Approximately 17% of adults in North America and Europe use antidepressants, which are effective but can cause various physiological side effects such as hyponatremia, QT prolongation, weight gain, and changes in blood pressure. These adverse effects may lead to poorer psychiatric outcomes and treatment discontinuation. Although clinicians are advised to discuss such side effects during prescribing, comparative evidence remains limited. A recent study published in The Lancet aimed to assess the relative effects of antidepressant monotherapy on renal, cardiometabolic, and hepatic parameters across major psychiatric disorders (bipolar disorder, major depressive disorder [MDD], and anxiety disorder) using network meta-analysis (NMA).
The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and was registered in PROSPERO (CRD42019159328). Researchers searched multiple databases, including the U.S. Food and Drug Administration (FDA) reports, Medline, ClinicalTrials.gov, and PsycINFO (N = 26,252 studies). Selected the single- and double-blinded randomized controlled trials (RCTs) that were published until April 21, 2025, with no language restrictions.
The included trials compared one antidepressant drug with another one or a placebo in patients (≥18 years) with psychiatric disorders for acute therapy (8 weeks). Data on clinical and physiological outcomes were extracted from the included RCTs. Analyses were done in R using NMA, and random meta-analysis models were used to assess publication bias, treatment effects, and heterogeneity. Exploratory and sensitivity analyses were used to examine the demographic influences and associations between changes in depressive symptoms and physiological changes.
Finally, 17 FDA study reports and 151 clinical studies were selected in this NMA. A total of 58,534 patients (mean age = 44.7±15.8 years, female = 62%, male = 38%, White = 74.8%) were included in this analysis. Of whom 41,937 received antidepressant treatment and 16,597 received a placebo. Median treatment duration for all the participants was found to = 8 weeks (IQR: 6.0-8.5). Across 116 studies (n = 44,836 participants), antidepressants showed approximately a 4kg difference in weight change (agomelatine: –2·44 [95% CI –3·74 to –1·13] vs maprotiline: 1·82 [0·88 to 2·77]).
In 80 studies, over 21 beats per minute difference in heart rate was observed in patients who received fluvoxamine (–8·18 [–11·65 to –4·72]) compared to those who received nortriptyline (13·77 [95% CI 10·42 to 17·11]). More than 11 mmHg difference in systolic blood pressure (nortriptyline: –6·68 [–12·09 to –1·26] vs duloxetine: 1·59 [0·59 to 2·60]) among 73 studies. Antidepressants such as venlafaxine (0·22 [0·11 to 0·32]), desvenlafaxine (0·27 [95% CI 0·16 to 0·38]), duloxetine (0·17 [0·08 to 0·27]), and paroxetine (0·16 [0·03 to 0·30]) increases total cholesterol levels and duloxetine also raised glucose levels (0·30 [95% CI 0·08 to 0·53]).
Levomilnacipran, duloxetine, and desvenlafaxine elevated the levels of liver enzymes such as ALP, AST, and ALT. However, these changes were not clinically significant. No antidepressant meaningfully affected the QTc, renal markers, and electrolytes. Higher baseline weight predicted greater rises in blood pressure (n = 38, estimate = 0·23 mmHg per 1 kg increase in weight [95% CI 0·08–0·37]; p = 0·0018; pFDR = 0·0081) and liver enzymes as well as older age predicted higher glucose levels (n = 11, estimate = 0·01 mmol/L per 1 year increase in age [0·01–0·02], p <0·0001, pFDR <0·0001). There was no association observed between metabolic alterations and improvements in depressive symptoms.
Study limitations included inconsistency across most NMAs, possible publication bias, lack of sex-stratified data, inclusion of short-term RCTs, and limited data for key metabolic outcomes.
In conclusion, this study found that antidepressants showed significant differences in cardiometabolic effects. Hence, there was a need to update the treatment guidelines to reflect these physiological risks. Antidepressant selection should be individualized based on clinicians, patients’ preferences, and carers.
Reference: Pillinger T, Arumuham A, McCutcheon RA, et al. The effects of antidepressants on cardiometabolic and other physiological parameters: a systematic review and network meta-analysis. The Lancet. 2025. doi:10.1016/S0140-6736(25)01293-0
