Lumateperone monotherapy for major depressive episodes associated with bipolar disorder: efficacy and safety in a randomized placebo-controlled trial.

This Phase 3, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of lumateperone to treat bipolar depression. Patients (18-75 years) with bipolar I or bipolar II disorder experiencing a major depressive episode were randomized 1:1:1 to 6-week lumateperone 28 mg ( n  = 183), lumateperone 42 mg ( n  = 185), or placebo ( n  = 186). Primary and key secondary endpoints were change from baseline to Day 43 in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total score and time to first sustained response (≥50% reduction from baseline in MADRS Total score), respectively. Safety assessments included adverse events, extrapyramidal symptoms (EPS), laboratory evaluations, and vital signs. Neither dose of lumateperone achieved significant improvement vs. placebo ( P > 0.05) in the primary endpoint (MADRS Total score, least squares mean difference vs. placebo: 28 mg, 0.9; 42 mg, -1.0) or in the key secondary endpoint (MADRS Total time to first sustained response hazard ratio vs. placebo: 28 mg, 1.00; 42 mg, 0.93), likely due to a high placebo response. Both lumateperone doses were well tolerated, with low EPS risk and minimal changes in weight, prolactin, and cardiometabolic or endocrine parameters. While study efficacy objectives were not met, both doses of lumateperone were generally safe and well tolerated in patients with bipolar depression.