The innate immune system is dysregulated in depression; however, less is known about the longitudinal associations of depression and inflammatory biomarkers. We investigated the prospective associations of depression and inflammatory biomarkers [interleukin-6 (IL-6), Tumor Necrosis Factor–Alpha (TNF-α), and C-reactive protein (CRP)] in community samples, both unadjusted and adjusted for covariates. The review, registered with PROSPERO, searched for published and unpublished studies via MEDLINE/PsycINFO/PsycARTICLES/EMBASE/Proquest Dissertation. Standardized Fisher transformations of the correlation/beta coefficients, both unadjusted and adjusted for covariates, were extracted from studies examining the prospective associations of depression and inflammatory biomarkers. Systematic review conducted in January, 2019 included 38 studies representing 58,256 participants, with up to 27 studies included in random-effects meta-analysis. Higher CRP/IL-6 were associated with future depressive symptoms, and higher depressive symptoms were associated with higher future CRP/IL-6 in both unadjusted and adjusted analyses – this is the first meta-analysis reporting an adjusted association of IL-6 with future depression. The adjusted prospective associations of depression with CRP/CRP with depression were substantially attenuated and small in magnitude. No significant associations were observed for TNF-α. No conclusive results were observed in studies of clinical depression. Meta-regression indicated that the association of depression and future CRP was larger in older samples and in studies not controlling for possible infection. Small, prospective associations of depression and inflammatory biomarkers are observed in both directions, particularly for IL-6; however, the strength and importance of this relationship is likely obscured by the heterogeneity in depression and profound study/methodological differences. Implications for future studies are discussed.

Inflammation has been implicated in depressive symptoms, but few studies use longitudinal designs with adolescents. Furthermore, the extant literature has yielded inconsistent results. Blood was collected from a community sample of 201 adolescents (109 female, age range = 12.3–20.0 years) and analyzed for inflammatory proteins. Up to five follow-up assessments of depressive symptoms were conducted. Multilevel modeling indicated that high C-reactive protein (CRP) but no other proinflammatory markers predicted depressive symptom increases. Three-way interactions between different inflammatory biomarkers, sex, and months to follow-up predicted change in depressive symptoms. Higher interleukin-6 predicted increased depressive symptoms at 13 to 31 months after baseline assessment of depression and inflammation for females. Higher tumor necrosis factor-α predicted increased depressive symptoms at < 1 month after baseline for males and 13 to 31 months after baseline for females. Higher interleukin-8 in males predicted lower depressive symptoms at 31 months after baseline. Exploratory post hoc analyses were used to examine these predictive associations for specific subsets of depressive symptoms. These findings are the first to support the predictive association of elevated CRP for depressive symptoms in a community adolescent sample and serve as preliminary evidence that the relationship between cytokines and later depressive symptoms differs by sex, time to follow-up, and the specific biomarker.

Since factors protecting and putting adolescents at risk of anxiety and depression exist at every level of the adolescent's ecological system, the study supports a community-based approach to youth mental health.

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