Key result
Tricyclic antidepressants are linked to disrupted insulin sensitivity, while SSRIs, SNRIs, and bupropion appear metabolically neutral.
Why the study?
Do FDA-approved antidepressants affect measures of insulin resistance in persons with depression?
Do FDA-approved antidepressants affect measures of insulin resistance in persons with depression?
The effect of antidepressants on insulin sensitivity is mixed, with tricyclic antidepressants potentially causing disruptions, while SSRIs, agomelatine, and bupropion appear metabolically neutral.
BACKGROUND: Persons with depression are disproportionately at risk for developing insulin resistance. Replicated evidence indicates that insulin resistance blunts acute antidepressant response; however, some antidepressants exacerbate insulin resistance risk. Herein, we aim to comprehensively evaluate previous literature reporting on the effects of antidepressants on measures of insulin resistance with the view to disaggregate class- and drug-specific effects. METHODS: A systematic search on PubMed, Ovid and Scopus (inception-July 2025) was conducted, with a manual search of Google Scholar and reference lists. Two reviewers (S.W. and G.H.L.) independently screened studies. Clinical trials investigating FDA-approved antidepressants on a validated measure of insulin resistance were included. Studies were assessed using the National Institute of Health quality assessment tools. RESULTS: Select tricyclic antidepressants (i.e., nortriptyline, amitriptyline, imipramine) were associated with acute and long-term disruptions in insulin sensitivity. SSRIs were not associated with acute alterations in insulin sensitivity. Preliminary evidence suggests agomelatine and bupropion are metabolically neutral and may improve insulin resistance in persons with diabetes mellitus. SNRIs do not adversely affect glucose-insulin signaling in the long-term. There was a paucity of studies reporting the effects of other antidepressant classes and agents. CONCLUSION: The effect of antidepressants on mechanisms mediating insulin sensitivity is mixed, with a relatively limited body of evidence currently available. While select SSRIs and tricyclic antidepressants may adversely affect glucose-insulin homeostasis, conclusions remain preliminary. The development of novel antidepressants may provide an opportunity to optimize psychiatric and metabolic outcomes. Identifying mechanisms contributing to insulin resistance could inform future discovery and development of antidepressants.
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Wong et al. (2026) studied this question. Select tricyclic antidepressants are associated with disrupted insulin sensitivity, whereas SSRIs, SNRIs, agomelatine, and bupropion appear metabolically neutral.
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