The safety and tolerability of aripiprazole once-monthly as maintenance treatment for bipolar I disorder: A double-blind, placebo-controlled, randomized withdrawal study

Background: Aripiprazole once-monthly 400 mg (AOM 400), an atypical long-acting injectable antipsychotic, has demonstrated efficacy and safety in maintenance treatment of bipolar I disorder (BP-I). We further assess safety and tolerability and characterize adverse events (AEs) across the duration of aripiprazole exposure. Methods: Patients with BP-I were stabilized on oral aripiprazole (2-8 weeks), AOM 400 (12-28 weeks), followed by 1:1 randomization of patients meeting stability criteria to a 52-week, double-blind, placebo-controlled withdrawal phase. Treatment-emergent AEs (TEAEs) were collected across study phases. AEs were counted in a phase if they were drug-related and continued from the baseline of that phase. A separate analysis on new-onset akathisia was conducted. Results: Among TEAEs occurring in >= 10% of patients during all study phases were akathisia (23.3%) and weight increased (10.6%). Median time to akathisia onset was 20 days after starting oral aripiprazole; median duration was 29 days for the first occurrence; 21/168 patients (12.5%) reporting akathisia experienced >1 episode. Episodes of new-onset akathisia decreased over time, with few events reported in the randomized phase. Weight gain was minimal with oral aripiprazole, generally starting within 3 months after the first AOM 400 injection, and appearing to plateau at 36 weeks. The mean weight gain within any study phase was <= 1.0 kg. Potentially clinically significant changes in metabolic parameters were uncommon. Limitations: Patients on placebo had AOM 400 exposure before randomization. Conclusion: These findings suggest that AEs with AOM 400 treatment were time-limited and support AOM 400 as a well-tolerated maintenance treatment of BP-I.