Lumateperone Improves Depression in Patients With Inadequate Antidepressant Response

Adding lumateperone (Caplyta; Johnson & Johnson) to ongoing antidepressant therapy (ADT) significantly improved depression severity in adults with major depressive disorder (MDD) who had not responded adequately to prior treatment, a study finds.¹

This randomized, double-blind, placebo-controlled trial is published in The American Journal of Psychiatry.

“These results support positive findings from a similarly designed phase 3 trial, further highlighting the efficacy and safety of lumateperone plus ADT in patients with MDD and inadequate response to ADT,” wrote the researchers of the study.

On November 6, 2025, the FDA approved lumateperone as an adjunctive treatment for adults with MDD who continue to experience symptoms despite antidepressant therapy.² As a novel antipsychotic modulating serotonin, dopamine, and glutamate neurotransmission, lumateperone offers once-daily dosing without titration. Its approval was based on 2 phase 3 trials showing significant improvements in Montgomery-Åsberg Depression Rating Scale (MADRS) and Clinical Global Impressions Scale (CGI-S) scores, with benefits seen as early as weeks 1 through 2, and a safety profile comparable to placebo.

In this study, eligible participants had a baseline MADRS score of at least 24 and were randomized 1:1 to receive either lumateperone 42 mg plus their existing ADT or placebo plus ADT for 6 weeks.¹ The ADT used was the most recent medication to which the patient had shown less than 50% improvement. Primary and key secondary endpoints were change from baseline to day 43 in MADRS total score and CGI-S severity score. Safety assessments included adverse events, extrapyramidal symptoms, laboratory evaluations, and monitoring for suicidal ideation and behavior.

Lumateperone plus ADT achieved significantly greater improvements in depression symptoms than placebo plus ADT. By day 43, patients receiving lumateperone had a larger reduction in MADRS total score, with a least squares mean difference of –4.5 and an effect size of –0.56.

Improvements in overall clinical severity were also greater, reflected in a CGI-S least squares mean difference of –0.5 (effect size, –0.51). Patient-reported symptoms improved as well, with a –2.2 difference on the Quick Inventory of Depressive Symptomatology–Self-Report total score (effect size, –0.45).

Lumateperone was generally well tolerated, though 12.4% of patients discontinued due to adverse events compared with 0.8% in the placebo group. The most common events included dizziness, somnolence, dry mouth, nausea, diarrhea, and fatigue. Rates of extrapyramidal symptoms, cardiometabolic abnormalities, weight gain, and suicidal ideation were low and comparable between groups.

However, the researchers acknowledged some limitations, such as its narrow population, as patients with treatment-resistant depression, imminent suicidal risk, or psychiatric comorbidities were excluded, reducing generalizability. The sample was also predominantly White, making subgroup analyses unreliable for other racial groups. Additionally, the trial did not include a specific measure to assess blinding effectiveness, leaving the potential for expectation bias.

Despite these limitations, the researchers believe the study supports adding lumateperone to ADT for patients with MDD when standalone therapy is inadequate.

“Following this 6-week, short-term study, it is now important to establish the durability of the treatment’s benefit and to conduct longer-term studies to assess the safety and tolerability of long-term treatment,” wrote the researchers. “An open-label, long-term study with adjunctive lumateperone 42 mg in MDD (NCT05061719) has recently been completed.”

References

1. Durgam S, Earley WR, Kozauer SG, et al. Adjunctive lumateperone in patients with major depressive disorder: Results from a randomized, double-blind, phase 3 trial. Am J Psychiatry. 2025;182(12):1072-1082. doi:10.1176/appi.ajp.20250292

2. Steinzor P. FDA approves lumateperone as add-on therapy for major depressive disorder. AJMC®. November 6, 2025. Accessed December 4, 2025. https://www.ajmc.com/view/fda-approves-lumateperone-as-add-on-therapy-for-major-depressive-disorder