Sex-specific associations of depression with inflammatory markers: a systematic review and meta-analysis
AI Summary
Modest cross-sex associations between depression and elevated systemic inflammation, with slightly stronger effect sizes in males.
Cross-sectional findings: depression linked to higher IL-6 in females, and higher CRP and IL-6 in males.
Longitudinally, elevated IL-6 predicted subsequent depression in females, elevated CRP predicted depression in males; depression did not predict later inflammation.
Transl Psychiatry. 2026 Jun 2. doi: 10.1038/s41398-026-04139-7. Online ahead of print.
ABSTRACT
INTRODUCTION: Converging evidence implicates elevated inflammation in the pathophysiology of depression and its medical comorbidities. Despite known sex differences in both inflammatory activity and depression, a dedicated large-scale review of these differences is lacking.
METHODS: We conducted a sex-stratified systematic review and meta-analysis of studies examining associations between depression and blood-based inflammatory markers in adult humans. Searches of PubMed, PsycINFO, and Scopus, and reference treeing, yielded 124 eligible papers including data from 423,421 participants (53% female). Analyses focused on depression and inflammatory markers C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-1β, and fibrinogen. Sex-stratified meta-analyses and meta regressions for the effects of sex were conducted, separately for cross-sectional and longitudinal designs.
RESULTS: Cross-sectionally, depression was modestly associated with higher levels of all markers combined in both females (Cohen’s d = 0.06, 95% CI [0.03-0.10]) and males (Cohen’s d = 0.14, 95% CI [0.09-0.19]). Depression was associated with elevated IL-6 in females, and elevated CRP and IL-6 in males. Longitudinally, elevated IL-6 was associated with subsequent depression among females and elevated CRP was associated with depression in males, whereas depression was not associated with subsequent inflammation in either sex.
CONCLUSION: Overall, results indicated modest associations between depression and elevated inflammation in both sexes, with slightly stronger associations in males. Associations between specific inflammatory markers (i.e., IL-6 in females and CRP in males) and subsequent depression differed by sex. These findings highlight the cross-sex relevance of inflammation in depression, and subtle sex differences in directionality and specific markers.
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