The effect of distress on circulating and stimulated inflammatory responses to acute stress: a systematic review and meta-analysis.

BACKGROUND

Acute stress induces a proinflammatory cytokine response with substantial heterogeneity between samples. This heterogeneity remains unexplained, but individual studies indicate that distress may contribute.

METHODS

This pre-registered meta-analysis [OSF 10.17605/OSF.IO/5P29J] included studies that assessed distress's relationship to serum or plasma inflammatory responses to acute stress among physically healthy samples. Searches were conducted in April 2025 across eight databases. Two reviewers independently evaluated studies, extracted data, and cross-checked for errors. Risk of bias was assessed using the NIH tool. Random effects meta-analysis used Hedges' G for categorical distress and Fisher's z for continuous symptoms.

RESULTS

Forty-three studies met inclusion criteria; 20 articles (1,824 participants) contributed to the meta-analysis. Neither continuous (k = 14; 33 effect sizes) nor categorical (k = 13; 27 effect sizes) distress predicted circulating cytokine reactivity (ps > 0.06). Continuous depressive symptoms (k = 14; 24 effect sizes; Fisher's z = 0.042, 95% CI: [0.001, 0.083], p = 0.046) - not anxiety symptoms (k = 3; 7 effect sizes; p = 0.39) - predicted greater circulating inflammatory reactivity to stress. Studies with covariates and with more females had lower effect sizes (ps < 0.036). Categorical depression (k = 12; 25 effect sizes; Hedges' g = 0.077, 95% CI: [0.019, 0.135], p = 0.022), but not PTSD (k = 2; 2 effect sizes; p = 0.22), predicted higher inflammatory reactivity. Distress was unrelated to stimulated cytokine reactivity (continuous: k = 3; 11 effect sizes; categorical: k = 4; 9 effect sizes; ps > 0.11), except for lower stimulated IL-6 reactivity (k = 3; 5 effect sizes; p = 0.044). Studies with older participants had lower effect sizes (p = 0.025).

CONCLUSIONS

Depression relates to greater circulating inflammatory responses, and there is preliminary evidence that distress may track with lower stimulated inflammatory responses - perhaps elevating risk for post-stress illness and chronic systemic inflammation. However, there were a limited number of studies assessing stimulated cytokines and other distress types; further investigation is warranted. Effect sizes were small and may accumulate with repeated stress.