Everything You Need to Know About the Approval of Lumateperone for Major Depressive Disorder

On November 6, 2025, the US Food and Drug Administration (FDA) approved Johnson & Johnson’s lumateperone (Caplyta) as an adjunctive therapy for the treatment of adults with major depressive disorder (MDD).¹ Here's what you need to know:

• Lumateperone (Caplyta) 42 mg daily is a well-tolerated, effective adjunct for adults with MDD not fully responding to antidepressants, offering comparable efficacy to other atypical adjuncts with significantly fewer metabolic and extrapyramidal risks—potentially setting a new standard for adjunctive pharmacotherapy in depression.
• This approval expands Caplyta’s indications beyond schizophrenia and bipolar depression to now include unipolar depression—both adjunctive and monotherapy use in related disorders.
• This approval is based on data from 2 phase 3 RCTs (studies 501 & 502):
• Both showed statistically significant improvements on the MADRS total score at 6 weeks with 42 mg/day Caplyta compared with placebo + antidepressant.
  • Effect size: ~4.5–4.9-point greater reduction vs placebo.
  • Patient populations continued their existing antidepressant regimen.

Open-label extension (Study 503):

• 80% response and 65% remission (MADRS ≤10) at 26 weeks.
• This suggests potential for sustained benefit and remission over time.

• Notable for minimal adverse effects typically seen in other atypical antipsychotics:
  • Low incidence of metabolic effects, weight gain, EPS, and prolactin elevation—comparable with placebo in prior schizophrenia and bipolar studies.
• Most common AEs (>5% and ≥2x placebo) were dry mouth, fatigue, tremor.
• Long-term data reaffirm low risk of weight gain and cardiometabolic impact.
• Clinicians may find it suitable for patients sensitive to metabolic or extrapyramidal side effects from other adjunctive antipsychotics (eg, aripiprazole, brexpiprazole).
• Lumateperone's tolerability and efficacy profile could make it a first-line adjunctive choice for patients not fully responding to SSRIs or SNRIs. It has the potential to bridge the gap between antidepressants and traditional atypical antipsychotics.
• Adjunctive use is recommended for adults with partial response to standard antidepressant therapy.
• Be sure to monitor mild sedation/fatigue, tremor, dry mouth; otherwise, there is minimal metabolic monitoring burden.
• As to onset, measurable improvement was observed by week 6, with potential for remission by 6 months in responders.
• Lumateperone could become a preferred adjunct in MDD for patients where metabolic or movement adverse effects are major concerns.

Suresh Durgam, MD, the primary investigator on these trials, discussed with Psychiatric Times the data and what Caplyta can offer patients.

"People living with MDD often spend years cycling through treatment options, searching for something that will provide adequate relief. For patients experiencing partial relief with their current treatment, adding Caplyta can offer hope that complete symptom relief is possible," said Durgam. "Remission is an important goal of MDD treatment, as patients who fail to achieve remission experience ongoing challenges in their daily lives. Despite treatment, 2 in 3 patients continue to experience lingering symptoms of depression, significantly impacting their quality of life. For patients who are experiencing partial relief from their oral antidepressants, adding Caplyta to their treatment plan can build on the benefit they are already receiving and offer hope that complete relief is possible."