Med Check

The anti-breast-cancer drug tamoxifen is effective in reducing manic symptoms in patients with bipolar I disorders, according to a randomized, double-blind, placebo-controlled, parallel-arms clinical trial published in the March Archives of General Psychiatry. Sixty-six adult patients currently in a manic or mixed state were randomly assigned to receive tamoxifen or placebo for three weeks. The tamoxifen group experienced significant reduction in mania compared with no improvement or worsening in the placebo group. The efficacy was measured by the Young Mania Rating Scale and Clinical Global Impression–Mania. Eighty-three percent of the patients in the tamoxifen group and 68 percent in the placebo group completed the study. The authors, led by Aysegul Yildiz, M.D., concluded that tamoxifen was “remarkably well tolerated” in this study, which included some severely ill patients. They also commented that the magnitude and time to patient response in this study were similar to previous data on lithium and divalproex. The antimanic effect of tamoxifen may be related to its inhibition of protein kinase C in the brain, as previous animal and human research suggested. The study was funded by a grant from the Stanley Medical Research Institute.

“Protein Kinase C Inhibition in the Treatment of Mania” is posted at<archpsyc.ama-assn.org/cgi/content/full/65/3/255>. 


Metformin, a diabetes-treatment drug, has been shown to attenuate weight gain due to the antipsychotic drug olanzapine in a double-blind, placebo-controlled study in the March American Journal of Psychiatry. A group of Chinese researchers randomly assigned 40 adults diagnosed with first-episode schizophrenia in a 1:1 ratio to receive either olanzapine and metformin 750 mg/day or olanzapine with placebo for 12 weeks. These patients did not have diabetes before enrolling in the study, nor had they taken any antipsychotic for at least three months before the study. Patients in the olanzapine-plus-metformin group had statistically significantly less increase in weight (1.90 kg versus 6.87 kg), body mass index (0.54 kg/m2 versus 2.26 kg/m2), waist circumference (0.46 cm versus 1.37 cm), and waist-to-hip ratio (0.004 versus 0.185) from baseline than those in the olanzapine-plus-placebo group did at the end of the study. The insulin and insulin-resistance index increased significantly from baseline in the olanzapine group but remained unchanged from baseline in the olanzapine-plus-metformin group. The positive and negative symptoms improved in both groups, with no significant differences. Metformin was “well tolerated by all patients,” the authors wrote. The study was supported by the Ministry of Science and Technology of the People's Republic of China.

“Metformin Addition Attenuates Olanzapine-Induced Weight Gain in Drug-Naïve First-Episode Schizophrenia Patients: A Double-Blind, Placebo-Controlled Study” is posted at<ajp.psychiatryonline.org/cgi/content/full/165/3/359>. Metformin labeling information is posted at<www.fda.gov/cder/foi/label/2006/020357s030,021202s015lbl.pdf>. 


An inhaled formulation of loxapine (known as Staccato loxapine or AZ-004), an antipsychotic drug, has reached the phase 3 clinical development stage, according to manufacturer Alexza Pharmaceuticals Inc. A multisite clinical trial to investigate its efficacy for acute agitation in patients with schizophrenia was initiated in February. Another phase 3 trial in patients with bipolar disorder is planned. The drug-delivery system of aerosol inhalation is supposed to deliver the medication rapidly and painlessly into the body system.


Memory Pharmaceuticals Corp. announced plans to develop MEM 3454, a nicotinic alpha-7 partial agonist for the treatment of schizophrenia. A clinical trial, funded by Roche, will be conducted this year to investigate the drug's pharmacologic effects on two important biomarkers, P50 sensory gating and mismatched negativity, in schizophrenia patients. The company is also studying the drug's effect on cognition of patients with Alzheimer's disease. P50 auditory evoked response and mismatched negativity are two electrophysiologic indicators that correspond to brain abnormalities in schizophrenia patients and are reversed by effective treatment.


Ziprasidone hydrochloride has been approved for marketing in Canada, according to an announcement by Pfizer Canada Inc. Health Canada, the counterpart of the U.S. Food and Drug Administration (FDA), approved the second-generation antipsychotic for the treatment of schizophrenia and related psychotic disorders in February. Ziprasidone, marketed in the United States under the trade name Geodon, will be called Zeldox in Canada.


In February Health Canada approved bupropion hydrochloride extended-release tablets (Wellbutrin XL) for prevention of seasonal major depressive illness with an autumn-winter pattern, according to the manufacturer Biovail Corporation. Bupropion had been approved for the same indication in the United States in 2006 and also carries indications for treating major depression and smoking cessation (under the trade name Zyban). GlaxoSmithKline has licensed the drug from Bioavail for worldwide sales, except in Canada.


The FDA has approved aripiprazole (Abilify), a second-generation antipsychotic marketed by Bristol-Myers Squibb and Otsuka Pharmaceuticals, for manic and mixed episodes associated with bipolar I disorder in youth as young as 10. The approval was based on a four-week, randomized, double-blind, placebo-controlled study of nearly 300 patients aged 10 to 17 with a diagnosis of bipolar I disorder and acute mania, according to the companies' press release. At week 4, patients who took aripiprazole saw a statistically significantly higher change from baseline in the Young-Mania total score than those who took placebo. The most common adverse reactions reported in the trial included somnolence, extrapyramidal symptoms, fatigue, nausea, and akathisia. Average weight gains after the four weeks were 0.6 kg, 0.9 kg, and 0.5 kg, respectively, in the aripiprazole 10 mg, aripiprazole 30 mg, and placebo groups. The recommended dose in pediatric patients is 10 mg/day.


Fluvoxamine maleate extended-release capsules (Luvox CR) have been approved by the FDA for social anxiety disorder and obsessive-compulsive disorder in adults. The drug formulation is manufactured by Jazz Pharmaceuticals Inc., based in Palo Alto, Calif., which had licensed the molecule from Solvay Pharmaceuticals and the Spheroidal Oral Drug Absorption System technology from Elan Pharmaceuticals to enable once-daily dosing. Fluvoxamine maleate, a selective serotonin-reuptake inhibitor, is available in generic, immediate-release tablet formulation.


Wyeth Pharmaceuticals announced that its new drug desvenlafaxine (Prisiq) has been approved by the FDA to treat major depressive disorder in adults. Desvenlafaxine is the major active metabolite of venlafaxine (Effexor) and has the same mechanism of action on serotonin and norepinephrine reuptake receptors. The main difference from venlafaxine is that desvenlafaxine bypasses the hepatic cytochrome P450 isoenzyme 2D6 (CYP2D6). This eliminates potential interactions with other CYP2D6-metabolized medications including fluoxetine and many other psychoactive drugs. The approval was based on four eight-week, randomized, double-blind, placebo-controlled, fixed-dose studies in adults with major depression. The recommended dose is 50 mg. Wyeth stated in its press release that the FDA had required the company to conduct and submit several postmarking surveillance studies to keep the agency informed about the drug's effects in terms of long-term maintenance, sexual dysfunction, pediatric efficacy, and lower doses.


Wyeth has decided to terminate its involvement in developing bifeprunox, a once-promising investigative agent for treating schizophrenia developed by Solvay Pharmaceuticals. Last summer the FDA issued a nonapproval letter for bifeprunox, citing concerns about the lackluster efficacy data for treating acute psychosis from phase 3 clinical trials. It is unclear if Solvay will continue to develop the molecule.


The Federal Trade Commission (FTC) is suing the maker of modafinil (Provigil) over alleged antitrust violations. The FTC claims that Cephalon has paid $200 million to several generic drug manufacturers in exchange for delayed availability of generic modafinil after the patent protection runs out. In 2005 and 2006 Cephalon had reached settlements with a number of manufacturers regarding patent disputes and marketing generic modafinil in the United States. According to a Reuters report, the FTC asked a federal district court to void these agreements so that generic modafinil can be marketed. Last year the Supreme Court refused to review a similar case involving an agreement between AstraZeneca and a generic drug maker for tamoxifen. ▪