Med Check

Research Briefs

• In a randomized, double-blind, placebo-controlled study, nursing-home residents with Alzheimer's disease saw no difference in psychotic symptoms after taking either aripiprazole or placebo for 10 weeks. The study, led by Joel Streim, M.D., a professor of geriatric psychiatry at the University of Pennsylvania, was published in the July American Journal of Geriatric Psychiatry. The study was supported by the makers of aripiprazole, Bristol-Myers Squibb and Otsuka Pharmaceutical. A total of 131 Alzheimer's patients aged 59 to 96 were randomized to the aripiprazole group, and 125 patients were randomized to the placebo group. Efficacy was evaluated by changes from baseline on the Neuropsychiatric Inventory-Nursing Home Version psychosis score and Clinical Global Impression severity score, and these scores were not significantly different between the two groups after 10 weeks of treatment.

“A Randomized, Double-Blind, Placebo-Controlled Study of Aripiprazole for the Treatment of Psychosis in Nursing Home Patients With Alzheimer Disease” is posted at<http://ajgponline.org/cgi/content/full/16/7/537>.

•Xanomeline, a selective muscarinic receptor agonist under investigation, shows promising effectiveness in a small study that was published in AJP in Advance in July. Twenty patients with acute exacerbation of schizophrenia or schizoaffective disorder were randomized in a 1:1 ratio to receive either xanomeline or placebo for four weeks in a double-blind design.

The xanomeline-treated patients had significantly greater symptomatic improvement from baseline compared with placebo-treated patients. Improvement was assessed by the Brief Psychiatric Rating Scale, the Positive and Negative Syndrome Scale, and cognitive tests. The most common adverse events reported more frequently in the xanomeline group than in the placebo group were nausea, vomiting, gastrointestinal distress, salivation, diarrhea, constipation, and sweating.

The study was led by Anantha Shekhar, M.D., Ph.D., associate dean for translational research, the Raymond E. Houk professor of psychiatry, and a professor of pharmacology and neurobiology at Indiana University School of Medicine, and colleagues and supported by Eli Lilly and Co.

“Selective Muscarinic Receptor Agonist Xanomeline as a Novel Treatment Approach for Schizophrenia” is posted at<ajp.psychiatryonline.org/cgi/reprint/appi.ajp.2008.06091591v1>.

• Pharmacotherapy for smoking cessation works, a meta-analysis published in the July 15 Canadian Medical Association Journal concluded. Mark Eisenberg, M.D., M.P.H., and colleagues pooled 69 randomized, placebo-controlled, clinical trials of various drug therapies, which involved nearly 33,000 participants. Varenicline, nicotine nasal spray, bupropion, transdermal nicotine patch, nicotine tablet, and nicotine gum were shown to be significantly more effective than placebo, with an odds ratio of approximately 2. The efficacy results for inhaled nicotine did not reach statistical significance. Varenicline was significantly more efficacious than bupropion in a direct comparison of data from three trials of varenicline that included a comparator bupropion group.

Varenicline has recently been linked to neuropsychiatric disturbances, such as severe mood and behavior changes, vivid and strange dreams, and suicidal ideation and behaviors. At the request of the Food and Drug Administration (FDA), Pfizer has revised the drug's prescribing information and medication guide to alert health care professionals and patients about these risks.

An abstract of “Pharmacotherapies for Smoking Cessation: A Meta-Analysis of Randomized, Controlled Trials” is posted at<www.cmaj.ca/cgi/content/abstract/179/2/135>. Prescribing information for varenicline is posted at<www.fda.gov/cder/foi/label/2008/021928s008lbl.pdf>.

•Dimebon, a drug being investigated for treatment of Alzheimer's and Huntington's diseases, is more effective than placebo in preventing cognitive-function decline in patients with mild-to-moderate Alzheimer's, according to a randomized, double-blind, placebo-controlled clinical trial published in the July 19 The Lancet. Cognition was measured with the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). The investigators, led by Rachelle Doody, M.D., Ph.D., of Baylor College of Medicine, enrolled 183 patients with Mini-Mental State Examination scores between 10 and 24 at 11 sites in Russia, including 89 patients who were randomized to 60 mg/day dimebon and 94 who were given placebo. After 26 weeks, the improvement from baseline was statistically significantly larger in the dimebon group than the placebo group. Dry mouth and depressed mood were the most frequently reported Adverse Events, both by 14 percent of patients. The trial was funded by Medivation Inc.

An abstract of “Effect of Dimebon on Cognition, Activities of Daily Living, Behaviour, and Global Function in Patients With Mild-to-Moderate Alzheimer's Disease: A Randomised, Double-Blind, Placebo-Controlled Study” is posted at<www.thelancet.com/journals/lancet/article/PIIS0140673608610740/abstract>.

Safety Briefs

• The package inserts for all antipsychotics, including but not limited to quetiapine, ziprasidone, paliperidone, haloperidol, and aripiprazole, have been modified with a new, standard subsection on dystonia under “Adverse Reactions, Extrapyramidal Symptoms.” The warning states that “Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment.” It warns that“ while these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.” This labeling change took effect for some of the drugs in April and others in May.

The announcement can be accessed at<www.fda.gov/medwatch/safety.htm> by clicking on the April and May lists.

• The package inserts for antidepressants such as paroxetine, sertraline, and fluvoxamine have been modified to include standard wording about potentially important drug interactions with warfarin and other drugs, such as aspirin and nonsteroidal anti-inflammatory drugs, which may increase the risk of bleeding. The warning states that“ serotonin release by platelets plays an important role in hemostasis” and “epidemiological studies.. .have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.” The label now specifically warns that “SSRIs and SNRIs ... may increase the risk of bleeding events.”

The announcement can be accessed at<www.fda.gov/medwatch/safety.htm>; by clicking on the March and April lists.

• The prescribing information for atomoxetine has been revised to include warnings about the drug's risks for adverse effects on blood pressure and heart rate, urinary retention and hesitation in adults, and potential interactions with drugs, such as the SSRI antidepressants, that inhibit the cytochrome P450 isoenzyme 2D6. Cardiovascular adverse events from new clinical trials in children, adolescents, and adults have been summarized in the package insert.

The updated atomoxetine prescribing information is posted at<www.fda.gov/medwatch/SAFETY/2008/May_PI/Strattera_PI.pdf>.

Regulatory Briefs

• In June the FDA approved methylphenidate extended-release tablets (Concerta) for treatment of attention-deficit/hyperactivity disorder in adults aged 18 to 65, according to an announcement by Ortho-McNeil-Janssen Pharmaceuticals, a subsidiary of Johnson and Johnson. The approved dosages range from 18 mg to 72 mg once daily.

• The FDA has approved a generic version of risperidone for marketing in the United States. The generic risperidone tablets are manufactured by Teva Pharmaceuticals, USA. The strengths of the tablets range from 0.25 mg to 4 mg.

• The FDA will no longer issue “approvable” or “not approvable” letters in response to drug companies' new drug applications, the agency announced in july. Instead it will outline the deficiencies of the application and recommendations to resolve them in a“ complete response” letter when an application is not approved. Previously, the “approvable” and “not approvable” letters implied a difference in the amount of revision or additional data required by the agency for future approval. This change was made to“ help the FDA adopt a more consistent and neutral way of conveying information” when an application is not approved, according to Janet Woodcock, M.D., director of the FDA's Center for Drug Evaluation and Research.▪