Oral Steroids Not Inferior to Intravenous Steroids in Multiple Sclerosis Relapses

Clinical question: Is there any difference between oral and intravenous methylprednisolone for multiple sclerosis relapses?

Background: 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.

Study design: Randomized, double-blinded, noninferiority trial.

Setting: Thirteen multiple sclerosis centers in France.

Synopsis: 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.

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.

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.

Bottom line: Consider using oral instead of IV steroids in patients with relapsing multiple sclerosis.

Citation: Le Page E, Veillard D, Laplaud DA, et al. Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial. Lancet. 2015;386(9997):974-981.

Clinical Trial on the Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia

Objective  To assess the efficacy, safety, and tolerability of dextromethorphan hydrobromide–quinidine sulfate for Alzheimer disease–related agitation.

Design, Setting, and Participants  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.

Interventions  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).

Main Outcomes and Measures  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]).

Results  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 z statistic, −3.95; P < .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; P<.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; P=.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.

Conclusions and Relevance  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.

Full text

Pharmacogenomic update on multiple sclerosis: a focus on actual and new therapeutic strategies

Action mechanism of IFN-α/β. (a) The interaction between IFNAR receptor, composed of two subunits IFNAR1 and IFNAR2, and IFN-α/β induces an immediate transcriptional response through JAK–STAT signal transduction pathway. (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. (c) STATs pass from the cytoplasm to the nucleus, promoting transcription of genes responsive to STAT. AAF, IFN-α-activated factor; IFN, interferon; ISRE, IFN-stimulated response elements; JAK, Janus kinase; GAS, IFN-γ-activated sequence; ISGF3, interferon-stimulated gene factor 3; IRF9, interferon regulatory factor 9; STAT, signal transducers and activators of transcription; TYK2, tyrosine kinase 2.

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 (Full text).

Do Antidepressants Really Work?

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 The New England Journal of Medicine provided a stinging rebuke of psychiatric drugs in general and of course the drug companies that manufacture them. Writing in The New York Review of Books Angell seemed to seriously consider the possibility that “psychoactive drugs are useless”. There were also highly visible pieces in USA Today and Newsweek, 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 placebo in most patients.
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.

Off-the-Shelf Drug Rapidly Clears Alzheimer’s Protein in Mice

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 “Why Does apoE4 Make Alzheimer’s More Likely?”). 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.
“This is quite an exciting paper; the effect on A-beta clearance is dramatic and rapid,” says Sam Gandy, who chairs the Alzheimer’s research program at Mount Sinai School of Medicine.
“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 Gary Landreth, 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 appears today in Science Express.
The study is based on observations, going back to the early 1990s, of a strong connection between Alzheimer’s and apolipoprotein-E (apoE). Researchers 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.
Recently scientists have determined the likely reason for the connection: A-beta 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 seems to stimulate the readiness of microglial cells to digest A-beta aggregates.
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.
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.
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.
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.

IVIg therapy: neurologic indications, contraindications, precautions, and complications

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.
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.
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.

Antipsychotic medications

INTRODUCTION — 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.

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.