Background:This randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov identifer NCT04285515) evaluated efficacy and safety of lumateperone to treat major depressive episodes (MDEs) associated with major depressive disorder (MDD) or bipolar depression with mixed features.
Procedures:Patients (18–75 years) with Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5)–defined MDD with mixed features (n = 185) or bipolar disorder with mixed features (n = 200) and experiencing an MDE were randomized 1:1 to 6-week placebo (n = 195) or lumateperone 42 mg (n = 193). Primary and key secondary endpoints were change from baseline to day 43 in Montgomery-Åsberg Depression Rating Scale Total and Clinical Global Impression Scale-Severity (CGI-S) scores in 3 populations with combined MDD/bipolar depression, individual MDD, and individual bipolar depression. Safety included adverse events (AEs), extrapyramidal symptoms, and laboratory parameters.
Results:Lumateperone met the primary endpoint, significantly improving Montgomery-Åsberg Depression Rating Scale total score at day 43 in populations with combined MDD/bipolar depression (least squares mean difference vs placebo [LSMD], −5.7; 95% confidence interval [CI], −7.60,−3.84; effect size [ES], −0.64; P < 0.0001), MDD (LSMD, −5.9; 95% CI, −8.61,−3.29; ES, −0.67; P < 0.0001), and bipolar depression (LSMD, −5.7; 95% CI, −8.29,−3.05; ES, −0.64; P < 0.0001). Lumateperone significantly improved CGI-S and Young Mania Rating Scale total scores at day 43 in these populations. Lumateperone was well-tolerated. Treatment-emergent AEs (≥5%, twice placebo) in the combined population were somnolence (placebo, 1.6%; lumateperone, 12.5%), dizziness (placebo, 2.1%; lumateperone, 12.0%), and nausea (placebo, 1.6%; lumateperone, 9.9%). There were no mania/hypomania treatment-emergent AEs with lumateperone and minimal extrapyramidal symptoms or metabolic risk.
Conclusions:Lumateperone 42 mg significantly improved depression symptoms and disease severity and was generally safe and well-tolerated in patients with MDD or bipolar depression with mixed features.