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

Objective

Lumateperone, a mechanistically novel antipsychotic, simultaneously modulates serotonin, dopamine, and glutamate neurotransmission. This phase 3, randomized, double-blind, placebo-controlled trial investigated efficacy and safety of adjunctive lumateperone 42 mg in patients with major depressive disorder (MDD) with inadequate antidepressant therapy (ADT) response.

Methods

From July 2021 to February 2024, eligible adult outpatients (18-65 years) had DSM-5-defined MDD with inadequate response to 1 or 2 ADTs in the current depressive episode and Montgomery-Åsberg Depression Rating Scale (MADRS) Total score ≥24, Clinical Global Impression Scale-Severity (CGI-S) score ≥4, and Quick Inventory of Depressive Symptomatology-Self Report-16 item (QIDS-SR-16) score ≥14. Patients were randomized to 6-week oral adjunctive placebo (n=243) or adjunctive lumateperone 42 mg (n=242). Primary and key secondary end points were change from baseline to day 43 in MADRS Total and CGI-S scores. Safety was assessed.

Results

Lumateperone + ADT met primary and key secondary end points, with significantly greater improvement at day 43 vs placebo + ADT in MADRS Total score (least squares mean difference [LSMD] vs placebo= -4.9; effect size [ES]= -0.61; P < .0001) and CGI-S score (LSMD =-0.7; ES = -0.67; P <.0001). Lumateperone + ADT significantly improved patient-reported depression vs placebo + ADT at day 43 (QIDS-SR-16 Total score, LSMD= -2.4; ES= -0.50; P < .0001). Lumateperone + ADT was generally well tolerated. Treatment-emergent adverse events (≥5%, twice placebo) were dry mouth (placebo + ADT, 2.1%; lumateperone + ADT, 10.8%), fatigue (2.1%; 9.5%), and tremor (0.4%; 5.0%), with minimal risk for weight gain or cardiometabolic abnormalities. Emergence of suicidal ideation was low (placebo + ADT, 3.5%; lumateperone + ADT, 1.4%).

Conclusions

Lumateperone 42 mg adjunctive to ADT significantly improved depression symptoms and disease severity vs adjunctive placebo and was generally well tolerated in patients with MDD with inadequate ADT response. Trial Registration: ClinicalTrials.gov identifier: NCT04985942.