Lumateperone as Adjunctive Therapy in Patients With Major Depressive Disorder and Anxious Distress: Post Hoc Analysis of a Phase 3, Randomized, Double-Blind Trial

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• Picked for Psychiatry and Mental Health (top studies of the week, 20 September 2026): Adjunctive lumateperone improves depression and anxiety scores

Abstract

Objective: Anxious distress is associated with poor outcomes in the treatment of major depressive disorder (MDD). This exploratory post hoc analysis utilized data from a phase 3 study to investigate adjunctive lumateperone 42 mg efficacy in patients with MDD with inadequate antidepressant therapy (ADT) response and anxious distress. Methods: Outpatients (18-65 y) had DSM-5-defined MDD with inadequate response to 1-2 ADTs in the current depressive episode, Montgomery-Åsberg Depression Rating Scale (MADRS) Total score ≥24, and Clinical Global Impression-Severity (CGI-S) score ≥4 (July 2021-February 2024). Patients were randomized to 6-week oral lumateperone 42 mg+ADT (n=239) or placebo+ADT (n=242). Efficacy was assessed in patients with or without DSM-5-defined anxious distress. Results: Of 481 patients, 43% met criteria for anxious distress. Lumateperone+ADT significantly improved MADRS Total score from baseline to Day 43 versus placebo+ADT in patients with anxious distress (least squares mean difference vs placebo [LSMD]= -6.8; 95% CI=-9.00 to -4.51; effect size [ES]=0.85; P<.0001) or without (LSMD=-3.5; 95% CI=-5.47 to -1.58; ES=0.44; P <.001). MADRS response and remission rates at Day 43 were significantly greater with lumateperone+ADT in both subgroups (P<.05). At Day 43, lumateperone+ADT significantly improved CGI-S score (P<.0001), MADRS inner tension item (P<.001), and Quick Inventory of Depressive Symptomatology-Self Report-16 item Total score (P<.05) in both subgroups. Generalized Anxiety Disorder-7 item Total score significantly improved at Day 43 with lumateperone+ADT in patients with anxious distress (P <.0001) but did not reach statistical significance in those without anxious distress (P=.379). Conclusion: Adjunctive lumateperone 42 mg significantly improved depression and anxiety symptoms in patients with MDD with inadequate ADT response and anxious distress. Trial Registration: ClinicalTrials.gov identifier: NCT04985942.

Abstract as published, via PubMed.