 1.54) [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=77" style="color: #0867ab; text-decoration: none;">77</a>]. Risks did not differ for the medications studied (<a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/184853&drug=true" style="color: #0867ab; text-decoration: none;">aripiprazole</a>,<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/185495&drug=true" style="color: #0867ab; text-decoration: none;">olanzapine</a>,<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/14699&drug=true" style="color: #0867ab; text-decoration: none;">quetiapine</a>, and risperidone). Most studies were less than three months duration.</span></li>
<li style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 5px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">A retrospective cohort study of 22,890 elderly patients receiving antipsychotic medications compared mortality risks with conventional versus atypical agents [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=78" style="color: #0867ab; text-decoration: none;">78</a>]. Significantly higher mortality was seen in patients taking conventional agents (OR 1.37). The increase in risk was greatest soon after therapy was initiated and with higher doses of conventional agents.</span></li>
<li style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 5px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">A Canadian retrospective study found increased mortality risk at 30 days for patients receiving atypical antipsychotics, compared to no antipsychotics, for both community-dwelling and long-term care patients (HR 1.31 and 1.55, respectively) [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=81" style="color: #0867ab; text-decoration: none;">81</a>]. Conventional antipsychotics were associated with greater 30-day mortality than atypical antipsychotics.</span></li>
<li style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 5px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">A trial in the UK compared mortality for 165 patients with Alzheimer disease who were randomly assigned to continue their antipsychotic medication or switch to placebo [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=82" style="color: #0867ab; text-decoration: none;">82</a>]. Survival at 12 and 24 months was significantly greater for the group assigned to placebo (at 24 months, 71 versus 46 percent for antipsychotic continuance).</span></li>
</ul>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">These studies evaluated mortality when antipsychotic medications are used to manage behavioral issues associated with dementia in the elderly. Behavioral disturbance and psychosis are separate problems, although the FDA-mandated warning specifies increased risk for “dementia-related psychosis.” Other treatment options are available for behavioral problems (eg, mood stabilizers, benzodiazepines), but there are no other medication options for delusions or hallucinations [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=83" style="color: #0867ab; text-decoration: none;">83</a>]. The only recourse for clinicians is to inform the patient, family, and caregivers of the risk associated with antipsychotic medications in the elderly, and to decide with them whether to treat with antipsychotic medications.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Schizophrenia</span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> — Although it has been suggested that treatment with antipsychotic medication may contribute to the higher mortality rates associated with schizophrenia, a population-based study drawing on Finland’s national data registries found that long-term treatment of schizophrenia with any antipsychotic was associated with a lower rate of mortality compared with not receiving these medications (hazard ratio (HR) = 0.81, 95% CI , 0.77–0.84) [<a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=84" style="color: #0867ab; text-decoration: none;">84</a>]. The relationship between antipsychotics and mortality varied by medication. Clozapine was associated with the greatest reduction in mortality (HR = 0.74, 95% CI 0.60–0.91), while quetiapine was associated with the largest increase (HR = 1.41, 95% CI 1.09–1.82).</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">INFORMATION FOR PATIENTS</span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> — Educational materials on this topic are available for patients. (See<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=mentl_h/4455" style="color: #0867ab; text-decoration: none;">“Patient information: Bipolar disorder (manic depression)”</a> and<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=mentl_h/2952" style="color: #0867ab; text-decoration: none;">“Patient information: Depression in adults”</a>.) We encourage you to print or e-mail these topics, or to refer patients to our public web site<span class="Apple-converted-space"> </span><a href="http://www.uptodate.com/patients" style="color: #0867ab; text-decoration: none;" target="_blank">www.uptodate.com/patients</a>, which includes these and other topics.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">SUMMARY AND RECOMMENDATIONS</span></span></div>
<ul style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 2em; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<li style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 5px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">The use of antipsychotic medications is widespread and often extends beyond approved indications, populations, and dosing strategies. The quality and quantity of evidence for these practices is variable, but often the medications are useful and well tolerated in these situations.</span></li>
<li style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 5px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">The conventional and atypical antipsychotics are comparable in efficacy in the treatment of psychosis, with the exception of<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/63838&drug=true" style="color: #0867ab; text-decoration: none;">clozapine</a> which is more effective but has serious side effects.<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/185495&drug=true" style="color: #0867ab; text-decoration: none;">Olanzapine</a> may also be somewhat more effective in long-term maintenance therapy for schizophrenia but carries greater risk of metabolic side effects. Generic<a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/223516&drug=true" style="color: #0867ab; text-decoration: none;">risperidone</a> may have cost-effectiveness advantages as the lowest cost atypical drug.</span></li>
</ul>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">For patients requiring long-term therapy with antipsychotic medication, we suggest starting with an atypical agent other than<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/63838&drug=true" style="color: #0867ab; text-decoration: none;">clozapine</a>, and basing this choice on the side effect profile preferred by the patient, and (when available) the patient’s previous history of medication response (<a href="http://www.uptodateonline.com/online/content/grade.do?gradeId=5&title=Grade+2B" style="color: #0867ab; text-decoration: none;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Grade 2B</b></a>). (See<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=psychiat/#H3" style="color: #0867ab; text-decoration: none;">‘Drug selection’</a> above.)</span></div>
<ul style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 2em; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<li style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 5px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/63838&drug=true" style="color: #0867ab; text-decoration: none;">Clozapine</a> is effective in 30 to 50 percent of patients with psychosis who have not responded to other antipsychotic drugs. Life-threatening agranulocytosis has been reported in one to two percent of patients. A schedule for monitoring has been designed requiring weekly CBC for the first six months, biweekly CBC for the second six months, and then testing every four weeks. We suggest that clozapine be prescribed by a specialist familiar with this medication. (See<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=psychiat/#H8" style="color: #0867ab; text-decoration: none;">‘Clozapine’</a> above.)</span></li>
</ul>
<ul style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 2em; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<li style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 5px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Augmentation strategies using drugs such as<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_l_z/146048&drug=true" style="color: #0867ab; text-decoration: none;">lithium</a>, anticonvulsants, or benzodiazepines may be helpful for patients refractory to antipsychotic monotherapy. We suggest not treating patients with refractory schizophrenia with two or more antipsychotic agents simultaneously (<a href="http://www.uptodateonline.com/online/content/grade.do?gradeId=5&title=Grade+2B" style="color: #0867ab; text-decoration: none;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Grade 2B</b></a>) (see<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=psychiat/#H9" style="color: #0867ab; text-decoration: none;">‘Augmentation’</a> above and<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=psychiat/#H10" style="color: #0867ab; text-decoration: none;">‘Combination therapy’</a> above.</span></li>
<li style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 5px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Tardive dyskinesia is the late onset of choreoathetotic movements.<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/63838&drug=true" style="color: #0867ab; text-decoration: none;">Clozapine</a> treatment is effective for patients with severe tardive dyskinesia symptoms (see<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=psychiat/#H12" style="color: #0867ab; text-decoration: none;">‘Tardive dyskinesia’</a> above.</span></li>
<li style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 5px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Patients under treatment with antipsychotic medications should be monitored closely for weight gain and switched to another antipsychotic medication if indicated (see<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=psychiat/#H13" style="color: #0867ab; text-decoration: none;">‘Weight gain’</a> above.</span></li>
<li style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 5px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Extrapyramidal symptoms can be addressed by change in medication or use of anticholinergic drugs,<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/11938&drug=true" style="color: #0867ab; text-decoration: none;">amantadine</a>, or<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=drug_a_k/83117&drug=true" style="color: #0867ab; text-decoration: none;">diphenhydramine</a> (see<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=psychiat/#H15" style="color: #0867ab; text-decoration: none;">‘Extrapyramidal symptoms’</a> above.</span></li>
<li style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 5px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Antipsychotic medications, both conventional and atypical, have been associated with increased mortality in the elderly when used to manage dementia-related behavioral issues (see<span class="Apple-converted-space"> </span><a href="http://www.uptodateonline.com/online/content/topic.do?topicKey=psychiat/#H21" style="color: #0867ab; text-decoration: none;">‘Elderly patients with dementia’</a> above.</span></li>
</ul>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
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<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">1.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Lehman, AF, Lieberman, JA, Dixon, LB, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry 2004; 161:1.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">2.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=2" style="color: #0867ab; text-decoration: none;">Tandon, R, Jibson, MD. Efficacy of newer generation antipsychotics in the treatment of schizophrenia. Psychoneuroendocrinology 2003; 28 Suppl 1:9.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">3.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=3" style="color: #0867ab; text-decoration: none;">Rummel, C, Hamann, J, Kissling, W, Leucht, S. New generation antipsychotics for first episode schizophrenia. Cochrane Database Syst Rev 2003; :CD004410.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">4.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=4" style="color: #0867ab; text-decoration: none;">Gardner, DM, Baldessarini, RJ, Waraich, P. Modern antipsychotic drugs: a critical overview. CMAJ 2005; 172:1703.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">5.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=5" style="color: #0867ab; text-decoration: none;">Lieberman, JA, Stroup, TS, McEvoy, JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353:1209.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">6.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=6" style="color: #0867ab; text-decoration: none;">Essock, SM, Covell, NH, Davis, SM, et al. Effectiveness of switching antipsychotic medications. Am J Psychiatry 2006; 163:2090.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">7.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=7" style="color: #0867ab; text-decoration: none;">Stroup, TS, Lieberman, JA, McEvoy, JP, et al. Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. Am J Psychiatry 2006; 163:611.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">8.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=8" style="color: #0867ab; text-decoration: none;">McEvoy, JP, Lieberman, JA, Stroup, TS, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 2006; 163:600.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">9.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=9" style="color: #0867ab; text-decoration: none;">Kane, J, Honigfeld, G, Singer, J, Meltzer, H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45:789.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">10.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=10" style="color: #0867ab; text-decoration: none;">Claghorn, J, Honigfeld, G, Abuzzahab FS, Sr, et al. The risks and benefits of clozapine versus chlorpromazine. J Clin Psychopharmacol 1987; 7:377.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">11.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=11" style="color: #0867ab; text-decoration: none;">Pickar, D, Owen, RR, Litman, RE, et al. Clinical and biologic response to clozapine in patients with schizophrenia. Crossover comparison with fluphenazine. Arch Gen Psychiatry 1992; 49:345.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">12.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=12" style="color: #0867ab; text-decoration: none;">Breier, A, Buchanan, RW, Kirkpatrick, B, et al. Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. Am J Psychiatry 1994; 151:20.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">13.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=13" style="color: #0867ab; text-decoration: none;">Carpenter, WT Jr, Conley, RR, Buchanan, RW, et al. Patient response and resource management: another view of clozapine treatment of schizophrenia. Am J Psychiatry 1995; 152:827.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">14.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=14" style="color: #0867ab; text-decoration: none;">Essock, SM, Hargreaves, WA, Covell, NH, Goethe, J. Clozapine’s effectiveness for patients in state hospitals: results from a randomized trial. Psychopharmacol Bull 1996; 32:683.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">15.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=15" style="color: #0867ab; text-decoration: none;">Csernansky, JG, Mahmoud, R, Brenner, R. A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia. N Engl J Med 2002; 346:16.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">16.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=16" style="color: #0867ab; text-decoration: none;">Kahn, RS, Fleischhacker, WW, Boter, H, et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet 2008; 371:1085.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">17.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=17" style="color: #0867ab; text-decoration: none;">Leucht, S, Corves, C, Arbter, D, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009; 373:31.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">18.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=18" style="color: #0867ab; text-decoration: none;">Leucht, S, Komossa, K, Rummel-Kluge, C, et al. A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am J Psychiatry 2009; 166:152.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">19.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=19" style="color: #0867ab; text-decoration: none;">Mellman, TA, Miller, AL, Weissman, EM, et al. Evidence-based pharmacologic treatment for people with severe mental illness: a focus on guidelines and algorithms. Psychiatr Serv 2001; 52:619.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">20.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=20" style="color: #0867ab; text-decoration: none;">Schneider, LS, Tariot, PN, Dagerman, KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med 2006; 355:1525.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">21.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=21" style="color: #0867ab; text-decoration: none;">Leucht, S, Barnes, TR, Kissling, W, et al. Relapse prevention in schizophrenia with new-generation antipsychotics: a systematic review and exploratory meta-analysis of randomized, controlled trials. Am J Psychiatry 2003; 160:1209.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">22.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry 2002; 159:1.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">23.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Jibson, MD, Tandon, R. Treatment of acute psychotic episodes. In: Schizophrenia: a new guide for clinicians, Csernansky, JG (Ed), Marcel Dekker, New York 2001. p.107.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">24.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=24" style="color: #0867ab; text-decoration: none;">Kinon, BJ, Basson, BR, Gilmore, JA, et al. Strategies for switching from conventional antipsychotic drugs or risperidone to olanzapine. J Clin Psychiatry 2000; 61:833.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">25.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=25" style="color: #0867ab; text-decoration: none;">Stanilla, JK, de Leon, J, Simpson, GM. Clozapine withdrawal resulting in delirium with psychosis: a report of three cases. J Clin Psychiatry 1997; 58:252.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">26.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=26" style="color: #0867ab; text-decoration: none;">Ahmed, S, Chengappa, KN, Naidu, VR, et al. Clozapine withdrawal-emergent dystonias and dyskinesias: a case series. J Clin Psychiatry 1998; 59:472.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">27.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=27" style="color: #0867ab; text-decoration: none;">Shiovitz, TM, Welke, TL, Tigel, PD, et al. Cholinergic rebound and rapid onset psychosis following abrupt clozapine withdrawal. Schizophr Bull 1996; 22:591.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">28.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=28" style="color: #0867ab; text-decoration: none;">Herrmann, N, Mamdani, M, Lanctot, KL. Atypical antipsychotics and risk of cerebrovascular accidents. Am J Psychiatry 2004; 161:1113.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">29.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=29" style="color: #0867ab; text-decoration: none;">Tapp, A, Wood, AE, Secrest, L, et al. Combination antipsychotic therapy in clinical practice. Psychiatr Serv 2003; 54:55.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">30.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=30" style="color: #0867ab; text-decoration: none;">Josiassen, RC, Joseph, A, Kohegyi, E, et al. Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry 2005; 162:130.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">31.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=31" style="color: #0867ab; text-decoration: none;">Anil Yagcioglu, AE, Kivircik Akdede, BB, Turgut, TI, et al. A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. J Clin Psychiatry 2005; 66:63.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">32.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=32" style="color: #0867ab; text-decoration: none;">Honer, WG, Thornton, AE, Chen, EY, et al. Clozapine alone versus clozapine and risperidone with refractory schizophrenia. N Engl J Med 2006; 354:472.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">33.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=33" style="color: #0867ab; text-decoration: none;">Saltz, BL, Woerner, MG, Kane, JM, et al. Prospective study of tardive dyskinesia incidence in the elderly. JAMA 1991; 266:2402.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">34.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=34" style="color: #0867ab; text-decoration: none;">Spivak, B, Mester, R, Abesgaus, J, et al. Clozapine treatment for neuroleptic-induced tardive dyskinesia, parkinsonism, and chronic akathisia in schizophrenic patients. J Clin Psychiatry 1997; 58:318.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">35.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=35" style="color: #0867ab; text-decoration: none;">Haro, JM, Salvador-Carulla, L. The SOHO (Schizophrenia Outpatient Health Outcome) study: implications for the treatment of schizophrenia. CNS Drugs 2006; 20:293.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">36.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=36" style="color: #0867ab; text-decoration: none;">Allison, DB, Mentore, JL, Heo, M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999; 156:1686.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">37.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=37" style="color: #0867ab; text-decoration: none;">Gianfrancesco, FD, Grogg, AL, Mahmoud, RA, et al. Differential effects of risperidone, olanzapine, clozapine, and conventional antipsychotics on type 2 diabetes: findings from a large health plan database. J Clin Psychiatry 2002; 63:920.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">38.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=38" style="color: #0867ab; text-decoration: none;">Kim, SF, Huang, AS, Snowman, AM, et al. Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase. Proc Natl Acad Sci U S A 2007; 104:3456.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">39.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=39" style="color: #0867ab; text-decoration: none;">Baptista, T, Martinez, J, Lacruz, A, et al. Metformin for prevention of weight gain and insulin resistance with olanzapine: a double-blind placebo-controlled trial. Can J Psychiatry 2006; 51:192.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">40.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=40" style="color: #0867ab; text-decoration: none;">Wu, RR, Zhao, JP, Jin, H, et al. Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: a randomized controlled trial. JAMA 2008; 299:185.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">41.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=41" style="color: #0867ab; text-decoration: none;">Klein, DJ, Cottingham, EM, Sorter, M, et al. A randomized, double-blind, placebo-controlled trial of metformin treatment of weight gain associated with initiation of atypical antipsychotic therapy in children and adolescents. Am J Psychiatry 2006; 163:2072.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">42.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=42" style="color: #0867ab; text-decoration: none;">Wu, RR, Zhao, JP, Guo, XF, et al. Metformin addition attenuates olanzapine-induced weight gain in drug-naive first-episode schizophrenia patients: a double-blind, placebo-controlled study. Am J Psychiatry 2008; 165:352.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">43.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=43" style="color: #0867ab; text-decoration: none;">Ko, YH, Joe, SH, Jung, IK, Kim, SH. Topiramate as an adjuvant treatment with atypical antipsychotics in schizophrenic patients experiencing weight gain. Clin Neuropharmacol 2005; 28:169.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">44.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=44" style="color: #0867ab; text-decoration: none;">Nickel, MK, Nickel, C, Muehlbacher, M, et al. Influence of topiramate on olanzapine-related adiposity in women: a random, double-blind, placebo-controlled study. J Clin Psychopharmacol 2005; 25:211.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">45.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=45" style="color: #0867ab; text-decoration: none;">Egger, C, Muehlbacher, M, Schatz, M, Nickel, M. Influence of topiramate on olanzapine-related weight gain in women: an 18-month follow-up observation. J Clin Psychopharmacol 2007; 27:475.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">46.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=46" style="color: #0867ab; text-decoration: none;">Graham, KA, Gu, H, Lieberman, JA, et al. Double-blind, placebo-controlled investigation of amantadine for weight loss in subjects who gained weight with olanzapine. Am J Psychiatry 2005; 162:1744.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">47.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=47" style="color: #0867ab; text-decoration: none;">Henderson, DC, Copeland, PM, Daley, TB, et al. A double-blind, placebo-controlled trial of sibutramine for olanzapine-associated weight gain. Am J Psychiatry 2005; 162:954.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">48.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=48" style="color: #0867ab; text-decoration: none;">Henderson, DC, Fan, X, Copeland, PM, et al. A double-blind, placebo-controlled trial of sibutramine for clozapine-associated weight gain. Acta Psychiatr Scand 2007; 115:101.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">49.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=49" style="color: #0867ab; text-decoration: none;">Bustillo, JR, Lauriello, J, Parker, K, et al. Treatment of weight gain with fluoxetine in olanzapine-treated schizophrenic outpatients. Neuropsychopharmacology 2003; 28:527.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">50.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=50" style="color: #0867ab; text-decoration: none;">Newcomer, JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 2005; 19 Suppl 1:1.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">51.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Fenton, WS, Chavez, MR. Medication-induced weight gain and dyslipidemia in patients with schizophrenia. Am J Psychiatry 2006; 163:1697.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">52.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=52" style="color: #0867ab; text-decoration: none;">Elias, AN, Hofflich, H. Abnormalities in glucose metabolism in patients with schizophrenia treated with atypical antipsychotic medications. Am J Med 2008; 121:98.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">53.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=53" style="color: #0867ab; text-decoration: none;">Lamberti, JS, Olson, D, Crilly, JF, et al. Prevalence of the metabolic syndrome among patients receiving clozapine. Am J Psychiatry 2006; 163:1273.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">54.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=54" style="color: #0867ab; text-decoration: none;">Lambert, BL, Cunningham, FE, Miller, DR, et al. Diabetes risk associated with use of olanzapine, quetiapine, and risperidone in veterans health administration patients with schizophrenia. Am J Epidemiol 2006; 164:672.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">55.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=55" style="color: #0867ab; text-decoration: none;">Meyer, JM, Davis, VG, Goff, DC, et al. Change in metabolic syndrome parameters with antipsychotic treatment in the CATIE Schizophrenia Trial: prospective data from phase 1. Schizophr Res 2008; 101:273.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">56.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=56" style="color: #0867ab; text-decoration: none;">Leslie, DL, Rosenheck, RA. Incidence of newly diagnosed diabetes attributable to atypical antipsychotic medications. Am J Psychiatry 2004; 161:1709.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">57.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=57" style="color: #0867ab; text-decoration: none;">Jin, H, Meyer, JM, Jeste, DV. Phenomenology of and risk factors for new-onset diabetes mellitus and diabetic ketoacidosis associated with atypical antipsychotics: an analysis of 45 published cases. Ann Clin Psychiatry 2002; 14:59.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">58.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=58" style="color: #0867ab; text-decoration: none;">Olfson, M, Marcus, SC, Corey-Lisle, P, et al. Hyperlipidemia following treatment with antipsychotic medications. Am J Psychiatry 2006; 163:1821.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">59.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004; 27:596.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">60.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=60" style="color: #0867ab; text-decoration: none;">van Winkel, R, De Hert, M, Van Eyck, D, et al. Screening for Diabetes and Other Metabolic Abnormalities in Patients With Schizophrenia and Schizoaffective Disorder: Evaluation of Incidence and Screening Methods. J Clin Psychiatry 2006; 67:1493.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">61.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=61" style="color: #0867ab; text-decoration: none;">Haupt, DW, Rosenblatt, LC, Kim, E, et al. Prevalence and predictors of lipid and glucose monitoring in commercially insured patients treated with second-generation antipsychotic agents. Am J Psychiatry 2009; 166:345.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">62.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=62" style="color: #0867ab; text-decoration: none;">Irwin, M, Sullivan, G, Van Putten, T. Propranolol as a primary treatment of neuroleptic-induced akathisia. Hillside J Clin Psychiatry 1988; 10:244.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">63.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=63" style="color: #0867ab; text-decoration: none;">Vinson, DR. Diphenhydramine in the treatment of akathisia induced by prochlorperazine. J Emerg Med 2004; 26:265.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">64.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=64" style="color: #0867ab; text-decoration: none;">Lima, AR, Soares-Weiser, K, Bacaltchuk, J, Barnes, TR. Benzodiazepines for neuroleptic-induced acute akathisia. Cochrane Database Syst Rev 2002; :CD001950.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">65.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=65" style="color: #0867ab; text-decoration: none;">Sachdev, P, Loneragan, C. Intravenous benztropine and propranolol challenges in acute neuroleptic-induced akathisia. Clin Neuropharmacol 1993; 16:324.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">66.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=66" style="color: #0867ab; text-decoration: none;">Poyurovsky, M, Pashinian, A, Weizman, R, et al. Low-dose mirtazapine: a new option in the treatment of antipsychotic-induced akathisia. A randomized, double-blind, placebo- and propranolol-controlled trial. Biol Psychiatry 2006; 59:1071.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">67.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=67" style="color: #0867ab; text-decoration: none;">Lima, AR, Bacalcthuk, J, Barnes, TR, Soares-Weiser, K. Central action beta-blockers versus placebo for neuroleptic-induced acute akathisia. Cochrane Database Syst Rev 2004; :CD001946.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">68.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=68" style="color: #0867ab; text-decoration: none;">Caroff, SN, Mann, SC. Neuroleptic malignant syndrome. Med Clin North Am 1993; 77:185.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">69.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=69" style="color: #0867ab; text-decoration: none;">Sink, KM, Holden, KF, Yaffe, K. Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence. JAMA 2005; 293:596.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">70.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=70" style="color: #0867ab; text-decoration: none;">Brodaty, H, Ames, D, Snowdon, J, et al. A randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation, and psychosis of dementia. J Clin Psychiatry 2003; 64:134.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">71.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Wooltorton, E. Risperidone (Risperdal): increased rate of cerebrovascular events in dementia trials. CMAJ 2002; 167:1269.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">72.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Wooltorton, E. Olanzapine (Zyprexa): increased incidence of cerebrovascular events in dementia trials. CMAJ 2004; 170:1395.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">73.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=73" style="color: #0867ab; text-decoration: none;">Gill, SS, Rochon, PA, Herrmann, N, et al. Atypical antipsychotic drugs and risk of ischaemic stroke: population based retrospective cohort study. BMJ 2005; 330:445.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">74.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=74" style="color: #0867ab; text-decoration: none;">Douglas, IJ, Smeeth, L. Exposure to antipsychotics and risk of stroke: self controlled case series study. BMJ 2008; 337:a1227.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">75.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=75" style="color: #0867ab; text-decoration: none;">Ray, WA, Chung, CP, Murray, KT, et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med 2009; 360:225.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">76.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Schneeweiss, S, Avorn, J. Antipsychotic agents and sudden cardiac death–how should we manage the risk?. N Engl J Med 2009; 360:294.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">77.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=77" style="color: #0867ab; text-decoration: none;">Schneider, LS, Dagerman, KS, Insel, P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 2005; 294:1934.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span lang="EN-GB" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">78.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=78" style="color: #0867ab; text-decoration: none;"><span lang="EN-GB" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Wang, PS, Schneeweiss, S, Avorn, J, et al. Risk of death in elderly users of conventional vs. atypical antipsychotic medications. N Engl J Med 2005; 353:2335.</span></a></span><span lang="EN-GB" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">79.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Ballard, C. Cochrane Database Syst Rev. 2006; 25:CD003476.</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">80.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">www.fda.gov/medwatch/safety/2008/safety08.htm#Antipsychotics (Accessed September 18, 2009).</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">81.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=81" style="color: #0867ab; text-decoration: none;">Gill, SS, Bronskill, SE, Normand, SL, et al. Antipsychotic drug use and mortality in older adults with dementia. Ann Intern Med 2007; 146:775.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">82.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=82" style="color: #0867ab; text-decoration: none;">Ballard, C, Hanney, ML, Theodoulou, M, et al. The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Lancet Neurol 2009; 8:151.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">83.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">www.fda.gov/cder/drug/InfoSheets/HCP/antipsychotics_conventional.htm (Accessed June 24, 2008).</span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 7.2pt; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">84.<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; line-height: normal; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> <span class="Apple-converted-space"> </span></span></span></span><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.uptodateonline.com/online/content/abstract.do?topicKey=psychiat%2F13586&refNum=84" style="color: #0867ab; text-decoration: none;">Tiihonen, J, Lönnqvist J, Wahlbeck K, et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet 2009; 374:620.</a></span></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
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Carlos Vázquezhttp://www.blogger.com/profile/09266699098392968330noreply@blogger.com1tag:blogger.com,1999:blog-7084351769408080486.post-43251780218939110522011-12-26T04:40:00.000-08:002012-11-23T10:55:24.807-08:00Selective serotonin reuptake inhibitors (SSRIs)<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Historical note and nomenclature</span></b></div>
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Since its discovery in the mid-20th century, serotonin, which is also called 5-hydroxytryptamine or<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG000RZ" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">5-HT</span></a>, has played an increasing part in understanding human diseases, particularly those involving the nervous system. Its plays a role in management of depression and other psychiatric disorders with the demonstration of pharmacological manipulation to prevent reuptake. Its role in other neurologic disorders has also expanded. Development of selective serotonin reuptake inhibitors, referred to by the abbreviation<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG00165" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">SSRI</span></a>, was a major pharmacological achievement. SSRIs are used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. Historical landmarks in serotonin, serotonin disorders, and drugs based on manipulation of this system are shown in Table 1. The best known SSRI,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KZ" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">fluoxetine</span></a>, was introduced into medical practice in 1988.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
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<div align="center" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: center; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Table 1. Historical Landmarks in Serotonin, Serotonin Disorders, and Drugs Based On Manipulation of the Serotonergic System</b></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
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<table border="0" cellpadding="0" cellspacing="0" style="-webkit-border-horizontal-spacing: 0px; -webkit-border-vertical-spacing: 0px; -webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; background-attachment: initial; background-clip: initial; background-color: white; background-image: initial; background-origin: initial; background-position: initial initial; background-repeat: initial initial; border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0.1in; margin-right: 0px; margin-top: 0px; min-width: 200px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><tbody style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 0.85in;" valign="top" width="82"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
<b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Year</b></div>
</td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 5.7in;" valign="top" width="547"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
<b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Finding</b></div>
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1911</div>
</td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 5.7in;" valign="top" width="547"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
Ramon Y Cajal described the raphe nuclei of the brainstem but did not know that they contain serotonin.</div>
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1928</div>
</td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 5.7in;" valign="top" width="547"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
Start of investigation of vasoconstrictors in blood by Irvin H Page</div>
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1948</div>
</td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 5.7in;" valign="top" width="547"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
Isolation and characterization of serum vasoconstrictor (serotonin) from blood<a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B19" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Rapport et al 1948)</span></a>.</div>
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1951</div>
</td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 5.7in;" valign="top" width="547"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
Synthesis of serotonin<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B11" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Hamlin and Fisher 1951)</span></a>.</div>
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1952</div>
</td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 5.7in;" valign="top" width="547"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
Enteramine, a smooth muscle-contracting substance found in the gut wall in 1952 by Erspamer, was found to be identical to serotonin<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B7" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Erspamer 1963)</span></a>.</div>
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<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 0.85in;" valign="top" width="82"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
1953</div>
</td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 5.7in;" valign="top" width="547"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
Identification of serotonin in various tissues<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B23" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Twarog and Page 1953)</span></a>.</div>
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<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 0.85in;" valign="top" width="82"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
1954</div>
</td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 5.7in;" valign="top" width="547"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
Discovery of the carcinoid syndrome (wherein tumors derived from chromaffin cells of the gut produce excess serotonin). This was the first disease in which serotonin was implicated<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B21" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Sjoerdsma and Palfreyman 1990)</span></a>.</div>
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<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 0.85in;" valign="top" width="82"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
1954</div>
</td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 5.7in;" valign="top" width="547"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
Development of urine chemical assay of 5-hydroxyindolacetic acid, a metabolite of serotonin<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B24" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Udenfriend 1959)</span></a>.</div>
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<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 0.85in;" valign="top" width="82"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
1954</div>
</td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 5.7in;" valign="top" width="547"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
Identification of serotonin in the brain and proposal of its role as a neurotransmitter<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B1" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Amin et al 1954)</span></a>.</div>
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<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 0.85in;" valign="top" width="82"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
1957</div>
</td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 5.7in;" valign="top" width="547"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
Hypothesis that serotonin and epinephrine might act as opposing central neurochemical systems<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B3" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Broddie and Shore 1957)</span></a>.</div>
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<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 0.85in;" valign="top" width="82"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
1960</div>
</td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 5.7in;" valign="top" width="547"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
Evidence for involvement of serotonin in migraine based on alleviation of symptoms of migraine by intravenous serotonin<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B15" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Kimball et al 1960)</span></a>.</div>
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1960s</div>
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Role of serotonin as a neurotransmitter was well recognized.</div>
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1965</div>
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Description of the anatomy of the serotonergic system of the brain–the wiring diagram of the neurochemical system<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B6" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Dahlstrom and Fuxe 1965)</span></a>.</div>
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1969</div>
</td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 5.7in;" valign="top" width="547"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
Development of selective serotonin reuptake inhibitors and demonstration of their efficacy as antidepressants<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B4" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Carlsson et al 1969)</span></a>.</div>
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1974</div>
</td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 5.7in;" valign="top" width="547"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
Discovery of fluoxetine by scientists at Eli Lilly<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B25" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Wong et al 1974)</span></a>.</div>
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1975</div>
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The possibility that some depressed patients have more of a “noradrenergic” depression and others had more of a “serotonergic depression” was suggested<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B17" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Maas 1975)</span></a>.</div>
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1979</div>
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Multiple 5-HT receptors were defined, ushering in the modern era of serotonin<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B18" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Peroutka and Snyder 1979)</span></a>.</div>
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1980s</div>
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Development of selective 5-HT receptor antagonists.</div>
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1982</div>
</td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 5.7in;" valign="top" width="547"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
First description of<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000JX" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">serotonin syndrome</span></a><span class="Apple-converted-space"> </span>due to excess of serotonin in humans<a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B12" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Insel et al 1982)</span></a>.</div>
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1983</div>
</td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 5.7in;" valign="top" width="547"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
First SSRI for depression, fluvoxamine, launched by Solvay.</div>
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1987</div>
</td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 5.7in;" valign="top" width="547"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
Alterations reported in serotonergic function in obsessive-compulsive states<a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B26" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Zohar and Insel 1987)</span></a>.</div>
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1988</div>
</td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 5.7in;" valign="top" width="547"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
Fluoxetine (<a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KZ" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Prozac</span></a>) introduced in the medical practice by Eli Lilly.</div>
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Currently approved SSRIs include the following:</div>
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• Citalopram</div>
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• Dapoxetine (approved only in some European countries; in phase III trials elsewhere)</div>
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• Escitalopram</div>
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• Fluoxetine</div>
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• Fluvoxamine</div>
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• Paroxetine</div>
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• Sertraline</div>
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• Zimelidine</div>
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<a href="http://knol.google.com/k/samuel-barrack/selective-serotonin-reuptake-inhibitors/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div>
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<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_26" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Pharmacology</span></b></div>
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<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLM006WL" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/mdiagram.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a> Serotonin (<a href="http://jneurology.wordpress.com/cip.asp?UID=MLG000RZ" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">5-HT</span></a>) receptors are a group of G protein-coupled receptors and ligand-gated ion channels found in the nervous system; they mediate both excitatory and inhibitory neurotransmission and are activated by the neurotransmitter serotonin, which acts as their endogenous ligand. The serotonin receptors modulate the release of many neurotransmitters, including glutamate,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG000XE" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">GABA</span></a>, dopamine, epinephrine/norepinephrine, and acetylcholine as well as many hormones, including oxytocin, prolactin, vasopressin, cortisol, corticosterone, corticotropin, and substance P, among others.</div>
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The 5-HT3 receptor is a ligand-gated ion channel activated by serotonin. Sites of expression include several brainstem nuclei and higher cortical areas such as the amygdala, hippocampus, and cortex. Presynaptic 5-HT3 receptors are involved in mediating or modulating neurotransmitter release whereas postsynaptic 5-HT3 receptors are preferentially expressed on interneurons<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B5" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Chameau and van Hooft 2006)</span></a>.</div>
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<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Pharmacodynamics.</b><span class="Apple-converted-space"> </span>SSRIs increase the extracellular level of the neurotransmitter serotonin by inhibiting its reuptake into the presynaptic cell, and, thus, increase the level of serotonin available to bind to the postsynaptic receptor. However, high serotonin levels not only activate the postsynaptic receptors but also activate autoreceptors, which act as a feedback sensor for the cell and may inhibit serotonin production, leading to serotonin deficiency. Gradual adaptation to this situation occurs by downregulation of the sensitivity of the autoreceptors.</div>
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In addition to action as an antidepressant, mechanisms of beneficial effects may include neuroprotective, antiinflammatory, and immunomodulatory actions.</div>
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<span class="Apple-converted-space"> </span><u>Antidepressant effect</u>. Antidepressant drug classes where serotonin is involved in the mechanism of action are listed in Table 2.</div>
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<b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Table 2. Classification of Antidepressant Drugs Where Serotonin Is Involved</b></div>
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<table border="0" cellpadding="0" cellspacing="0" style="-webkit-border-horizontal-spacing: 0px; -webkit-border-vertical-spacing: 0px; -webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; background-attachment: initial; background-clip: initial; background-color: white; background-image: initial; background-origin: initial; background-position: initial initial; background-repeat: initial initial; border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0.1in; margin-right: 0px; margin-top: 0px; min-width: 200px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><tbody style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 326.7pt;" valign="top" width="436"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
<b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Drug category</b></div>
</td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 144.9pt;" valign="top" width="193"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
<b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Example</b></div>
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Serotonin reuptake enhancer</div>
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</td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 144.9pt;" valign="top" width="193"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
Tianeptine</div>
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Serotonin and norepinephrine reuptake inhibitors</div>
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Venlafaxine</div>
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Noradrenergic (alpha2 antagonism) and specific (5-HT2 and 5-HT3 antagonist) serotonergic antidepressants</div>
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Mirtazapine</div>
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Selective serotonin reuptake inhibitors (SSRIs)</div>
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Fluoxetine</div>
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SSRI and norepinephrine reuptake inhibitor</div>
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Duloxetine</div>
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According to the monoamine hypothesis, depression is due to deficiency of at least 1 of 3 biogenic amines: serotonin, epinephrine, or dopamine. Therefore, every antidepressant drug is expected to increase neurotransmission of 1 or more of these amines. SSRIs accomplish this by blocking 1 or more of the reuptake pumps or receptors whereas other antidepressants inhibit the enzyme monoamine oxidase. SSRIs are described as “selective” because they affect only the reuptake pumps responsible for serotonin, as opposed to earlier antidepressants that affect other monoamine neurotransmitters as well. The only antidepressants that ignore the serotonin system are selective noradrenaline inhibitors and bupropion, which is a selective norepinephrine and dopamine reuptake inhibitor. The therapeutic and side effects profile of these 2 categories of compounds is different from other antidepressants. Because of selective action, SSRIs lack some of the side effects seen with antidepressants that have a more general action. Thus, the knowledge of mechanisms of action helps to explain the differences in profiles of side effects of antidepressants. There is no significant difference in effectiveness between SSRIs and tricyclic antidepressants, which were the most commonly used class of antidepressants before the development of SSRIs.</div>
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<span class="Apple-converted-space"> </span><u>Neuroprotective effect</u>. SSRIs may protect against neurotoxicity caused by several toxic compounds.<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KZ" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Fluoxetine</span></a><span class="Apple-converted-space"> </span>suppresses kainic acid-induced neuronal loss in the rat hippocampus, and the neuroprotective effect is associated with its antiinflammatory effects<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B13" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Jin et al 2009)</span></a>. SSRIs may promote the growth of new neural pathways or neurogenesis in experimental animals. The neuroprotective effect has not been demonstrated in humans. Repinotan, a serotonin agonist (5HT1A receptor subtype), was investigated as a neuroprotective agent in acute<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT00064" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">stroke</span></a>, but further development was discontinued due to lack of efficacy.</div>
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<span class="Apple-converted-space"> </span><u>Effect on premature ejaculation</u>. Dapoxetine, a short-acting<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG00165" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">SSRI</span></a>, is approved for the treatment of premature ejaculation in some countries and is the only drug with regulatory approval for such treatment<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B14" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Kendirci et al 2007)</span></a>. It is in phase III clinical trials in the United States.</div>
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<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Pharmacokinetics.</b><span class="Apple-converted-space"> </span>The metabolism and pharmacokinetics of SSRIs vary between assorted drugs. The half-life of fluoxetine is 3 days whereas its metabolite norfluoxetine has a half-life of about 1 week. This is an advantage over other SSRIs that have a half-life of about 1 day or less. In spite of occasional missed doses, fluoxetine and norfluoxetine concentrations remain in the therapeutic range. Another advantage of this long half-life is that the patients are unlikely to experience withdrawal effects from sudden discontinuation of fluoxetine, an event that can occur following withdrawal of a SSRI with a short half-life. In vivo pharmacokinetic data, however, do not precisely predict clinical response or adverse effects.</div>
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Most reports of metabolic enzyme inhibition by SSRIs have focused on changes in concentration of the affected drug. For example, studies have addressed elevated desipramine concentrations with paroxetine, increases in imipramine concentrations with fluvoxamine, and increased<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KH" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">phenytoin</span></a><span class="Apple-converted-space"> </span>concentrations with sertraline. Due to interindividual variability in drug disposition, plasma concentrations of SSRIs vary significantly among individuals. Change in enzyme activity as a result of drug-to-drug interaction may be equally clinically relevant for heterozygous extensive metabolizers (toward poor-metabolizer status) and homozygous extensive metabolizers (toward heterozygous extensive-metabolizer status). A possible cause of significant interindividual differences in the magnitude of<span class="Apple-converted-space"> </span><i style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">CYP2D6</i><span class="Apple-converted-space"> </span>inhibition is the pharmacokinetic variability of the inhibitor itself. Another determinant of overall interaction magnitude is unbound drug concentration in plasma and hepatocytes. A similar extent of intersubject variability in hepatocyte drug concentration is likely at the site of enzyme inhibition. Gender-related differences in pharmacokinetics of SSRIs have been shown to result in different pharmacological responses, but their clinical relevance remains unproven.</div>
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Positive and significant correlations between paroxetine and fluoxetine concentrations and<i style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">CYP2D6</i><span class="Apple-converted-space"> </span>inhibition illustrate the role of plasma concentrations and dosage on magnitude of enzyme inhibition. The potential of paroxetine, a<span class="Apple-converted-space"> </span><i style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">CYP2D6</i><span class="Apple-converted-space"> </span>substrate, as an inhibitor may be further affected by specific genotype and basal metabolic capacity of individual subjects.</div>
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<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Pharmacogenetics.</b><span class="Apple-converted-space"> </span>There is strong evidence from association studies that some gene<a href="http://jneurology.wordpress.com/cip.asp?UID=MLG0017W" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">polymorphisms</span></a><span class="Apple-converted-space"> </span>are associated with SSRI response. Approximately one third of patients with depression do not respond to an initial trial of SSRI treatment, possibly as a result of structural variations in the 5-HT(1A) receptor<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B16" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Levin et al 2007)</span></a>. The serotonin transporter-linked polymorphic region (5-HTTLPR) is the most widely studied<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG0017W" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">polymorphism</span></a><span class="Apple-converted-space"> </span>of the 5-HTT gene,<i style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">SLC6A4</i>, and is suspected of conferring vulnerability to elderly depression and resistance to treatment. 5-HTTLPR seems to influence the likelihood of adverse effects, and the promoter region may contribute to response variability during the initial stages of treatment, which is explained, in part, by a gene-concentration interaction for paroxetine. Subjects with the S<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG0018K" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">allele</span></a>may be at an increased risk of adverse drug reactions and may require higher initial SSRI plasma concentrations to maximize response whereas patients with the L/L genotype may respond even at lower concentrations<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B9" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Gerretsen and Pollock 2008)</span></a>. However, no randomized trials have yet tested the efficacy of genetic tests to improve outcome in those with treatment resistance or treatment intolerance to SSRIs<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B20" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Rasmussen-Torvik and McAlpine 2007)</span></a>. Single nucleotide polymorphisms of the 5-HT(2A) gene correlate with increased paroxetine discontinuation but not with discontinuation of mirtazapine, a non-SSRI antidepressant.</div>
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<a href="http://knol.google.com/k/samuel-barrack/selective-serotonin-reuptake-inhibitors/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div>
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<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_27" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Clinical trials</span></b></div>
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Worldwide more than 200 clinical trials have been conducted with various SSRIs during the past 5 years. As of June 2009, over 1000 clinical trials relevant to SSRIs either have been completed or are in progress. Some of these are planned and can be tracked on the NIH’s Clinical Trials web site (<a href="http://clinicaltrials.gov/ct2/results?term=selective+serotonin+reuptake+inhibitors" style="color: #0867ab; text-decoration: none;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">http://clinicaltrials.gov/ct2/results?term=selective+serotonin+reuptake+inhibitors</span></a>). These trials include use of approved SSRIs and those in development as well as other drugs in patients that fail to respond to SSRIs. Trials for managing adverse effects of SSRIs are also included. The PRISE-MD Study is evaluating “Personalized Indicators for Predicting Response to<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG00165" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">SSRI</span></a><span class="Apple-converted-space"> </span>Treatment in Major Depression.”</div>
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<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_16" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Indications</span></b></div>
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Indications for use of SSRIs include the following conditions:</div>
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• Anxiety disorders</div>
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• Depression, including that associated with neurologic disorders</div>
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• Eating disorders</div>
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–<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLM00450" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Anorexia nervosa</span></a></div>
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–<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLM00450" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Bulimia nervosa</span></a></div>
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– Binge-eating disorders</div>
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– Obesity</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Migraine: acute attacks</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Nausea and<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000Q4" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">vomiting</span></a><span class="Apple-converted-space"> </span>due to chemotherapy</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Obsessive-compulsive disorders</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Pain:<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG001CC" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">neuropathic pain</span></a><span class="Apple-converted-space"> </span>and fibromyalgia</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Panic disorders</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Premenstrual dysphoric disorder</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Schizophrenia</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Sexual disorders: premature ejaculation</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Off-label and investigational uses.</b><span class="Apple-converted-space"> </span>SSRIs are under investigation for the following conditions:</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Alcohol withdrawal</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Autism</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Cerebellar ataxia</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Dementia</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Drug addiction</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Irritable bowel syndrome</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Migraine prophylaxis</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Myoclonus</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Neuroprotection in<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT00064" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">stroke</span></a></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Pain syndromes</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Sleep disorders</div>
<div align="right" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://knol.google.com/k/samuel-barrack/selective-serotonin-reuptake-inhibitors/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_17" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Contraindications</span></b></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
A major contraindication of SSRIs is the concomitant use of monoamine oxidase inhibitors, as it is likely to cause severe<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000JX" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">serotonin syndrome</span></a>.</div>
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Liver impairment is another contraindication for use of SSRIs. SSRIs are extensively metabolized in the liver, resulting in decreased clearance and increased plasma concentrations in patients with hepatic dysfunction.</div>
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<a href="http://knol.google.com/k/samuel-barrack/selective-serotonin-reuptake-inhibitors/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div>
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<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_28" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Goals and duration of treatment</span></b></div>
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It may take several weeks for the drug to reach its optimal effect. Duration of treatment varies according to the condition and the<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG00165" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">SSRI</span></a><span class="Apple-converted-space"> </span>selected. Individualization of the treatment is also considered.</div>
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<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Individualization of SSRI treatment.</b><span class="Apple-converted-space"> </span>In spite of advantages of SSRIs over other antidepressants, not all patients benefit from treatment; some do not respond adequately whereas others may react adversely. This necessitates a review of the initial treatment choice, often involving extended periods of illness while a more suitable therapy is sought. Such a scenario could be avoided were it possible to determine the most suitable drug prior to treatment.</div>
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The Mayo Clinic (Rochester, MN) is offering a new genetic test through Mayo Medical Laboratories to help US physicians identify patients who are likely to have side effects from drugs commonly used to treat depression. The test is based on a key genetic biomarker, 5HTT-LPR that identifies people who respond differently to antidepressants including SSRIs. The 5HTT-LPR biomarker has potential to improve management of patients with major depression and others who benefit from SSRI treatment. It provides unique information relating to drug response: side effect and compliance.</div>
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The physician can make a better choice of antidepressant medications for their patients based on their serotonin transporter genotype used in conjunction with CYP450 genotyping. Depending on genotypes, some patients should respond well to SSRIs, some may respond to SSRIs but more slowly, and some patients may respond more effectively to non-SSRI antidepressants.</div>
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International guidelines for rational therapeutic drug monitoring are recognized for personalized treatment with antidepressants and antipsychotics. Retrospective analysis of genotyping of patients with depression suggests a good agreement between the poor metabolism and ultrarapid metabolism genotypes, the therapeutic drug monitoring data and clinical outcome<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B22" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Sjoqvist and Eliasson 2007)</span></a>. Therapeutic drug monitoring combined with genotyping of<span class="Apple-converted-space"> </span><i style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">CYP2D6</i><span class="Apple-converted-space"> </span>is particularly useful in verifying concentration-dependent adverse drug reactions due to poor metabolism and diagnosing pharmacokinetic reasons, eg, ultrarapid metabolism for drug failure. This is because adverse drug reactions may mimic the psychiatric illness itself, and therapeutic failure due to ultrarapid metabolism may be mistaken for poor compliance with the prescription.</div>
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<a href="http://knol.google.com/k/samuel-barrack/selective-serotonin-reuptake-inhibitors/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div>
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<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_9" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Dosing</span></b></div>
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Dosing is detailed in the clinical summaries for individual SSRIs and in the<span class="Apple-converted-space"> </span><i style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Physician’s Desk Reference</i>.</div>
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<a href="http://knol.google.com/k/samuel-barrack/selective-serotonin-reuptake-inhibitors/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div>
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<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_29" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Precautions and use in special groups</span></b></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Pediatric.</b><span class="Apple-converted-space"> </span>Pediatric patients should be monitored closely for the risk of suicide with any<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG00165" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">SSRI</span></a>. Only<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KZ" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">fluoxetine</span></a><span class="Apple-converted-space"> </span>is approved for use in treating depression in pediatric patients. Fluoxetine, sertraline, and fluvoxamine are approved for obsessive-compulsive disorder in pediatric patients. None of the drugs is approved for other psychiatric indications in children. Pediatric patients being treated with antidepressants for any indication should be observed daily by caregivers for clinical worsening as well as for agitation, irritability, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy or at times of dose changes–either increases or decreases.</div>
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<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Geriatric.</b><span class="Apple-converted-space"> </span>SSRIs are generally well tolerated by the elderly. Geriatric patients are more likely to be on multiple drugs, some of which may interact with SSRIs, and this requires a careful check to avoid drug interactions. SSRIs should not be used if hepatic function is impaired in the elderly patients.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Pregnancy.</b><span class="Apple-converted-space"> </span>SSRIs fall in the category C of the United States Food and Drug Administration classification regarding safety of use during pregnancy. Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.</div>
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Studies reporting primary data on the rate of fetal malformations after early in utero exposure to paroxetine have been analyzed. Given the inconsistency of the findings and limitations of the methodology of the published studies, the teratogenic potential of paroxetine that has been reported in some studies remains unproven<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B8" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Gentile and Bellantuono 2009)</span></a>. A prospective observational study is currently evaluating the efficacy of treatment of depression during pregnancy with SSRIs and looking for any effects of these medications on the newborn infant.</div>
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In pregnant women, SSRIs cross the placenta and have the potential to affect newborns. Sertraline and paroxetine have been associated with congenital malformations. SSRIs have also been associated with neonatal complications, such as neonatal abstinence syndrome and persistent pulmonary hypertension. According to a warning from the Food and Drug Administration in 2006, physicians prescribing SSRIs to pregnant women must discuss with them the potential risks.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Anesthesia.</b><span class="Apple-converted-space"> </span>Adjustment of dose of local anesthetic may be necessary as SSRIs inhibit the cytochrome P450 and affect local anesthetic metabolism.</div>
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Because there are no specific interactions between SSRIs and anesthetic agents, SSRIs are generally considered safe to use during the perioperative period. However, discontinuation of SSRIs during the perioperative period may lead to the development of withdrawal symptoms. Moreover, reinstituting the drugs at patients’ previous dosage, which may be the maximum dosage for some patients, may lead to the development of<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000JX" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">serotonin syndrome</span></a>.</div>
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<a href="http://knol.google.com/k/samuel-barrack/selective-serotonin-reuptake-inhibitors/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div>
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<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_11" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Interactions</span></b></div>
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SSRIs may interact with the following drugs and increase their blood levels to produce toxic effects:</div>
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• Antiarrhythmic agents</div>
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• Anticonvulsants:<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KF" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">carbamazepine</span></a><span class="Apple-converted-space"> </span>and phenytoin</div>
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• Antipsychotic drugs: clozapine and haloperidol</div>
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• Benzodiazepines</div>
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• Beta blockers</div>
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• Cisapride</div>
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• Digoxin</div>
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• Pimozide</div>
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• Theophylline</div>
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• Tricyclic antidepressants</div>
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• Warfarin</div>
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SSRI toxicity may increase by interaction with the following drugs:</div>
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• CNS depressants</div>
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• Diuretics</div>
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• Lithium</div>
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• Pseudoephedrine</div>
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• Tamadol: synergistic serotoninergic effect may induce seizures</div>
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• Zolpidem</div>
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<a href="http://knol.google.com/k/samuel-barrack/selective-serotonin-reuptake-inhibitors/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div>
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<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_12" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Adverse effects</span></b></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
General side effects include apathy,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000Q4" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">nausea</span></a><span class="Apple-converted-space"> </span>or<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000Q4" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">vomiting</span></a>, drowsiness or somnolence, headache, sleep disturbances,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000O5" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">dizziness</span></a>, urinary retention,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000I9" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">tremors</span></a>, autonomic dysfunction such as orthostatic hypotension, increased or reduced sweating, and photosensitivity.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Sexual side effects.</b><span class="Apple-converted-space"> </span>SSRIs can cause various types of sexual dysfunction, such as loss of orgasm, erectile dysfunction, and diminished libido. Some sexual symptoms persist or begin after the discontinuation of SSRIs. The effect of SSRIs to slow down sexual stimulation may be used as treatment for premature ejaculation.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">SSRI discontinuation syndrome.</b><span class="Apple-converted-space"> </span>SSRIs may produce some dependence, resulting in withdrawal effects. However, SSRIs have little to no abuse potential.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Suicidal ideation.</b><span class="Apple-converted-space"> </span>There is a black box warning on SSRIs and other antidepressant medications regarding the increased risk of suicidality in patients younger than 24 years of age. Various studies on SSRIs and suicide among adolescents are equivocal. There are also studies showing that higher rates of<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG00165" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">SSRI</span></a><span class="Apple-converted-space"> </span>prescriptions are associated with lower rates of suicide in children, although the true nature of the relationship is unclear<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B10" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Gibbons et al 2006)</span></a>. In adults, SSRIs overall reduce the incidence of suicide; however, in susceptible patients paradoxical adverse effects can still occur, which may precipitate suicide. Based on data from observational studies, use of SSRIs may be associated with a reduced risk of suicide in adults with depression, and among adolescents, use of SSRIs may increase suicidality<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/selective-serotonin-reuptake-inhibitors-1l9yjtm0t2xwn-20/#MLT002M0_B2" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Barbui et al 2009)</span></a>.</div>
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<b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Management</b></div>
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Most of the general side effects are in the early adaption phase and disappear later. If the side effects persist, SSRIs should be discontinued and replaced with another medication.<a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000L3" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Ropinirole</span></a><span class="Apple-converted-space"> </span>has completed clinical trials for treatment of sexual disorders resulting from SSRIs and is in phase IV studies. One of the serious side effects is<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000JX" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">serotonin syndrome</span></a>, and its management is described in a separate clinical summary.</div>
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<b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">References cited</span></b></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B1" style="color: #0867ab; text-decoration: none;"></a></span>Amin AH, Crawford BB, Gaddum JH. Distribution of 5-hydroxytryptamine and substance P in central nervous system. J Physiology (London) 1954;126:596-618.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B2" style="color: #0867ab; text-decoration: none;"></a>Barbui C, Esposito E, Cipriani A. Selective serotonin reuptake inhibitors and risk of suicide: a systematic review of observational studies. CMAJ 2009;180(3):291-7.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B3" style="color: #0867ab; text-decoration: none;"></a>Broddie BB, Shore PA. A concept for the role of serotonin and norepinephrine as chemical mediators in the brain. Ann NY Acad Sci 1957;66:631-42.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B4" style="color: #0867ab; text-decoration: none;"></a>Carlsson AH, Corrodi H, Fuxe K, Hokfelt T. Effect of antidepressant drugs on the depletion of intraneural brain 5-hydroxytryptamine stores caused by 4-methyl-alpha-ethyl-meta-tyramine. Eur J Pharmacol 1969;5:357-66.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B5" style="color: #0867ab; text-decoration: none;"></a>Chameau P, van Hooft JA. Serotonin 5-HT(3) receptors in the central nervous system. Cell Tissue Res 2006;326(2):573-81.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B6" style="color: #0867ab; text-decoration: none;"></a>Dahlstrom A, Fuxe K. Evidence for the existence of monoamine-containing neurons in the central nervous system I. Demonstration of monoamines in the cell bodies of the brainstem neurons. Acta Physiol Scand 1965;64 (suppl 247):1-55.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B7" style="color: #0867ab; text-decoration: none;"></a>Erspamer E. 5-hydroxytryptamine. In: von Eueler US, Heller H, editors. Comparative Endocrinology. Vol 2. New York: Academic Press, 1963:159-81.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B8" style="color: #0867ab; text-decoration: none;"></a>Gentile S, Bellantuono C. Selective serotonin reuptake inhibitor exposure during early pregnancy and the risk of fetal major malformations: focus on paroxetine. J Clin Psychiatry 2009;70(3):414-22.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B9" style="color: #0867ab; text-decoration: none;"></a>Gerretsen P, Pollock BG. Pharmacogenetics and the serotonin transporter in late-life depression. Expert Opin Drug Metab Toxicol 2008;4(12):1465-78.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B10" style="color: #0867ab; text-decoration: none;"></a>Gibbons RD, Hur K, Bhaumik DK, Mann JJ. The relationship between antidepressant prescription rates and rate of early adolescent suicide. Am J Psychiatry 2006;163(11):1898-904.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B11" style="color: #0867ab; text-decoration: none;"></a>Hamlin KE, Fisher FE. Synthesis of 5-hydroxytryptamine. J Am Chem Soc 1951;73:5007-8.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B12" style="color: #0867ab; text-decoration: none;"></a>Insel TR, Roy BF, Cohen RM, Murphy DL. Possible development of serotonin syndrome in man. Am J Psychiatry 1982;139:954-5.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B13" style="color: #0867ab; text-decoration: none;"></a>Jin Y, Lim CM, Kim SW, et al. Fluoxetine attenuates kainic acid-induced neuronal cell death in the mouse hippocampus. Brain Res 2009;1281:108-16.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B14" style="color: #0867ab; text-decoration: none;"></a>Kendirci M, Salem E, Hellstrom WJ. Dapoxetine, a novel selective serotonin transport inhibitor for the treatment of premature ejaculation. Ther Clin Risk Manag 2007;3(2):277-89.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B15" style="color: #0867ab; text-decoration: none;"></a>Kimball RW, Friedman AP, Valeejo E. Effect of serotonin in migraine patients. Neurology 1960;10:107-11.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B16" style="color: #0867ab; text-decoration: none;"></a>Levin GM, Bowles TM, Ehret MJ, et al. Assessment of human serotonin 1A receptor polymorphisms and SSRI responsiveness. Mol Diagn Ther 2007;11(3):155-60.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B17" style="color: #0867ab; text-decoration: none;"></a>Maas JW. Biogenic amines and depression: biochemical and pharmacological separation of two types of depression. Arch Gen Psychiatry 1975;32:1357-61.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B18" style="color: #0867ab; text-decoration: none;"></a>Peroutka SJ, Snyder SH. Multiple serotonin receptors: differential binding of [3H]5-hydroxytryptamine, [3H]lysergic acid diethylamide and [3H]spiroperidol. Mol Pharmacol 1979;16:323-8.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B19" style="color: #0867ab; text-decoration: none;"></a>Rapport MM, Green AA, Page IH. Serum vasoconstrictor (serotonin): isolation and characterization. J Biol Chem 1948;176:1243-51.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B20" style="color: #0867ab; text-decoration: none;"></a>Rasmussen-Torvik LJ, McAlpine DD. Genetic screening for SSRI drug response among those with major depression: great promise and unseen perils. Depress Anxiety 2007;24(5):350-7.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B21" style="color: #0867ab; text-decoration: none;"></a>Sjoerdsma A, Palfreyman MG. History of serotonin and serotonin disorders. Ann NY Acad Sci 1990;600:1-7.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B22" style="color: #0867ab; text-decoration: none;"></a>Sjoqvist F, Eliasson E. The convergence of conventional therapeutic drug monitoring and pharmacogenetic testing in personalized medicine: focus on antidepressants. Clin Pharmacol Ther 2007;81:899-902.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B23" style="color: #0867ab; text-decoration: none;"></a>Twarog BM, Page IH. Serotonin content of some mammalian tissues and urine and a method for its determination. Am J Physiol 1953;175:157-61.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B24" style="color: #0867ab; text-decoration: none;"></a>Udenfriend S. Biochemistry of serotonin and other indoleamines. Vitam Horm 1959;17:133-51.</div>
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<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B25" style="color: #0867ab; text-decoration: none;"></a>Wong DT, Horing JS, Bymaster FP, Hauser KL, Molloy BB. A selective inhibitor of serotonin uptake: Lilly 110140, 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine. Life Sci 1974;15:471-9.</div>
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<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=4325178021893911052" name="MLT002M0_B26" style="color: #0867ab; text-decoration: none;"></a>Zohar J, Insel TR. Obsessive-compulsive disorder: psychobiological approaches to diagnosis, treatment and pathophysiology. Biological Psychiatry 1987;22:667-87.</div>
Carlos Vázquezhttp://www.blogger.com/profile/09266699098392968330noreply@blogger.com1tag:blogger.com,1999:blog-7084351769408080486.post-71503802669117295562011-12-26T04:39:00.001-08:002012-11-23T10:56:13.271-08:00Anticholinergics<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Historical note and nomenclature</span></b></div>
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Anticholinergics are substances that block the neurotransmitter acetylcholine in the central and peripheral nervous systems and are administered to reduce the effects mediated by acetylcholine on acetylcholine receptors in neurons through competitive inhibition. Antimuscarinic agents, a type of anticholinergics, are so called because they block muscarine, a poisonous substance found in the Amanita muscaria, a non-edible mushroom species. Muscarine is a toxic compound that competes with acetylcholine for the same receptors. Antimuscarinic agents are atropine, scopolamine, and ipratropium bromide. Atropine and scopolamine are alkaloids naturally occurring in<span class="Apple-converted-space"> </span><i style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Atropa belladonna</i><span class="Apple-converted-space"> </span>and<span class="Apple-converted-space"> </span><i style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Datura stramonium</i>plants whereas ipratropium bromide is a derivative of atropine used to treat asthma.</div>
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Anticholinergic drugs are used in treating a variety of conditions, such as disorders of gastrointestinal (including<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000Q4" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">nausea and vomiting</span></a>), genitourinary, and respiratory systems. Atropine, an anticholinergic agent, is used as premedication in anesthesia to reduce upper respiratory secretions. This clinical summary focuses on the neurologic applications of anticholinergic drugs, mainly in<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000OW" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Parkinson disease</span></a>, as well as adverse neurologic effects of anticholinergic agents–anticholinergic syndrome.</div>
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Historically anticholinergic agents were known more for their toxicity than for their therapeutic effects.<span class="Apple-converted-space"> </span><i style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Datura stramonium</i><span class="Apple-converted-space"> </span>was described as a poison by Homer in<span class="Apple-converted-space"> </span><i style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">The Odyssey</i>. Anticholinergics agents were introduced as the first effective drugs for Parkinson disease by Charcot at the end of 19th century. With the advent of<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KJ" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">levodopa</span></a><span class="Apple-converted-space"> </span>and other new drugs for Parkinson disease, and also because of their adverse effects, the use of anticholinergics declined but continues in several other disorders.</div>
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Another use of atropine that is of historical interest now is atropine-induced non-convulsive<a href="http://jneurology.wordpress.com/cip.asp?UID=MLG001QD" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">coma</span></a><span class="Apple-converted-space"> </span>for treatment of various psychoses and obsessive-compulsive disorder between 1950 and 1975 in the United States and some parts of Europe<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/anticholinergics-1l9yjtm0t2xwn-18/#MLT002LX_B3" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Gazdag et al 2005)</span></a>. Although atropine use was eventually abandoned, initial therapeutic results with atropine coma were favorable, and it seemed to be safer and more effective than the widely used insulin coma.<br />
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<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=7150380266911729556" name="MLT002LX_26" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Pharmacology</span></b></div>
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Anticholinergic agents are classified into 2 categories according to the receptors that they act on:</div>
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(1) Antimuscarinic agents constitute the majority of anticholinergic drugs; they act on the muscarinic acetylcholine receptors.</div>
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(2) Antinicotinic agents act on the nicotinic acetylcholine receptors. The majority of these are non-depolarizing skeletal muscle relaxants for anesthetic use.</div>
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<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Antimuscarinic agents.</b><span class="Apple-converted-space"> </span>A classical example is atropine, which blocks acetylcholine receptor sites, opposes the actions of the vagus nerve, increases firing of the sinoatrial node and conduction through the atrioventricular node of the heart, and decreases bronchiole secretions. Overall effect of atropine is to lower the parasympathetic activity of all muscles and glands regulated by the parasympathetic nervous system because acetylcholine is the main neurotransmitter used by the parasympathetic nervous system. Therefore, it may cause swallowing difficulties and reduced secretions.</div>
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In addition to classical antimuscarinic agents, drugs from other categories may have antimuscarinic effect. Examples of such drugs are antihistamines, cimetidine, prednisolone, theophylline, and digoxin. These agents are listed in Table 1 as causative agents of anticholinergic syndrome.</div>
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The effects of scopolamine on the peripheral nervous system are similar to the effects of atropine. However, scopolamine is a central nervous system depressant and constitutes a highly effective treatment to prevent motion sickness although at high doses it causes excitement with side effects similar to those caused by high doses of atropine.</div>
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Most of the approved anticholinergic agents for the treatment of<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000OW" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Parkinson disease</span></a><span class="Apple-converted-space"> </span>are nonselective antimuscarinic receptor antagonists.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Antinicotinic agents.</b><span class="Apple-converted-space"> </span>These anticholinergic agents are ganglionic blockers, which target nicotinic receptors in nerve cells of either sympathetic or parasympathetic systems. The most used ganglionic blockers are trimethaphan and mecamylamine, which is used to treat hypertension.</div>
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Neuromuscular anticholinergic agents act on motor nerve choline receptors. They prevent the transmission of signals from motor nerves to neuromuscular structures of the skeletal muscle. Neuromuscular blockers are very useful as muscle relaxants in several surgical procedures, either as an adjuvant to anesthesia or as a premedication for anesthesia. Their main therapeutic use is in surgical procedures. Examples of the first group are mivacurium, tubocurarine, metocurine, doxacurium, and atracurium; the second group consists of rocuronium, vecuronium, pipecuronium, and pancuronium.</div>
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<a href="http://knol.google.com/k/samuel-barrack/anticholinergics/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div>
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<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=7150380266911729556" name="MLT002LX_27" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Clinical trials</span></b></div>
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There are few trials of anticholinergic drugs in recent years for treatment of neurologic disorders. A randomized, double blind, placebo-controlled, crossover study of ipratropium bromide was conducted in subjects with<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000OW" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Parkinson disease</span></a><span class="Apple-converted-space"> </span>and bothersome drooling<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/anticholinergics-1l9yjtm0t2xwn-18/#MLT002LX_B10" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Thomsen et al 2007)</span></a>. Although it did not affect objective measures of saliva production, there was a mild effect on subjective measures of sialorrhea. The treatment was well tolerated.</div>
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A prospective, 12-week dose titration trial of controlled-release oxybutynin chloride evaluated the efficacy and tolerability of higher doses of the drug in patients with neurogenic bladder and<a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000A3" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">multiple sclerosis</span></a>, spinal cord injury, or Parkinson disease<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/anticholinergics-1l9yjtm0t2xwn-18/#MLT002LX_B1" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Bennett et al 2004)</span></a>.</div>
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<a href="http://knol.google.com/k/samuel-barrack/anticholinergics/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div>
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<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=7150380266911729556" name="MLT002LX_16" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Indications</span></b></div>
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In neurologic disorders, anticholinergic drugs are used for the following conditions:</div>
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<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Parkinson disease.</b><span class="Apple-converted-space"> </span>Anticholinergics are used for symptomatic treatment of certain manifestations of<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000OW" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Parkinson disease</span></a>, such as sialorrhea, drug-induced dyskinesia, and urinary urgency or frequency.</div>
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<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Hyperactive bladder.</b><span class="Apple-converted-space"> </span>Anticholinergics may be used for hyperactive bladder in neurologic disorders other than Parkinson disease, for example, oxybutynin in<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000A3" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">multiple sclerosis</span></a>. However, a systematic review of clinical trials of anticholinergics versus other treatments showed no significant difference between the 2 treatments in any efficacy outcome measure, and the available evidence did not support the use of anticholinergics in multiple sclerosis<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/anticholinergics-1l9yjtm0t2xwn-18/#MLT002LX_B8" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Nicholas et al 2009)</span></a>.</div>
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Urinary incontinence is common in patients with dementia. Central cholinergic stimulation is the mainstay in the treatment of cognitive decline. The use of anticholinergic medications for detrusor overactivity in demented patients carries the risk of mental deterioration, and further studies are needed to define treatment regimens for elderly individuals with both dementia and urinary dysfunction<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/anticholinergics-1l9yjtm0t2xwn-18/#MLT002LX_B9" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Sakakibara et al 2008)</span></a>.</div>
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<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Drug-induced dyskinesias.</b><span class="Apple-converted-space"> </span>Rabbit syndrome, a movement disorder generally associated with prolonged use of antipsychotics, responds favorably to anticholinergic drugs<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/anticholinergics-1l9yjtm0t2xwn-18/#MLT002LX_B2" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Catena et al 2007)</span></a>.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Treatment of nerve agent poisoning.</b><span class="Apple-converted-space"> </span>Atropine is recommended as the first-line treatment of sarin poisoning, and the dose should be titrated, with the goal of drying secretions and the resolution of bronchoconstriction. Atropine autoinjection is indicated as an initial treatment of the muscarinic symptoms of nerve agent poisonings. Each prefilled autoinjector provides a dose of the antidote atropine, an anticholinergic drug that reduces secretions in the mouth and respiratory passages, relieves the constriction and spasm of respiratory passages, and may reduce the paralysis of respiration, which results from actions of the toxic agent on the central nervous system. Physostigmine is also an effective treatment against sarin intoxication.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Diagnostic procedures in neurologic disorders.</b><span class="Apple-converted-space"> </span>The pupillary light reflex test for<a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000OU" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Alzheimer disease</span></a><span class="Apple-converted-space"> </span>involves tropicamide blockade of cholinergic oculomotor functions. Pupillary constriction amplitude correlates significantly with severity of dementia, and cholinesterase inhibitor therapy may partially normalize pupillary light reflex abnormalities in these patients<a href="http://jneurology.wordpress.com/article/anticholinergics-1l9yjtm0t2xwn-18/#MLT002LX_B4" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Granholm et al 2003)</span></a>.</div>
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<a href="http://knol.google.com/k/samuel-barrack/anticholinergics/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=7150380266911729556" name="MLT002LX_17" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Contraindications</span></b></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
Anticholinergic drugs are contraindicated in patients with urinary retention due to bladder neck obstruction,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000D9" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">myasthenia gravis</span></a>, severe decreased gastrointestinal motility conditions, and uncontrolled narrow angle glaucoma.</div>
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<a href="http://knol.google.com/k/samuel-barrack/anticholinergics/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=7150380266911729556" name="MLT002LX_28" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Goals and duration of treatment</span></b></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
Most anticholinergic therapies are short-term or intermittent. Chronic or long-term use is limited by neurotoxicity of many of these compounds. They are mostly symptomatic and do not correct the underlying pathology of the disease.</div>
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<a href="http://knol.google.com/k/samuel-barrack/anticholinergics/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=7150380266911729556" name="MLT002LX_9" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Dosing</span></b></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
Numerous anticholinergic agents are in use. The<span class="Apple-converted-space"> </span><i style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Physician’s Desk Reference</i><span class="Apple-converted-space"> </span>should be consulted for doses of individual agents.</div>
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<a href="http://knol.google.com/k/samuel-barrack/anticholinergics/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div>
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<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=7150380266911729556" name="MLT002LX_29" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Precautions and use in special groups</span></b></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Pediatric.</b><span class="Apple-converted-space"> </span>Anticholinergic drugs have been used in children, for example in the treatment of overactive bladder. Although some of the drugs are approved, few clinical trials have been conducted specifically in pediatric populations. There are no specific precautions in children, and contraindications are the same as in adults.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Geriatric.</b><span class="Apple-converted-space"> </span>Although many of the conditions for which anticholinergic drugs are used occur more frequently in the elderly, several precautions are necessary in this age group. Cognitive decline, renal function impairment, slowing of gastrointestinal motility, urinary obstruction due to prostatic hyperplasia, and cardiac rhythm disorders are some of the conditions that are more common in the elderly and require caution in the use of anticholinergic drugs.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Pregnancy.</b><span class="Apple-converted-space"> </span>The effect of anticholinergic agents on pregnancy is not well documented due to the lack of animal experimental or human studies, and caution should be exercised for use during pregnancy. The administration of anticholinergics should be avoided in patients with severe preeclampsia. There are no available data on excretion in breast milk, but anticholinergics suppress lactation; use in breastfeeding mothers should be avoided.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Anesthesia.</b><span class="Apple-converted-space"> </span>Anticholinergics have been used extensively as pre-anesthetic medications, for muscle relaxation and for postoperative complications such as<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000Q4" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">nausea and vomiting</span></a>.</div>
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<a href="http://knol.google.com/k/samuel-barrack/anticholinergics/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=7150380266911729556" name="MLT002LX_11" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Interactions</span></b></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
Patients with<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000OU" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Alzheimer disease</span></a><span class="Apple-converted-space"> </span>being treated with cholinesterase inhibitors have a greater decline in their mental status after taking concurrent anticholinergic drugs for prolonged periods. This combination should be avoided as anticholinergic drugs reduce the therapeutic efficacy of cholinesterase inhibitors. Moreover, anticholinergic drugs can interact with cholinesterase inhibitors to produce bradycardia.</div>
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Use of anticholinergic drugs for overactive bladder together with those prescribed for psychiatric or neurologic indications that also have anticholinergic properties can lead to pharmacodynamic drug interactions that might produce an anticholinergic toxicity<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/anticholinergics-1l9yjtm0t2xwn-18/#MLT002LX_B6" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Michel et al 2009)</span></a>.</div>
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Levels of the anticholinergic drugs can be increased to high levels by CYP3A4 inhibitors such as macrolide antibiotics (eg, erythromycin, anti-<a href="http://jneurology.wordpress.com/cip.asp?UID=MLG000YM" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">HIV</span></a><span class="Apple-converted-space"> </span>agents, antidepressants, and calcium channel blockers). Therefore, this combination is contraindicated.</div>
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<a href="http://knol.google.com/k/samuel-barrack/anticholinergics/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=7150380266911729556" name="MLT002LX_12" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Adverse effects</span></b></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
Adverse effects of anticholinergics may be neurologic or non-neurologic. Non-neurologic symptoms and signs of anticholinergic effect include: dry, sore throat due to decreased mucous production and cessation of perspiration leading to increased body temperature as well as tachycardia, urinary retention,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLM0048X" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">constipation</span></a>, and increased intraocular pressure, which may be dangerous for people with narrow-angle glaucoma.</div>
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Neurologic signs of anticholinergic effect include<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000MZ" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">ataxia</span></a>, pupil dilation with blurred vision, and<a href="http://jneurology.wordpress.com/cip.asp?UID=MLT002LJ" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">diplopia</span></a>. Effects in the central nervous system resemble those associated with<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG001QE" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">delirium</span></a>. Neurotoxicity of anticholinergics is termed “acute cholinergic syndrome,” and other manifestations besides those of delirium include cognitive impairment and visual, auditory, and sensory hallucinations. Seizures,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG001QD" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">coma</span></a>, and death may occur rarely. Anticholinergic syndrome is more likely to be caused by drugs with central anticholinergic effects that cross the<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000L9" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">blood-brain barrier</span></a><span class="Apple-converted-space"> </span>and block muscarinic cholinergic receptors<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/anticholinergics-1l9yjtm0t2xwn-18/#MLT002LX_B7" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Moos 2007)</span></a>. Drugs reported to be associated with anticholinergic syndrome are listed in Table 1.</div>
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<b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Table 1. Drugs That Can Produce Anticholinergic Syndrome</b></div>
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• Anesthesia, analgesia, and postoperative medications</div>
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– Atropine sulfate</div>
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– Benzodiazepines</div>
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– Halothane</div>
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– Hyoscine</div>
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– Influrane</div>
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– Ketamine</div>
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– Opioids</div>
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– Transdermal scopolamine</div>
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• Antiarrhythmics</div>
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– Propafenone</div>
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– Quinidine</div>
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• Antiasthmatics</div>
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– Ipratropium bromide</div>
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• Antiemetics</div>
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– Cyclizine</div>
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– Meclizine</div>
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• Antihistaminics with anticholinergic activity</div>
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– Brompheniramine</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Chlorpheniramine</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Cyclizine</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Diphenylhydramine</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Promezathine</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Anti-incontinence agents</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Oxybutynin</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Propantheline bromide</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Antiparkinsonian medications</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Amantadine</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Benzotropine</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Biperiden</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Ethopropazine</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Procyclidine</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Trihexyphenidyl</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Antipsychotics</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Clozapine</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Chlorpromazine</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Chlorprothixene</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Thioridazine</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Antispasmodics for the gastrointestinal tract</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Hexocyclium</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Hyoscyamine</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Isopropamide</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Oxyphenonium</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Propantheline</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Tridihexethyl</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Baclofen</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
• Ophthalmic preparations</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Atropine 1% ophthalmic solution</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Cyclopentolate</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
– Eucatropine</div>
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– Tropicamide</div>
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• Tricyclic antidepressants</div>
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– Amitriptyline</div>
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– Imipramine</div>
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– Clomipramine</div>
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• Drug interactions</div>
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– Desipramine and venlafaxine</div>
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– Venlafaxine-<a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KZ" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">fluoxetine</span></a></div>
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– Paroxetine and clozapine</div>
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Source: Updated from<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/anticholinergics-1l9yjtm0t2xwn-18/#MLT002LX_B5" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Jain 2001)</span></a></div>
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<br /></div>
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<span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Management.</b><span class="Apple-converted-space"> </span>Acute anticholinergic syndrome is completely reversible and subsides once all of the toxin has been excreted. Usually no specific treatment is indicated, but in severe cases, especially those that involve severe distortions of mental state, a reversible cholinergic agent such as physostigmine may be used as 1 mg intravenous dose.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">References cited</span></b></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=7150380266911729556" name="MLT002LX_B1" style="color: #0867ab; text-decoration: none;"></a></span><a href="http://jneurology.wordpress.com/cip.asp?UID=14713802" style="color: #0867ab; text-decoration: none;" title="Link to abstract"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Bennett N, O’Leary M, Patel AS, Xavier M, Erickson JR, Chancellor MB. Can higher doses of oxybutynin improve efficacy in neurogenic bladder? J Urol 2004;171(2 Pt 1):749-51.</span></a></div>
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<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=7150380266911729556" name="MLT002LX_B2" style="color: #0867ab; text-decoration: none;"></a>Catena M, Fagiolini A, Consoli G, et al. The rabbit syndrome: state of the art. Curr Clin Pharmacol 2007;2(3):212-6.</div>
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<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=7150380266911729556" name="MLT002LX_B3" style="color: #0867ab; text-decoration: none;"></a><a href="http://jneurology.wordpress.com/cip.asp?UID=16301877" style="color: #0867ab; text-decoration: none;" title="Link to abstract"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Gazdag G, Bitter I, Ungvári G, Gerevich J. Atropine coma: a historical note. J ECT 2005;21(4):203-6.</span></a></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
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<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=7150380266911729556" name="MLT002LX_B4" style="color: #0867ab; text-decoration: none;"></a>Granholm E, Morris S, Galasko D, Shults C, Rogers E, Vukov B. Tropicamide effects on pupil size and pupillary light reflexes in Alzheimer’s and Parkinson’s disease. Int J Psychophysiol 2003;47(2):95-115.</div>
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<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=7150380266911729556" name="MLT002LX_B5" style="color: #0867ab; text-decoration: none;"></a>Jain KK. Drug-induced Neurological Disorders. 2nd edition. Hogrefe & Huber, 2001:380.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
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<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=7150380266911729556" name="MLT002LX_B6" style="color: #0867ab; text-decoration: none;"></a>Michel MC, Schäfers RF, de la Rosette JJ. Drug-drug interactions in urology. Urologe A 2009;48(3):264-9.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
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<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=7150380266911729556" name="MLT002LX_B7" style="color: #0867ab; text-decoration: none;"></a>Moos DD. Central anticholinergic syndrome: a case report. J Perianesth Nurs 2007;22(5):309-21.</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=7150380266911729556" name="MLT002LX_B8" style="color: #0867ab; text-decoration: none;"></a>Nicholas RS, Friede T, Hollis S, Young CA. Anticholinergics for urinary symptoms in multiple sclerosis. Cochrane Database Syst Rev 2009;(1):CD004193.**</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
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<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=7150380266911729556" name="MLT002LX_B9" style="color: #0867ab; text-decoration: none;"></a>Sakakibara R, Uchiyama T, Yamanishi T, Kishi M. Dementia and lower urinary dysfunction: with a reference to anticholinergic use in elderly population. Int J Urol 2008;15(9):778-88.**</div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<br /></div>
<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;">
<a href="http://www.blogger.com/blogger.g?blogID=7084351769408080486#editor/target=post;postID=7150380266911729556" name="MLT002LX_B10" style="color: #0867ab; text-decoration: none;"></a>Thomsen TR, Galpern WR, Asante A, Arenovich T, Fox SH. Ipratropium bromide spray as treatment for sialorrhea in Parkinson’s disease. Mov Disord 2007;22(15):2268-73.</div>
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Carlos Vázquezhttp://www.blogger.com/profile/09266699098392968330noreply@blogger.com1tag:blogger.com,1999:blog-7084351769408080486.post-61330061574910922922011-12-26T04:36:00.000-08:002011-12-26T04:36:07.601-08:00Anticonvulsants<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Historical note and nomenclature</span></b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> The term “anticonvulsant” is applied to a drug used for the treatment of epileptic seizures, hence, the synonym “antiepileptic,” which is often denoted by the abbreviation AED. This term is applied to other agents such as ketogenic diet and procedures such as vagal nerve stimulation when used for control of seizures. Some drugs from other pharmacological categories have anticonvulsant effect, eg, acetazolamide, which is a carbonic anhydrase inhibitor. Anticonvulsants are also being used in the<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000VA" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">treatment of neuropathic pain</span></a><span class="Apple-converted-space"> </span>and as mood stabilizers in the treatment of psychiatric disorders such as bipolar disorder.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> The era of anticonvulsant drugs started with the introduction of bromides in 1857 and was followed by the discovery of the anticonvulsant effect of barbiturates in 1912<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/anticonvulsants-1l9yjtm0t2xwn-19/#MLT002LY_B4" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Hauptman 1912)</span></a>.<a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KH" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Phenytoin</span></a><span class="Apple-converted-space"> </span>(diphenylhydantoin), synthesized in 1908, was not introduced for the treatment of<a href="http://jneurology.wordpress.com/cip.asp?UID=MLT00018" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">epilepsy</span></a><span class="Apple-converted-space"> </span>until 1938<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/anticonvulsants-1l9yjtm0t2xwn-19/#MLT002LY_B8" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Merritt and Putnam 1938)</span></a>. Although carbamazepine was shown to have antiepileptic properties in 1954, it was first approved in 1968 for the treatment of trigeminal neuralgia and was approved in 1974 for the treatment of epilepsy. Anticonvulsant properties of<a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KK" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">valproic acid</span></a>, which is structurally unrelated to other antiepileptic drugs, were discovered by chance in 1963; however, it did not become a major anticonvulsant drug until the 1970s. For the next 2 decades, the older anticonvulsant drugs with new variations remained the mainstay for treatment of epilepsy. During the past 2 decades, several new anticonvulsant drugs have been approved worldwide, and the use of anticonvulsant drugs in indications other than epilepsy has increased. The newer approved anticonvulsants include<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KE" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">vigabatrin</span></a>,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000NZ" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">zonisamide</span></a>,<a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000MG" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">oxcarbazepine</span></a>,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KI" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">lamotrigine</span></a>, felbamate,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KG" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">gabapentin</span></a>,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000L4" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">topiramate</span></a>,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT002H6" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">tiagabine</span></a>,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000N5" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">levetiracetam</span></a>,<a href="http://jneurology.wordpress.com/cip.asp?UID=MLT002KC" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">pregabalin</span></a>, rufinamide, stiripentol, and lacosamide. Several new drugs are in development.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> Several anticonvulsant drugs are reviewed individually in other clinical summaries. This summary compares various anticonvulsants and describes their uses for other indications besides epilepsy.</div><div align="right" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://knol.google.com/k/samuel-barrack/anticonvulsants/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_26" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Pharmacology</span></b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Pharmacodynamics.</b><span class="Apple-converted-space"> </span>The main actions of currently used anticonvulsants are:</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> (1) Modulation of voltage-gated sodium and calcium channels.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> (2) Synaptic inhibitory neurotransmission by agonist effect on the<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG000XE" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">GABA</span></a><span class="Apple-converted-space"> </span>system.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> (3) Attenuation of brain excitation by decreased glutamate transmission.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> Anticonvulsants can be classified according to their predominant mode of action as shown in Table 1, but some drugs have more than one mechanism of action, and some of the mechanisms are not known. The modifications in channel behavior that are induced by anticonvulsant drugs are often functionally opposite to defects in channel properties that are caused by mutations associated with<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT00018" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">epilepsy</span></a><span class="Apple-converted-space"> </span>in humans<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/anticonvulsants-1l9yjtm0t2xwn-19/#MLT002LY_B12" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Rogawski and Loscher 2004)</span></a>.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div align="center" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: center; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Table 1. Predominant Mode of Action of Anticonvulsant Drugs</b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><table border="0" cellpadding="0" cellspacing="0" style="background-color: white; border-collapse: collapse; border-color: rgb(221, 221, 221); border-style: solid; border-width: 1px; color: #444444; font-family: Arial,Helvetica,sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin: 0px 0px 10px 0.1in; min-width: 200px; orphans: 2; padding: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; width: 652px; word-spacing: 0px;"><tbody style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 106.2pt;" valign="top" width="142"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Sodium channel</b></div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 94.5pt;" valign="top" width="126"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Calcium channel</b></div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1.5in;" valign="top" width="144"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">GABA</b></div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 81pt;" valign="top" width="108"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Glutamate</b></div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 99pt;" valign="top" width="132"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Other mechanisms</b></div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 106.2pt;" valign="top" width="142"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Carbamazepine</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KI" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Lamotrigine</span></a></div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000MG" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Oxcarbazepine</span></a></div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KH" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Phenytoin</span></a></div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Rufinamide</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Zonisamide</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 94.5pt;" valign="top" width="126"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Ethosuximide</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT002KC" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Pregabalin</span></a></div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Zonisamide</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1.5in;" valign="top" width="144"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Barbiturates</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Benzodiazepines</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KG" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Gabapentin</span></a></div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT002H6" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Tiagabine</span></a></div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Valproate</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Vigabatrin</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 81pt;" valign="top" width="108"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Felbamate</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Topiramate</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 99pt;" valign="top" width="132"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Levetiracetam</div></td></tr>
</tbody></table><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Use of anticonvulsants in epilepsy.</b><span class="Apple-converted-space"> </span>The primary criterion for the selection of anticonvulsant drugs is the patient’s seizure type; determination is largely based on drug studies that assess the drugs’ effectiveness for specific seizure types rather than the defined causes of seizures. Despite restriction to partial seizures, the response to an investigational anticonvulsant is quite variable. The reasons for this include: (1) patient-to-patient variation in the metabolism of the drug, (2) variations in the ability of drug to bind to the target, (3) variations in the amount of drug target produced by different individuals, and (4) different pathophysiological events accounting for the same seizure phenotype.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> No single anticonvulsant is clearly superior to others. Causes of variability of effects of anticonvulsants include genetic differences, pathogenesis and severity of epilepsy, age, nutritional status, renal and liver function, concomitant illnesses, and drug interactions.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Effect of anticonvulsants as analgesics.</b><span class="Apple-converted-space"> </span>Similarities between the pathophysiological phenomena observed in some epilepsy models and in<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG001CC" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">neuropathic pain</span></a><span class="Apple-converted-space"> </span>models justify the use of anticonvulsants in the symptomatic management of neuropathic pain. Pain-relieving effects require doses that are in each drug’s antiepileptic dose range. Given their diverse chemistries and different patterns of activity in seizure models, it seems exceedingly unlikely that these anticonvulsants are all working on neuropathic pain via the same mechanism. Table 2 shows the mechanism of action as well as indications for use of various anticonvulsant drugs for management of pain.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div align="center" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: center; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Table 2. Use of Anticonvulsant Drugs for Management of Pain</b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><table border="0" cellpadding="0" cellspacing="0" style="background-color: white; border-collapse: collapse; border-color: rgb(221, 221, 221); border-style: solid; border-width: 1px; color: #444444; font-family: Arial,Helvetica,sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin: 0px 0px 10px 0.1in; min-width: 200px; orphans: 2; padding: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; width: 646px; word-spacing: 0px;"><tbody style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 102.9pt;" valign="top" width="137"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Drug</b></div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 201.3pt;" valign="top" width="268"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Mechanism of action</b></div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 2.5in;" valign="top" width="240"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Uses in pain</b></div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 102.9pt;" valign="top" width="137"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Carbamazepine</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 201.3pt;" valign="top" width="268"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Slows recovery rate of voltage-gated sodium channels. Stabilization of cell membrane.</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 2.5in;" valign="top" width="240"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">First line therapy of trigeminal neuralgia, glossopharyngeal neuralgia</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 102.9pt;" valign="top" width="137"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Gabapentin</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 201.3pt;" valign="top" width="268"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Inhibits repetitive firing of neurons by action at calcium channels</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 2.5in;" valign="top" width="240"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Neuropathic pain, migraine</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 102.9pt;" valign="top" width="137"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Ganaxalone</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 201.3pt;" valign="top" width="268"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">An epalon that modulates GABA receptors</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 2.5in;" valign="top" width="240"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Migraine</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 102.9pt;" valign="top" width="137"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Lamotrigine</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 201.3pt;" valign="top" width="268"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Inhibits repetitive firing of neurons by action at sodium channels</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 2.5in;" valign="top" width="240"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Neuropathic pain, migraine</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 102.9pt;" valign="top" width="137"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Phenytoin</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 201.3pt;" valign="top" width="268"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Enhances active sodium extrusion and inhibits passive sodium entry, leading to normalization of the sodium gradient and stabilization of the membrane.</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 2.5in;" valign="top" width="240"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Second line therapy of trigeminal neuralgia</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 102.9pt;" valign="top" width="137"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Pregabalin</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 201.3pt;" valign="top" width="268"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Enhancement of GABA-mediated inhibition</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 2.5in;" valign="top" width="240"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Shown to be effective in controlled studies in<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG0007K" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">diabetic neuropathy</span></a><span class="Apple-converted-space"> </span>and<a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000FF" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">postherpetic neuralgia</span></a></div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 102.9pt;" valign="top" width="137"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Rufinamide</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 201.3pt;" valign="top" width="268"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Inhibits repetitive firing of neurons by action at sodium channels</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 2.5in;" valign="top" width="240"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Neuropathic pain</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 102.9pt;" valign="top" width="137"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Topiramate</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 201.3pt;" valign="top" width="268"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Suppresses repetitive depolarization from injured sensory neurons.</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 2.5in;" valign="top" width="240"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Neuropathic pain, migraine, diabetic neuropathy</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 102.9pt;" valign="top" width="137"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Valproic acid</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 201.3pt;" valign="top" width="268"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Inhibits repetitive firing of neurons by action at sodium channels</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 2.5in;" valign="top" width="240"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Migraine</div></td></tr>
</tbody></table><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Effect of anticonvulsants in psychiatric disorders.</b><span class="Apple-converted-space"> </span>Anticonvulsant drugs are widely used in psychiatric indications. These include mainly alcohol and benzodiazepine withdrawal syndromes, panic and anxiety disorders, dementia,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT002K4" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">schizophrenia</span></a>, mood disorders (bipolar<a href="http://jneurology.wordpress.com/cip.asp?UID=MLT0008O" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">affective disorders</span></a><span class="Apple-converted-space"> </span>in particular), and, to some extent, personality disorders<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/anticonvulsants-1l9yjtm0t2xwn-19/#MLT002LY_B2" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Grunze 2008)</span></a>.<a href="http://jneurology.wordpress.com/cip.asp?UID=MLG0008K" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Electroconvulsive therapy</span></a><span class="Apple-converted-space"> </span>can be safely and effectively administered to patients treated with various anticonvulsants, but there is no evidence that combination of the 2 treatment modalities augments therapeutic efficacy<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/anticonvulsants-1l9yjtm0t2xwn-19/#MLT002LY_B13" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Sienaert and Peuskens 2007)</span></a>. An analysis of randomized controlled trials shows that although anticonvulsant mood stabilizers are clearly beneficial in some patients, they cannot be recommended at present for routine use in the treatment of behavioral and psychological symptoms of dementia<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/anticonvulsants-1l9yjtm0t2xwn-19/#MLT002LY_B6" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Konovalov et al 2008)</span></a>.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> The relative neurocognitive effects of the various psychotropic anticonvulsant drugs in patients with bipolar disorder are consistent with relative effects in patients with epilepsy. Lamotrigine and oxcarbazepine have the least neurotoxicity, whereas<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000L4" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">topiramate</span></a>,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KK" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">valproic acid</span></a>, and<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KF" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">carbamazepine</span></a><span class="Apple-converted-space"> </span>have the most<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/anticonvulsants-1l9yjtm0t2xwn-19/#MLT002LY_B3" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Gualtieri and Johnson 2006)</span></a>.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> The effectiveness of anticonvulsants in mood disorders raises the question whether the analgesic effects of antiepileptic drugs in patients with neuropathic pain may result, at least in part, from their beneficial effects on mood. For example, gabapentin treatment significantly ameliorates depression, anxiety, fatigue, and other mood symptoms and also improves sleep in patients with postherpetic neuralgia and painful diabetic neuropathy.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Pharmacokinetics.</b><span class="Apple-converted-space"> </span>Pharmacokinetics is described in the articles dealing with individual anticonvulsant drugs.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Pharmacogenetics.</b><span class="Apple-converted-space"> </span>Pharmacogenetic alterations can affect efficacy, tolerability, and safety of anticonvulsants, including variation in genes encoding drug target, drug transport, drug metabolization, and human leucocyte antigen proteins. The current studies associating particular genes and their variants with seizure control or adverse events have inherent weaknesses and have not provided unifying conclusions. However, several observations (eg, that Asian patients with a particular<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG000YO" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">HLA</span></a><span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG0018K" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">allele</span></a>,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG000YO" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">HLA</span></a>-B*1502, are at a higher risk for<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG001Q5" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Stevens-Johnson syndrome</span></a><span class="Apple-converted-space"> </span>when using carbamazepine) are helpful in improving our knowledge of how genetic variation affects the treatment of epilepsy<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/anticonvulsants-1l9yjtm0t2xwn-19/#MLT002LY_B7" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Loscher et al 2009)</span></a>. A better understanding of the genetic influences on epilepsy outcome is key to developing the much needed new therapeutic strategies for individual patients with epilepsy.</div><div align="right" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://knol.google.com/k/samuel-barrack/anticonvulsants/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_27" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Clinical trials</span></b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> Numerous clinical trials in<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT00018" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">epilepsy</span></a><span class="Apple-converted-space"> </span>have been conducted with newer anticonvulsant drugs, often as add-on to established older drugs. These are described in the clinical summaries for individual anticonvulsants. There are fewer clinical trials comparing monotherapies using various anticonvulsants. Remarks on specific trials are given according to indication categories such as epilepsy, pain, and psychiatric disorders.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Epilepsy.</b><span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KF" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Carbamazepine</span></a><span class="Apple-converted-space"> </span>has been a drug of choice for the treatment of simple or<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000DZ" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">complex partial seizures</span></a><span class="Apple-converted-space"> </span>and secondary<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG001Q0" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">generalized seizures</span></a><span class="Apple-converted-space"> </span>in adults and children. After introduction of<a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KE" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">vigabatrin</span></a>, an open prospective trial showed that vigabatrin is safe and effective as primary monotherapy for epilepsy in children, with a similar proportion of side effects as carbamazepine<a href="http://jneurology.wordpress.com/article/anticonvulsants-1l9yjtm0t2xwn-19/#MLT002LY_B14" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Sobaniec et al 2005)</span></a>. Following clinical trials,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000N5" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">levetiracetam</span></a><span class="Apple-converted-space"> </span>and controlled-release carbamazepine were shown to produce similar seizure-free rates in newly diagnosed epilepsy at optimal dosing in a setting resembling clinical practice<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/anticonvulsants-1l9yjtm0t2xwn-19/#MLT002LY_B1" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Brodie et al 2007)</span></a>.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Pain.</b><span class="Apple-converted-space"> </span>Clinical trials with individual anticonvulsant medications for pain are mentioned in the clinical summaries discussing the individual drugs. Most of the trials are in patients with pain refractory to treatment with conventional analgesics. One anticonvulsant agent is usually not compared against another in clinical trials.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> Cochrane Database review of clinical trials shows that anticonvulsants reduce migraine frequency by about 1.3 attacks per 28 days compared with placebo–more than double the number of patients for whom migraine frequency is reduced by 50% relative to placebo<a href="http://jneurology.wordpress.com/article/anticonvulsants-1l9yjtm0t2xwn-19/#MLT002LY_B9" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Mulleners and Chronicle 2008)</span></a>. Sodium valproate/<a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KK" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">divalproex sodium</span></a><span class="Apple-converted-space"> </span>and topiramate were better than placebo, whereas acetazolamide, clonazepam,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KI" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">lamotrigine</span></a>, and vigabatrin were not.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Psychiatric disorders.</b><span class="Apple-converted-space"> </span>Clinical trials of anticonvulsant disorders are described in the clinical summaries discussing the individual anticonvulsant agents. There few studies that compare one anticonvulsant agent against another in psychiatric disorders. In a randomized, single-blind treatment of hypomanic symptoms in patients with bipolar disorder,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000MG" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">oxcarbazepine</span></a><span class="Apple-converted-space"> </span>was found to be as effective as<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KK" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">valproic acid</span></a><span class="Apple-converted-space"> </span>in the treatment of hypomania<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/anticonvulsants-1l9yjtm0t2xwn-19/#MLT002LY_B15" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Suppes et al 2007)</span></a>.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Clinical trial databases.</b><span class="Apple-converted-space"> </span>Information about current clinical trials can be obtained from various databases accessible on the Internet. As of June 2009, the largest number of clinical trials on anticonvulsants were listed on the clinical trial database of the National Institutes of Health (<a href="http://clinicaltrials.gov/ct2/search/browse?brwse=intr_cat_AntiConv" style="color: #0867ab; text-decoration: none;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">www.ClinicalTrials.gov</span></a>). Of the 858 clinical trials, the largest numbers involved etiracetam,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KG" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">gabapentin</span></a>, lamotrigine,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT002KC" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">pregabalin</span></a>, and topiramate.</div><div align="right" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://knol.google.com/k/samuel-barrack/anticonvulsants/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_16" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Indications</span></b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> Anticonvulsant medications have been approved for the treatment of<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT00018" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">epilepsy</span></a>, pain, and psychiatric disorders. Details of indications are given in the clinical summaries dealing with individual anticonvulsants.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Off-label and investigational uses.</b><span class="Apple-converted-space"> </span>Several studies of newer anticonvulsants in epilepsy, pain and psychiatric disorders are still on-going.</div><div align="right" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://knol.google.com/k/samuel-barrack/anticonvulsants/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_17" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Contraindications</span></b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> Contraindications are specified for each drug individually (see individual clinical summaries for each drug). There are no contraindications for anticonvulsants as a class.</div><div align="right" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://knol.google.com/k/samuel-barrack/anticonvulsants/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_28" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Goals and duration of treatment</span></b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> Goals vary according to the disease and anticonvulsant used. Duration varies for acute to chronic, with most of the indications being chronic conditions.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Personalized approach to use of anticonvulsants.</b><span class="Apple-converted-space"> </span>Physicians try to match a drug to a patient by trial and error. The final choice may take several months and depends on the efficacy and tolerability of adverse effects. However, the problems still remain of adverse side effects and failure to control seizures in more than 30% of patients.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> Control of<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT00018" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">epilepsy</span></a><span class="Apple-converted-space"> </span>with<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KH" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">phenytoin</span></a><span class="Apple-converted-space"> </span>can be a difficult and lengthy process because of the wide range of doses required by different patients and the drug’s narrow therapeutic index. Similarly, appropriate doses of<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KF" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">carbamazepine</span></a><span class="Apple-converted-space"> </span>take time to determine because of the drug’s variable affects on patient metabolism and its potential neurologic side effects. People with epilepsy are genetically different from one another, and some of those differences affect their responses to drugs in a predictable manner. Variants of 2 genes have been identified that are more likely to be found in patients who required higher dosages of the antiepileptic drugs carbamazepine and phenytoin<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/anticonvulsants-1l9yjtm0t2xwn-19/#MLT002LY_B16" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Tate et al 2005)</span></a>. One variant of the gene that encodes<span class="Apple-converted-space"> </span><i style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">CYP2C9</i><span class="Apple-converted-space"> </span>shows a significant association with the maximum dose of phenytoin taken by patients with epilepsy. Moreover, a variant of a second gene, called<span class="Apple-converted-space"> </span><i style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">SCN1A</i>, with activity in the brain, is found significantly more often in patients on the highest doses of both carbamazepine and phenytoin.<span class="Apple-converted-space"> </span><i style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">SCN1A</i><span class="Apple-converted-space"> </span>has been implicated in many inherited forms of epilepsy and is the drug target for phenytoin. Detection of these gene variants might determine, in advance, which patients will need the higher dose and enable a more optimal dose schedule at the start. Otherwise, it could take months to get the seizures under control. These new findings provide a direction for a dosing scheme that could be tested in a clinical trial to assess whether pharmacogenetic testing can improve dosing decisions. Such a trial might also enable physicians to identify patients who might safely take a smaller dose, thereby minimizing their risk for adverse side effects.</div><div align="right" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://knol.google.com/k/samuel-barrack/anticonvulsants/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_9" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Dosing</span></b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> The doses are specified in the individual clinical summaries for each anticonvulsant.</div><div align="right" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://knol.google.com/k/samuel-barrack/anticonvulsants/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_29" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Precautions and use in special groups</span></b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Pediatric.</b><span class="Apple-converted-space"> </span>Many of the anticonvulsants used in adults also have been used in children without any extra risk. However, safety of anticonvulsants for the treatment of psychiatric disorders in the pediatric age group is not supported by adequate clinical trials.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Geriatric.</b><span class="Apple-converted-space"> </span>The use of anticonvulsants in the elderly for the management of<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT00018" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">epilepsy</span></a><span class="Apple-converted-space"> </span>is safe.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Pregnancy.</b><span class="Apple-converted-space"> </span>There is concern about teratogenicity as the incidence of congenital malformations in offspring of women treated with anticonvulsants during pregnancy is somewhat higher than in offspring of women not exposed to these drugs. Most anticonvulsant drugs fall into category C of the United States Food and Drug Administration. Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> For women on anticonvulsant therapy who are breast-feeding, there are still limited data regarding the degree to which anticonvulsants cross the placenta and penetrate into breast milk. In general, women with epilepsy can breast-feed their babies safely with some cautions<a href="http://jneurology.wordpress.com/article/anticonvulsants-1l9yjtm0t2xwn-19/#MLT002LY_B5" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Hovinga and Pennell 2008)</span></a>. Phenobarbital and<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT002F9" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">primidone</span></a><span class="Apple-converted-space"> </span>should be avoided, and with ethosuximide,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000N5" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">levetiracetam</span></a>,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KI" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">lamotrigine</span></a>,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000L4" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">topiramate</span></a>, and zonisamide there is a potential for significant breast milk concentrations.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Anesthesia.</b><span class="Apple-converted-space"> </span>There are no anesthetic implications for use of anticonvulsants.</div><div align="right" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://knol.google.com/k/samuel-barrack/anticonvulsants/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_11" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Interactions</span></b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> Anticonvulsant drugs may interact with each other as well as with other drugs. These are specified in the individual clinical summaries for each agent.</div><div align="right" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://knol.google.com/k/samuel-barrack/anticonvulsants/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_12" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Adverse effects</span></b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> The adverse effects of anticonvulsants involve practically every system of the body. These are described in the separate clinical summaries of individual anticonvulsants. However, some adverse effects are common to most anticonvulsant agents, for example, adverse skin reactions, dose-related neurotoxicity, and psychiatric complications. Long-term use of anticonvulsants may lead to some metabolic and endocrine disturbances.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Drug resistance.</b><span class="Apple-converted-space"> </span>Problems with the use of anticonvulsants include loss of efficacy and development of drug resistance. One third of patients with<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT00018" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">epilepsy</span></a><span class="Apple-converted-space"> </span>develop resistance to drugs, which is associated with an increased risk of death and debilitating psychosocial consequences. Because this form of epilepsy is resistant to multiple anticonvulsant drugs, the mode of resistance is considered to be nonspecific, involving drug-efflux transporters. Another mechanism underlying drug resistance in epilepsy may be the same as in cancer: a cellular pump called P-glycoprotein, which protects cells from toxic substances by actively exporting the offending compounds. In epilepsy resistant to<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KH" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">phenytoin</span></a>, low levels of phenytoin have been demonstrated in association with high levels of P-glycoprotein expression, the product of the<i style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">MDR1</i><span class="Apple-converted-space"> </span>gene. Genotyping differences have been shown between responders and non-responders. Further studies in this direction might eventually enable the drugs to be tailored to the patient’s profile.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> Cellular mechanisms underlying drug resistance have been studied by comparing resected hippocampal tissue from 2 groups of patients with<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000DZ" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">temporal lobe epilepsy</span></a>; the first group displaying a clinical response to the anticonvulsant<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KF" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">carbamazepine</span></a><span class="Apple-converted-space"> </span>and the second with therapy-resistant seizures<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/anticonvulsants-1l9yjtm0t2xwn-19/#MLT002LY_B11" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Remy et al 2003)</span></a>. It was shown that the mechanism of action of carbamazepine, use-dependent block of voltage-dependent sodium channels, is completely lost in carbamazepine-resistant patients. Likewise, seizure activity elicited in human hippocampal slices is insensitive to carbamazepine. In marked contrast, carbamazepine-induced use-dependent block of sodium channels blocked seizure activity in vitro in patients clinically responsive to this drug. These data suggest that study of changes in ion channel pharmacology and their contribution to the loss of anticonvulsant drug efficacy in human epilepsy may provide an important impetus for the development of novel anticonvulsants specifically targeted to modified ion channels in the epileptic brain. It is possible to use human tissue for the demonstration of drug resistance in an in vitro preparation, providing a unique tool in the search for novel, more efficient anticonvulsants.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> A study of the properties of transmitter receptors of tissues removed during surgical treatment of drug-resistant temporal lobe epilepsy showed use-dependent rundown of neocortical GABAA-receptor<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/anticonvulsants-1l9yjtm0t2xwn-19/#MLT002LY_B10" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Ragozzino et al 2005)</span></a>. This represents a temporal lobe epilepsy-specific dysfunction in contrast to stable GABAA-receptor function in the cell membranes isolated from the temporal lobe of temporal lobe epilepsy patients afflicted with neoplastic, traumatic, or ischemic temporal lesions and can be antagonized by brain-derived neurotrophic factor. These findings may help to develop new treatments for drug-resistant temporal lobe epilepsy.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Management.</b><span class="Apple-converted-space"> </span>Treatment of adverse effects of anticonvulsants usually requires discontinuation of the offending agent and replacement with one that is better tolerated.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">References cited</span></b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="" name="MLT002LY_B1" style="color: #0867ab; text-decoration: none;"></a></span>Brodie MJ, Perucca E, Ryvlin P, Ben-Menachem E, Meencke HJ; Levetiracetam Monotherapy Study Group. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology 2007;68(6):402-8.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_B2" style="color: #0867ab; text-decoration: none;"></a>Grunze HC. The effectiveness of anticonvulsants in psychiatric disorders. Dialogues Clin Neurosci 2008;10(1):77-89.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_B3" style="color: #0867ab; text-decoration: none;"></a>Gualtieri CT, Johnson LG. Comparative neurocognitive effects of 5 psychotropic anticonvulsants and lithium. MedGenMed 2006;8(3):46.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_B4" style="color: #0867ab; text-decoration: none;"></a>Hauptman A. Luminal bei epilepsie. München Med Wochenschr 1912;59:1907-9.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_B5" style="color: #0867ab; text-decoration: none;"></a>Hovinga CA, Pennell PB. Antiepileptic drug therapy in pregnancy II: fetal and neonatal exposure. Int Rev Neurobiol 2008;83:241-58.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_B6" style="color: #0867ab; text-decoration: none;"></a>Konovalov S, Muralee S, Tampi RR. Anticonvulsants for the treatment of behavioral and psychological symptoms of dementia: a literature review. Int Psychogeriatr 2008;20(2):293-308.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_B7" style="color: #0867ab; text-decoration: none;"></a>Loscher W, Klotz U, Zimprich F, Schmidt D. The clinical impact of pharmacogenetics on the treatment of epilepsy. Epilepsia 2009;50:1-23.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_B8" style="color: #0867ab; text-decoration: none;"></a>Merritt HH, Putnam TJ. Sodium diphenyl hydantoinate in the treatment of convulsive disorders. JAMA 1938;111:1068-73.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_B9" style="color: #0867ab; text-decoration: none;"></a>Mulleners WM, Chronicle EP. Anticonvulsants in migraine prophylaxis: a Cochrane review. Cephalalgia 2008;28(6):585-97.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_B10" style="color: #0867ab; text-decoration: none;"></a>Ragozzino D, Palma E, Di Angelantonio S, et al. Rundown of GABA type A receptors is a dysfunction associated with human drug-resistant mesial temporal lobe epilepsy. Proc Natl Acad Sci U S A 2005;102:15219-23.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_B11" style="color: #0867ab; text-decoration: none;"></a><a href="http://jneurology.wordpress.com/cip.asp?UID=22551955" style="color: #0867ab; text-decoration: none;" title="Link to abstract"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Remy S, Gabriel S, Urban BW, et al. A novel mechanism underlying drug resistance in chronic epilepsy. Ann Neurol 2003;53:469-79.</span></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_B12" style="color: #0867ab; text-decoration: none;"></a>Rogawski MA, Loscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci 2004;5(7):553-64.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_B13" style="color: #0867ab; text-decoration: none;"></a>Sienaert P, Peuskens J. Anticonvulsants during electroconvulsive therapy: review and recommendations. J ECT 2007;23(2):120-3.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_B14" style="color: #0867ab; text-decoration: none;"></a>Sobaniec W, Ku?ak W, Strzelecka J, Smigielska-Kuzia J, Bo?kowski L. A comparative study of vigabatrin vs. carbamazepine in monotherapy of newly diagnosed partial seizures in children. Pharmacol Rep 2005;57(5):646-53.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_B15" style="color: #0867ab; text-decoration: none;"></a>Suppes T, Kelly DI, Hynan LS, et al. Comparison of two anticonvulsants in a randomized, single-blind treatment of hypomanic symptoms in patients with bipolar disorder. Aust N Z J Psychiatry 2007;41(5):397-402.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002LY_B16" style="color: #0867ab; text-decoration: none;"></a><a href="http://jneurology.wordpress.com/cip.asp?UID=15805193" style="color: #0867ab; text-decoration: none;" title="Link to abstract"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Tate SK, Depondt C, Sisodiya SM, et al. Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin. Proc Natl Acad Sci U S A 2005;102:5507-12.</span></a></div><div style="border-width: 0px; color: #444444; font-family: Arial,Helvetica,sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin: 0px 0px 10px; orphans: 2; padding: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div>Carlos Vázquezhttp://www.blogger.com/profile/09266699098392968330noreply@blogger.com0tag:blogger.com,1999:blog-7084351769408080486.post-51492444092691428012011-12-26T04:21:00.000-08:002011-12-26T04:21:00.492-08:00Triptans<div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Historical note and nomenclature</span></b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> Triptans, belonging to a family of tryptamine-based drug, are selective serotonin receptor (<a href="http://jneurology.wordpress.com/cip.asp?UID=MLG000RZ" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">5-HT</span></a>) agonists used in the treatment of acute migraine attacks and<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT0005K" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">cluster headaches</span></a>. Basis for the discovery of triptans was laid in 1960s by observations that vasoconstriction produced by 5-HT, ergotamine, and noradrenaline reduced migraine attacks. Platelet 5-HT levels were found to be reduced during migraine. As 5-HT itself could not be researched, efforts were focused on the receptors of 5-HT in order to discover and develop a more specific agonist for 5-HT receptors. This led to discovery of several types and subtypes of 5-HT. Several compounds were tested and discarded because of low bioavailability. Continued research led to the discovery of the first triptan drug,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KO" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">sumatriptan</span></a>, that had both vasoconstriction effect as well as better oral bioavailability. Sumatriptan was first launched in Europe in 1991 and became available 1993 in the United States. Several other triptans have been developed since then. Marketed triptans for migraine are:</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Almotriptan</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Eletriptan</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Frovatriptan</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Naratriptan</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Rizatriptan</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Sumatriptan</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Zolmitriptan</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> Sumatriptan/naproxen, combination of a triptan with a long-acting nonsteroidal antiinflammatory drug, is approved for acute treatment and sustained relief of migraine.</div><div align="right" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://knol.google.com/k/samuel-barrack/triptans/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002M1_26" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Pharmacology</span></b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Pharmacodynamics.</b><span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG000RZ" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">5-HT</span></a><span class="Apple-converted-space"> </span>receptors are all G-protein coupled receptors except for 5-HT3, which is a ligand-gated ion channel. The receptors that have been found to be involved in migraine are 5-HT1B, 5-HT1D, and 5-HT1F receptors. 5-HT1B receptors are found in meningeal arteries. The 5-HT1D receptors are located primarily in the trigeminal nerve in the central nervous system; they are also found in vascular smooth muscles. The amino acids contributing to the binding of ligands to the receptor are aspartic acid, phenylalanine, serine, threonine, tryptophan, and tyrosine.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><u>Effect on migraine</u>. Triptans are specific and selective agonists for the 5-HT1 receptors. There is an increase in the rate of brain serotonin (5-HT) synthesis during migraine attacks, and triptans exert a negative feedback regulation of brain serotonin synthesis along with modulation of pain pathways<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/triptans-1l9yjtm0t2xwn-21/#MLT002M1_B7" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Sakai et al 2008)</span></a>.<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KO" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Sumatriptan</span></a><span class="Apple-converted-space"> </span>binds to 5-HT1D receptors; zolmitriptan, rizatriptan, naratriptan, almotriptan, and frovatriptan binds to 5-HT1B/1D; and eletriptan binds to 5-HT1B/1D/1F receptors. Triptans have no significant activity at 5-HT2 or 5-HT3 receptors or at dopamine, gamma-aminobutyric acid, or adrenoreceptors. The beneficial effect of triptans in patients with migraine is related to their multiple mechanisms of action at sites implicated in the pathophysiology of migraine. These mechanisms include:</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Vasoconstriction of painfully dilated cerebral vessels without affecting cerebral circulation.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Inhibition of nociceptive neurotransmission.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Inhibition of the release of vasoactive peptides by trigeminal nerves.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Sumatriptan has direct scavenging activity on free radicals and nitric oxide, but it inhibits the nitric oxide response by inhibiting trigeminal activation and<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG001N2" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">CGRP</span></a><span class="Apple-converted-space"> </span>release.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Neither peripheral nor central trigeminovascular neurons are directly inhibited by triptans, but the action appears to be exerted through presynaptic 5HT1 receptors in the dorsal horn to block synaptic transmission between axon terminals of the peripheral trigeminovascular neurons and cell bodies of their central counterparts.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><u>Effect on non-migrainous pain</u>. 5-HT receptors are not localized to afferents in the head but are found throughout the body, suggesting that the triptans should be able to modulate non-migrainous pain; triptans have been shown effective in various non-cranial, non-migrainous pain states. Triptans have no effect on acute pain, but they profoundly reverse experimental hypersensitivity in behavioral models of inflammatory pain in mice. The ability of the triptans to regulate inflammatory pain is affected by the expression and localization of the 5-HT receptor, which is upregulated in persistent injury and pain. Thus, these results suggest that triptans can provide treatment of prolonged or<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000O8" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">chronic pain</span></a>. Advantages of using triptans as analgesics are:</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Triptans are non-addictive and less susceptible to substance abuse, unlike other analgesics such as morphine.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Triptans may potentiate the analgesic effects when used in combination with other analgesics.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Such combination therapy may allow lower doses of drugs to be effective, reduce tolerance in long-term efficacy, and increase the therapeutic index.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Pharmacokinetics.</b><span class="Apple-converted-space"> </span>The pharmacokinetics of oral triptans is shown in Table 1.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div align="center" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: center; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Table 1. Pharmacokinetics of Oral Triptans</b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><table border="0" cellpadding="0" cellspacing="0" style="background-color: white; border-collapse: collapse; border-color: rgb(221, 221, 221); border-style: solid; border-width: 1px; color: #444444; font-family: Arial,Helvetica,sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin: 0px 0px 10px 0.1in; min-width: 200px; orphans: 2; padding: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; width: 646px; word-spacing: 0px;"><tbody style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 88.2pt;" valign="top" width="118"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Triptan</b></div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 81pt;" valign="top" width="108"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Bio-</b></div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">availability</b></div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 84.5pt;" valign="top" width="113"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Renal clearance (mL/min-1)</b></div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 72.8pt;" valign="top" width="97"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Protein binding</b></div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 68.5pt;" valign="top" width="91"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">tmax (h)</b></div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 89.2pt;" valign="top" width="119"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Excretion</b></div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 88.2pt;" valign="top" width="118"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Sumatriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 81pt;" valign="top" width="108"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">14%</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 84.5pt;" valign="top" width="113"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">260</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 72.8pt;" valign="top" width="97"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">10%-21%</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 68.5pt;" valign="top" width="91"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">2-2.5</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 89.2pt;" valign="top" width="119"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Urine (57%)</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Feces (38%)</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 88.2pt;" valign="top" width="118"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Zolmitriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 81pt;" valign="top" width="108"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">40%</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 84.5pt;" valign="top" width="113"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">193</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 72.8pt;" valign="top" width="97"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">25%</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 68.5pt;" valign="top" width="91"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">2</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 89.2pt;" valign="top" width="119"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Urine (65%)</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Feces (30%)</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 88.2pt;" valign="top" width="118"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Naratriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 81pt;" valign="top" width="108"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">63%-74%</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 84.5pt;" valign="top" width="113"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">220</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 72.8pt;" valign="top" width="97"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">28%-31%</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 68.5pt;" valign="top" width="91"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">2-3</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 89.2pt;" valign="top" width="119"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Urine</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 88.2pt;" valign="top" width="118"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Rizatriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 81pt;" valign="top" width="108"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">47%</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 84.5pt;" valign="top" width="113"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">414</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 72.8pt;" valign="top" width="97"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">14%</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 68.5pt;" valign="top" width="91"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">1.3</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 89.2pt;" valign="top" width="119"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Urine</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 88.2pt;" valign="top" width="118"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Almotriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 81pt;" valign="top" width="108"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">69%</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 84.5pt;" valign="top" width="113"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">—-</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 72.8pt;" valign="top" width="97"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">35%</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 68.5pt;" valign="top" width="91"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">1.4-3.8</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 89.2pt;" valign="top" width="119"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Urine (40%)</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Feces (13%)</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 88.2pt;" valign="top" width="118"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Eletriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 81pt;" valign="top" width="108"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">50%</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 84.5pt;" valign="top" width="113"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">597</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 72.8pt;" valign="top" width="97"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">85%</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 68.5pt;" valign="top" width="91"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">1-2</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 89.2pt;" valign="top" width="119"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Urine (40%)</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 88.2pt;" valign="top" width="118"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Frovatriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 81pt;" valign="top" width="108"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">24%-30%</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 84.5pt;" valign="top" width="113"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">132-216</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 72.8pt;" valign="top" width="97"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">20%-30%</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 68.5pt;" valign="top" width="91"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">2-4%</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 89.2pt;" valign="top" width="119"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">—-</div></td></tr>
</tbody></table><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> After absorption, triptans are extensively metabolized to an inactive indoleacetic acid analog that is excreted mainly in the urine. Pharmacokinetics varies according to the method of delivery. A linear relationship is observed between total applied current and sumatriptan delivery to reach therapeutic blood levels following transdermal delivery by an iontophoresis patch, which uses an electrical current to propel sumatriptan across intact skin into underlying tissue.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> Relatively short<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG0018T" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">tmax</span></a><span class="Apple-converted-space"> </span>and good bioavailability are associated with rapid onset of action. Ability to cross the<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000L9" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">blood-brain barrier</span></a><span class="Apple-converted-space"> </span>and relatively long terminal elimination half-life may result in a lower incidence of headache recurrence. Sumatriptan and rizatriptan undergo first-pass hepatic metabolism and result in lower bioavailability.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Formulations and methods of delivery of triptans.</b><span class="Apple-converted-space"> </span>The delivery system of triptans plays an important role in the onset of action. Subcutaneous injection is the fastest way to control rapidly progressing migraine attacks. The sumatriptan nasal spray provides faster onset of action than the tablets, but it is not suitable for all patients because of bad taste and lack of consistency of response.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> The drawbacks of triptans for the treatment of migraine are: (1) low oral bioavailability and (2) low concentration of active metabolites. Improved formulations and methods of delivery would be beneficial. Currently available routes of administration of triptans include subcutaneous (sumatriptan), nasal spray (sumatriptan and zolmitriptan), rectal (sumatriptan), rapidly-dissolving wafer (rizatriptan and zolmitriptan), and oral tablets (all).</div><div align="right" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://knol.google.com/k/samuel-barrack/triptans/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002M1_27" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Clinical trials</span></b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> Clinical trials on triptans can be located by searching the U.S. National Institute of Health’s ClinicalTrials.gov web site. A search for all trials on migraine shows 282 studies as of June 2009:<span class="Apple-converted-space"> </span><a href="http://clinicaltrials.gov/ct2/results?term=migraine" style="color: #0867ab; text-decoration: none;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">http://clinicaltrials.gov/ct2/results?term=migraine</span></a>. A search for triptans shows 22 studies:<a href="http://clinicaltrials.gov/ct2/results?term=Triptans" style="color: #0867ab; text-decoration: none;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">http://clinicaltrials.gov/ct2/results?term=Triptans</span></a>. A search also can be performed for individual triptans; for example,<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KO" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">sumatriptan</span></a><span class="Apple-converted-space"> </span>is shown in relation to 54 studies:<a href="http://clinicaltrials.gov/ct2/results?term=sumatriptan" style="color: #0867ab; text-decoration: none;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">http://clinicaltrials.gov/ct2/results?term=sumatriptan</span></a>. Triptans in clinical trials are shown in Table 2.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div align="center" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: center; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Table 2. Triptans in Clinical Trials</b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><table border="0" cellpadding="0" cellspacing="0" style="-webkit-border-horizontal-spacing: 0px; -webkit-border-vertical-spacing: 0px; -webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; background-attachment: initial; background-clip: initial; background-color: white; background-image: initial; background-origin: initial; background-position: initial initial; background-repeat: initial initial; border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-collapse: collapse; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0.1in; margin-right: 0px; margin-top: 0px; min-width: 200px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><tbody style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 110.7pt;" valign="top" width="148"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Drug</b></div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 3.75in;" valign="top" width="360"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Indication/method of delivery</b></div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1.25in;" valign="top" width="120"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Phase/status</b></div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 110.7pt;" valign="top" width="148"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Almotriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 3.75in;" valign="top" width="360"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Safety of oral almotriptan for the treatment of migraine in adolescents</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1.25in;" valign="top" width="120"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Open-label</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 110.7pt;" valign="top" width="148"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Eletriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 3.75in;" valign="top" width="360"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Efficacy of early intervention on mild versus moderate to severe pain intensity of migraine</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1.25in;" valign="top" width="120"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Phase IV</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 110.7pt;" valign="top" width="148"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Eletriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 3.75in;" valign="top" width="360"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Follow-up of patients treated for menstrual migraine</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1.25in;" valign="top" width="120"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Phase IV</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 110.7pt;" valign="top" width="148"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Frovatriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 3.75in;" valign="top" width="360"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Long-acting triptan for prophylaxis of menstrually associated migraine</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1.25in;" valign="top" width="120"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Phase III</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 110.7pt;" valign="top" width="148"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Frovatriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 3.75in;" valign="top" width="360"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Prevention of hunger-induced migraine</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1.25in;" valign="top" width="120"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Phase II</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 110.7pt;" valign="top" width="148"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Naratriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 3.75in;" valign="top" width="360"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Psychotic personality disorder</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1.25in;" valign="top" width="120"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Phase IV</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 110.7pt;" valign="top" width="148"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Rizatriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 3.75in;" valign="top" width="360"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Early treatment of acute migraine</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1.25in;" valign="top" width="120"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Phase III</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 110.7pt;" valign="top" width="148"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Rizatriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 3.75in;" valign="top" width="360"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Acute migraine in patients with unilateral<a href="http://jneurology.wordpress.com/cip.asp?UID=MLG0002U" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">autonomic symptoms</span></a></div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1.25in;" valign="top" width="120"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Phase IV</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 110.7pt;" valign="top" width="148"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Rizatriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 3.75in;" valign="top" width="360"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Distinction between pharmacological effects, placebo effects, and their interactions in relief of symptoms of acute migraine</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1.25in;" valign="top" width="120"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Phase IV</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 110.7pt;" valign="top" width="148"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Rizatriptan + acetaminophen</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 3.75in;" valign="top" width="360"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Efficacy of combination for treatment of acute migraine</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1.25in;" valign="top" width="120"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Phase IV</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 110.7pt;" valign="top" width="148"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Sumatriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 3.75in;" valign="top" width="360"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">5HT1 agonist, needle-free injection</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1.25in;" valign="top" width="120"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Phase II</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 110.7pt;" valign="top" width="148"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Sumatriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 3.75in;" valign="top" width="360"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Transdermal delivery</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1.25in;" valign="top" width="120"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Phase II</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 110.7pt;" valign="top" width="148"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Sumatriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 3.75in;" valign="top" width="360"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Self-injection for the treatment of migraine or<a href="http://jneurology.wordpress.com/cip.asp?UID=MLT0005K" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">cluster headache</span></a><span class="Apple-converted-space"> </span>attack</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1.25in;" valign="top" width="120"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Phase III</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 110.7pt;" valign="top" width="148"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Sumatriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 3.75in;" valign="top" width="360"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">4mg STATdose injection for cluster headache</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1.25in;" valign="top" width="120"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Phase IV</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 110.7pt;" valign="top" width="148"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Sumatriptan + naproxen</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 3.75in;" valign="top" width="360"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Migraine with aura</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1.25in;" valign="top" width="120"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Phase III</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 110.7pt;" valign="top" width="148"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Sumatriptan + naproxen</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 3.75in;" valign="top" width="360"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Migraine not responding to eletriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1.25in;" valign="top" width="120"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 110.7pt;" valign="top" width="148"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Zolmitriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 3.75in;" valign="top" width="360"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Nasal spray for treatment of acute migraine</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1.25in;" valign="top" width="120"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Phase III</div></td></tr>
</tbody></table><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> In comparative clinical trials, oral triptans outperform oral ergotamine mostly because of the extremely low oral bioavailability of ergotamine; compared with NSAIDs, triptans are not, in most cases, superior to aspirin<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/triptans-1l9yjtm0t2xwn-21/#MLT002M1_B10" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Tfelt-Hansen 2009)</span></a>.</div><div align="right" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://knol.google.com/k/samuel-barrack/triptans/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002M1_16" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Indications</span></b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> Triptans are indicated for the treatment of migraine headaches.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Off-label and investigational uses.</b><span class="Apple-converted-space"> </span>Triptans are under investigation for migraine variants, and special methods of administration are also being studied. Triptans seem to be safe and effective treatment for most<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT0006T" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">hemiplegic migraine</span></a><span class="Apple-converted-space"> </span>patients<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/triptans-1l9yjtm0t2xwn-21/#MLT002M1_B1" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Artto et al 2007)</span></a>. Investigational uses include those for non-migraine headaches and other conditions:</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • High-altitude headache.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Post-dural puncture headache. An<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG000HN" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">open-label</span></a><span class="Apple-converted-space"> </span>study suggests efficacy of oral frovatriptan for this condition<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/triptans-1l9yjtm0t2xwn-21/#MLT002M1_B2" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Bussone et al 2007)</span></a>.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Post-electroconvulsive therapy headache.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Headache in professional sports.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Headache of<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLM0048V" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">subarachnoid hemorrhage</span></a>.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Trigeminal neuralgia.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Prevention of<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000K2" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">acute mountain sickness</span></a>.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Acute posttraumatic headache.</div><div align="right" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://knol.google.com/k/samuel-barrack/triptans/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002M1_17" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Contraindications</span></b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> Contraindications for triptan therapy are:</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Patients with coronary artery disease or hypertension.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Patients with hemiplegic or<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT002H9" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">basilar artery migraine</span></a>.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Patients receiving ergot compounds. Triptans should not be given intravenously within 24 hours of administration of an ergot compound.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Patients who have demonstrated hypersensitivity to any triptan.</div><div align="right" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://knol.google.com/k/samuel-barrack/triptans/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002M1_28" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Goals and duration of treatment</span></b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> Clinical studies show that most patients who fail to obtain adequate alleviation of symptoms with one triptan may be successfully treated with a different triptan. The 7 available triptans show more similarities than differences in action. Almotriptan 12.5 mg is as effective as<a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KO" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">sumatriptan</span></a><span class="Apple-converted-space"> </span>100 mg and zolmitriptan 2.5 mg<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/triptans-1l9yjtm0t2xwn-21/#MLT002M1_B5" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Chen and Ashcroft 2007)</span></a>. None of the available triptans produce an effective response in every migraine attack, and prolonged use of triptans may produce an increase in the migraine frequency and headache. A survey has shown that compliance with triptan therapy included satisfaction and confidence in triptans’ ability to stop the migraine and associated symptoms<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/triptans-1l9yjtm0t2xwn-21/#MLT002M1_B4" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Cady et al 2009)</span></a>.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">The ideal triptan for migraine.</b><span class="Apple-converted-space"> </span>Some of the disadvantages of triptans have been overcome with the introduction of newer triptans such as zolmitriptan and naratriptan, but the search for new agents continues. The desirable properties sought for a drug for acute migraine are:</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • It should be more efficacious than currently available drugs.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • It should be tolerated better.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • The recurrence rate should be low.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • It should have a prophylactic role as well.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • It should provide improved patient choice.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Individualization of use of triptans for migraine.</b><span class="Apple-converted-space"> </span>With a large number of triptans now available, it may be possible to match individual patient needs with the specific characteristics of the individual triptans to optimize therapeutic benefit. Pharmacogenetics provides the possibility of tailoring the therapeutic approach to individual patients in order to maximize treatment efficacy while minimizing the potential for unwanted side-effects<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/triptans-1l9yjtm0t2xwn-21/#MLT002M1_B3" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Buzzi 2008)</span></a>. Pain relief by triptans is significantly modulated by a common genetic variant–G protein beta3<a href="http://jneurology.wordpress.com/article/triptans-1l9yjtm0t2xwn-21/#MLT002M1_B8" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Schurks et al 2007)</span></a>. Genetic profiling of predisposition to migraine should facilitate the development of more effective diagnostic and therapeutic applications. The development of the International Hap Map project could provide a powerful tool for identification of the candidate genes in this complex disease, and pharmacogenomics research could be the promise for individualized treatments and prevention of adverse drug response<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/triptans-1l9yjtm0t2xwn-21/#MLT002M1_B6" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Piane et al 2007)</span></a>. Pharmacogenomics will most likely provide a stronger scientific basis for optimizing triptan therapy on the basis of each patient’s genetic constitution<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/triptans-1l9yjtm0t2xwn-21/#MLT002M1_B11" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Tfelt-Hansen and Brosen 2008)</span></a>.</div><div align="right" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://knol.google.com/k/samuel-barrack/triptans/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002M1_9" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Dosing</span></b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> Doses, formulations, and duration of action of triptans are shown in Table 3.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div align="center" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: center; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Table 3. Doses, Formulations, and Duration of Action of Triptans</b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><table border="0" cellpadding="0" cellspacing="0" style="background-color: white; border-collapse: collapse; border-color: rgb(221, 221, 221); border-style: solid; border-width: 1px; color: #444444; font-family: Arial,Helvetica,sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin: 0px 0px 10px 0.1in; min-width: 200px; orphans: 2; padding: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; width: 652px; word-spacing: 0px;"><tbody style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 88.2pt;" valign="top" width="118"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Drug</b></div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 103.5pt;" valign="top" width="138"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Formulations</b></div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 81pt;" valign="top" width="108"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Doses (mg)</b></div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 76.5pt;" valign="top" width="102"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Maximum daily dose (mg)</b></div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 67.5pt;" valign="top" width="90"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Onset of action (min)</b></div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1in;" valign="top" width="96"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Duration of action</b></div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 88.2pt;" valign="top" width="118"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Sumatriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 103.5pt;" valign="top" width="138"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Tablets</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Nasal spray</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Subcutaneous</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> injection</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Suppositories</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 81pt;" valign="top" width="108"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">25, 50, 100</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">5, 20</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">6</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">25</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 76.5pt;" valign="top" width="102"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">300</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">40</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">12</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">50</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 67.5pt;" valign="top" width="90"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">30-60</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">15-30</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">10-15</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">30-60</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1in;" valign="top" width="96"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Short</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 88.2pt;" valign="top" width="118"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Zolmitriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 103.5pt;" valign="top" width="138"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Tablets</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Orally</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> disintegrating</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> tablets</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Nasal spray</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 81pt;" valign="top" width="108"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">2.5, 5</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">2.5, 5</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">2.5, 5</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 76.5pt;" valign="top" width="102"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">10</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">10</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">10</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 67.5pt;" valign="top" width="90"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">45</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">-</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">10-15</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1in;" valign="top" width="96"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Short</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 88.2pt;" valign="top" width="118"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Naratriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 103.5pt;" valign="top" width="138"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Tablets</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 81pt;" valign="top" width="108"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">1, 2.5</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 76.5pt;" valign="top" width="102"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">5</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 67.5pt;" valign="top" width="90"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">60-180</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1in;" valign="top" width="96"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Long</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 88.2pt;" valign="top" width="118"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Rizatriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 103.5pt;" valign="top" width="138"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Tablets</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Orally</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> disintegrating</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"> tablets</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 81pt;" valign="top" width="108"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">5, 10</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">5, 10</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 76.5pt;" valign="top" width="102"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">30</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">30</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 67.5pt;" valign="top" width="90"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">30-120</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">-</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1in;" valign="top" width="96"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Short</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 88.2pt;" valign="top" width="118"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Almotriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 103.5pt;" valign="top" width="138"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Tablets</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 81pt;" valign="top" width="108"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">25, 12.5</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 76.5pt;" valign="top" width="102"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">25</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 67.5pt;" valign="top" width="90"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">60-180</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1in;" valign="top" width="96"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Short</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 88.2pt;" valign="top" width="118"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Eletriptan</div><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><br />
</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 103.5pt;" valign="top" width="138"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Tablets</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 81pt;" valign="top" width="108"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">20, 40</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 76.5pt;" valign="top" width="102"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">80</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 67.5pt;" valign="top" width="90"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><60</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1in;" valign="top" width="96"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">-</div></td></tr>
<tr style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 88.2pt;" valign="top" width="118"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Frovatriptan</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 103.5pt;" valign="top" width="138"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Tablets</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 81pt;" valign="top" width="108"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">2.5</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 76.5pt;" valign="top" width="102"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">7.5</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 67.5pt;" valign="top" width="90"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">60-120</div></td><td style="border-bottom-color: rgb(221, 221, 221); border-bottom-style: solid; border-bottom-width: 1px; border-color: initial; border-image: initial; border-left-color: rgb(221, 221, 221); border-left-style: solid; border-left-width: 1px; border-right-color: rgb(221, 221, 221); border-right-style: solid; border-right-width: 1px; border-style: initial; border-top-color: rgb(221, 221, 221); border-top-style: solid; border-top-width: 1px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 6px; padding-right: 6px; padding-top: 0px; text-align: left; vertical-align: top; width: 1in;" valign="top" width="96"><div style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Long</div></td></tr>
</tbody></table><div align="right" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://knol.google.com/k/samuel-barrack/triptans/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002M1_29" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Precautions and use in special groups</span></b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Pediatric.</b><span class="Apple-converted-space"> </span>Safety in children has not been established.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Geriatric.</b><span class="Apple-converted-space"> </span>No information is known about the safety in patients over the age of 65 years because they were excluded from clinical trials.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Pregnancy.</b><span class="Apple-converted-space"> </span>Triptans fall into category C of the United States Food and Drug Administration regarding safety of use during pregnancy. Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Although pregnancy registries are maintained by the manufacturer, triptan use in pregnancy has not been extensively studied. There are no data to suggest teratogenicity for any of the triptans although preterm birth rates appear to be elevated<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/triptans-1l9yjtm0t2xwn-21/#MLT002M1_B9" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Soldin et al 2008)</span></a>. Caution should be exercised in recommending the use of triptans during pregnancy.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> Triptans are secreted in human milk, and caution should be exercised when administering any of the triptans to nursing mothers.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Anesthesia.</b><span class="Apple-converted-space"> </span>No special precautions are required for patients on triptans.</div><div align="right" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://knol.google.com/k/samuel-barrack/triptans/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002M1_11" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Interactions</span></b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> Triptans are compatible with most of the commonly used drugs, including those used for the treatment of headaches. Concomitant use of triptans and<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT002M0" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">SSRIs</span></a><span class="Apple-converted-space"> </span>or selective serotonin/norepinephrine reuptake inhibitors can lead to<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000JX" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">serotonin syndrome</span></a>. An alert was issued by the United States Food and Drug Administration in 2006 for this interaction based on reports of 27 cases in a 5-year period, which have not been validated or have not met the criteria of serotonin syndrome diagnosis. In view of the small number of case reports among a large number of patients who take this drug combination, one publication states that this combination can be used where clinically appropriate and that physicians should familiarize themselves with detection of serotonin syndrome<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/article/triptans-1l9yjtm0t2xwn-21/#MLT002M1_B12" style="color: #0867ab; text-decoration: none;" title="Link to reference"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">(Wenzel et al 2008)</span></a>. Interactions may also occur with the following categories of drugs:</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Ergot-containing compounds</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Monoamine oxidase inhibitors</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Calcium channel-blocking antagonists</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Beta blockers</div><div align="right" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://knol.google.com/k/samuel-barrack/triptans/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002M1_12" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Adverse effects</span></b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> Triptans are generally well tolerated with minor adverse effects. Those reported include the following:</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Chest pain due to myocardial ischemia</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> • Reversible cerebral arterial<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLG000QY" style="color: #0867ab; text-decoration: none;" title="Link to glossary definition"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">vasospasm</span></a><span class="Apple-converted-space"> </span>and<span class="Apple-converted-space"> </span><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT00064" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">cerebral infarction</span></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"> <span class="Apple-converted-space"> </span><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Management.</b><span class="Apple-converted-space"> </span>The management of adverse effects is according to the event. The important factors are the prevention of adverse effects and their differentiation from complications of migraine.</div><div align="right" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://knol.google.com/k/samuel-barrack/triptans/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002M1_w1" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Other pertinent drugs</b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT002M0" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">SSRIs</span></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KO" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Sumatriptan</span></a></div><div align="right" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://knol.google.com/k/samuel-barrack/triptans/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002M1_w2" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Related summaries</span></b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT0007C" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Childhood migraine</span></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT0006T" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Hemiplegic migraine</span></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000KO" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Sumatriptan</span></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://jneurology.wordpress.com/cip.asp?UID=MLT000JX" style="color: #0867ab; text-decoration: none;" title="Link to clinical summary"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">Serotonin syndrome</span></a></div><div align="right" style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="http://knol.google.com/k/samuel-barrack/triptans/1l9yjtm0t2xwn/SectionJump%28%27#DocTop%27%29" style="color: #0867ab; text-decoration: none;"><img border="0" src="http://knol.google.com/k/samuel-barrack/-/1l9yjtm0t2xwn/images/top.gif" style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;" /></a></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002M1_w5" style="color: #0867ab; text-decoration: none;"></a><b style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;">References cited</span></b></div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><span style="border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; font-size: 14px; margin-bottom: 0px; margin-left: 0px; margin-right: 0px; margin-top: 0px; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; vertical-align: baseline;"><a href="" name="MLT002M1_B1" style="color: #0867ab; text-decoration: none;"></a></span>Artto V, Nissilä M, Wessman M, Palotie A, Färjjukä, Kallela M. Treatment of hemiplegic migraine with triptans. Eur J Neurol 2007;14(9):1053-6.**</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002M1_B2" style="color: #0867ab; text-decoration: none;"></a>Bussone G, Tullo V, d’Onofrio F, et al. Frovatriptan for the prevention of postdural puncture headache. Cephalalgia 2007;27(7):809-13.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002M1_B3" style="color: #0867ab; text-decoration: none;"></a>Buzzi MG. Pathways to the best fit of triptans for migraine patients. Cephalalgia 2008;28(Suppl 2):21-7.**</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002M1_B4" style="color: #0867ab; text-decoration: none;"></a>Cady RK, Maizels M, Reeves DL, Levinson DM, Evans JK. Predictors of adherence to triptans: factors of sustained vs lapsed users. Headache 2009;49(3):386-94.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002M1_B5" style="color: #0867ab; text-decoration: none;"></a>Chen LC, Ashcroft DM. Meta-analysis examining the efficacy and safety of almotriptan in the acute treatment of migraine. Headache 2007;47(8):1169-77.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002M1_B6" style="color: #0867ab; text-decoration: none;"></a>Piane M, Lulli P, Farinelli I, et al. Genetics of migraine and pharmacogenomics: some considerations. J Headache Pain 2007;8:334-9.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002M1_B7" style="color: #0867ab; text-decoration: none;"></a>Sakai Y, Dobson C, Diksic M, Aubé M, Hamel E. Sumatriptan normalizes the migraine attack-related increase in brain serotonin synthesis. Neurology 2008;70(6):431-9.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002M1_B8" style="color: #0867ab; text-decoration: none;"></a>Schurks M, Kurth T, Stude P, et al. G protein beta3 polymorphism and triptan response in cluster headache. Clin Pharmacol Ther 2007;82(4):396-401.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002M1_B9" style="color: #0867ab; text-decoration: none;"></a>Soldin OP, Dahlin J, O’Mara DM. Triptans in pregnancy. Ther Drug Monit 2008;30(1):5-9.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002M1_B10" style="color: #0867ab; text-decoration: none;"></a>Tfelt-Hansen P. Triptans versus other migraine medicine–secondary publication. Ugeskr Laeger 2009;171(18):1485-7.</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002M1_B11" style="color: #0867ab; text-decoration: none;"></a>Tfelt-Hansen P, Brosen K. Pharmacogenomics and migraine: possible implications. J Headache Pain 2008;9:13-8.**</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><br />
</div><div style="-webkit-text-size-adjust: auto; -webkit-text-stroke-width: 0px; border-bottom-width: 0px; border-color: initial; border-image: initial; border-left-width: 0px; border-right-width: 0px; border-style: initial; border-top-width: 0px; color: #444444; font-family: Arial, Helvetica, sans-serif; font-size: 14px; font-style: normal; font-variant: normal; font-weight: normal; letter-spacing: normal; line-height: 20px; margin-bottom: 10px; margin-left: 0px; margin-right: 0px; margin-top: 0px; orphans: 2; padding-bottom: 0px; padding-left: 0px; padding-right: 0px; padding-top: 0px; text-align: -webkit-auto; text-indent: 0px; text-transform: none; vertical-align: baseline; white-space: normal; widows: 2; word-spacing: 0px;"><a href="" name="MLT002M1_B12" style="color: #0867ab; text-decoration: none;"></a>Wenzel RG, Tepper S, Korab WE, Freitag F. Serotonin syndrome risks when combining SSRI/SNRI drugs and triptans: is the FDA’s alert warranted? Ann Pharmacother 2008;42(11):1692-6.</div>Carlos Vázquezhttp://www.blogger.com/profile/09266699098392968330noreply@blogger.com0tag:blogger.com,1999:blog-7084351769408080486.post-24161302500998574592011-10-25T05:01:00.000-07:002011-10-25T05:01:27.712-07:00Changes in magnetic resonance imaging disease measures over 3 years in mildly disabled patients with relapsing-remitting multiple sclerosis receiving interferon beta-1a in the COGnitive Impairment in MUltiple Sclerosis (COGIMUS) study<h4>
Background</h4>
Conventional magnetic resonance imaging (MRI) has improved the diagnosis and monitoring of multiple sclerosis (MS). In clinical trials, MRI has been found to detect treatment effects with greater sensitivity than clinical measures; however, clinical and MRI outcomes tend to correlate poorly.<br />
<h4>
Methods</h4>
In this observational study, patients (n=550; 18-50 years; relapsing-remitting MS [Expanded Disability Status Scale score <=4.0]) receiving interferon (IFN) beta-1a therapy (44 or 22 ug subcutaneously [sc] three times weekly [tiw]) underwent standardized MRI, neuropsychological and quality-of-life (QoL) assessments over 3 years. In this post hoc analysis, MRI outcomes and correlations between MRI parameters and clinical and functional outcomes were analysed. <br />
<h4>
Results</h4>
MRI data over 3 years were available for 164 patients. T2 lesion and T1 gadolinium-enhancing (Gd+) lesion volumes, but not black hole (BH) volumes, decreased significantly from baseline to Year 3 (P<0.0001). Percentage decreases (baseline to Year 3) were greater with the 44 ug dose than with the 22 ug dose for T2 lesion volume (-10.2% vs -4.5%, P=0.025) and T1 BH volumes (-7.8% vs +10.3%, P=0.002). A decrease in T2 lesion volume over 3 years predicted stable QoL over the same time period. Treatment with IFN beta-1a, 44 ug sc tiw, predicted an absence of cognitive impairment at Year 3.<br />
<h4>
Conclusion</h4>
Subcutaneous IFN beta-1a significantly decreased MRI measures of disease, with a significant benefit shown for the 44 ug over the 22 ug dose; higher-dose treatment also predicted better cognitive outcomes over 3 years.<br />
<br />
<a href="http://www.biomedcentral.com/content/pdf/1471-2377-11-125.pdf">Full text </a>Carlos Vázquezhttp://www.blogger.com/profile/09266699098392968330noreply@blogger.com0tag:blogger.com,1999:blog-7084351769408080486.post-84983150277537479142011-09-24T02:14:00.000-07:002011-09-24T02:14:39.594-07:00Donepezil Impairs Memory in Healthy Older Subjects: Behavioural, EEG and Simultaneous EEG/fMRI Biomarkers<div style="text-align: justify;">
Rising life expectancies coupled with an increasing awareness of age-related cognitive decline have led to the unwarranted
use of psychopharmaceuticals, including acetylcholinesterase inhibitors (AChEIs), by significant numbers of healthy older
individuals. This trend has developed despite very limited data regarding the effectiveness of such drugs on non-clinical
groups and recent work indicates that AChEIs can have negative cognitive effects in healthy populations. For the first time,
we use a combination of EEG and simultaneous EEG/fMRI to examine the effects of a commonly prescribed AChEI
(donepezil) on cognition in healthy older participants. The short- and long-term impact of donepezil was assessed using two
double-blind, placebo-controlled trials. In both cases, we utilised cognitive (paired associates learning (CPAL)) and
electrophysiological measures (resting EEG power) that have demonstrated high-sensitivity to age-related cognitive decline.
Experiment 1 tested the effects of 5 mg/per day dosage on cognitive and EEG markers at 6-hour, 2-week and 4-week followups.
In experiment 2, the same markers were further scrutinised using simultaneous EEG/fMRI after a single 5 mg dose.
Experiment 1 found significant negative effects of donepezil on CPAL and resting Alpha and Beta band power. Experiment 2
replicated these results and found additional drug-related increases in the Delta band. EEG/fMRI analyses revealed that
these oscillatory differences were associated with activity differences in the left hippocampus (Delta), right frontal-parietal
network (Alpha), and default-mode network (Beta). We demonstrate the utility of simple cognitive and EEG measures in
evaluating drug responses after acute and chronic donepezil administration. The presentation of previously established
markers of age-related cognitive decline indicates that AChEIs can impair cognitive function in healthy older individuals. To
our knowledge this is the first study to identify the precise neuroanatomical origins of EEG drug markers using simultaneous
EEG/fMRI. The results of this study may be useful for evaluating novel drugs for cognitive enhancement.</div>
<div style="text-align: justify;">
<a href="http://www.tara.tcd.ie/bitstream/2262/59506/1/Donepezil%20Impairs%20Memory%20in%20Healthy%20Older%20Subjects-%20Behavioural,%20EEG%20and%20Simultaneous%20EEG%3AfMRI%20Biomarkers.pdf">Full text </a></div>
Carlos Vázquezhttp://www.blogger.com/profile/09266699098392968330noreply@blogger.com0tag:blogger.com,1999:blog-7084351769408080486.post-28843427269866641832011-09-18T11:15:00.000-07:002011-09-18T11:38:30.076-07:00Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment<h4 style="text-align: justify;">
OBJECTIVE: </h4>
<div style="text-align: justify;">
To examine the effects of intranasal insulin administration on cognition, function, cerebral glucose metabolism, and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease (AD).</div>
<h4 style="text-align: justify;">
DESIGN: </h4>
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Randomized, double-blind, placebo-controlled trial.</div>
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SETTING: </h4>
<div style="text-align: justify;">
Clinical research unit of a Veterans Affairs medical center.</div>
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PARTICIPANTS: </h4>
<div style="text-align: justify;">
The intent-to-treat sample consisted of 104 adults with amnestic mild cognitive impairment (n = 64) or mild to moderate AD (n = 40). Intervention Participants received placebo (n = 30), 20 IU of insulin (n = 36), or 40 IU of insulin (n = 38) for 4 months, administered with a nasal drug delivery device (Kurve Technology, Bothell, Washington).</div>
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MAIN OUTCOME MEASURES: </h4>
<div style="text-align: justify;">
Primary measures consisted of delayed story recall score and the Dementia Severity Rating Scale score, and secondary measures included the Alzheimer Disease's Assessment Scale-cognitive subscale (ADAS-cog) score and the Alzheimer's Disease Cooperative Study-activities of daily living (ADCS-ADL) scale. A subset of participants underwent lumbar puncture (n = 23) and positron emission tomography with fludeoxyglucose F 18 (n = 40) before and after treatment.</div>
<h4 style="text-align: justify;">
RESULTS: </h4>
<div style="text-align: justify;">
Outcome measures were analyzed using repeated-measures analysis of covariance. Treatment with 20 IU of insulin improved delayed memory (P < .05), and both doses of insulin (20 and 40 IU) preserved caregiver-rated functional ability (P < .01). Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD (P < .05). Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group, but, in exploratory analyses, changes in memory and function were associated with changes in the Aβ42 level and in the tau protein-to-Aβ42 ratio in cerebrospinal fluid. Placebo-assigned participants showed decreased fludeoxyglucose F 18 uptake in the parietotemporal, frontal, precuneus, and cuneus regions and insulin-minimized progression. No treatment-related severe adverse events occurred.</div>
<table cellpadding="0" cellspacing="0" class="tr-caption-container" style="float: right; margin-left: 0px; margin-right: 0px; text-align: left;"><tbody>
<tr><td style="text-align: center;"><a href="http://archneur.ama-assn.org/content/vol0/issue2011/images/medium/nct15003f3.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="204" src="http://archneur.ama-assn.org/content/vol0/issue2011/images/medium/nct15003f3.jpg" width="320" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">A, Areas of hypometabolism at baseline (scan 1) and month 4 (scan 2), along with
changes in hypometabolism (<img alt="{Delta}" border="0" src="math/Delta.gif" /> time
2 – time 1) within each group, and differences in change between the placebo
group and the 20-IU or 40-IU dose insulin group (<img alt="{Delta}" border="0" src="math/Delta.gif" /> nasal insulin – <img alt="{Delta}" border="0" src="math/Delta.gif" /> placebo). The red and orange colors, compared with the
green and blue colors, indicate areas of greater hypometabolism from time 1 to
time 2, and from placebo group to insulin groups. B, Change in mean regional
<i>z</i> scores with standard errors of mean (error bars) for the right and left
frontal regions and the left parietal region for the placebo, 20-IU dose
insulin, and 40-IU dose insulin groups. For the right and left frontal
volume-of-interest (VOI) values, placebo-assigned participants had reduced
activity during the 4-month period, whereas the 20-IU and 40-IU dose insulin
groups had preserved or slightly increased activity (treatment group <span style="font-family: arial,helvetica;">x</span> time interaction: <i>P</i> = .04 for comparison
between placebo group and 20-IU dose insulin group; <i>P</i> = .03 for similar
comparison between placebo group and 40-IU dose insulin group). Similar analyses
for left medial parietal VOI values revealed reduced activity over time for the
placebo group compared with the 40-IU dose insulin group (time <span style="font-family: arial,helvetica;">x</span> treatment group interaction: <i>P</i> = .05).</td></tr>
</tbody></table>
<h4 style="text-align: justify;">
CONCLUSIONS: </h4>
<div style="text-align: justify;">
These results support longer trials of intranasal insulin therapy for patients with amnestic mild cognitive impairment and patients with AD. Trial Registration clinicaltrials.gov Identifier: NCT00438568.</div>
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<br /></div>
<b>Reference:</b> Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M,
Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B.
Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive
Impairment: A Pilot Clinical Trial. Arch Neurol. 2011 Sep 12 <a href="http://archneur.ama-assn.org/cgi/content/full/archneurol.2011.233v1">Full text</a> Carlos Vázquezhttp://www.blogger.com/profile/09266699098392968330noreply@blogger.com0tag:blogger.com,1999:blog-7084351769408080486.post-23622691987391962752011-06-23T13:51:00.000-07:002011-09-18T11:36:07.536-07:00Donepezil for language dysfunction in Alzheimer's disease<h4 style="text-align: justify;">
Introduction</h4>
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</div>
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Progressive language impairment is among the primary components of cognitive decline in Alzheimer's disease (AD). Because expressive and receptive language helps maintain emotional connection to caregivers and supports management of AD functional needs, language plays a critical role in patients' emotional and physical health. Using data from a large prospective clinical trial comparing two doses of donepezil in patients with moderate to severe AD, we performed a post hoc analysis to determine whether a higher dose of donepezil was associated with greater benefits in language function. </div>
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</div>
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Methods</h4>
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</div>
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In the original randomized, double-blind clinical trial, 1467 patients with moderate to severe AD (baseline Mini-Mental State Examination [MMSE] scores 0-20) were randomized 2:1 to receive donepezil 23 mg/d or to continue on donepezil 10 mg/d for 24 weeks. In this post hoc analysis, the Severe Impairment Battery language (SIB-L) scale and a new 21-item SIB-derived language scale (the SIB[lang]) were used to explore differences in language function between the treatment groups. Correlations between SIB-L and SIB[lang] scores and scores on the severe version of the Alzheimer's Disease Cooperative Study-Activities of Daily Living inventory (ADCS-ADL-sev), the Clinician's Interview-Based Impression of Severity/Change-plus caregiver input (CIBIS/CIBIC-plus), and the MMSE were also investigated. </div>
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</div>
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Results</h4>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
At Week 24, treatment with donepezil 23 mg/d was associated with an improvement in language in the full intention-to-treat (ITT) population, whereas language function declined with donepezil 10 mg/d (SIB-L treatment difference 0.8, P = 0.0013; SIB[lang] treatment difference 0.8, P = 0.0009). Similar results were observed in a cohort of patients with more severe baseline disease (MMSE, 0-16). At baseline and Week 24, correlations between the SIB-derived language scales and the ADCS-ADL-sev and CIBIC-plus were moderate, but were stronger between the language scales and MMSE. </div>
<div style="text-align: justify;">
</div>
<h4 style="text-align: justify;">
Conclusions</h4>
<div style="text-align: justify;">
</div>
<div style="text-align: justify;">
Patients with moderate to severe AD receiving donepezil 23 mg/d showed greater language benefits compared with those receiving 10 mg/d, as measured by SIB-derived language assessments. Increasing the dose of donepezil to 23 mg/d may provide language benefits in patients with moderate to severe AD, for whom preservation of language abilities is especially critical. ClinicalTrials.gov identifier: NCT00478205.</div>
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The complete article is available as a <a href="http://alzres.com/content/pdf/alzrt84.pdf">provisional PDF</a>. The fully formatted PDF and HTML versions are in production. </h4>
Carlos Vázquezhttp://www.blogger.com/profile/09266699098392968330noreply@blogger.com0