Sex-specific associations of depression with inflammatory markers: a systematic review and meta-analysis

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.