Lumateperone Treatment in Patients With Major Depressive Disorder and Mixed Features: Results From a Randomized Controlled Trial

Introduction: Lumateperone is an FDA-approved antipsychotic to treat schizophrenia and bipolar depression. A recent randomized, double-blind, placebo-controlled trial (NCT04285515) demonstrated efficacy and safety of lumateperone 42mg in major depressive disorder (MDD) or bipolar depression with mixed features. This analysis reports lumateperone 42mg efficacy and safety in patients with MDD with mixed features.

Methods: Adults with DSM-5–diagnosed MDD with mixed features experiencing a major depressive episode (Montgomery-Asberg Depression Rating Scale [MADRS] Total score≥24, Clinical Global Impression Scale-Severity [CGI-S] score≥4) were randomized 1:1 to lumateperone 42mg or placebo. Primary and key secondary efficacy outcomes were change from baseline to Day 43 in MADRS Total score and CGI-S score, respectively. Safety assessments included adverse events (AEs), vital signs, laboratory parameters, and extrapyramidal symptoms.

Results: In patients with MDD with mixed features (placebo, n=93; lumateperone, n=92), lumateperone significantly improved MADRS Total score (least squares mean difference vs placebo [LSMD]=–5.9; 95% CI=–8.61, –3.29; effect size=–0.67; P < .0001) and CGI-S score (LSMD=–0.6; 95% CI=–0.89, –0.27; effect size=–0.57; P < .001) from baseline to Day 43. Lumateperone treatment was generally safe and well tolerated, consistent with prior studies. No notable changes occurred in vital signs, metabolic parameters, or extrapyramidal symptom scales. The most common treatment-emergent AEs (TEAEs; ≥5% and twice placebo) were dizziness, somnolence, and nausea. No TEAEs of mania/hypomania were reported.

Conclusion: Lumateperone 42mg demonstrated robust efficacy over placebo in patients with MDD with mixed features and was generally well tolerated, supporting lumateperone as a promising new treatment option for this population.