A Randomized, Double-Blind, Placebo-Controlled 26-Week Trial of Aripiprazole in Recently Manic Patients With Bipolar I Disorder

Paul E. Keck, Jr., M.D.; Joseph R. Calabrese, M.D.; Robert D. McQuade, Ph.D.; William H. Carson, M.D.; Berit X. Carlson, Ph.D.; Linda M. Rollin, Ph.D.; Ronald N. Marcus, M.D.; and Raymond Sanchez, M.D.; for the Aripiprazole Study Group

Objective: To investigate the safety and efficacy of aripiprazole in preventing relapse of
a mood episode in recently manic- or mixed-episode patients with bipolar I disorder stabilized on aripiprazole.

Method: This randomized, double-blind, parallel-group, placebo-controlled, multicenter study enrolled patients from 76 centers in 3 countries (Argentina, Mexico, United States) from March 2000 to June 2003. Bipolar I disorder (DSM-IV) patients who had recently been hospitalized and treated for a manic or mixed episode entered an open-label stabilization phase (aripiprazole monotherapy: 15 or 30 mg/day, 6-18 weeks). After meeting stabilization criteria (Young Mania Rating Scale score of < = 10 and Montgomery-Asberg Depression Rating Scale score of < = 13 for 6 consecutive weeks), 161 patients were randomly assigned to aripiprazole or placebo for the 26-week, double-blind phase. The primary endpoint was time to relapse for a manic, mixed, or depressive episode (defined by discontinuation caused by lack of efficacy).

Results: Aripiprazole was superior to placebo in delaying the time to relapse (p = .020). Aripiprazole-treated patients had significantly fewer relapses (25%) than placebo patients (43%; p = .013). Aripiprazole was superior to placebo in delaying the time to manic relapse (p = .01); however, no significant differences were observed in time to depressive relapse (p = .68). Weight gain (> = 7% increase) occurred in 7 (13%) aripiprazole-treated and 0 placebo-treated patients. Adverse events (> = 5% incidence and twice that of placebo) reported by aripiprazole-treated patients were akathisia, pain in the extremities, tremor, and vaginitis.

Conclusions: Aripiprazole, 15 or 30 mg/day, was superior to placebo in maintaining efficacy
in patients with bipolar I disorder with a recent manic or mixed episode who were stabilized and maintained on aripiprazole treatment for 6 weeks, as shown by a longer time to relapse.

(J Clin Psychiatry 2006;67:626-637)

Received April 22, 2005; accepted Feb. 10, 2006. From the Psychopharmacology Research Program, Department of Psychiatry, University of Cincinnati College of Medicine and the General Clinical Research Center and Mental Health Service Line, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio (Dr. Keck); Case University School of Medicine, University Hospitals of Cleveland, Cleveland, Ohio (Dr. Calabrese); Otsuka America Pharmaceutical, Inc., Princeton, N.J. (Drs. McQuade and Carson); Bristol-Myers Squibb Co., Plainsboro, N.J. (Dr. Carlson); and Bristol-Myers Squibb Co., Wallingford, Conn. (Drs. Rollin, Marcus, and Sanchez).

Supported by Bristol-Myers Squibb Co., New York, N.Y., and Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan.

Financial disclosure appears at the end of the article.

Editorial assistance was provided by ApotheCom Associates LLC, Yardley, Penn. Members of the Aripiprazole Study Group are listed at the end of this article.

Corresponding author and reprint requests: Paul E. Keck, Jr., M.D., Psychopharmacology Research Program, Department of Psychiatry, University of Cincinnati College of Medicine, Martin Luther King Dr., Cincinnati, OH 45267 (e-mail: paul.keck@uc.edu).