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

Phase 3 data suggest CAPLYTA may extend its bipolar depression profile to acute mania in bipolar I disorder, pending further results and approval.

Rhea-AI Summary

Johnson & Johnson (JNJ) reported positive topline results from a pivotal Phase 3 trial of CAPLYTA (lumateperone) 42 mg once daily for acute manic episodes in adults with bipolar I disorder.

The randomized, double-blind Study 451 showed CAPLYTA achieved 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), with significant improvement observed as early as Day 3 and sustained through Week 3. Patients on CAPLYTA also had greater improvement in overall illness severity on the Clinical Global Impression–Severity scale (least-squares mean difference −0.5; p<.0001) and roughly double the clinical response rate, defined as ≥50% YMRS reduction, compared with placebo (45.8% vs. 20.9%; p<.0001). CAPLYTA’s safety and tolerability were consistent with its established profile, with low discontinuation rates; common treatment-related adverse events ≥5% and at least twice placebo were dry mouth and nausea (each 7.9% vs. 3.4% and 2.3%, respectively). CAPLYTA is not approved for treating manic episodes in bipolar I disorder, and a second Phase 3 mania study has completed enrollment with data analysis ongoing.

Positive

• Primary endpoint met: 4.8-point greater YMRS reduction vs. placebo at Week 3 (effect size −0.69; p<.0001).
• Rapid onset: statistically significant YMRS improvement seen by Day 3 and sustained through Week 3.
• Clinical response doubled: ≥50% YMRS reduction in 45.8% on CAPLYTA vs. 20.9% on placebo (p<.0001).
• Key secondary met: greater improvement in CGI-S overall illness severity (LSMD −0.5; p<.0001).
• Safety profile described as consistent with existing CAPLYTA experience with low discontinuation rates.

Negative

• CAPLYTA is not approved for treatment of manic episodes in bipolar I disorder.
• Treatment-related AEs: dry mouth 7.9% vs. 3.4% and nausea 7.9% vs. 2.3% for CAPLYTA vs. placebo.
• Boxed risks: increased mortality in elderly with dementia-related psychosis and elevated risk of suicidal thoughts and actions in patients 24 and younger.

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CAPLYTA^® significantly reduced the signs and symptoms of acute manic episodes associated with bipolar I disorder as early as Day 3, with benefits sustained through Week 3

Results build on the established efficacy, safety and tolerability profile of CAPLYTA^®, further supporting its potential to reach more patients across bipolar I and II disorders

TITUSVILLE, N.J., Sept. 21, 2026 /PRNewswire/ -- Johnson & Johnson (NYSE: JNJ) today 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 in a late-breaking presentation at the 2026 Psych Congress Annual Meeting (September 15-19, New Orleans, LA), among 24 Johnson & Johnson neuropsychiatry presentations featured at this year's meeting.

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.¹ Manic episodes, a defining feature of bipolar I disorder, can escalate quickly and often require hospitalization.^2,3 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.⁴ 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.^a "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).⁴

• 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.
• 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).
• 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).
• 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.

Editor's Note
^a Michael E. Thase, M.D., Professor of Psychiatry and Chief, Division of Mood and Anxiety Disorders Treatment & Research Program, University of Pennsylvania, has provided consulting, advisory, and speaking services to Johnson & Johnson. He has not been paid for any media work.

ABOUT BIPOLAR MANIA
Bipolar disorder affects an estimated 37 million people worldwide.¹ Mania is a defining feature of bipolar I disorder—a period of abnormally elevated or irritable mood and/or increased energy or activity that most people experience alongside depressive episodes over the course of the illness.² Symptoms of mania can include grandiosity, decreased need for sleep, racing thoughts, distractibility, and risk-taking behavior.² Manic episodes can escalate quickly, often requiring hospitalization for safety and treatment.³ These noticeable behavioral changes often differ markedly from an individual's baseline and can have serious consequences for a person's safety, relationships, career, and finances, contributing to its standing as one of the leading causes of disability worldwide.¹ Rapid and sustained control of manic symptoms remains an important treatment goal in the management of bipolar I disorder.

ABOUT CAPLYTA^® (lumateperone)
CAPLYTA^® is an oral, once daily atypical antipsychotic approved by the U.S. Food and Drug Administration in adults for the treatment of depressive episodes associated with bipolar I or II disorder (bipolar depression), as monotherapy or as adjunctive therapy with lithium or valproate; for the treatment of schizophrenia; and as adjunctive therapy with antidepressants for the treatment of major depressive disorder (MDD).

CAPLYTA^® is not approved for the treatment of manic episodes associated with bipolar I disorder.

While the mechanism of action of CAPLYTA^® is unknown, the efficacy of CAPLYTA^® could be mediated through a combination of antagonist activity at central serotonin 5-HT2A receptors and partial agonist activity at central dopamine D₂ receptors.

CAPLYTA^® IMPORTANT SAFETY INFORMATION

What is CAPLYTA (lumateperone)?

CAPLYTA^® (lumateperone) is a prescription medicine used in adults along with an antidepressant to treat major depressive disorder (MDD); to treat depressive episodes associated with bipolar I or bipolar II disorder (bipolar depression) alone or with lithium or valproate; or to treat schizophrenia. It is not known if CAPLYTA is safe and effective in children.

IMPORTANT SAFETY INFORMATION

What is the most important information I should know about CAPLYTA?

• Medicines like CAPLYTA can raise the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). CAPLYTA is not approved for treating people with dementia-related psychosis.
• CAPLYTA and antidepressant medicines increase the risk of suicidal thoughts and actions in people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions.
  • Patients and their families or caregivers should watch for new or worsening depression symptoms, especially sudden changes in mood, behaviors, thoughts, or feelings. This is very important when CAPLYTA or an antidepressant medicine is started or when the dose is changed.
  • Report any changes in these symptoms to your healthcare provider immediately.

thoughts about suicide or dying new or worse depression new or worse anxiety suicide attempts an extreme increase in activity and talking (mania)

feeling very agitated or restless trouble sleeping panic attacks new or worse irritability

acting aggressive, being angry or violent acting on dangerous impulses other unusual changes in behavior or mood

Do not take CAPLYTA if you are allergic to any of its ingredients. Get emergency medical help if you are having an allergic reaction (e.g., rash, itching, hives, swelling of the tongue, lip, face, or throat).

What are the possible side effects of CAPLYTA?

CAPLYTA may cause serious side effects, including:

• Stroke (cerebrovascular problems) in elderly people with dementia-related psychosis that can lead to death.
• Neuroleptic malignant syndrome (NMS): high fever, confusion, changes in your breathing, heart rate, and blood pressure, stiff muscles, and increased sweating; these may be symptoms of a rare but potentially fatal condition. Contact your healthcare provider or go to the emergency room if you experience signs and symptoms of NMS.
• Uncontrolled body movements (tardive dyskinesia, TD) in your face, tongue, or other body parts. TD may not go away, even if you stop taking CAPLYTA. It may also occur after you stop taking CAPLYTA.
• Problems with your metabolism including high blood sugar, diabetes, increased fat (cholesterol and triglyceride) levels in your blood and weight gain. Your healthcare provider should check your blood sugar, fat levels, and weight before you start and during your treatment with CAPLYTA.
• Extremely high blood sugar levels can lead to coma or death. Call your healthcare provider if you have any of the following symptoms of high blood sugar: feeling very thirsty, hungry, sick to your stomach, needing to urinate more than usual, weak/tired, or confused, or your breath smells fruity.
• Low white blood cell count. Your healthcare provider may do blood tests during the first few months of treatment with CAPLYTA.
• Decreased blood pressure (orthostatic hypotension). You may feel lightheaded, dizzy, or faint when you rise too quickly from a sitting or lying position.
• Falls. CAPLYTA may make you sleepy or dizzy, may cause a decrease in your blood pressure when changing position (orthostatic hypotension), and can slow your thinking and motor skills which may lead to falls that can cause broken bones or other injuries.
• Seizures (convulsions).
• Sleepiness, drowsiness, feeling tired, difficulty thinking and doing normal activities. Until you know how CAPLYTA affects you, do not drive, operate heavy machinery, or do other dangerous activities.
• Problems controlling your body temperature so that you feel too warm. Avoid getting overheated or dehydrated while taking CAPLYTA.
• Difficulty swallowing that can cause food or liquid to get into the lungs.

The most common side effects of CAPLYTA include sleepiness, dizziness, nausea, dry mouth, feeling tired, and diarrhea.

These are not all the possible side effects of CAPLYTA.

Before taking CAPLYTA, tell your healthcare provider about all of your medical conditions, including if you: have or have had heart problems or a stroke, high or low blood pressure, diabetes, or high blood sugar, problems with cholesterol, have or have had a low white blood cell count, seizures (convulsions), or kidney or liver problems.

CAPLYTA may cause fertility problems in females and males. You should notify your healthcare provider if you become pregnant or intend to become pregnant while taking CAPLYTA. There is a pregnancy registry for females who are exposed to CAPLYTA during pregnancy. CAPLYTA may cause abnormal involuntary movements and/or withdrawal symptoms in newborn babies exposed to CAPLYTA during the third trimester. Talk to your healthcare provider if you breastfeed or are planning to breastfeed as CAPLYTA passes into breast milk.

Tell your healthcare provider about all the medicines you're taking. CAPLYTA may affect the way other medicines work, and other medicines may affect how CAPLYTA works, causing possible serious side effects. Do not start or stop any medicines while taking CAPLYTA without talking to your healthcare provider. You are encouraged to report negative side effects of prescription drugs. Contact Intra-Cellular Therapies, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CAPLYTA is available in 42 mg, 21 mg, and 10.5 mg capsules.

Please see full Prescribing Information, including Boxed WARNINGS, and Medication Guide for CAPLYTA.

cp-548761v3

About Johnson & Johnson
At Johnson & Johnson, we believe health is everything. Our strength in healthcare innovation empowers us to build a world where complex diseases are prevented, treated, and cured, where treatments are smarter and less invasive, and solutions are personal. Through our expertise in Innovative Medicine and MedTech, we are uniquely positioned to innovate across the full spectrum of healthcare solutions today to deliver the breakthroughs of tomorrow and profoundly impact health for humanity.

Learn more at https://www.jnj.com/ or at www.innovativemedicine.jnj.com. Follow us at @JNJInnovMed.

© Johnson & Johnson and its affiliates 2026. All rights reserved.

Cautions Concerning Forward-Looking Statements
This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 related to product development and the potential benefits and treatment impact of CAPLYTA^® (lumateperone). The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behavior and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's most recent Annual Report on Form 10-K, including in the sections captioned "Cautionary Note Regarding Forward-Looking Statements" and "Item 1A. Risk Factors," and in Johnson & Johnson's subsequent Quarterly Reports on Form 10-Q and other filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com, www.investor.jnj.com or on request from Johnson & Johnson. Johnson & Johnson does not undertake to update any forward-looking statement as a result of new information or future events or developments.

Footnotes

1. World Health Organization. Bipolar disorder. September 2025. Accessed August 2026. https://www.who.int/news-room/fact-sheets/detail/bipolar-disorder 
2. Oliva V., Fico G., De Prisco M. et al. Bipolar disorders: an update on critical aspects. The Lancet Regional Health. 2024;48. doi:10.1016/j.lanepe.2024.101135.
3. Cleveland Clinic. Mania. April 2026. Accessed August 2026. https://my.clevelandclinic.org/health/diseases/21603-mania
4. CAPLYTA BPM poster Cutler A.J., Earley, W.R., Hayes, R. et al. Lumateperone Treatment of Manic Episodes With or Without Mixed Features in Bipolar I disorder: Results From a Double-Blind, Placebo-Controlled, Randomized, Phase 3 Trial. Psych Congress 2026; September 15-19, 2026. Poster 72.

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SOURCE Johnson & Johnson

FAQ

AI-generated questions and answers. How Rhea-AI works. Not financial advice.

What was the design and dosing regimen of the Phase 3 mania study (Study 451)?

Study 451 was a randomized, double-blind, placebo-controlled Phase 3 trial in adults with manic episodes, with or without mixed features, associated with bipolar I disorder. Participants received once-daily CAPLYTA 42 mg or placebo for three weeks.

What key efficacy measures were used to assess CAPLYTA in bipolar I mania?

The primary endpoint was change from baseline in Young Mania Rating Scale (YMRS) total score at Week 3. Secondary measures included overall illness severity using the Clinical Global Impression–Severity (CGI-S) score and clinical response, defined as a ≥50% reduction in YMRS total score.

What are the most common treatment-related adverse events reported in this mania study?

The most common treatment-related adverse events occurring in at least 5% of CAPLYTA-treated patients and at least twice the rate of placebo were dry mouth (7.9% vs. 3.4%) and nausea (7.9% vs. 2.3%).

What is the status of the second Phase 3 mania study of CAPLYTA?

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

For which psychiatric indications is CAPLYTA currently approved?

CAPLYTA is approved in adults for treatment of depressive episodes associated with bipolar I or II disorder (bipolar depression) as monotherapy or adjunctive to lithium or valproate, for treatment of schizophrenia, and as adjunctive therapy with antidepressants for major depressive disorder. It is not approved for treating manic episodes in bipolar I disorder.

What serious safety warnings are associated with CAPLYTA beyond the common adverse events?

Serious risks include increased mortality in elderly patients with dementia-related psychosis, increased risk of suicidal thoughts and actions in people 24 years and younger when used with antidepressants, neuroleptic malignant syndrome, tardive dyskinesia, metabolic problems such as high blood sugar and lipid changes, low white blood cell count, orthostatic hypotension and falls, seizures, problems controlling body temperature, and difficulty swallowing.