Summary:
Antidepressants are commonly prescribed for psychiatric disorders, including major depressive disorder, anxiety, and bipolar disorder, affecting up to 17% of adults in Europe and North America. While effective, these medications can cause physiological side effects such as weight gain, changes in blood pressure, altered glucose and cholesterol levels, liver enzyme changes, and electrolyte disturbances. Understanding the risk of these effects across different antidepressants is important for treatment decisions, yet comparative data are limited. This study is a meta-analysis of randomized controlled trials examining the physiological impacts of 30 antidepressants. Data from 151 studies and 17 FDA reports were included, covering 58,534 participants. The analysis found marked differences between antidepressants in cardiometabolic and hepatic effects. Weight changes varied by approximately 4kg between agomelatine and maprotiline. Heart rate changes differed between fluvoxamine and nortriptyline, and systolic blood pressure varied between nortriptyline and doxepin. Paroxetine, duloxetine, desvenlafaxine, and venlafaxine increased total cholesterol, and duloxetine increased glucose. Duloxetine, desvenlafaxine, and levomilnacipran elevated liver enzymes. This study shows that antidepressants differ substantially in their physiological effects, particularly regarding weight, blood pressure, heart rate, cholesterol, glucose, and liver function. Clinical guidelines should incorporate these differences, and antidepressant selection should consider individual patient characteristics, baseline health, and treatment preferences to minimize risk.
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.
Article Publication Date: 01/11/2025
DOI: 10.1016/S0140-6736(25)01293-0
