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Adjunctive Aripiprazole in Major Depressive Disorder: Analysis of Efficacy and Safety in Patients With Anxious and Atypical Features

Madhukar H. Trivedi, M.D.; Michael E. Thase, M.D.; Maurizio Fava, M.D.; J. Craig Nelson, M.D.; Huyuan Yang, Ph.D.; Ying Qi, Ph.D.; Quynh-Van Tran, Pharm.D.; Andrei Pikalov, M.D., Ph.D.; Berit X. Carlson, Ph.D.; Ronald N. Marcus, M.D.; and Robert M. Berman, M.D.

Objective: To evaluate the efficacy of adjunctive aripiprazole to standard antidepressant therapy (ADT) for patients with DSM-IV major depressive disorder with anxious/atypical features at baseline.

Method: Data from 2 identical 14-week studies (an 8-week prospective ADT treatment phase and a 6-week randomized, double-blind phase) of aripiprazole augmentation were pooled to evaluate efficacy and safety in the 2 subgroups. The primary efficacy endpoint was mean change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from end of ADT treatment to end of randomized treatment (last observation carried forward). Anxious depression was defined by a Hamilton Rating Scale for Depression anxiety/somatization factor score >= 7, and atypical depression was defined by previously described criteria on the Inventory of Depressive Symptomatology-Self-Report. Both anxious and atypical subtypes were defined based on symptoms at entry into prospective ADT (week 0). Patients were enrolled between June 2004 and April 2006 in one study and from September 2004 to December 2006 in the other (total randomized population, N = 742; anxious/nonanxious population, N = 740; atypical/nonatypical population, N = 737).

Results: Completion rates were between 84% and 90% and comparable across all subgroups, with low discontinuations due to adverse events. Patients receiving adjunctive aripiprazole demonstrated significantly greater improvement in MADRS total score versus patients receiving adjunctive placebo, starting at week 1 or week 2 and continuing through to endpoint (anxious: -8.72 vs. -6.17, p <= .001; nonanxious: -8.61 vs. -4.97, p <= .001; atypical: -9.31 vs. -5.15, p <= .001; nonatypical: -8.08 vs.
-6.22, p < .05). At endpoint, remission rates were also significantly higher with adjunctive aripiprazole versus adjunctive placebo (p < .05) in all subgroups. Treatment emergent adverse event profile was similar in all subgroups and comparable to the total population. Reporting of akathisia and weight gain on aripiprazole treatment did not differ between subgroups.

Conclusion: Adjunctive aripiprazole is an effective treatment for patients with major depression presenting with either anxious or atypical features.

Trial Registration: clinicaltrials.gov Identifiers: NCT00095823 and NCT00095758

(J Clin Psychiatry 2008;69:1928-1936. Online Ahead of Print December 2, 2008.)

Received June 20, 2008; accepted Sept. 3, 2008. From the University of Texas Southwestern Medical Center, Dallas (Dr. Trivedi); the Departments of Psychiatry, University of Pittsburgh Medical Center and University of Pennsylvania School of Medicine, Philadelphia, and the Philadelphia Veterans Affairs Medical Center, Pa. (Dr. Thase); Depression Clinical and Research Program, Massachusetts General Hospital, Boston (Dr. Fava); the Department of Psychiatry, University of California, San Francisco (Dr. Nelson); Bristol-Myers Squibb, Plainsboro, N.J. (Drs. Yang, Qi, and Carlson); Otsuka America Pharmaceutical, Inc., Rockville, Md. (Drs. Tran and Pikalov); and Bristol-Myers Squibb, Wallingford, Conn. (Drs. Marcus and Berman).

This study was supported by Bristol-Myers Squibb (Princeton, N.J.) and Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan). Editorial support for the preparation of this manuscript was provided by Ogilvy Healthworld Medical Education (London, United Kingdom); funding was provided by Bristol-Myers Squibb.

Data were presented at the 46th annual meeting of the American College of Neuropsychopharmacology, December 9-13, 2007, Boca Raton, Fla., and at the 161st annual meeting of the American Psychiatric Association, May 3-8, 2008, Washington, D.C.

Financial disclosure appears at the end of the article.

Corresponding author and reprints: Madhukar H. Trivedi, M.D., UT Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-9119 (e-mail: Madhukar.Trivedi@UTSouthwestern.edu).
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