From Bipolar to Unipolar: Lumateperone FDA Approved as Adjunct for MDD
Lumateperone is an oral, once-daily atypical antipsychotic developed by Intra‑Cellular Therapies (later acquired by Johnson & Johnson).
- Initially approved in the U.S. in December 2019 for adults with schizophrenia.
- Subsequently, in December 2021 it was approved for depressive episodes associated with bipolar I or II disorder (monotherapy and adjunctive with lithium or valproate).
- More recently, as of November 6, 2025, the FDA approved it for the adjunctive treatment of adult MDD.
In the following video, Dr. Harvinder Singh explores the newly approved CAPLYTA (lumateperone) as adjunctive therapy for Major Depressive Disorder (MDD) — breaking down its clinical relevance for practicing clinicians.
Topics covered in this video:
Existing FDA-Approved Antipsychotics for MDD Augmentation
Lumateperone: Mechanism of Action
Lumateperone’s Path to FDA Approval for MDD
Lumateperone: Dosing, Drug Interactions & Cautions
Lumateperone: Most Common Adverse Reactions
Key Clinical Implications for Medical Professionals
WATCH FULL DISCUSSION
Summary of Findings (Clinical Trial Evidence)
The new MDD adjunctive indication is founded on two pivotal Phase III randomized, double-blind, placebo-controlled trials (referred to as Study 501 and Study 502) plus a longer‐term open‐label extension.
Study 501 (NCT04985942)
Enrolled adults with MDD who had persistent symptoms despite an antidepressant.
Patients randomized to lumateperone 42 mg + antidepressant vs antidepressant + placebo once daily.
Primary endpoint: change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 6.
Lumateperone group achieved a mean separation of –4.9 points versus placebo (effect size ~0.61).
Key secondary endpoint: Clinical Global Impression – Severity (CGI-S) change, also statistically significant.
Safety profile: similar to placebo on weight, metabolic parameters, sexual side-effects; most common adverse events included dizziness, dry mouth, somnolence/sedation.
Study 502 (NCT05061706)
A second confirmatory trial in a similar population.
At Week 6, lumateperone 42 mg + antidepressant achieved a reduction in MADRS of –4.5 points vs placebo (effect size ~0.56).
CGI-S separation also met key secondary endpoint
Open-Label Extension (Study 503)
Six-month open-label safety study in adjunctive MDD population.
Data: ~80% of patients achieved response, and ~65% reached remission (MADRS ≤ 10) at six months.
Tolerability over this extended period remained consistent with prior data, with low incidence of weight gain, metabolic effects, extrapyramidal symptoms.
Key Clinical Implications
New adjunctive option in MDD: For adult patients with MDD who have an inadequate response to an antidepressant, CAPLYTA offers a once-daily adjunctive therapy without the need for titration (42 mg daily) according to the label.
Effect size and clinical meaningfulness: While a ~4.5-4.9 point MADRS separation may appear modest, the effect size (~0.56-0.61) is in line with other approved adjunctive therapies in MDD. The remission rate data (~65% at 6 months) are particularly encouraging.
Tolerability profile: A key differentiator may be the favorable safety/tolerability profile: minimal weight gain or metabolic impact, low sexual side-effect burden, and low EPS risk — important given known adverse-effect burdens of some adjunctive agents.
Positioning in treatment algorithm: CAPLYTA may be implemented as an adjunct in patients with residual depressive symptoms while on antidepressants, especially when concerns exist about tolerability of other adjunctive antipsychotics. Clinical decision-making should weigh individual patient history, comorbidities (e.g., metabolic risk) and prior treatment response.
Remission as a goal: With the remission potential supported by extension data, the pathophysiologic goal of full symptom resolution is reinforced rather than mere partial response.
Labelled population: The current indication is for adjunctive use only — i.e., in combination with an antidepressant. The studies were 6 weeks in duration for acute efficacy; longer-term data (open-label) exist but controlled long-term relapse prevention data are pending.
📚 References
FDA approval of CAPLYTA® (lumateperone) has the potential to reset treatment expectations, offering hope for remission in adults with major depressive disorder. Johnson & Johnson press release. November 6, 2025. JNJ.com+1
Durgam S, Earley WR, Kozauer SG, et al. Lumateperone as adjunctive therapy in patients with major depressive disorder: Results from a randomized, double-blind, Phase 3 trial. J Clin Psychiatry. 2025;86(4):25m15848. Pharmacy Times+1
Intra-Cellular Therapies Announces Positive Topline Results in Second Phase 3 Trial Evaluating Lumateperone as Adjunctive Therapy in Patients With Major Depressive Disorder (Study 502). June 18, 2024. GlobeNewswire+1
Caplyta (lumateperone) prescribing information. Caplyta+1
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