The Efficacy and Safety of Aripiprazole as Adjunctive Therapy in Major Depressive Disorder: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study

Robert M. Berman, M.D.; Ronald N. Marcus, M.D.; René Swanink, M.S.; Robert D. McQuade, Ph.D.; William H. Carson, M.D.; Patricia K. Corey-Lisle, Ph.D., R.N.; and Arif Khan, M.D.

Objective: To assess the efficacy and safety of aripiprazole versus placebo as adjunctive treatment to standard antidepressant therapy (ADT) in patients with major depressive disorder (MDD) who showed an incomplete response to 1 prospective and 1 to 3 historical courses of ADT within the current episode.

Method: The study comprised a 7- to 28-day screening phase, an 8-week prospective treatment phase, and a 6-week double-blind treatment phase. Patients with DSM-IV-TR-defined MDD were enrolled between June 16, 2004, and April 27, 2006. During prospective treatment, patients received ADT: escitalopram, fluoxetine, paroxetine controlled-release, sertraline, or venlafaxine extended-release, each with single-blind, adjunctive placebo. Incomplete responders continued ADT and were randomly assigned to double-blind, adjunctive placebo or adjunctive aripiprazole (2-15 mg/day with fluoxetine or paroxetine; 2-20 mg/day with all others). The primary efficacy endpoint was the mean change from end of prospective treatment to end of double-blind treatment (week 14, last observation carried forward) in Montgomery-Asberg Depression Rating Scale (MADRS) total score (analysis of covariance).

Results: A total of 178 patients were randomly assigned to adjunctive placebo and 184 to adjunctive aripiprazole. Baseline demographics were similar between groups (mean MADRS total score of 26.0). Mean change in MADRS total score was significantly greater with adjunctive aripiprazole (-8.8) than adjunctive placebo (-5.8; p < .001). Adverse events (AEs) that occurred in >= 10% of patients with adjunctive placebo or adjunctive aripiprazole were akathisia (4.5% vs. 23.1%), headache (10.8% vs. 6.0%), and restlessness (3.4% vs. 14.3%). Discontinuations due to AEs were low with adjunctive placebo (1.7%) and adjunctive aripiprazole (2.2%); only 1 adjunctive aripiprazole-treated patient discontinued due to akathisia.

Conclusions: In patients with MDD who showed an incomplete response to ADT, adjunctive aripiprazole was efficacious and well tolerated.

Clinical Trials Registration: ClinicalTrials.gov identifier NCT00095823.

(J Clin Psychiatry 2007;68:843-853)

Received Feb. 2, 2007; accepted April 30, 2007. From Bristol-Myers Squibb Co., Wallingford, Conn. (Drs. Berman, Marcus, and Corey-Lisle); Bristol-Myers Squibb Co., Braine-l'Alleud, Belgium (Mr. Swanink); Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, N.J. (Drs. McQuade and Carson); and Northwest Clinical Research Center, Bellevue, Wash. (Dr. Khan).

This study was supported by Bristol-Myers Squibb Co. (Princeton, N.J) and Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan).

These data have been presented at the 160th annual meeting of the American Psychiatric Association, May 19-24, 2007, San Diego, Calif.

Acknowledgments are listed at the end of the article.

Drs. Berman, Marcus, and Corey-Lisle and Mr. Swanink are employees of Bristol-Myers Squibb, and Drs. Berman and Corey-Lisle are Bristol-Myers Squibb shareholders. Drs. McQuade and Carson are employees of Otsuka Pharmaceutical Development & Commercialization, and Dr. McQuade is a former employee of Bristol-Myers Squibb and a current Bristol-Myers Squibb shareholder. Dr. Khan has been the principal investigator of over 200 clinical trials sponsored by more than 40 pharmaceutical companies.

Corresponding author and reprints: Robert M. Berman, M.D., Bristol-Myers Squibb Co., 5 Research Parkway, Wallingford, CT 06492 (e-mail: Robert.Berman@bms.com).