Background: Antidepressants (ADs) are commonly prescribed medications, but their long-term health effects are debated. ADs disrupt multiple adaptive processes regulated by evolutionarily ancient biochemicals, potentially increasing mortality. However, many ADs also have anticlotting properties that can be efficacious in treating cardiovascular disease. We conducted a meta-analysis assessing the effects of ADs on all-cause mortality and cardiovascular events in general-population and cardiovascular-patient samples. Methods: Two reviewers independently assessed articles from PubMed, EMBASE, and Google Scholar for AD-related mortality controlling for depression and other comorbidities. From these articles, we extracted information about cardiovascular events, cardiovascular risk status, and AD class. We conducted mixed-effect meta-analyses testing sample type and AD class as moderators of all-cause mortality and new cardiovascular events. Results: Seventeen studies met our search criteria. Sample type consistently moderated health risks. In general-population samples, AD use increased the risks of mortality (HR = 1.33, 95% CI: 1.14-1.55) and new cardiovascular events (HR = 1.14, 95% CI: 1.08-1.21). In cardiovascular patients, AD use did not significantly affect risks. AD class also moderated mortality, but the serotonin reuptake inhibitors were not significantly different from tricyclic ADs (TCAs) (HR = 1.10, 95% CI: 0.93-1.31, p = 0.27). Only “other ADs” were differentiable from TCAs (HR = 1.35, 95% CI: 1.08-1.69). Mortality risk estimates increased when we analyzed the subset of studies controlling for premedication depression, suggesting the absence of confounding by indication. Conclusions: The results support the hypothesis that ADs are harmful in the general population but less harmful in cardiovascular patients.

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IMPORTANCE Antidepressants are commonly used worldwide to treat major depressive disorder. Symptomatic response to antidepressants can vary depending on differences between individuals; however, this variability may reflect nonspecific or random factors.OBJECTIVES To investigate the assumption of systematic variability in symptomatic response to antidepressants and to assess whether this variability is associated with severity of major depressive disorder, antidepressant class, or year of study publication.DATA SOURCES Data used were from a recent network meta-analysis of acute treatment with licensed antidepressants in adults with major depressive disorder. The following databases were searched from inception to January 8, 2016: the Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, and PsycINFO. Additional sources were international trial registries, drug approval agency websites, and key scientific journals.STUDY SELECTION Analysis was restricted to double-blind, randomized placebo-controlled trials with available data at the study's end point. DATA EXTRACTION AND SYNTHESISBaseline and end point means, SDs, number of participants in each group, antidepressant class, and publication year were extracted. The data were analyzed between August 14 and November 18, 2019. MAIN OUTCOMES AND MEASURESWith the use of validated methods, coefficients of variation were derived for antidepressants and placebo, and their ratios were calculated to compare outcome variability between antidepressant and placebo. Ratios were entered into a random-effects model, with the expectation that response to antidepressants would be more variable than response to placebo. Analysis was repeated after stratifying by baseline severity of depression, antidepressant class (selective serotonin reuptake inhibitors: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vilazodone; serotonin and norepinephrine reuptake inhibitors: desvenlafaxine and venlafaxine; norepinephrinedopamine reuptake inhibitor: bupropion; noradrenergic agents: amitriptyline and reboxetine; and other antidepressants: agomelatine, mirtazapine, and trazodone), and publication year. RESULTSIn the 87 eligible randomized placebo-controlled trials (17 540 unique participants), there was significantly more variability in response to antidepressants than to placebo (coefficients of variation ratio, 1.14; 95% CI, 1.11-1.17; P < .001). Baseline severity of depression did not moderate variability in response to antidepressants. Variability in response to selective serotonin reuptake inhibitors was lower than variability in response to noradrenergic agents (coefficients of variation ratio, 0.88; 95% CI, 0.80-0.97; P = .01), as was the variability in response to other antidepressants compared with noradrenergic agents (coefficients of variation ratio, 0.87; 95% CI, 0.79-0.97; P = .001). Variability also tended to be lower in studies that were published more recently, with coefficients of variation chang...