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

Abstract

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).

Figures

Figure 1

Number of New-Onset Akathisia Events for Adjunctive Aripiprazole Patients Experiencing Akathisia (n = 91) by Week of Treatmenta aTwo adjunctive aripiprazole-treated patients with missing dosing information were not included.

Figure 2

Change in Mean BARS Global Clinical Assessment of Akathisia Scores for Adjunctive Aripiprazole Patients Experiencing Akathisia (n = 91) by Interventiona aBARS Global Clinical Assessment of Akathisia scores: 0 = absent, 1 = questionable, 2 = mild akathisia, 3 = moderate akathisia, 4 = marked akathisia, and 5 = severe akathisia. Abbreviation: BARS = Barnes Akathisia Rating Scale.

Figure 3

Predictors of Akathisia Events in Patients Treated With Adjunctive Aripiprazole (n = 371)a aPredictors of akathisia (gender, age group [18–40, 41–50, or > 50 y], antidepressant therapy, number of previous episodes, and duration of current episode) were assessed for the adjunctive aripiprazole group (n = 371) only. Odds ratios and 95% CIs for each predictor comparing the akathisia and nonakathisia groups were estimated using logistic regression analysis.