Since its discovery in the mid-20th century, serotonin, which is also called 5-hydroxytryptamine or5-HT, 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 abbreviationSSRI, 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,fluoxetine, was introduced into medical practice in 1988.
Table 1. Historical Landmarks in Serotonin, Serotonin Disorders, and Drugs Based On Manipulation of the Serotonergic System
Ramon Y Cajal described the raphe nuclei of the brainstem but did not know that they contain serotonin.
Start of investigation of vasoconstrictors in blood by Irvin H Page
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(Sjoerdsma and Palfreyman 1990).
Development of urine chemical assay of 5-hydroxyindolacetic acid, a metabolite of serotonin(Udenfriend 1959).
Identification of serotonin in the brain and proposal of its role as a neurotransmitter(Amin et al 1954).
Fluoxetine (Prozac) introduced in the medical practice by Eli Lilly.
Currently approved SSRIs include the following:
• Dapoxetine (approved only in some European countries; in phase III trials elsewhere)
Serotonin (5-HT) 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,GABA, dopamine, epinephrine/norepinephrine, and acetylcholine as well as many hormones, including oxytocin, prolactin, vasopressin, cortisol, corticosterone, corticotropin, and substance P, among others.
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(Chameau and van Hooft 2006).
Pharmacodynamics.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.
In addition to action as an antidepressant, mechanisms of beneficial effects may include neuroprotective, antiinflammatory, and immunomodulatory actions.
Antidepressant effect. Antidepressant drug classes where serotonin is involved in the mechanism of action are listed in Table 2.
Table 2. Classification of Antidepressant Drugs Where Serotonin Is Involved
Serotonin reuptake enhancer
Serotonin and norepinephrine reuptake inhibitors
Noradrenergic (alpha2 antagonism) and specific (5-HT2 and 5-HT3 antagonist) serotonergic antidepressants
Selective serotonin reuptake inhibitors (SSRIs)
SSRI and norepinephrine reuptake inhibitor
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.
Neuroprotective effect. SSRIs may protect against neurotoxicity caused by several toxic compounds.Fluoxetinesuppresses kainic acid-induced neuronal loss in the rat hippocampus, and the neuroprotective effect is associated with its antiinflammatory effects(Jin et al 2009). 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 acutestroke, but further development was discontinued due to lack of efficacy.
Effect on premature ejaculation. Dapoxetine, a short-actingSSRI, is approved for the treatment of premature ejaculation in some countries and is the only drug with regulatory approval for such treatment(Kendirci et al 2007). It is in phase III clinical trials in the United States.
Pharmacokinetics.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.
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 increasedphenytoinconcentrations 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 ofCYP2D6inhibition 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.
Positive and significant correlations between paroxetine and fluoxetine concentrations andCYP2D6inhibition illustrate the role of plasma concentrations and dosage on magnitude of enzyme inhibition. The potential of paroxetine, aCYP2D6substrate, as an inhibitor may be further affected by specific genotype and basal metabolic capacity of individual subjects.
Pharmacogenetics.There is strong evidence from association studies that some genepolymorphismsare 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(Levin et al 2007). The serotonin transporter-linked polymorphic region (5-HTTLPR) is the most widely studiedpolymorphismof the 5-HTT gene,SLC6A4, 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 Sallelemay 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(Gerretsen and Pollock 2008). 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(Rasmussen-Torvik and McAlpine 2007). Single nucleotide polymorphisms of the 5-HT(2A) gene correlate with increased paroxetine discontinuation but not with discontinuation of mirtazapine, a non-SSRI antidepressant.
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 (http://clinicaltrials.gov/ct2/results?term=selective+serotonin+reuptake+inhibitors). 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 toSSRITreatment in Major Depression.”
Indications for use of SSRIs include the following conditions:
• Anxiety disorders
• Depression, including that associated with neurologic disorders
A major contraindication of SSRIs is the concomitant use of monoamine oxidase inhibitors, as it is likely to cause severeserotonin syndrome.
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.
Goals and duration of treatment
It may take several weeks for the drug to reach its optimal effect. Duration of treatment varies according to the condition and theSSRIselected. Individualization of the treatment is also considered.
Individualization of SSRI treatment.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.
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.
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.
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(Sjoqvist and Eliasson 2007). Therapeutic drug monitoring combined with genotyping ofCYP2D6is 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.
Dosing is detailed in the clinical summaries for individual SSRIs and in thePhysician’s Desk Reference.
Precautions and use in special groups
Pediatric.Pediatric patients should be monitored closely for the risk of suicide with anySSRI. Onlyfluoxetineis 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.
Geriatric.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.
Pregnancy.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.
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(Gentile and Bellantuono 2009). 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.
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.
Anesthesia.Adjustment of dose of local anesthetic may be necessary as SSRIs inhibit the cytochrome P450 and affect local anesthetic metabolism.
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 ofserotonin syndrome.
SSRIs may interact with the following drugs and increase their blood levels to produce toxic effects:
SSRI toxicity may increase by interaction with the following drugs:
• CNS depressants
• Tamadol: synergistic serotoninergic effect may induce seizures
General side effects include apathy,nauseaorvomiting, drowsiness or somnolence, headache, sleep disturbances,dizziness, urinary retention,tremors, autonomic dysfunction such as orthostatic hypotension, increased or reduced sweating, and photosensitivity.
Sexual side effects.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.
SSRI discontinuation syndrome.SSRIs may produce some dependence, resulting in withdrawal effects. However, SSRIs have little to no abuse potential.
Suicidal ideation.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 ofSSRIprescriptions are associated with lower rates of suicide in children, although the true nature of the relationship is unclear(Gibbons et al 2006). 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(Barbui et al 2009).
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.Ropinirolehas completed clinical trials for treatment of sexual disorders resulting from SSRIs and is in phase IV studies. One of the serious side effects isserotonin syndrome, and its management is described in a separate clinical summary.
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