FDA approval of CAPLYTA® (lumateperone) has the potential to reset treatment expectations, offering hope for remission in adults with major depressive disorder

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Nov 06, 2025, 07:30 ET

CAPLYTA^®, in combination with an oral antidepressant, demonstrated superior efficacy with a favorable safety and tolerability profile consistent with established indications^1,2

In pivotal trials, CAPLYTA^® did not increase mean weight gain, metabolic changes, or reported sexual side effects^1,2

In a six-month open-label extension safety study, safety profile was consistent with pivotal studies and 80% of MDD patients taking CAPLYTA^® achieved response, with 65% of patients reaching remission from depression³

CAPLYTA^® offers a new option for the 2 in 3 people who experience residual symptoms despite their current antidepressant treatment^1,2,3

TITUSVILLE, N.J., Nov. 6, 2025 /PRNewswire/ -- Johnson & Johnson (NYSE: JNJ) announced today that the U.S. Food and Drug Administration (FDA) approved CAPLYTA^® (lumateperone) as an adjunctive therapy with antidepressants for the treatment of major depressive disorder (MDD) in adults. The approval – the first under J&J leadership following its acquisition of Intra-Cellular Therapies, Inc. – provides patients with a safe and effective new treatment option that can enable a path to remission. CAPLYTA^® makes it easy to start and stay on treatment without the need for titration. Weight gain and other metabolic side effects that typically lead to discontinuation of care were similar to placebo. This approval marks the fourth indication for CAPLYTA^®, the first and only FDA-approved treatment for bipolar I and II depression in adults, as an adjunctive and monotherapy; also approved for the treatment of schizophrenia in adults.

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MDD, or clinical depression, is one of the most common psychiatric disorders, affecting about 22 million American adults.^4,5 While oral antidepressants may offer relief for some, 2 in 3 people living with MDD continue to experience residual symptoms despite treatment, significantly impacting their overall quality of life.⁶ Beyond its toll on patients' wellbeing, MDD has a substantial economic burden and is the leading cause of disability in the U.S.⁷

"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, M.D., FRCPC, Professor of Psychiatry and Pharmacology, University of Toronto.^a "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."

This approval is based on positive results from two Phase 3, global, double-blind, placebo-controlled trials – Study 501 and 502 – which both met their primary and key secondary endpoints, providing statistically significant and clinically meaningful improvement in depression symptoms compared to 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.^1,2

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).^1,2

In pivotal 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 were not common. The most common side effects of CAPLYTA^® include sleepiness, dizziness, nausea, dry mouth, feeling tired, and diarrhea.

"Major depressive disorder affects millions of Americans, impacting how a person feels, thinks, and acts," said Michael Pollock, CEO of Depression and Bipolar Support Alliance (DBSA). "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."

Long-term data, evidenced by the 503 open-label extension safety study, 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.⁸ 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.³

Although its exact mechanism of action is unknown, CAPLYTA^® is characterized by high serotonin 5-HT_2A receptor occupancy and moderate amounts of dopamine D₂ receptor occupancy at therapeutic doses. CAPLYTA^® does not need dose titration, allowing patients to start treatment at the effective dose of 42 mg.⁸

"CAPLYTA^®has the potential to become a new standard of care across multiple mental health disorders, including major depressive disorder," said Bill Martin, Ph.D., Global Therapeutic Area Head, Neuroscience, Johnson & Johnson Innovative Medicine. "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."

This additional FDA approval builds upon the established, robust clinical efficacy and proven real-world safety profile of CAPLYTA^® for the treatment of adults living with schizophrenia and for the treatment of depressive episodes associated with bipolar I or II disorder.

A supplemental New Drug Application (sNDA) for CAPLYTA^® with long-term data evaluating the safety and efficacy of the medication for the prevention of relapse in schizophrenia was recently submitted to the FDA. The medication is also being studied for other neuropsychiatric and neurological disorders. CAPLYTA^® is not FDA-approved for these disorders.

Editor's note:

a. Roger S. McIntyre, M.D., FRCPC, Professor of Psychiatry and Pharmacology, University of Toronto, has provided consulting, advisory, and speaking services to Johnson & Johnson. He has not been paid for any media work.

About Major Depressive Disorder (MDD)
MDD is one of the most common psychiatric disorders and a leading cause of disability worldwide, impacting an estimated 332 million people – or about 4 percent of the population.⁴ In the U.S. alone, about 22 million adults are living with the disease.⁵ While depression is typically treated with a "one-size-fits-all" approach, no two cases are the same. MDD is a complex, heterogeneous disorder involving multiple regions of the brain and presenting with as many as 256 unique symptom combinations. As a result, responses to treatment vary widely.^9,10 With current standard-of-care oral antidepressants, 2 in 3 MDD patients experience residual or persistent symptoms.⁶ Moreover, MDD is a risk factor for the development and worsening of a range of comorbidities, illustrating the importance of integrating mental and general health care.¹¹

About Study 501 and Study 502
Studies 501 and 502 are two positive Phase 3 global, double-blind, placebo-controlled studies in patients with a primary diagnosis of MDD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria who have had an inadequate response to ongoing antidepressant therapy. CAPLYTA^®, added to an antidepressant, demonstrated robust efficacy for the treatment of MDD in the primary endpoint, the MADRS Total score, with a large separation versus placebo of 4.9 points (effect size 0.61) in Study 501 and 4.5 points (effect size 0.56) versus placebo in Study 502. The efficacy of CAPLYTA^® is complemented with a favorable safety and tolerability profile – including a favorable metabolic, weight, and movement disorder profile. In the pooled safety data for Studies 501 and 502, the most commonly reported adverse events that were observed at a rate greater than or equal to 5% for lumateperone and greater than twice the rate of placebo were dizziness, dry mouth, somnolence/sedation, nausea, fatigue, and diarrhea. Importantly, metabolic and weight changes were similar to placebo and the rates of extrapyramidal symptoms were low.

About Study 503
Study 503 is a 26-week, open-label extension study that investigated the long-term safety of adjunctive CAPLYTA^® 42mg in patients who completed Study 501 or 502. The primary endpoint was safety and tolerability of CAPLYTA^®, measured by adverse events (AEs), extrapyramidal symptoms (EPS), suicidality, and changes in laboratory parameters, vital signs, and electrocardiogram (ECG) measures. The secondary endpoint was improvement/maintenance of depressive symptoms, measured by MADRS Total score and CGI-S score change from Study 501 or 502 baseline to Week 26 of open-label treatment. Mean changes from baseline to end of treatment were minimal for body morphology, cardiometabolic laboratory values, prolactin levels, pulse rate, blood pressure, and ECG measures. During the 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. No patients reported emergence of serious suicidal ideation or suicidal behavior during the study. Symptoms of depression improved as measured by mean change from baseline to Week 26 in MADRS Total score (−22.9) and CGI-S score (−2.7).

About CAPLYTA^® (lumateperone)
CAPLYTA^® 42 mg is an oral, once daily atypical antipsychotic approved in adults as an adjunctive therapy with antidepressants for major depressive disorder (MDD), schizophrenia, and depressive episodes associated with bipolar I or II disorder (bipolar depression), as monotherapy, and as adjunctive therapy with lithium or valproate.

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-HT_2A receptors and partial agonist activity at central dopamine D₂ receptors.

INDICATIONS

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

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.

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).

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. Tell your healthcare provider 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 1-888-611-4824 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.

US-CAP-2500827

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

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.

Cautions Concerning Forward-Looking Statements

For full financial data, non-GAAP reconciliations and cautionary statements, please refer to Johnson & Johnson's earnings release issued on October 14, 2025, available at https://www.investor.jnj.com/financials/quarterly-results/default.aspx

This document contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding future operating and financial performance. You are cautioned not to rely on these forward-looking statements, which are based on current expectations of future events. For important information about the risks and uncertainties that could cause actual results to vary materially from the assumptions, expectations, and projections expressed in any forward-looking statements, review the "Note to Investors Concerning Forward-Looking Statements" included in the Johnson & Johnson earnings release issued on October 14, 2025, as well as the most recently filed Johnson & Johnson Reports on Forms 10-K and 10-Q. Johnson & Johnson does not undertake to update any forward-looking statement as a result of new information or future events or developments.

Footnotes

Martin M. Lumateperone as Adjunctive Therapy in Patients with Major Depressive Disorder: Results from a Randomized, Double-Blind, Phase 3 Trial. American Society of Clinical Psychopharmacology Annual Meeting; May 27-30, 2025. Poster W31
Earley W. Adjunctive Lumateperone in Patients with Major Depressive Disorder: Results from an Additional Randomized, Double-Blind, Phase 3 Trial. American College of Neuropsychopharmacology Annual Meeting; December 8-11, 2024. Poster P232
Earley W. Long-Term Adjunctive Lumateperone Treatment in Major Depressive Disorder: Results from a Six-Month Open-Label Extension Study. American Psychiatric Association Annual Meeting; May 17-21, 2025. Poster P08-063
Depressive disorder (depression). World Health Organization. Accessed November 2025. https://www.who.int/news-room/fact-sheets/detail/depression
Key substance use and mental health indicators in the United States: Results from the 2023 National Survey on Drug Use and Health. Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. Accessed November 2025. https://www.samhsa.gov/data/sites/default/files/reports/rpt47095/National%20Report/National%20Report/2023-nsduh-annual-national.pdf
Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006 Nov;163(11):1905-17. doi:10.1176/ajp.2006.163.
Zhdanava M, Pilon D, Ghelerter I, et al. The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United States. J Clin Psychiatry. 2021;82(2):20m13699. doi:10.4088/JCP.20m13699
CAPLYTA^® [Prescribing Information]. Bedminster, NJ: Intra-Cellular Therapies, Inc.
Su YA and Si T. Progress and challenges in research of the mechanisms of anhedonia in major depressive disorder. Gen Psychiatr. 2022;35:e100724. doi:10.1136/gpsych-2021-100724
Pandya M, et al. Where in the Brain Is Depression? Curr Psychiatry Rep. 2012;14:634–642. doi:10.1007/s11920-012-0322-7
Zhu L et al. Economic burden and antidepressant treatment patterns among patients with major depressive disorder in the United States. J Manag Care Spec Pharm. 2022;28(11-a suppl):S2–S13. doi:10.18553/jmcp.2022.28.11-a.s1