Safety and Tolerability of Adjunctive Aripiprazole in Major Depressive Disorder: A Pooled Post Hoc Analysis (studies CN138-139 and CN138-163)

Objective: To evaluate the safety and tolerability
of aripiprazole adjunctive to standard antidepressant therapy (ADT) for patients with major depressive disorder (DSM-IV-TR criteria).

Method: Data from 2 identical studies of aripiprazole augmentation (8 weeks of prospective ADT treatment followed by 6 weeks of randomized double-blind adjunctive treatment) were pooled. The incidence of treatment-emergent adverse events (TEAEs) and weight, electrocardiogram (ECG), and laboratory measurements were assessed during the 6-week phase, including time course, severity, resolution, and predictors. The studies were conducted from June 2004 to April 2006 and September 2004 to December 2006.

Results: The safety analysis included 737 outpatients (aripiprazole, n = 371; placebo, n = 366). The majority of patients completed the trials (aripiprazole, 86%; placebo, 88%). Common TEAEs (≥ 5% and twice the placebo rate) with aripiprazole were akathisia (25%), restlessness (12%), insomnia (8%), fatigue (8%), blurred vision (6%), and constipation (5%). Most TEAEs were of mild to moderate severity (aripiprazole, 89%; placebo, 95%). TEAE rates in the aripiprazole and placebo groups were not affected by ADT, age, or gender. Discontinuation due to TEAEs was low (aripiprazole, 3%; placebo, 1%). Mean weight change was higher with aripiprazole versus placebo (1.73 kg vs 0.38 kg, P < .001). At endpoint, clinical laboratory parameters, vital signs, and ECG indices (including QT_c interval) were similar between groups. Akathisia with aripiprazole generally occurred in the first 3 weeks (76%), was of mild to moderate severity (92%), and led to discontinuation in 3 patients (0.8%). Within the aripiprazole group, age (18-40 years) was the only positive predictor for akathisia.

Conclusions: In this short-term post hoc analysis, aripiprazole as augmentation to ADT demonstrated a safety and tolerability profile similar to that in monotherapy studies in other psychiatric populations. Controlled long-term safety and efficacy data of aripiprazole as adjunctive to ADT are warranted.

Trial Registration: clinicaltrials.gov Identifiers: NCT00095823 (CN138-139) and NCT00095758 (CN138-163)