CAPLYTA (lumateperone) shows significant and rapid improvement in bipolar mania in pivotal Phase 3 study – Johnson & Johnson

Johnson & Johnson announced positive topline results from the pivotal Phase 3 study evaluating CAPLYTA (lumateperone) for the treatment of manic episodes with or without mixed features in adults with bipolar I disorder.
The study met its primary endpoint, with CAPLYTA demonstrating a statistically significant and rapid reduction in manic symptoms versus placebo at Week 3, with significant improvement seen as early as Day 3. The findings were presented at the 2026 Psych Congress Annual Meeting, New Orleans, LA.

Bipolar disorder is a complex, lifelong condition affecting an estimated 37 million people worldwide and marked by recurring depressive and manic episodes that can profoundly affect a person’s health and daily life. Manic episodes, a defining feature of bipolar I disorder, can escalate quickly and often require hospitalization. Treatment options remain limited by variability in response and tolerability concerns, underscoring the need for therapies that can provide rapid and robust symptom control.

Study 451 is the first of two pivotal Phase 3 studies evaluating CAPLYTA in adults with manic episodes associated with bipolar I disorder. These findings build on the established efficacy of CAPLYTA in bipolar depression and support its potential to address both depressive and acute manic episodes associated with bipolar I disorder. CAPLYTA is not approved for the treatment of manic episodes associated with bipolar I disorder.

“Mania is among the most dangerous and worrisome phases of bipolar disorder, and treating it effectively takes more than partial or temporary relief of symptoms; it means bringing the episode itself under control as quickly as possible,” said Michael E. Thase, M.D., Professor of Psychiatry and Chief, Division of Mood and Anxiety Disorders Treatment & Research Program, University of Pennsylvania.“These results are encouraging because CAPLYTA not only significantly improved the symptoms of mania, but did so as early as Day 3, with benefits sustained through Week 3, supporting its potential to meaningfully advance how we treat acute mania in bipolar I disorder.”

The Phase 3 randomized, double-blind study evaluated once-daily CAPLYTA 42mg versus placebo over three weeks in adults with manic episodes, with or without mixed features, associated with bipolar I disorder (Study 451; NCT06462586).

i) Rapid improvement in manic symptoms: The study met the primary endpoint, with CAPLYTA demonstrating a statistically significant 4.8-point greater reduction in Young Mania Rating Scale (YMRS) total score versus placebo at Week 3 (effect size −0.69; p<.0001). Significant improvement was observed as early as Day 3 and sustained through Week 3.

ii) Improvement in overall illness severity: Patients treated with CAPLYTA also showed significantly greater improvement in overall illness severity versus placebo at Week 3, as measured by the Clinical Global Impression–Severity (CGI-S) score, a key secondary endpoint (least-squares mean difference [LSMD], –0.5; P<.0001).

iii) Greater clinical response: Twice as many patients treated with CAPLYTA achieved clinical response, defined as a ≥50% reduction in YMRS total score, compared to placebo (45.8% vs. 20.9%; p<.0001).

iv) Safety and tolerability consistent with established profile: CAPLYTA was well-tolerated, with low rates of discontinuation and a safety profile consistent with its established profile. The most common treatment-related adverse events (AEs) reported at a rate of at least 5% with CAPLYTA and at least twice the rate of placebo were dry mouth (7.9% vs. 3.4%) and nausea (7.9% vs. 2.3%).

“Bipolar I disorder is a lifelong, cycling illness, and managing it means navigating both manic and depressive episodes over time, each with distinct treatment needs,” said Jane Tiller, Vice President, Global Head of Development, Neuroscience, Johnson & Johnson. “These Phase 3 results build on the established efficacy of CAPLYTA in bipolar depression and represent an important step in evaluating its potential to address both depressive and acute manic episodes associated with bipolar I disorder.”

A second pivotal Phase 3 study (Study 452) evaluating CAPLYTA for the treatment of manic episodes in adults with bipolar I disorder has been completed, and data analysis is underway.