What question did this study set out to answer?

This study investigates the long-term safety and efficacy of lumateperone adjunctive to antidepressant therapy in major depressive disorder.

March 26, 2026Open Access

Long-term adjunctive lumateperone 42 mg treatment in major depressive disorder: Results from a 6-month open-label extension study

Key Points

This study investigates the long-term safety and efficacy of lumateperone adjunctive to antidepressant therapy in major depressive disorder.
Phase 3 open-label extension study with 809 participants
Participants had major depressive disorder with inadequate response to 1-2 antidepressants
Lumateperone 42 mg was administered daily for 26 weeks alongside antidepressant therapy
Primary endpoints included safety/tolerability and secondary endpoints were efficacy measures using MADRS and CGI-S.
80% of participants achieved a response at the end of treatment
65% of participants reached remission by the end of the study
Minimal adverse effects reported, with 67.7% experiencing treatment-emergent adverse events
Most common adverse events included headache, dizziness, and dry mouth
Significant improvement observed in depression scales (MADRS: mean change -22.9; CGI-S: mean change -2.7)

Abstract

• Adjunctive lumateperone 42 mg for 26 weeks was well tolerated in patients with MDD. • Minimal changes occurred in EPS scales, body morphology, and cardiometabolic values. • Lumateperone + ADT showed clinically meaningful improvement in depression symptoms. • Around 80% and 65% of patients achieved response and remission at end of treatment. • Long-term lumateperone + ADT was safe and effective in MDD with inadequate response. This Phase 3 open-label extension study (NCT05061719) investigated long-term safety of lumateperone 42mg (simultaneous modulator of serotonin, dopamine, and glutamate neurotransmission) adjunctive to antidepressant therapy (ADT) in patients with major depressive disorder (MDD) with inadequate ADT response. Eligible adults (18-65years) completed 6-week double-blind treatment (NCT04985942; NCT05061706) and 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 at lead-in study entry. Patients received 26-week, open-label, oral lumateperone 42mg+ADT once-daily. The primary endpoint was safety/tolerability, assessed by adverse events (AEs), vital signs, and laboratory parameters. The secondary endpoint was efficacy, assessed by MADRS Total score and CGI-S score changes from double-blind baseline to open-label Week 26. Of 809 patients treated, 84.5% completed open-label treatment; 67.7% experienced ≥1 treatment-emergent AE (TEAE). Most common TEAEs (≥5%) were headache (16.6%), dizziness (10.6%), dry mouth (8.0%), nausea (7.7%), somnolence (7.2%), diarrhea (6.2%), and nasopharyngitis (5.2%). The majority (98.9%) of TEAEs were mild-to-moderate severity. Rate of extrapyramidal symptom (EPS)-related TEAEs per broad standardized MedDRA query was low (3.8%). No notable changes in EPS scales, body morphology, or cardiometabolic parameters occurred from double-blind baseline to end of open-label treatment. No emergence of suicidal behavior occurred during treatment. Symptoms of depression improved with lumateperone+ADT from double-blind baseline to open-label Week 26 (mean change: MADRS Total score=−22.9, P <.0001; CGI-S score=−2.7, P <.0001). Overall, lumateperone 42mg+ADT was safe and effective during 26-week treatment in patients with MDD with inadequate ADT response.

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