Adjunctive Lumateperone in Patients With Major Depressive Disorder: Results From a Randomized, Double-Blind, Phase 3 Trial

OBJECTIVE: This phase 3, randomized, double-blind, placebo-controlled trial evaluated lumateperone 42 mg (a simultaneous modulator of serotonin, dopamine, and glutamate neurotransmission) adjunctive to antidepressant therapy (ADT) in patients with major depressive disorder (MDD) and inadequate ADT response. METHODS: -defined MDD and inadequate response to one to two ADTs in the current depressive episode and a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥24. Patients were randomized in a 1:1 ratio to 6 weeks of oral placebo plus ADT (N=238) or lumateperone 42 mg plus ADT (N=242), once daily in the evening; the ADT was the latest drug to which they had inadequate response (i.e., <50% improvement). Primary and key secondary outcomes were change from baseline to day 43 in MADRS total score and Clinical Global Impressions Scale severity (CGI-S) score. Safety measures included adverse events, extrapyramidal symptoms, laboratory assessments, and suicidal ideation and behavior. RESULTS: Lumateperone+ADT met primary and key secondary endpoints, significantly improving MADRS total score (least squares mean difference [LSMD] versus placebo=-4.5; effect size=-0.56) and CGI-S score (LSMD=-0.5; effect size=-0.51) versus placebo+ADT at day 43. Patient-reported depression significantly improved with lumateperone+ADT versus placebo+ADT at day 43 (16-item Quick Inventory of Depressive Symptomatology-Self-Report, total score: LSMD=-2.2; effect size=-0.45). Lumateperone+ADT was generally well tolerated. The most common treatment-emergent adverse events (≥5%, twice the rate in the placebo+ADT group) were dizziness, somnolence, dry mouth, nausea, diarrhea, and fatigue; 12.4% versus 0.8% of patients discontinued treatment due to treatment-emergent adverse events in the lumateperone+ADT arm versus the placebo+ADT arm. There was minimal risk of extrapyramidal symptoms. Cardiometabolic abnormalities and weight gain were similar between the lumateperone+ADT arm and the placebo+ADT arm. Emergence of suicidal ideation was low. CONCLUSIONS: Patients receiving lumateperone 42 mg plus ADT had statistically significant and clinically meaningful improvement in depression symptoms and disease severity compared with those receiving placebo+ADT. Lumateperone+ADT was generally safe and well tolerated in patients with MDD with inadequate ADT response.