FDA approves novel antipsychotic lumateperone as a new adjunctive treatment for depression
The US 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 randomised 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, diarrhoea, 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.[381][382] An accompanying open-label extension study suggests this favourable tolerability profile may persist over 6 months.[383]
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.
Summary
Your Organisational Guidance
ebpracticenet urges you to prioritise the following organisational guidance:
Depressie bij volwassenen. DiagnostiekPublished by: Domus Medica | SSMGLast published: 2017La dépression chez l’adultePublished by: Domus Medica | SSMGLast published: 2017Depressie bij volwassenen. BeleidPublished by: Domus MedicaLast published: 2017Definition
History and exam
Key diagnostic factors
- presence of risk factors
- depressed mood
- anhedonia
- functional impairment
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
Risk factors
- postnatal 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
- co-existing medical conditions
- female sex
- comorbid substance use
- personality disorders
- history of violent victimisation
- obesity
- older age (≥65 years)
- separated/divorced marital status
Diagnostic investigations
1st investigations to order
- clinical diagnosis
- metabolic panel
- FBC
- 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
Treatment algorithm
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
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 here.
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