Cytokine alterations in pediatric internalizing disorders: Systematic review and exploratory multi-variate meta-analysis

Pediatric internalizing disorders are prevalent and characterized by a maladaptive cognitive, emotional response to a perceived stressor. The hypothesized effect of this response is observable changes in behavior mediated by homeostatic inflammatory cytokines. The aim of this study was to synthesize the literature and analyze the effect of cytokines on pediatric internalizing disorders. Influential moderating variables, including mean body mass index, fasting status at blood collection, participant sex, cytokine type, mean age, percentage of sample medicated, and diagnosis, were also assessed. A systematic literature search was performed in electronic databases (Medline, PubMed, and PsycINFO) from January 1, 1980 to June 15, 2022. Case-control studies of pediatric internalizing disorders, specifically anxiety and depression, were reviewed for their association with peripheral cytokine levels. Meta-analyses were performed using a random effects multi-variate model and effect sizes were calculated using Hedge's g for IL-2, CRP, IL-6, TNF-α, IL-1β, IFN-γ, and IL-10. Thirty-three studies were reviewed and 28 studies were included in the meta-analysis (n = 1322 cases and n = 3617 controls). Peripheral cytokine levels were elevated in pediatric internalizing disorders compared to controls (Hedge's g = 0.19, p < 0.001). In the moderator analyses, depression diagnosis (Hedge's g = 0.18, p = 0.009) and non-fasting blood collection (Hedge's g = 0.20, p = 0.006) were significant. The meta-analytic findings are limited by methodological variation between studies, high heterogeneity, and low statistical power. Despite this, the findings suggest that elevated peripheral cytokine levels may play a role in the etiology and/or symptom maintenance of pediatric internalizing disorders.