Med Check

Research briefs

• Supplementation of vitamins B6, B12, and folic acid does not significantly lower the risk of the emergence of depression in elderly men with hypertension, according to a two-year study published online in the Journal of Clinical Psychiatry on June 10.

A group of Australian men aged 75 years of age or older were randomly assigned to take vitamin B supplement (n=149) or placebo (n=150) in a double-blind manner; 118 in the vitamin B group and 123 men in the placebo group completed two years of follow-up. All participants had hypertension, but no depression, at baseline.

The emergence of depression symptoms, measured by change in the Beck Depression Index (BDI) score from baseline, did not differ significantly between the vitamin B-supplemented group and the placebo group. At the end of two years, 84.3 percent of the men taking vitamin B supplements and 79.1 percent of those taking placebo remained free of clinically significant depressive symptoms, and this difference was not statistically significant.

An abstract of “Vitamins B12, B6, and Folic Acid for Onset of Depressive Symptoms in Older Men: Results From a 2-Year Placebo-Controlled Randomized Trial” is posted at<www.psychiatrist.com/abstracts/oap/ej07m03884.htm>.

• The combination of nortriptyline and electroconvulsive therapy (ECT) is more effective than nortriptyline alone as a long-term maintenance treatment of psychotic depression in elderly patients who initially respond to acute ECT treatment, according to a study conducted by researchers at the University of Barcelona and Institut d'Investigaciones Biomediques Agusti Pi I Sunyer in Spain published in the June American Journal of Geriatric Psychiatry.

Patients 60 years of age or older with a DSM-IV diagnosis of severe, major depression with psychotic symptoms and a baseline score on the Hamilton rating Scale for Depression of 21 or higher were first given acute bilateral ECT three times a week until they reached remission or showed no further improvement after three consecutive treatments. Patients who reached remission were randomly assigned to receive a maintenance regimen with either nortriptyline alone (n=17) or nortriptyline and ECT (n=16) for two years.

Thirteen patients in the nortriptyline monotherapy group completed the study, including five without relapse or recurrence, two with relapse, and six with recurrence during the study. Twelve patients in the combination therapy group completed the study, including 11 who had no relapse or recurrence, and only one who had relapse. Relapse was defined as the reemergence of depressive symptoms within six months of the initial remission. Recurrence was defined as a new episode of depression after at least six months of the initial remission.

Statistical analyses showed that the combined nortriptyline and ECT treatment was significantly more effective than monotherapy nortriptyline in terms of time to relapse or recurrence. The authors reported that both groups tolerated the treatment well.

The study personnel who evaluated patient outcomes and analyzed the data were blinded to treatment assignment. The patients were not blinded. The maintenance ECT was given weekly in the first month, every two weeks in the second month, and monthly thereafter.

An abstract of “Continuation/Maintenance Treatment with Nortriptyline Versus Combined Nortriptyline and ECT in Late-Life Psychotic Depression: A Two-Year Randomized Study” is posted at<ajgponline.org/cgi/content/abstract/16/6/498>.

• Elan Corporation and Wyeth Pharmaceuticals released the results of a phase 2 clinical trial that showed a biologic agent known as bapineuzumab to have some clinical activity in treating patients with mild to moderate Alzheimer's disease. The randomized, double-blind, placebo-controlled, multidose study enrolled approximately 240 patients and lasted 18 months.

Bapineuzumab did not reach statistically significant superiority over placebo in all study participants. However, it beat placebo in certain measures of clinical outcomes among patients who do not carry the apolipoportein E4 (ApoE4) allele, suggesting a genetic factor in treatment responses.

Bapineuzumab is a monoclonal antibody—a manufactured antibody that attacks and reduces beta amyloid in the brain. Beta amyloid has long been associated with the formation of plaques seen in the brain of Alzheimer patients. The antibody is given through intravenous infusion. The two companies said in a press release that they plan to continue the ongoing phase 3 development of this drug for Alzheimer's disease.

• In a phase 2, placebo-controlled clinical trial, tarenflurbil has shown efficacy in slowing the neurological decline in patients with Alzheimer's disease, according to a study published in the June Lancet Neurology. Two hundred and ten patients with mild Alzheimer's disease were randomized to receive either tarenflurbil or placebo for a maximum of two years. Patients with mild disease (that is, a mini-mental state examination [MMSE] score of 15 to 19) and taking tarenflurbil, 300 mg twice daily, had slower decline in several outcome measures than those taking placebo, but the drug was not more effective than placebo in patients with moderate disease (that is, an MMSE score of 20 to 26).

Tarenflurbil reduces the production of the beta amyloid peptide Aβ42, a molecule that has been suspected to contribute to the pathogenesis of Alzheimer's disease. The study was sponsored by Myriad Pharmaceuticals, the maker of the drug.

An abstract of “Efficacy and Safety of Tarenflurbil in Mild to Moderate Alzheimer's Disease: A Randomised Phase II Trial” can be accessed by going to<www.sciencedirect.com/science/journal/14744422> and clicking on “Volume 7, Issue 6” in the left column.

Regulatory Briefs

• The FDA has approved quetiapine fumerate as an adjunct to lithium or divalproex for the maintenance treatment of bipolar I disorder, the manufacturer AstraZeneca announced in May. The approval was based on data from two long-term clinical trials in adult bipolar I patients who were treated with quetiapine for an average of 213 days. The primary endpoint was time to recurrence of a depressive, manic, or mixed mood episode. Patients on quetiapine, in addition to lithium or divalproex, had a significantly lower risk of having a recurrent episode than those treated with placebo plus lithium or divalproex.

Quetiapine has been previously approved for treating schizophrenia, depressive episodes in bipolar disorder, and acute manic episodes in bipolar I.

The prescribing information of quetiapine is posted at<www1.astrazeneca-us.com/pi/Seroquel.pdf>.

• Aripiprazole has been approved by the FDA as a maintenance treatment for manic and mixed episodes in bipolar I patients 10 to 17 years old and for schizophrenia in adolescent patients 13 to 17 years old, the manufacturers Otuska and Bristol-Myers Squibb announced in May. The indication for pediatric bipolar disorder was derived from a four-week, randomized, placebo-controlled clinical trial, and the schizophrenia indication in adolescents was based on a six-week, randomized, placebo-controlled trial. Approximately 200 participants were enrolled in each trial.

Aripiprazole was previously approved by the FDA for the acute treatment of manic and mixed episodes in bipolar I patients 10 to 17 years old and the acute treatment of schizophrenia in adolescents 13 to 17.

The prescribing information of aripiprazole is posted at<packageinserts.bms.com/pi/pi_abilify.pdf>.

• The Committee for Medicinal Products for Human Use (CHMP), the advisory committee for the European Union's European Medicines Agency (EMEA), has issued an opinion against the approval of ramelteon, a sleeping aid manufactured by Takeda. Ramelteon has already been approved in the United States to treat insomnia.

In a memo released on May 30, CHMP cited concerns about the company's clinical trial data, which, CHMP believes, have not adequately demonstrated the efficacy of ramelteon. They noted that ramelteon was significantly more effective than placebo in only one outcome measure—sleep onset—in only one of three studies, and the difference was considered too small to be clinically relevant. Other aspects of insomnia were not significantly improved by the drug compared with placebo. The Committee also noted a lack of evidence for the long-term effectiveness of ramelteon.

Takeda has submitted a request to EMEA for the reexamination of the negative opinion, according to a company announcement dated June 17.

The CHMP decision letter is posted at<www.emea.europa.eu/pdfs/human/opinion/Ramelteon_26821608en.pdf>.

Legal Brief

• A United Kingdom court recently ruled in favor of the pharmaceutical company in an ongoing legal battle over the government's decision to restrict certain drugs for the treatment of Alzheimer's disease. The National Institute for Health and Clinical Excellence (NICE) of England and Wales had released a guideline that advised the National Health Services to limit the use of cholinesterase inhibitors for treating patients with moderate but not mild disease, because the drugs do not meet NICE's cost-effectiveness standard. The Japanese company Eisai, which makes donepezil, has been challenging the guideline in court. Last August, the company's argument that drug cost should not be factored into national health-care decisions was dismissed by a judge (Psychiatric News, September 7, 2007). This new verdict agreed with Eisai's claim that NICE's cost-effective evaluation was not made transparent by the organization. NICE said it would provide the evaluation model to the company for comments and appeals.

NICE is an independent organization that compares and evaluates the effectiveness of medical treatments and advises the National Health Services on clinical decisions. ▪