Aripiprazole Monotherapy for Maintenance Therapy in Bipolar I Disorder: A 100-Week, Double-Blind Study Versus Placebo

Paul E. Keck, Jr., M.D.; Joseph R. Calabrese, M.D.; Roger S. McIntyre, M.D., F.R.C.P.C.; Robert D. McQuade, Ph.D.; William H. Carson, M.D.; James M. Eudicone, M.S.; Berit X. Carlson, Ph.D.; Ronald N. Marcus, M.D.; and Raymond Sanchez, M.D., for the Aripiprazole Study Group

Objective: A 26-week, double-blind, placebo-controlled relapse prevention study of aripiprazole was designed a priori with a prospective, 74-week, double-blind, placebo-controlled extension phase. Efficacy and tolerability of aripiprazole for relapse prevention in bipolar I disorder was, therefore, evaluated for 100 weeks.

Method: Patients with DSM-IV bipolar I disorder, recent manic or mixed episode, received open-label aripiprazole 15 or 30 mg/day (started at 30 mg/day) for 6 to 18 weeks. Patients achieving stabilization (Young Mania Rating Scale score <= 10 and Montgomery-Asberg Depression Rating Scale score <= 13 for 6 consecutive weeks) entered the double-blind phase, at which point they were randomly assigned to double-blind treatment with aripiprazole or placebo for 26 weeks. The primary endpoint was time to relapse for any mood episode. Patients who completed the 26-week stabilization continued in a double-blind fashion with aripiprazole or placebo for an additional 74 weeks and were monitored for relapse, efficacy, and tolerability. The study was conducted from March 2000 to June 2003.

Results: In total, 161 patients met the stabilization criteria and were randomly assigned to aripiprazole (N = 78) or placebo (N = 83). At 100 weeks, time to relapse was significantly longer with aripiprazole (N = 7) than placebo (N = 5; hazard ratio = 0.53 [p = .011; 95% CI = 0.32 to 0.87]); however, a further 24 patients had discontinued due to study closure. Aripiprazole was superior to placebo in delaying time to manic relapse (p = .005; hazard ratio = 0.35 [95% CI = 0.16 to 0.75]); however, no significant differences were observed in time to depressive relapse (p = .602; hazard ratio = 0.81 [95% CI = 0.36 to 1.81]). The adverse events reported during 100 weeks of treatment with aripiprazole versus placebo (>= 5% incidence and twice placebo rate) were tremor, akathisia, dry mouth, hypertension, weight gain, vaginitis, abnormal thinking, pharyngitis, and flu syndrome. Mean weight change from baseline to 100 weeks (last observation carried forward) was +0.4 ± 0.8 kg with aripiprazole and -1.9 ± 0.8 kg with placebo.

Conclusions: Over a 100-week treatment period, aripiprazole monotherapy was effective for relapse prevention in patients who were initially stabilized on aripiprazole for 6 consecutive weeks, and it maintained a good safety and tolerability profile.

Clinical Trials Registration: ClinicalTrials.gov identifier NCT00036348.

(J Clin Psychiatry 2007;68:1480-1491)

Received May 31, 2007; accepted Aug. 27, 2007. From the Psychopharmacology Research Program, Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio (Dr. Keck); Case Western Reserve University School of Medicine/University Hospitals Case Medical Center, Cleveland, Ohio (Dr. Calabrese); Mood Disorders Psychopharmacology Unit, University of Toronto, Toronto, Ontario, Canada (Dr. McIntyre); Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, N.J. (Drs. McQuade and Carson); Bristol-Myers Squibb Co., Plainsboro, N.J. (Mr. Eudicone and Dr. Carlson); Bristol-Myers Squibb Co., Wallingford, Conn. (Dr. Marcus); and Bristol-Myers Squibb Co., Paris, France (Dr. Sanchez).

This study was supported by Bristol-Myers Squibb Co. (Princeton, N.J.) and Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan). Editorial support for the preparation of this article was provided by Michelle O'Donovan, Ph.D., Ogilvy Healthworld Medical Education; funding was provided by Bristol-Myers Squibb Co., and Dr. O'Donovan reports no additional financial or other relationship relevant to the subject of the article.

Presented at the 45th meeting of the American College of Neuropsychopharmacology, Dec. 3-7, 2006, Hollywood, Fla.

Members of the Aripiprazole Study Group are listed at the end of the article.

Disclosure of commercial interest appears at the end of the article.

Corresponding author and reprints: Paul E. Keck, Jr., M.D., Psychopharmacology Research Program, Department of Psychiatry, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML0559, Cincinnati, OH 45267-0559 (e-mail: paul.keck@uc.edu).