Efficacy of Adjunctive Lumateperone 42 mg on Anhedonia and Across a Broad Range of Depressive Symptoms in Major Depressive Disorder: Post Hoc Analysis of a Phase 3, Randomized, Placebo-Controlled Trial

Purpose: Lumateperone is a mechanistically novel Food and Drug Administration-approved antipsychotic to treat schizophrenia, depressive episodes associated with bipolar I and II disorder, and major depressive disorder (MDD). This analysis of the Phase 3, randomized, double-blind, placebo-controlled, multicenter Study 501 (NCT04985942) evaluated the broad efficacy of lumateperone across depression symptoms assessed by Montgomery-Åsberg Depression Rating Scale (MADRS) anhedonia factor and single-item scores. Patients and Methods: Eligible adults (18– 65 years) met DSM-5 criteria for MDD with inadequate response to 1 or 2 ADTs in the current depressive episode and had MADRS Total score ≥ 24, Clinical Global Impression–Severity score ≥ 4, and Quick Inventory of Depressive Symptomatology-Self-Report 16-item score ≥ 14. Patients were randomized to oral placebo or lumateperone 42 mg adjunctive to ADT for 6 weeks. A post hoc analysis assessed anhedonia symptoms according to MADRS anhedonia factor. MADRS Total score and MADRS anhedonia factor score were analyzed by baseline anhedonia factor score (median value: ≥ 18). A prospective analysis investigated change in individual MADRS items. Results: Lumateperone+ADT significantly improved anhedonia symptoms versus placebo+ADT at every visit according to MADRS anhedonia factor score (Day 43: least squares mean difference vs adjunctive placebo [LSMD], − 2.5; effect size [ES], − 0.50; P < 0.0001). In patients with baseline anhedonia scores equal to or more than the median, significant improvements in MADRS Total score (LSMD, − 5.4; 95% CI, − 7.21, − 3.59; ES, − 0.67; P < 0.0001) and anhedonia factor score (LSMD, − 2.8; 95% CI, − 3.91, − 1.65; ES, − 0.55; P < 0.0001) were observed for lumateperone+ADT versus placebo+ADT at Day 43, with significant between-group differences observed at all study visits. At Day 43, 9 of the 10 MADRS items significantly improved with adjunctive lumateperone compared with adjunctive placebo. Conclusion: Lumateperone 42mg+ADT significantly improved symptoms of anhedonia and a broad range of depression symptoms compared with placebo+ADT in patients with MDD with inadequate response.