Does inflammation explain the association between vitamin D and depression? Results of a cross-sectional study in children and adolescents <jats:title>Abstract</jats:title> <jats:p>Vitamin D has been associated with depression, potentially via anti-inflammatory mechanisms, yet data is scarce, particularly in adolescence. We investigated (1) whether lower vitamin D status is associated with greater depression severity and (2) whether this association is statistically moderated by inflammation in patients of a child and adolescent psychiatry department. At admission fasting morning venous blood was drawn. Serum vitamin D (25(OH)D) and C-reactive protein (CRP) were analyzed in all participants [n=465 (64.7%♀; 11.3-18.9 years)]. In a subsample [n=177], we additionally measured tumor necrosis factor-alpha, interferon-gamma and interleukin (IL)-1β, IL-6, IL-8, IL-10. Depression severity was assessed by the Beck Depression Inventory-II (BDI-II) [n=450], the Diagnostic System for Mental Disorders in Childhood and Adolescence via self-assessment (DISYPS Self) [n=441], and parent-assessment (DISYPS Proxy) [n=422]. Overall, 43.2% [n=201] were at risk for vitamin D deficiency (&lt;30nmol/L), and 73.5%-83.2% –depending on assessment tool– showed at least mild depression. Linear regression revealed an inverse association between 25(OH)D and BDI-II in both crude and CRP-adjusted full-sample models. Logistic regressions showed a robust inverse association between 25(OH)D and DISYPS Proxy, but not for DISYPS Self. Although 25(OH)D was inversely correlated with some pro-inflammatory markers, neither their inclusion in regression models nor formal mediation analyses supported inflammation as a mediator of the vitamin D–depression association. Overall, our results suggest that vitamin D relates modestly to both depression and inflammation in adolescence. However, based on the measured parameters, we cannot confirm that anti-inflammatory effects are the link between vitamin D and depression.</jats:p> 1-37 1-37 Cambridge University Press (CUP)