Efficacy of aripiprazole adjunctive to lithium or valproate in the long-term treatment of patients with bipolar I disorder with an inadequate response to lithium or valproate monotherapy: a multicenter, double-blind, randomized study

Objectives: To evaluate the efficacy and safety of aripiprazole (ARI) adjunctive to lithium (Li) or valproate (Val) (ARI + Li / Val) compared with placebo (PLB) adjunctive to Li or Val (PLB + Li / Val) as maintenance therapy for patients with bipolar I disorder who had an inadequate response to Li or Val monotherapy. Methods: Patients with a current manic/mixed episode received Li or Val for at least 2 weeks. Those with an inadequate response [Young Mania Rating Scale (YMRS) total score >= 16 and < 35% decrease from baseline at 2 weeks] received adjunctive single-blind ARI plus mood stabilizer. Patients who achieved stability [YMRS and Montgomery-Asberg Depression Rating Scale (MADRS) score < 12] for 12 consecutive weeks were randomized to double-blind ARI (10-30 mg/day) or PLB + Li / Val. Relapse was monitored for 52 weeks. Adverse events (AEs) were also evaluated. Results: A total of 337 patients were randomized to ARI + Li / Val (n = 168) or PLB + Li / Val (n = 169). The Kaplan-Meier relapse rate at 52 weeks was 17% with ARI + Li / Val and 29% with PLB + Li / Val. ARI + Li / Val significantly delayed time to any relapse compared with PLB + Li / Val; hazard ratio = 0.54 (95% confidence interval: 0.33-0.89; log-rank p = 0.014). The most common AEs >= 5% (ARI + Li / Val versus PLB + Li / Val) were headache (13.2% versus 10.8%), weight increase (9.0% versus 6.6%), tremor (6.0% versus 2.4%), and insomnia (5.4% versus 9.6%). Conclusions: Continuation of ARI + Li / Val treatment increased the time to relapse to any mood episode compared with Li or Val monotherapy, and was relatively well tolerated during the one-year study. These findings suggest that there is a long-term benefit in continuing ARI adjunctive to a mood stabilizer after sustained remission is achieved.