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Depression in adults

Last reviewed: 30 Oct 2025
Last updated: 28 Nov 2025
28 Nov 2025

FDA approves novel antipsychotic lumateperone as a new adjunctive treatment for depression

The Food and Drug Administration (FDA) has approved lumateperone, a drug originally developed to treat psychosis, as an adjunctive treatment for major depressive disorder.

Lumateperone is an atypical antipsychotic with a distinctive mechanism of action. It is a serotonin 5-HT2A receptor antagonist and a partial agonist at central dopamine D2 receptors​. Already approved for schizophrenia and depressive episodes associated with bipolar disorder, lumateperone gained approval in November 2025 as an adjunctive therapy to antidepressants for major depressive disorder in adults who experience only partial response to standard antidepressants.

The decision was underpinned by two positive phase 3 randomized controlled trials, demonstrating that lumateperone, when added to an oral antidepressant, significantly reduced depressive symptoms compared with placebo. Participants tolerated the treatment well over six weeks, with somnolence, dry mouth, diarrhea, and dizziness the most frequently reported adverse effects. Importantly, rates of metabolic disturbance, extrapyramidal symptoms, and prolactin elevation, often problematic with other antipsychotic augmentation strategies, remained low.[382][383]​ An accompanying open-label extension study suggests this favorable tolerability profile may persist over 6 months.[384]

Lumateperone’s unique mechanism of action and safety profile may make it a valuable option in the future for select patients with depression, particularly those with a partial response to antidepressants, or for whom there are concerns about tolerability with other augmentation treatments. However, longer-term and real-world data are lacking, and head-to-head trials with established augmentation drugs are still needed. Additionally, availability in the US is limited by cost. Lumateperone is not currently approved in Europe.

See Management: emerging

Original source of update

Summary

Definition

History and exam

Key diagnostic factors

  • depressed mood
  • anhedonia
  • functional impairment
Full details

Other diagnostic factors

  • weight change
  • libido changes
  • sleep disturbance
  • changes in movement
  • low energy
  • excessive guilt
  • poor concentration
  • suicidal ideation
  • somatic symptoms
  • bipolar disorder excluded
  • substance abuse/medication side effects excluded
  • medical illness excluded
  • schizophrenia excluded
Full details

Risk factors

  • postpartum status
  • personal or family history of depressive disorder or suicide
  • history of an anxiety disorder, or anxiety symptoms
  • adverse childhood experiences
  • dementia
  • corticosteroid use
  • interferon use
  • oral contraceptive use
  • coexisting medical conditions
  • female sex
  • comorbid substance use
  • personality disorders
  • history of violent victimization
  • obesity
  • older age (≥65 years)
  • separated/divorced marital status
Full details

Diagnostic tests

1st tests to order

  • clinical diagnosis
  • metabolic panel
  • CBC
  • thyroid function tests
  • Patient Health Questionnaire-2 (PHQ-2)
  • Patient Health Questionnaire-9 (PHQ-9)
  • Edinburgh Postnatal Depression Scale
  • Geriatric Depression Scale
  • Cornell Scale for Depression in Dementia
Full details

Tests to consider

  • 24-hour free cortisol
  • vitamin B12
  • folic acid
Full details

Treatment algorithm

ACUTE

at risk of harm to self or others (psychotic, suicidal, severe psychomotor retardation impeding activities of daily living, catatonia, or severe agitation): nonpregnant

at risk of harm to self or others (psychotic, suicidal, severe psychomotor retardation impeding activities of daily living, catatonia, or severe agitation): pregnant

more severe depression (PHQ score ≥16): nonpregnant

less severe depression (PHQ <16): nonpregnant

treatment-resistant/refractory depression

pregnant

ONGOING

treatment responsive

recurrent episode

Contributors

Authors

Dean F. MacKinnon, MD

Associate Professor

Psychiatry and Behavioral Sciences

The Johns Hopkins Hospital

Baltimore

MD

Disclosures

DFM declares that he has no competing interests.

Acknowledgements

Dr Dean F. MacKinnon would like to gratefully acknowledge Dr Roger S. McIntyre, Dr Tonya Fancher, and Dr Richard Kravitz, the previous contributors to this topic.

Disclosures

RSM has received research funds from Stanley Medical Research Institute and National Alliance for Research on Schizophrenia and Depression (NARSAD). RSM is on the advisory board for AstraZeneca, Bristol-Myers Squibb, France Foundation, GlaxoSmithKline, Janssen-Ortho, Solvay/Wyeth, Eli Lilly, Organon, Lundbeck, Biovail, Pfizer, Shire, and Schering-Plough. RSM is on the Speakers Bureau for Janssen-Ortho, AstraZeneca, Eli Lilly, Lundbeck, Biovail, and Wyeth. RSM has received research grants from Eli Lilly, Janssen-Ortho, Shire, and AstraZeneca. RSM has received travel funds from Bristol-Myers Squibb. TF declares that she has no competing interests. RK has received research grants from Pfizer on non-depression-related topics.

Peer reviewers

Christopher Dowrick, BA MBChB MSc MD

Emeritus Professor

University of Liverpool

UK

Disclosures

CD has been reimbursed by Novartis for participating in an educational event.

Erin K. Ferenchick, MD

Center for Family and Community Medicine

Columbia University Medical Center

Upper Manhattan

NY

Disclosures

EKF declares that she has no competing interests.

Peer reviewer acknowledgements

BMJ Best Practice topics are updated on a rolling basis in line with developments in evidence and guidance. The peer reviewers listed here have reviewed the content at least once during the history of the topic.

Disclosures

Peer reviewer affiliations and disclosures pertain to the time of the review.

References

Our in-house evidence and editorial teams collaborate with international expert contributors and peer reviewers to ensure that we provide access to the most clinically relevant information possible.

Key articles

American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 5th ed., text revision (DSM-5-TR). Washington, DC: American Psychiatric Publishing; 2022.

National Institute for Health and Care Excellence. Depression in adults: treatment and management. Jun 2022 [internet publication].Full text

American College of Physicians. Nonpharmacologic and pharmacologic treatments of adults in the acute phase of major depressive disorder: a living clinical guideline from the American College of Physicians. Feb 2023 [internet publication].Full text

Reference articles

A full list of sources referenced in this topic is available to users with access to all of BMJ Best Practice.
  • Differentials

    • Adjustment disorder with depressed mood
    • Substance-/medication- or medical illness-associated and other depressive disorders
    • Bipolar disorder
    More Differentials
  • Guidelines

    • Mental Health Gap Action Programme (mhGAP) guideline for mental, neurological and substance use disorders
    • WHO Clinical descriptions and diagnostic requirements for ICD-11 mental, behavioral and neurodevelopmental disorders (CDDR)
    More Guidelines
  • Patient information

    Depression in adults: what is it?

    Depression in adults: what are the treatment options?

    More Patient information
  • Calculators

    Geriatric Depression Scale

    Depression (any) Screening by a Two Item PHQ-2

    More Calculators
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