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

AI Summary

Adjunctive lumateperone 42 mg significantly reduced anhedonia versus adjunctive placebo at all visits; Day 43 LSMD -2.5, effect size -0.50, P<0.0001.
Patients with baseline anhedonia ≥ median showed greater benefit: MADRS Total LSMD -5.4, ES -0.67; anhedonia LSMD -2.8, ES -0.55, P<0.0001.
Adjunctive lumateperone improved nine of ten individual MADRS items at Day 43, demonstrating broad efficacy across depressive symptoms in inadequate responders.

AI Summary

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.

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.

Basic summary

Neuropsychiatr Dis Treat. 2026 Jun 19;22:594893. doi: 10.2147/NDT.S594893. eCollection 2026.

ABSTRACT

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.

PMID:42344568 | PMC:PMC13289650 | DOI:10.2147/NDT.S594893

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