FDA Approves Lumateperone as Add-On Therapy for Major Depressive Disorder

The FDA approved lumateperone (Caplyta; Johnson & Johnson) as an adjunctive treatment for major depressive disorder (MDD) in adults, offering a new option for patients whose symptoms persist despite antidepressant therapy.¹

Lumateperone is a novel antipsychotic that modulates serotonin, dopamine, and glutamate neurotransmission.² Recent data from the 38th European College of Neuropsychopharmacology Annual Congress highlighted its potential as an adjunctive therapy for MDD.

Clinical trials showed significant symptom improvement and potential for remission, with a safety profile similar to placebo.¹ The once-daily oral medication requires no titration and expands lumateperone’s indications, which include schizophrenia and bipolar I and II depression.

“Depression is a complex disorder that affects each person differently, underscoring the urgent need for a range of effective and well-tolerated treatment options,” said Roger S. McIntyre, MS, FRCPC, professor of psychiatry and pharmacology, University of Toronto, in a statement. “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 FDA approval of lumateperone was supported by 2 phase 3, global, double-blind, placebo-controlled trials (Study 501 and Study 502) evaluating its efficacy and safety as an adjunctive treatment for adults with MDD. Participants who continued to experience depressive symptoms despite antidepressant therapy were randomized to receive lumateperone 42 mg or placebo alongside their existing medication. Efficacy was measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impression-Severity (CGI-S) scale.

In Study 501, lumateperone demonstrated a 4.9-point greater reduction in MADRS total score vs. placebo (effect size 0.61) and a 0.7-point greater improvement in CGI-S score (effect size 0.67) at 6 weeks. Study 502 showed similar results, with a 4.5-point MADRS difference (effect size 0.56) and a 0.5-point CGI-S difference (effect size 0.51). Separation from placebo occurred as early as week 1 in Study 501 and week 2 in Study 502.

Across both trials, no new safety concerns were identified. Rates of weight gain, metabolic changes (including lipid and glucose levels), akathisia, and restlessness were similar to placebo. Reports of sexual side effects were uncommon. The most frequently reported adverse events were mild or moderate in nature and included sleepiness, dizziness, nausea, dry mouth, fatigue, and diarrhea.

Long-term data from the 26-week open-label extension study (Study 503) further supported lumateperone’s tolerability, showing a low risk of weight gain, cardiometabolic effects, and extrapyramidal symptoms.

Overall, lumateperone demonstrated a favorable safety and tolerability profile, supporting its use as a well-balanced adjunctive therapy for adults with MDD.

“Caplyta has the potential to become a new standard of care across multiple mental health disorders, including major depressive disorder,” said Bill Martin, PhD, global therapeutic area head, neuroscience, Johnson & Johnson, in a statement. “This approval is a testament to our nearly 70-year commitment of bringing innovative and differentiated therapies that redefine treatment expectations—and introduce the possibility of remission—to patients living with some of today’s most prevalent and debilitating mental health conditions.”

References

1. FDA approval of Caplyta (lumateperone) has the potential to reset treatment expectations, offering hope for remission in adults with major depressive disorder. Johnson & Johnson. Press release. November 6, 2025. Accessed November 6, 2025. https://www.jnj.com/media-center/press-releases/
2. Kuntz L. New ECNP poster data on adjunctive lumateperone for major depressive disorder. Psychiatric Times®. October 10, 2025. Accessed November 6, 2025. https://www.psychiatrictimes.com/view/new-ecnp-poster-data-on-adjunctive-lumateperone-for-major-depressive-disorder