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

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.