Aripiprazole in combination with lamotrigine for the long-term treatment of patients with bipolar I disorder (manic or mixed): a randomized, multicenter, double-blind study (CN138-392)

Carlson BX, Ketter TA, Sun W, Timko K, McQuade RD, Sanchez R, Vester-Blokland E, Marcus R. Aripiprazole in combination with lamotrigine for the long-term treatment of patients with bipolar I disorder (manic or mixed): a randomized, multicenter, double-blind study (CN138-392). Bipolar Disord 2012: 14: 41–53. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives:  To evaluate the efficacy and safety of aripiprazole (ARI) plus lamotrigine (LTG) compared with placebo (PBO) plus LTG, for long-term treatment in bipolar I disorder patients with a recent manic/mixed episode. Methods:  After a 9–24 week stabilization phase receiving single-blind ARI (10–30 mg/day) plus open-label LTG (100 or 200 mg/day), patients maintaining stability (Young Mania Rating Scale/Montgomery–Asberg Depression Rating Scale total scores ≤ 12) with ARI + LTG for eight consecutive weeks were randomized to continue on double-blind ARI + LTG or to receive PBO + LTG, after removing ARI from ARI + LTG treatment, and followed up for 52 weeks. The primary outcome measure was time from randomization to relapse into a manic/mixed episode. Results:  A total of 787 patients entered the stabilization phase, and 351 were randomized to ARI + LTG (n = 178) or PBO + LTG (n = 173). ARI + LTG yielded a numerically longer time to manic/mixed relapse than PBO + LTG, but it was not statistically significant [hazard ratio (HR) = 0.55; 95% confidence interval (CI): 0.30–1.03; p = 0.058]. The estimated relapse rates at Week 52 were 11% for ARI + LTG and 23% for PBO + LTG, yielding a number needed-to-treat of nine (95% CI: 5–121). The three most common adverse events were akathisia [10.8%, 6.1% for ARI + LTG and PBO + LTG, respectively; number needed-to-harm (NNH) = 22], insomnia (7.4%, 11.5%), and anxiety (7.4%, 3.6%). Mean weight change was 0.43 kg and −1.81 kg, respectively (last observation carried forward, p = 0.001). Rates of ≥ 7% weight gain with ARI + LTG and PBO + LTG were 11.9% and 3.5%, respectively (NNH = 12). Conclusions:  ARI + LTG delayed the time to manic/mixed relapse but did not reach statistical significance. Safety and tolerability results revealed no unexpected adverse events for ARI combination with LTG.