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Antidepressants Differ Significantly in Cardiometabolic Side Effects

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A large analysis reveals clinically relevant differences in weight, blood pressure, and heart rate across 30 antidepressants.

A new study offered compelling evidence that antidepressants vary in their physiological impact, especially on cardiometabolic parameters.1

“Our findings show frequent and heterogeneous physiological side-effects across different antidepressants,” wrote study investigator Toby Pillinger, PhD, from the Institute of Psychiatry, Psychology and Neuroscience at King’s College London, and colleagues.1 “The magnitude of some physiological alterations, in particular change in weight, heart rate, and blood pressure, is large and clinically relevant.”

In this study, investigators compared and ranked antidepressants based on physiological side effects, including weight, total cholesterol, glucose, heart rate, systolic blood pressure, diastolic blood pressure, corrected QT interval, aspartate transferase (AST), and alanine transaminase (ALT). The team searched MEDLINE, EMBASE, PsycINFO, ClinicalTrials.gov, and the US Food & Drug Administration (FDA) website from database inception to April 21, 2025, including 151 single- and double-blinded randomized controlled trials (RCTs) comparing antidepressants and placebo in acute monotherapy of any psychiatric disorder (n = 151) and 17 FDA reports.

The sample included 58,534 patients (mean age, 44.7 years; 62% females), comparing 30 antidepressants with placebo. RCTs had a median treatment duration of 8 weeks (IQR, 6.0 – 8.5).

The 30 antidepressants included agomelatine (n=2), amitriptyline (n=20), bupropion (n = 3), citalopram (n=5), clomipramine (n=3), desipramine (n=1), desvenlafaxine (n=11), doxepin (n=3), duloxetine (n=27), escitalopram (n=9), fluoxetine (n=32), fluvoxamine (n=7), imipramine (n=15), levomilnacipran (n=6), maprotiline (n=3), mianserin (n=2), milnacipran (n=3), mirtazapine (n=10), moclobemide (n=4), nortriptyline (n=4), paroxetine (n=27), phenelzine (n=1), reboxetine (n=5), selegiline (n=1), sertraline (n=14), trazodone (n=4), trimipramine (n=3), venlafaxine (n=31), vilazodone (n=6), and vortioxetine (n=2). Trials evaluated these antidepressants for MDD, MDD with generalized anxiety disorder (GAD), MDD with pain, MDD with multi-somatoform disorder, psychotic depression, atypical depression, dysthymia, obsessive compulsive disorder, GAD, social anxiety disorder, panic disorder, PTSD, fibromyalgia, and bipolar affective disorder.

The study found significant differences between antidepressants in terms of metabolic and hemodynamic effects, discovering an approximate 4 kg difference in weight change between agomelatine and maprotiline.

“We estimate that some antidepressants (eg, maprotiline and amitriptyline) cause clinically important weight gain in almost half of individuals prescribed them,” investigators wrote.

Moreover, investigators observed an 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.

The study found strong evidence of the following:

Weight Loss: Agomelatine, maclobemide, fluoxetine, levomilnacipran, sertraline, venlafaxine, duloxetine, citalopram, desvenlafaxine, and paroxetine

Weight Gain: Maprotiline, amitriptyline, milnacipran, mianserin, fluvoxamine, and mirtazapine.

Increased Cholesterol: Desvenlafaxine, venlafaxine, duloxetine

Increased Glucose Concentrations: Duloxetine

Increased Heart Rate: Nortriptyline, clomipramine, imipramine, amitriptyline, doxepin, levomilnacipran, reboxetine, desvenlafaxine, venlafaxine, and duloxetine

Reduced Heart Rate: fluvoxamine and moclobemide

Increased Systolic Blood Pressure: Amitriptyline, levomilnacipran, fluoxetine, venlafaxine, imipramine, desvenlafaxine, and duloxetine

Reduction in Systolic Blood Pressure: Nortriptyline

Increased Diastolic Blood Pressure: amitriptyline, maprotiline, levomilnacipran, venlafaxine, imipramine, desvenlafaxine, and duloxetine

Increase in both AST and ALT: duloxetine and levomilnacipran

Increase in ALT alone: Reboxetine, desvenlafaxine, sertraline, levomilnacipran, venlafaxine, bupropion, paroxetine, and duloxetine

Reduction in Sodium Concentrations: Duloxetine and venlafaxine

Additionally, higher bodyweight was associated with antidepressant-induced increases in systolic blood pressure, ALT, AST. Older baseline age was associated with larger antidepressant-induced increases in glucose.

The study displayed strong evidence of duloxetine, desvenlafaxine, and levomilnacipran increasing AST, ALT, and ALP concentrations, although the rises were not clinically significant. Moreover, the study did not provide strong evidence of any antidepressant significantly affecting corrected QT interval or concentrations of sodium, potassium, urea, or creatinine. Investigators found no link between changes in depressive symptoms and metabolic disturbance.

Antidepressant adverse events can lead to several consequences, including treatment discontinuation and poorer psychiatric outcomes.2 These findings help inform which antidepressants have stronger associations with specific adverse events.

“Given the recognized comorbid physical health burden in people with psychiatric conditions, these results can be used by clinicians and patients to guide the choice of antidepressant,” investigators wrote.1

References

  1. Pillinger T, Arumuham A, McCutcheon R, et al. The effects of antidepressants on cardiometabolic and other physiological parameters: a systematic review and network meta-analysis. 2025. https://doi.org/10.1016/ S0140-6736(25)01293-0
  2. Milea D, Guelfucci F, Bent-Ennakhil N, Toumi M, Auray JP. Antidepressant monotherapy: A claims database analysis of treatment changes and treatment duration. Clin Ther. 2010;32(12):2057-2072. doi:10.1016/j.clinthera.2010.11.011



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