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Original Research

Efficacy of Dose Increase Among Nonresponders to Low-Dose Aripiprazole Augmentation in Patients With Inadequate Response to Antidepressant Treatment: A Randomized, Double-Blind, Placebo-Controlled, Efficacy Trial

David Mischoulon, MD, PhD; Janet Witte, MD; Michael Levy, MD† ; George I. Papakostas, MD; L. Russell Pet, MD; Wen-hua Hsieh, PhD; Michael J. Pencina, PhD; Sean Ward, MBA; Mark H. Pollack, MD; and Maurizio Fava, MD

Published: September 20, 2011

Article Abstract

ABSTRACT

Objective: To examine the efficacy of a dose increase of aripiprazole to 5 mg/d in subjects with major depressive disorder (MDD) who did not respond to 4 weeks of treatment with aripiprazole 2 mg/d in a randomized, double-blind, placebo-controlled, parent study.

Method: 221 Subjects with Structured Clinical Interview for DSM-IV Axis I Disorders-Patient Edition-diagnosed DSM-IV-TR MDD (mean ± SD age, 45 ± 11 years; 64% women) with inadequate antidepressant response were recruited from September 2008-July 2009 and randomized to 60 days of double-blind augmentation with either aripiprazole or placebo in two 30-day phases. The study was performed across 8 academic hospital sites and 14 nonacademic (private clinic) sites throughout the United States. Randomization in a 2:3:3 ratio per sequential parallel comparison design was drug/drug (aripiprazole 2 mg/d in phase 1 and 5 mg/d in phase 2), placebo/placebo (placebo in both phases), and placebo/drug (placebo in phase 1 and aripiprazole 2 mg/d in phase 2). In phase 2, we examined efficacy of an aripiprazole dose increase to 5 mg/d in nonresponders to 2 mg/d by assessing response rates (≥ 50% reduction in Montgomery-Asberg Depression Rating Scale [MADRS] score [primary outcome measure]) and score changes in MADRS, Quick Inventory of Depressive Symptomatology-Self-Report, 9-item Patient Health Questionnaire (PHQ-9), the Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) scales, and patient-rated versions of the CGI-I and CGI-S scales.

Results: Response rate for aripiprazole 2 mg/d in phase 1 was 18.5% (n/n = 10/54). Among 39 nonresponders who increased their dose to 5 mg/d, response rate was 12.8% (95% CI, 4.30%-27.43%), with significant overall mean ± SD reductions in MADRS scores (−9.46 ± 7.83 [95% CI, −12.00 to -6.92]; P < .0001), Symptoms Questionnaire Distress scores (19.51 ± 17.73 [95% CI, 13.60 to 25.43]; P < .0001), PHQ-9 scores (−7.92 ± 5.92 [95% CI, −9.89 to -5.94]; P < .0001), and CGI-S scores (−0.86 ± 0.86 [95% CI, −1.15 to -0.58]; P < .0001). Differences in efficacy between drug and placebo groups were nonsignificant, however. Aripiprazole and placebo were well tolerated.

Conclusions: Augmentation with aripiprazole 5 mg/d may provide only a modest additional benefit in patients who do not benefit from lower doses.

Trial Registration: clinicaltrials.gov Identifier: NCT00683852

J Clin Psychiatry, 2012; 73(3): 353-357

Volume: 72

Quick Links: Depression (MDD)

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Letter to the Editor

Stigma Kills Psychiatric Patients and Is Now Killing Clinical Research Too

Robert M. Post, MD, argues that NIMH should abandon the RDoC framework and restore funding for clinical...

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