Lumateperone: FDA Approval for Adjunctive Treatment of Major Depressive Disorder In Adults

MDD is one of the most prevalent psychiatric disorders, impacting approximately 22 million adults in the United States. It places a significant economic burden on society and stands as the leading cause of disability in the nation. While oral antidepressants may provide benefits for some, an alarming two-thirds of patients still suffer from residual symptoms despite treatment, severely compromising their quality of life.

Lumateperone, a second-generation antipsychotic, is now recognized as an effective adjunctive therapy to antidepressants for adults with MDD. This marks the fourth approved indication for Lumateperone, which is also utilized in the treatment of schizophrenia and bipolar I or II disorder, either as adjunctive or monotherapy. Such approvals offer vital solutions and alternatives to empower patients in their fight against these mental health challenges.

Understanding MDD and Schizophrenia

Schizophrenia, affecting an estimated 2.8 million adults in the United States, is significantly undertreated, with roughly 40 percent of those affected not receiving the care they need. Untreated schizophrenia can result in devastating episodes of psychosis, hallucinations, and other disruptive behaviors that profoundly affect the lives of both patients and their families. Relapses, defined as the recurrence of symptoms, lead to significant functional decline, increased caregiver burden, and a heightened chance of hospitalization. On average, an adult with schizophrenia experiences nine relapses within less than six years. Therefore, preventing these relapses must be a central focus for the long-term management of this debilitating disorder.

Research reveals that the first three to five years following diagnosis—termed "the critical period"—are crucial for effective treatment, as this phase is when symptoms escalate most rapidly. An all-encompassing treatment plan, which includes medication, therapy, and psychosocial support, is essential for delaying relapses in adults with schizophrenia. Recent studies provide compelling evidence that effective relapse prevention is essential for sustaining long-term patient stability, breaking the cycle of hospitalization, and managing symptom progression.

Highlights of Studies 501 and 502

• Study design: Studies 501 and 502 were pivotal Phase 3, global, randomized, double-blind, placebo-controlled trials.

• Population: Adults with MDD (DSM-5 diagnosis) who had an inadequate response to ongoing antidepressant therapy.
• Intervention: Lumateperone added to an antidepressant versus placebo added to an antidepressant.
• Primary endpoint: Change in MADRS Total score.
• Efficacy results (vs placebo):
  • Study 501: –4.9 points (effect size 0.61)
  • Study 502: –4.5 points (effect size 0.56)
• Overall safety/tolerability: Favorable profile, including metabolic, weight, and movement disorder considerations.
• Pooled safety (≥5% and >2× placebo): dizziness, dry mouth, somnolence/sedation, nausea, fatigue, diarrhea.
• Key safety notes: Metabolic and weight changes comparable to placebo; low incidence of extrapyramidal symptoms (EPS) 

Insights from Study 503

• Study design: Study 503 was a 26-week, open-label extension evaluating adjunctive lumateperone 42 mg in patients who completed Study 501 or 502.
• Primary endpoint (safety/tolerability): Assessed via
  • Adverse events (AEs)
  • Extrapyramidal symptoms (EPS)
  • Suicidality
  • Changes in laboratory parameters, vital signs, and ECG measures
• Secondary endpoint (symptom outcomes): Improvement/maintenance of depressive symptoms, measured by
  • MADRS Total score change
  • CGI-S score change (from baseline to Week 26)
• Key safety findings: Minimal changes from baseline in
  • Body morphology
  • Cardiometabolic laboratory values
  • Prolactin
  • Pulse rate and blood pressure
  • ECG measures
• Efficacy outcomes (26 weeks):
  • Response rate: 80%
  • Remission rate: 65% (MADRS ≤ 10) at ~6 months
  • Suicidality: No serious suicidal ideation or behavior reported
• Symptom improvement (baseline to Week 26):
  • MADRS: –22.9
  • CGI-S: –2.7

Empowering Patients with Lumateperone

Lumateperone (CAPLYTA®), dosed at 42 mg once daily, is an atypical antipsychotic approved for adults as an adjunctive therapy with antidepressants for major depressive disorder. This treatment provides an important option for those seeking effective management of their mental health challenges.

Source

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. November 6, 2025. Accessed December 2025
2. Supplemental new drug application submitted to U.S. FDA for CAPLYTA® (lumateperone) with data demonstrating significant schizophrenia relapse prevention compared to placebo. News release. July 8, 2025. Accessed December 2025