FDA
Caplyta gains indication for adjunctive use in major depression
On November 6, 2025, FDA approved Caplyta (lumateperone) as an adjunctive therapy with antidepressants for the treatment of major depressive disorder (MDD) in adults.
Caplyta had previously been approved for the treatment of adults with schizophrenia and for the treatment of depressive episodes associated with bipolar I or II disorder.
Efficacy
Approval was based on positive results from two phase 3, global, double-blind, placebo-controlled trials – Study 501 (NCT04985942) and 502 (NCT05061706) – which both met their primary and key secondary endpoints, providing statistically significant and clinically meaningful improvement in depression symptoms compared with an oral antidepressant plus placebo, as measured by Montgomery-Asberg Depression Rating Scale (MADRS) and Clinical Global Impression Scale-Severity index (CGI-S) total scores.
A large separation in total MADRS score was seen between Caplyta and placebo in Study 501 (-4.9 points, effect size 0.61) and Study 502 (-4.5 points, effect size 0.56), at six weeks. Separation from placebo was seen as early as one week in Study 501 and two weeks in Study 502. Significant reductions in the key secondary endpoint of mean change in total CGI-S scores from baseline were also demonstrated at six weeks in Study 501 (-0.7 points, effect size 0.67) and Study 502 (-0.5 points, effect size 0.51).
Long-term data from the 503 open-label extension safety study (NCT05061719), showed Caplyta was safe and well tolerated, consistent with the safety profile of Studies 501 and 502. Patients experienced low risk of weight gain, cardiometabolic effects, and extrapyramidal symptoms. Caplyta also demonstrated the potential to help patients achieve remission. During this 26-week safety study, 80% of patients responded to treatment and 65% of patients experienced remission (defined as MADRS Total score ≤ 10) at 6 months.
Safety
In the clinical trials, the Caplyta safety profile was consistent with the existing body of clinical data in its schizophrenia and bipolar depression I and II indications. No new safety concerns were identified. Weight gain and metabolic changes (lipid and glucose levels), as well as akathisia and restlessness, were similar to placebo. Reports of sexual side effects weren’t common.
The most common adverse effects in MDD trials were dizziness, dry mouth, somnolence/sedation, nausea, fatigue, and diarrhea.
Sources:
Caplyta (lumateperone) [package insert]. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/209500s016lbl.pdf Revised November 2025. Accessed November 7, 2025.
FDA approval of Caplyta® (lumateperone) has the potential to reset treatment expectations, offering hope for remission in adults with major depressive disorder. [News release]. 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