FDA Approves Lumateperone as Adjunct Therapy for Major Depressive Disorder

The FDA approved lumateperone (Caplyta) as an adjunct therapy in combination with antidepressants for the treatment of major depressive disorder in adults. This is the fourth approval for the drug, which is also approved for bipolar I and II as an adjunctive and monotherapy and for the treatment of schizophrenia.¹

"Depression is a complex disorder that affects each person differently, underscoring the urgent need for a range of effective and well-tolerated treatment options," Roger S. McIntyre, MD, FRCPC, professor of psychiatry and pharmacology at the University of Toronto, said in a news release.¹ "For people who are still experiencing lingering depressive symptoms while on an antidepressant, adding Caplyta to a patient's treatment regimen may offer early improvement, with the potential for remission—the ultimate goal of treatment."

The approval was based on 2 phase 3 double-blind and placebo-controlled trials, Study 501 (NCT04985942) and Study 502 (NCT05061706), which showed the drug provided statistically significant and clinically meaningful improvement in depression symptoms compared with an oral antidepressant and the placebo. Both Study 501 and 502 contained a screening period of up to 2 weeks prior to the study, a 6-week treatment period, and a 1-week safety follow-up period. Patients received either the placebo or lumateperone 43 mg once daily. The primary outcome was change from baseline to day 43 in the Montgomery-Åsberg Depression Rating Scale (MADRS), and the secondary outcome was change from baseline to day 43 in the Clinical Global Impression Scale-Severity (CGI-S).^1-3

When compared with the placebo group, investigators found that lumateperone combined with an antidepressant significantly improved both the MADRS total score and the CGI-S score. Furthermore, the rates of MADRS total score response were 42.9% for the study drug compared with 24.6% for the placebo, and remission was 25.5% and 13.6%, respectively. Self-reported depressive symptoms were also significantly improved with the study drug at the end of treatment when compared with the placebo, according to the study authors.⁴

As for the safety of the drug, investigators reported that the profile was consistent with the existing body of clinical data in the schizophrenia and bipolar depression I and II indications. Weight gain and metabolic changes were similar to the placebo. Common adverse events included sleepiness, dizziness, nausea, dry mouth, feeling tired, and diarrhea.¹

“Major depressive disorder affects millions of Americans, impacting how a person feels, thinks, and acts,” Michael Pollock, CEO of the Depression and Bipolar Support Alliance (DBSA), said in the news release.¹ “DBSA believes that all individuals have the right to direct their own treatment, and we understand that for many people, ongoing antidepressant therapy alone may not offer meaningful relief. The introduction of new treatment options and continued innovation in mental health, has enabled us to reset expectations for living with depression and offers people hope that achieving lasting wellness and remission is possible.”

READ MORE: Mental and Behavioral Health Resource Center

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REFERENCES

1. FDA approval of Caplyta (lumateperone) has the potential to reset treatment expectations, offering hope for remission in adults with major depressive disorder. News release. Johnson and Johnson. November 6, 2025. Accessed November 6, 2025. https://www.jnj.com/media-center/press-releases/fda-approval-of-caplyta-lumateperone-has-the-potential-to-reset-treatment-expectations-offering-hope-for-remission-in-adults-with-major-depressive-disorder

2. Clinical trial of lumateperone as adjunctive therapy in the treatment of patients with major depressive disorder. ClinicalTrials.gov identification: NCT04985942. May 2, 2025. Accessed November 6, 2025. https://clinicaltrials.gov/study/NCT04985942

3. Multicenter study of lumateperone as adjunctive therapy in the treatment of patients with major depressive disorder. ClinicalTrials.gov identification: NCT05061706. May 9, 2025. Accessed November 6, 2025. https://clinicaltrials.gov/study/NCT05061706

4. Durgam S, Earley W, Kozauer S, Chen C, Edwards J, Jain R. 612. Efficacy of lumateperone 42 mg in the treatment of major depressive disorder: a pooled analysis of phase 3 randomized controlled trials. Int J Neuropsychopharmacol. 2025;28(Suppl 2):ii77-ii78. Published 2025 Aug 18. doi:10.1093/ijnp/pyaf052.153