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

Marcus, Ronald N. MD*; McQuade, Robert D. PhD†; Carson, William H. MD†; Hennicken, Delphine MS‡; Fava, Maurizio MD§; Simon, Jeffrey S. MD∥; Trivedi, Madhukar H. MD¶; Thase, Michael E. MD**; Berman, Robert M. MD*

Journal of Clinical Psychopharmacology: April 2008 - Volume 28 - Issue 2 - pp 156-165
doi: 10.1097/JCP.0b013e31816774f9
Original Contributions

Nonresponse to one or more antidepressants is common and an important public health problem. This study evaluated the efficacy and safety of adjunctive aripiprazole or placebo to standard antidepressant therapy (ADT) in patients with major depressive disorder who showed an inadequate response to at least 1 and up to 3 historical and 1 additional prospective ADT. The study comprised a 7-28-day screening, an 8-week prospective treatment, and a 6-week randomization phase. During prospective treatment, patients experiencing a major depressive episode (17-item Hamilton Rating Scale for Depression total score ≥18) received single-blind adjunctive placebo plus clinicians' choice of ADT (escitalopram, fluoxetine, paroxetine controlled-release, sertraline, or venlafaxine extended-release). Subjects with inadequate response were randomized to adjunctive placebo (n = 190) or adjunctive aripiprazole (n = 191) (starting dose 5 mg/d, dose adjustments 2-20 mg/d, mean end-point dose of 11.0 mg/d). The primary efficacy endpoint was the mean change in Montgomery-Åsberg Depression Rating Scale total score from end of prospective treatment phase to end of randomized treatment phase (last observation carried forward). Mean change in Montgomery-Åsberg Depression Rating Scale total score was significantly greater with adjunctive aripiprazole than placebo (−8.5 vs −5.7; P = 0.001). Remission rates were significantly greater with adjunctive aripiprazole than placebo (25.4% vs 15.2%; P = 0.016) as were response rates (32.4% vs 17.4%; P < 0.001). Adverse events occurring in 10% of patients or more with adjunctive placebo or aripiprazole were akathisia (4.2% vs 25.9%), headache (10.5% vs 9.0%), and fatigue (3.7% vs 10.1%). Incidence of adverse events leading to discontinuation was low (adjunctive placebo [1.1%] vs adjunctive aripiprazole [3.7%]). Aripiprazole is an effective and safe adjunctive therapy as demonstrated in this short-term study for patients who are nonresponsive to standard ADT.

*Bristol-Myers Squibb, Wallingford, CT; †Otsuka Pharmaceutical Development & Commercialization, Inc, Princeton, NJ; ‡Bristol-Myers Squibb, Braine-l'Alleud, Belgium; §Depression Clinical and Research Program, Massachusetts General Hospital, Boston, MA; ∥Northbrooke Research Center, Brown Deer, WI; ¶The University of Texas Southwestern Medical Center, Dallas, TX; and **Department of Psychiatry, University of Pittsburgh Medical Center, University of Pennsylvania School of Medicine, and the Philadelphia Veterans Affairs Medical Center, Pennsylvania, PA.

Received August 29, 2007; accepted after revision January 7, 2008.

This study was supported by Bristol-Myers Squibb (Princeton, NJ) and Otsuka Pharmaceutical Co, Ltd (Tokyo, Japan). Editorial support for the preparation of this manuscript was provided by Michelle O'Donovan, PhD, Ogilvy Healthworld Medical Education (London, UK); funding was provided by Bristol-Myers Squibb.

Address correspondence and reprint requests to Robert M. Berman, MD, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492. E-mail:

© 2008 Lippincott Williams & Wilkins, Inc.