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 inception to April 21, 2025. We included single/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/diastolic blood pressure, corrected QT (QTc) interval, 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 patients, comparing 30 antidepressants and placebo. Median treatment duration was 8 weeks (IQR: 6-8.5). We observed clinically significant differences between antidepressants in terms of metabolic and haemodynamic effects. This included an approximate 4kg difference in weight-change between agomelatine and maprotiline, over 21 beats-per-minute difference in heart rate-change between fluvoxamine and nortriptyline, and over 11mmHg 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 levels, despite all drugs reducing body weight. There was strong evidence of duloxetine, desvenlafaxine, and levomilnacipran increasing AST, ALT, and ALP levels, although the magnitudes of these alterations were not considered clinically significant. We did not find strong evidence of any antidepressant affecting QTc interval, or levels of sodium, potassium, urea, and creatinine to a clinically significant extent. Higher baseline body weight was associated with larger antidepressant-induced increases in systolic blood pressure, ALT, and AST; 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.
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 inception to April 21, 2025. We included single/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/diastolic blood pressure, corrected QT (QTc) interval, 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 patients, comparing 30 antidepressants and placebo. Median treatment duration was 8 weeks (IQR: 6-8.5). We observed clinically significant differences between antidepressants in terms of metabolic and haemodynamic effects. This included an approximate 4kg difference in weight-change between agomelatine and maprotiline, over 21 beats-per-minute difference in heart rate-change between fluvoxamine and nortriptyline, and over 11mmHg 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 levels, despite all drugs reducing body weight. There was strong evidence of duloxetine, desvenlafaxine, and levomilnacipran increasing AST, ALT, and ALP levels, although the magnitudes of these alterations were not considered clinically significant. We did not find strong evidence of any antidepressant affecting QTc interval, or levels of sodium, potassium, urea, and creatinine to a clinically significant extent. Higher baseline body weight was associated with larger antidepressant-induced increases in systolic blood pressure, ALT, and AST; 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.
| Original language | English |
|---|---|
| Journal | The Lancet |
| Publication status | Accepted/In press - 19 Jun 2025 |