Caplyta From Johnson & Johnson

The FDA recently approved lumateperone (Caplyta; Johnson & Johnson) as an adjunct therapy with antidepressants for the treatment of adults with major depressive disorder (MDD).¹

MDD is a condition marked by a persistently low mood and loss of interest in enjoyable activities along with changes in sleep, appetite, and thinking. Nearly 5% to 17% of individuals are affected by MDD at some point in their lives, with symptoms ranging from mild to severe and typically lasting most of the day and nearly every day for at least 2 weeks. Common signs and symptoms include persistent sadness or irritability, loss of interest in usual activities, changes in appetite or weight, sleep problems, low energy, slowed thinking or movement, feelings of worthlessness or guilt, difficulty concentrating, and, in severe cases, thoughts of death or suicide.²

MDD can occur at any age; however, it most often starts in one's 20s and is more common in women and individuals who lack close relationships or are divorced, separated, or widowed. The exact cause of MDD is unknown but is likely a result of a combination of factors, including disruptions in brain chemistry and neural circuits, genetic risk, adverse childhood experiences, and stressful life events.²

Treatment for MDD involves medications, psychotherapy, or both, and previous research shows that using these approaches together is more effective than using either one alone. Although oral antidepressants help some individuals, approximately two-thirds of individuals with MDD still experience lingering symptoms that significantly affect their quality of life.²

Pharmacology and Pharmacokinetics

Lumateperone 42 mg is an oral, once-daily atypical antipsychotic approved for adults as an adjunct to antidepressants for MDD. The treatment is also indicated for schizophrenia and bipolar depression, either alone or with lithium or valproate. The FDA is currently reviewing an additional application for its use in preventing schizophrenia relapse, with further studies underway in other neuropsychiatric and neurological conditions.¹

The oral medication offers a new option for the 2 in 3 individuals who experience residual MDD symptoms despite antidepressant treatment. Although its exact mechanism is unknown, lumateperone works by strongly targeting serotonin 5-HT2A receptors and moderately targeting dopamine D2 receptors. It can be started at its effective 42-mg dose without the need for titration.¹

Clinical Trials

The FDA approval for lumateperone 42 mg is based on data from 2 phase 3 global, double-blind, placebo-controlled trials, ITI-007-501 (NCT04985942) and ITI-007-502 (NCT05061706), which highlighted lumateperone’s efficacy and safety for this indication. Both studies met their primary and key secondary end points, showing statistically significant and clinically meaningful improvements in depression symptoms compared with an oral antidepressant plus placebo, based on the Montgomery-Asberg Depression Rating Scale (MADRS) and Clinical Global Impression Scale-Severity index scores.^1,3,4

In study 501, patients were randomly assigned to receive either a 6-week oral adjunctive placebo (n = 243) or adjunctive lumateperone 42 mg (n = 242), with investigators observing the change from baseline to day 43 in the MADRS total score.¹ Across both studies, lumateperone showed a strong efficacy signal, with MADRS score improvements of 4.9 and 4.5 points over placebo, and it demonstrated a favorable safety profile with minimal metabolic, weight, or movement-related effects. In pooled data, the most common adverse events were dizziness, dry mouth, sleepiness, nausea, fatigue, and diarrhea.¹

Long-term results from the ITI-007-503 open-label extension study (NCT05061719) showed that lumateperone remained safe and well tolerated with a low risk of weight gain, metabolic issues, or extrapyramidal symptoms. Over 26 weeks, 80% of patients responded to treatment and 65% achieved remission, defined as a MADRS score of 10 or below.^1,5

Contraindications, Warnings, and Precautions

Lumateperone can increase the risk of death in older adults with dementia-related psychosis and is not approved for this population. It could also raise the risk of suicidal thoughts and actions in individuals 24 years or younger, especially early in treatment or after dose changes, emphasizing the importance of monitoring any new or worsening mood or behavior changes.¹

REFERENCES

1. FDA approval of CAPLYTA (lumateperone) has the potential to reset treatment expectations, offering hope for remission in adults with major depressive disorder. News release. Johnson & Johnson. November 6, 2025. Accessed November 20, 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

2. Clinical depression (major depressive disorder). Cleveland Clinic. Updated November 30, 2022. Accessed November 20, 2025. https://my.clevelandclinic.org/health/diseases/24481-clinical-depression-major-depressive-disorder

3. Clinical trial of lumateperone as adjunctive therapy in the treatment of patients with major depressive disorder. ClinicalTrials.gov. Updated May 2, 2025. Accessed November 20, 2025. https://www.clinicaltrials.gov/study/NCT04985942

4. Multicenter study of lumateperone as adjunctive therapy in the treatment of patients with major depressive disorder. ClinicalTrials.gov. Updated May 9, 2025. Accessed November 20, 2025. https://www.clinicaltrials.gov/study/NCT05061706

5. An open-label study of lumateperone as adjunctive therapy in the treatment of patients with major depressive disorder. ClinicalTrials.gov. Updated November 3, 2025. Accessed November 20, 2025. https://www.clinicaltrials.gov/study/NCT05061719