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The longitudinal associations of inflammatory biomarkers and depression revisited: systematic review, meta-analysis, and meta-regression

Molecular Psychiatry volume 26, pages 3302–3314 (2021)Cite this article

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Abstract

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 The review, registered with PROSPERO, searched for published and unpublished studies via MEDLINE/PsycINFO/PsycARTICLES/EMBASE/Proquest Dissertation.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 CRP and future depression 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.

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Fig. 1: Systematic review and meta-analysis flowchart.
Fig. 2: Forest plots of baseline CRP and future depressive symptoms.
Fig. 3: Forest plots of baseline IL-6 and future depressive symptoms.
Fig. 4: Forest plots of baseline depressive symptoms and future CRP and future IL-6.

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Acknowledgements

This research was supported by National Institute of Mental Health Grants MH079369 and MH101168 to LBA, National Institute of Mental Health Grants MH118545 and MH096478 to LME and National Research Service Award F31MH118808 as well as an American Psychological Foundation grant to NMG.

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  1. Department of Psychology, Temple University, Philadelphia, PA, USA

    Naoise Mac Giollabhui, Tommy H. Ng, Lauren M. Ellman & Lauren B. Alloy

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Mac Giollabhui, N., Ng, T.H., Ellman, L.M. et al. The longitudinal associations of inflammatory biomarkers and depression revisited: systematic review, meta-analysis, and meta-regression. Mol Psychiatry 26, 3302–3314 (2021). https://doi.org/10.1038/s41380-020-00867-4

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