. 2025 Nov 1;406(10515):2063-2077.

doi: 10.1016/S0140-6736(25)01293-0. Epub 2025 Oct 21.

The effects of antidepressants on cardiometabolic and other physiological parameters: a systematic review and network meta-analysis

Toby Pillinger¹, Atheeshaan Arumuham², Robert A McCutcheon³, Enrico D'Ambrosio⁴, Georgios Basdanis⁵, Marco Branco⁶, Richard Carr⁷, Valeria Finelli⁷, Toshi A Furukawa⁸, Siobhan Gee⁵, Adrian Heald⁹, Sameer Jauhar¹⁰, Zihan Ma¹¹, Valentina Mancini¹², Calum Moulton¹³, Georgia Salanti¹⁴, David M Taylor¹⁵, Anneka Tomlinson¹⁶, Allan H Young¹⁰, Orestis Efthimiou¹⁷, Oliver D Howes², Andrea Cipriani¹⁶

Affiliations

¹ Institute of Psychiatry, Psychology and Neuroscience, Department of Psychosis Studies, King's College London, London, UK; South London and Maudsley NHS Foundation Trust, Maudsley Hospital, Denmark Hill, London, UK. Electronic address: toby.pillinger@kcl.ac.uk.
² Institute of Psychiatry, Psychology and Neuroscience, Department of Psychosis Studies, King's College London, London, UK; South London and Maudsley NHS Foundation Trust, Maudsley Hospital, Denmark Hill, London, UK.
³ Institute of Psychiatry, Psychology and Neuroscience, Department of Psychosis Studies, King's College London, London, UK; Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK; Oxford Health NHS Foundation Trust, Oxford, UK.
⁴ Institute of Psychiatry, Psychology and Neuroscience, Department of Psychosis Studies, King's College London, London, UK; Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Bari, Italy.
⁵ South London and Maudsley NHS Foundation Trust, Maudsley Hospital, Denmark Hill, London, UK.
⁶ Department of Psychosis Studies, King's College London, London, UK.
⁷ Institute of Psychiatry, Psychology and Neuroscience, Department of Psychosis Studies, King's College London, London, UK.
⁸ Kyoto University Office of Institutional Advancement and Communications, Kyoto University, Kyoto, Japan.
⁹ The School of Medicine and Manchester Academic Health Sciences Centre, Manchester University, Manchester, UK; Department of Endocrinology and Diabetes, Salford Royal Hospital, Salford, UK.
¹⁰ Division of Psychiatry, Department of Brain Sciences, Imperial College London, The Hammersmith Hospital, London, UK.
¹¹ Division of Psychiatry, University College London, London, UK.
¹² Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK; Oxford Health NHS Foundation Trust, Oxford, UK; Wellcome Centre for Integrative Neuroimaging & Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
¹³ Division of Psychiatry, Department of Brain Sciences, Imperial College London, The Hammersmith Hospital, London, UK; Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, King's College London, London, UK; St Mark's Hospital, London North West University Healthcare NHS Foundation Trust, London, UK.
¹⁴ Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
¹⁵ South London and Maudsley NHS Foundation Trust, Maudsley Hospital, Denmark Hill, London, UK; Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, King's College London, London, UK; Institute of Pharmaceutical Science, King's College London, London, UK.
¹⁶ Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK; Oxford Health NHS Foundation Trust, Oxford, UK; Oxford Precision Psychiatry Lab, National Institute for Health and Care Research Oxford Health Biomedical Research Centre, Oxford, UK.
¹⁷ Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; Institute of Primary Health Care, University of Bern, Bern, Switzerland.

PMID: 41135546
DOI: 10.1016/S0140-6736(25)01293-0

Free article

The effects of antidepressants on cardiometabolic and other physiological parameters: a systematic review and network meta-analysis

Toby Pillinger et al. Lancet. 2025.

Free article

. 2025 Nov 1;406(10515):2063-2077.

doi: 10.1016/S0140-6736(25)01293-0. Epub 2025 Oct 21.

Authors

Affiliations

¹ Institute of Psychiatry, Psychology and Neuroscience, Department of Psychosis Studies, King's College London, London, UK; South London and Maudsley NHS Foundation Trust, Maudsley Hospital, Denmark Hill, London, UK. Electronic address: toby.pillinger@kcl.ac.uk.
² Institute of Psychiatry, Psychology and Neuroscience, Department of Psychosis Studies, King's College London, London, UK; South London and Maudsley NHS Foundation Trust, Maudsley Hospital, Denmark Hill, London, UK.
³ Institute of Psychiatry, Psychology and Neuroscience, Department of Psychosis Studies, King's College London, London, UK; Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK; Oxford Health NHS Foundation Trust, Oxford, UK.
⁴ Institute of Psychiatry, Psychology and Neuroscience, Department of Psychosis Studies, King's College London, London, UK; Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Bari, Italy.
⁵ South London and Maudsley NHS Foundation Trust, Maudsley Hospital, Denmark Hill, London, UK.
⁶ Department of Psychosis Studies, King's College London, London, UK.
⁷ Institute of Psychiatry, Psychology and Neuroscience, Department of Psychosis Studies, King's College London, London, UK.
⁸ Kyoto University Office of Institutional Advancement and Communications, Kyoto University, Kyoto, Japan.
⁹ The School of Medicine and Manchester Academic Health Sciences Centre, Manchester University, Manchester, UK; Department of Endocrinology and Diabetes, Salford Royal Hospital, Salford, UK.
¹⁰ Division of Psychiatry, Department of Brain Sciences, Imperial College London, The Hammersmith Hospital, London, UK.
¹¹ Division of Psychiatry, University College London, London, UK.
¹² Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK; Oxford Health NHS Foundation Trust, Oxford, UK; Wellcome Centre for Integrative Neuroimaging & Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
¹³ Division of Psychiatry, Department of Brain Sciences, Imperial College London, The Hammersmith Hospital, London, UK; Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, King's College London, London, UK; St Mark's Hospital, London North West University Healthcare NHS Foundation Trust, London, UK.
¹⁴ Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
¹⁵ South London and Maudsley NHS Foundation Trust, Maudsley Hospital, Denmark Hill, London, UK; Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, King's College London, London, UK; Institute of Pharmaceutical Science, King's College London, London, UK.
¹⁶ Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK; Oxford Health NHS Foundation Trust, Oxford, UK; Oxford Precision Psychiatry Lab, National Institute for Health and Care Research Oxford Health Biomedical Research Centre, Oxford, UK.
¹⁷ Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; Institute of Primary Health Care, University of Bern, Bern, Switzerland.

PMID: 41135546
DOI: 10.1016/S0140-6736(25)01293-0

Abstract

Background: Antidepressants induce physiological alterations; however, the degree to which these occur in treatment with various antidepressants is unclear. We aimed to compare and rank antidepressants based on physiological side-effects by synthesising data from randomised controlled trials (RCTs).

Methods: We searched MEDLINE, EMBASE, PsycINFO, ClinicalTrials.gov, and the US Food and Drug Administration (FDA) website from database inception to April 21, 2025. We included single-blinded and double-blinded RCTs comparing antidepressants and placebo in acute monotherapy of any psychiatric disorder. We did frequentist random-effects network meta-analyses to investigate treatment-induced changes in weight; total cholesterol; glucose; heart rate; systolic and diastolic blood pressure; corrected QT interval (QTc); sodium; potassium; aspartate transferase (AST); alanine transaminase (ALT); alkaline phosphatase (ALP); bilirubin; urea; and creatinine. We did meta-regressions to examine study-level associations between physiological change and age, sex, and baseline weight. We estimated the correlation between depressive symptom severity change and metabolic parameter change.

Findings: Of 26 252 citations, 151 studies and 17 FDA reports met inclusion criteria. The overall sample included 58 534 participants, comparing 30 antidepressants with placebo. Median treatment duration was 8 weeks (IQR 6·0-8·5). We observed clinically significant differences between antidepressants in terms of metabolic and haemodynamic effects, including an approximate 4 kg difference in weight-change between agomelatine and maprotiline, over 21 beats-per-minute difference in heart rate change between fluvoxamine and nortriptyline, and over 11 mmHg difference in systolic blood pressure between nortriptyline and doxepin. Paroxetine, duloxetine, desvenlafaxine, and venlafaxine were associated with increases in total cholesterol and, for duloxetine, glucose concentrations, despite all drugs reducing bodyweight. There was strong evidence of duloxetine, desvenlafaxine, and levomilnacipran increasing AST, ALT, and ALP concentrations, although the magnitudes of these alterations were not considered clinically significant. We did not find strong evidence of any antidepressant affecting QTc, or concentrations of sodium, potassium, urea, and creatinine to a clinically significant extent. Higher baseline bodyweight was associated with larger antidepressant-induced increases in systolic blood pressure, ALT, and AST, and higher baseline age was associated with larger antidepressant-induced increases in glucose. We did not observe an association between changes in depressive symptoms and metabolic disturbance.

Interpretation: We found strong evidence that antidepressants differ markedly in their physiological effects, particularly for cardiometabolic parameters. Treatment guidelines should be updated to reflect differences in physiological risk, but choice of antidepressant should be made on an individual basis, considering clinical presentation and preferences of patients, carers, and clinicians.

Funding: National Institute for Health Research, Maudsley Charity, Wellcome Trust, Medical Research Council.

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Conflict of interest statement

Declaration of interests TP has received speaker or consultancy fees from Boehringer Ingelheim, Recordati, Lundbeck, Otsuka, Janssen, CNX Therapeutics, Sunovion, ROVI Biotech, Schwabe Pharma, and Lecturing Minds Stockholm AB; he receives book royalties from Wiley Blackwell; and he co-directs a company that designs digital resources to support treatment of mental illness. RAM has participated in advisory and speaker meetings organised by Otsuka, Karuna, Boehringer Ingelheim, and Janssen. GB has participated in speaker meetings organised by Pfizer. SJ has participated in educational speaker meetings organised by Lundbeck, Otsuka, Sunovion, Janssen, and Boehringer Ingelheim. ODH has received investigator-initiated research funding from or participated in advisory and speaker meetings organised by Angelini, Autifony, Biogen, Boehringer Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, Rand, Recordati, Roche, and Viatris–Mylan. AHY has delivered paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: AstraZenaca, Boehringer Ingelheim, Eli Lilly, LivaNova, Lundbeck, Sunovion, Servier, Janssen, Allergan, Bionomics, Sumitomo Dainippon Pharma, COMPASS, Sage, Novartis, and Neurocentrx. AC has received research, educational, and consultancy fees from the Italian Network for Paediatric Trials, CARIPLO Foundation, Lundbeck, and Angelini Pharma outside the submitted work. TAF reports personal fees from Boehringer Ingelheim, Daiichi Sankyo, DT Axis, Micron, Shionogi, SONY, and UpToDate, and a grant from DT Axis and Shionogi, outside the submitted work. TAF has a patent (7448125) and a pending patent (2022–082495), and has licensed intellectual properties for Kokoro-app to DT Axis. ED’A received lecture fees from Lundbeck. DMT has received investigator-initiated research grants and spoken at events for AstraZeneca, Eli Lilly, Janssen, Lundbeck, Otsuka, Viatris, and Recordati, and has shares in Myogenes, Saladax, and 428-Pharma. AT has received research, educational, and consultancy fees from Angelini Pharma and lecture fees from Takeda outside the submitted work. CM has participated in educational speaker meetings organized by AbbVie, Dr Falk, Ferring, Lilly, and Takeda. All other authors declare no competing interests.

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The effects of antidepressants on cardiometabolic and other physiological parameters: a systematic review and network meta-analysis

Affiliations

The effects of antidepressants on cardiometabolic and other physiological parameters: a systematic review and network meta-analysis

Authors

Affiliations

Abstract

Conflict of interest statement

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