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Meta-Analysis
. 2025 Sep 1;82(9):896-904.
doi: 10.1001/jamapsychiatry.2025.1362.

Incidence and Nature of Antidepressant Discontinuation Symptoms: A Systematic Review and Meta-Analysis

Michail Kalfas  1 , Dimosthenis Tsapekos  1 , Matthew Butler  2 , Robert A McCutcheon  3   4   5 , Toby Pillinger  5   6 , Rebecca Strawbridge  1 , Bhagyashree Bhaskar Bhat  7 , Peter M Haddad  8 , Philip J Cowen  3 , Oliver D Howes  5   6 , Dan W Joyce  9 , David J Nutt  10 , David S Baldwin  11 , Carmine M Pariante  1   5 , Gemma Lewis  12 , Allan H Young  1   6   10 , Glyn Lewis  12 , Joseph F Hayes  12 , Sameer Jauhar  1   6   10
Affiliations
Meta-Analysis

Incidence and Nature of Antidepressant Discontinuation Symptoms: A Systematic Review and Meta-Analysis

Michail Kalfas et al. JAMA Psychiatry. .

Erratum in

  • Omitted Disclosures.
    [No authors listed] [No authors listed] JAMA Psychiatry. 2025 Jul 22:e252398. doi: 10.1001/jamapsychiatry.2025.2398. Online ahead of print. JAMA Psychiatry. 2025. PMID: 40694362 Free PMC article. No abstract available.

Abstract

Importance: The incidence and nature of discontinuation symptoms following antidepressant cessation remain unclear.

Objective: To examine the presence of discontinuation symptoms using standardized scales (eg, Discontinuation-Emergent Signs and Symptoms [DESS]) and the incidence of individual discontinuation symptoms in individuals who stop taking antidepressants.

Data sources: The databases Embase, PsycINFO, Ovid MEDLINE, and Cochrane Library were systematically searched from inception until November 7, 2023.

Study selection: Randomized clinical trials (RCTs) reporting discontinuation symptoms using a standardized scale or individual symptoms (eg, adverse events) following antidepressant cessation were included.

Data extraction and synthesis: Data extracted were cross-checked by 2 reviewers. Additional unpublished data from 11 RCTs were included. A random-effects meta-analysis was conducted to calculate standardized mean difference between individuals who discontinued an antidepressant vs those who continued an antidepressant or discontinued placebo. A proportion and odds ratio (OR) meta-analysis was performed to assess incidence of individual discontinuation symptoms compared to placebo. Subgroup analyses were conducted to compare different antidepressants. Data analysis was conducted between September 2024 and December 2024.

Main outcomes and measures: The primary outcomes were incidence and nature of antidepressant discontinuation symptoms measured using standardized or unstandardized scales.

Results: A total of 50 studies were included, 49 of which were included in meta-analyses. The 50 studies included 17 828 participants in total, with 66.9% female participants and mean participant age of 44 years. Follow-up was between 1 day and 52 weeks. The DESS meta-analysis indicated increased discontinuation symptoms at 1 week in participants stopping antidepressants (standardized mean difference, 0.31; 95% CI, 0.23-0.39; number of studies [k] = 11; n = 3915 participants) compared to those taking placebo or continuing antidepressants. The effect size was equivalent to 1 more symptom on the DESS. Discontinuation of antidepressants was associated with increased odds of dizziness (OR, 5.52; 95% CI, 3.81-8.01), nausea (OR, 3.16; 95% CI, 2.01-4.96), vertigo (OR, 6.40; 95% CI, 1.20-34.19), and nervousness (OR, 3.15; 95% CI, 1.29-7.64) compared to placebo discontinuation. Dizziness was the most prevalent discontinuation symptom (risk difference, 6.24%). Discontinuation was not associated with depression symptoms, despite being measured in people with major depressive disorder (k = 5).

Conclusions and relevance: This systematic review and meta-analysis indicated that the mean number of discontinuation symptoms at week 1 after stopping antidepressants was below the threshold for clinically significant discontinuation syndrome. Mood worsening was not associated with discontinuation; therefore, later presentation of depression after discontinuation is indicative of depression relapse.

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Conflict of interest statement

Conflict of Interest Disclosures: Mr Kalfas reported personal fees from Neurocentrx Pharma outside the submitted work; employment by King's College London; and funding by the UK National Institute for Health Research (NIHR) Biomedical Research Centre. Dr Butler reported serving as a Wellcome Trust Doctoral Clinical Research Fellow (227515/Z/23/Z); royalty fees from Taylor & Francis; teaching fees from Infomed; and work as a medic on clinical trials sponsored by pharmaceutical companies, including Janssen, outside the submitted work. Dr McCutcheon reported personal fees from Boehringer Ingelheim, Janssen, Lundbeck, Newron, and Viatris outside the submitted work and codirecting a company that designs digital resources to support treatment of mental ill health. Dr Strawbridge reported personal fees from Janssen outside the submitted work. Dr Haddad reported honoraria for authorship of articles on antidepressant discontinuation symptoms published in journal supplements sponsored by Eli Lilly in 1997, 2000, and 2006. Dr Howes reported research funding from and/or participation in advisory or speaker meetings organized by AbbVie, Alkermes, Angelini, Autifony Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb (Karuna), Delix Therapeutics, Eli Lilly, Elysium, Global Medical Education, Invicro, Janssen, Karuna Therapeutics, Lundbeck, Merck, Neumora Therapeutics, Neurocrine Biosciences, Ono Pharmaceutical, Ontrack Therapeutics/Pangea Bio, Otsuka Pharmaceutical, Recordati, Roche, Rovi, Sosei Heptares (now Nxera Pharma), Sunovion Pharmaceuticals, Teva Pharmaceuticals, and Viatris/Mylan; previous part-time employment by Lundbeck; and holding a patent for the use of dopaminergic imaging. Dr Nutt reported lecture fees from Janssen, Lundbeck, and Takeda; materials for research from Compass Pathways and the Usona Institute; and personal fees from Awakn Life Sciences outside the submitted work. Dr Baldwin reported editors fees from Elsevier and Wiley; grants to his institution from Idorsia, the NIHR Health Technology Assessment, and the NIHR Applied Research Collaborations outside the submitted work; and serving as Medical Patron of Anxiety UK, a mutual aid organization. Dr Pariante reported grants from the NIHR Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London during the conduct of the study; consultant or speaker fees from GH Research, Lundbeck, and Värde Partners; grants from Compass Pathways outside the submitted work; and funding by a Wellcome Trust strategy award to the Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) Consortium (2015-2023; 104025/Z/14/Z), which was also funded by GlaxoSmithKline, Janssen, Lundbeck, and Pfizer. Dr Lewis reported grants to University College London (UCL) from the NIHR during the conduct of the study; grants to UCL from the NIHR and the Wellcome Trust; and travel fees from the European College of Neuropsychopharmacology (ECNP) in 2023 outside the submitted work. Dr Young reported personal fees from Flow Neuroscience, Novartis, Roche, Janssen, Takeda, Noema Pharma, Compass, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Co, LivaNova, Lundbeck, Sunovion, Servier, Allergan, Bionomics, Sumitomo Dainippon Pharma, Sage, Neurocentrx, and Otsuka and grants from the National Institute of Mental Health, Canadian Institutes of Health Research, National Alliance for Research on Schizophrenia and Depression, Stanley Medical Research Institute, Medical Research Council, Wellcome Trust, Royal College of Physicians, British Medical Association, UBC & VGH Hospital Foundation, WEDC, Canadian Cancer Society Depression Research Fund, Michael Smith Health Research BC, National Institute for Health and Care Research, Janssen, and Horizon 2020. Dr Hayes reported consultancy fees from juli health, Swiss Re, and the Wellcome Trust outside the submitted work and a pending patent with juli health. Dr Jauhar reported speaker fees from Boehringer Ingelheim, the Dubai Masterclass conference, Janssen, Lundbeck, and Recordati; serving as a nonpaid member of the UK National Institute for Health and Care Excellence (NICE) Health Technology Appraisal committee; serving as a committee member and on the funding panel for the Wellcome Trust; and advisory board fees from Boehringer Ingelheim and LB Pharmaceuticals outside the submitted work. No other disclosures were reported.

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