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Peripheral Alterations in Cytokine and Chemokine Levels After Antidepressant Drug Treatment for Major Depressive Disorder: Systematic Review and Meta-Analysis

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Abstract

Mounting evidence suggests that aberrations in immune-inflammatory pathways contribute to the pathophysiology of major depressive disorder (MDD), and individuals with MDD may have elevated levels of predominantly pro-inflammatory cytokines and C-reactive protein. In addition, previous meta-analyses suggest that antidepressant drug treatment may decrease peripheral levels of interleukin-1 beta (IL-1β) and IL-6. Recently, several new studies examining the effect of antidepressants on these cytokines have been published, and so we performed an updated meta-analysis of studies that measured peripheral levels of cytokines and chemokines during antidepressant treatment in patients with MDD. The PubMed/MEDLINE, EMBASE, and PsycInfo databases were searched from inception through March 9, 2017. Forty-five studies met inclusion criteria (N = 1517). Peripheral levels of IL-6, tumor necrosis factor-alpha (TNF-α), IL-1β, IL-10, IL-2, IL-4, interferon-γ, IL-8, the C-C motif ligand 2 chemokine (CCL-2), CCL-3, IL-1 receptor antagonist, IL-13, IL-17, IL-5, IL-7, and the soluble IL-2 receptor were measured in at least three datasets and thus were meta-analyzed. Antidepressant treatment significantly decreased peripheral levels of IL-6 (Hedges g = −0.454, P <0.001), TNF-α (g = −0.202, P = 0.015), IL-10 (g = −0.566, P = 0.012), and CCL-2 (g = −1.502, P = 0.006). These findings indicate that antidepressants decrease several markers of peripheral inflammation. However, this meta-analysis did not provide evidence that reductions in peripheral inflammation are associated with antidepressant treatment response although few studies provided separate data for treatment responders and non-responders.

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Acknowledgements

CAK is supported by a postdoctoral fellowship award from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil). MM is supported by a visiting research fellowship from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; Brazil). AFC is supported by a research fellowship award from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; Brazil).

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Author notes

  1. Cristiano A. Köhler and Thiago H. Freitas contributed equally as first authors.

Authors and Affiliations

  1. Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty of Medicine, Fortaleza, CE, Brazil

    Cristiano A. Köhler, Thiago H. Freitas, Nayanna Q. de Andrade & André F. Carvalho

  2. Physiotherapy Department, South London and Maudsley, NHS Foundation Trust, London, UK

    Brendon Stubbs

  3. Health Service and Population Research Department, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, De Crespigny Park, London, UK

    Brendon Stubbs

  4. IMPACT Strategic Research Centre, School of Medicine, Deakin University, Geelong, Australia

    Michael Maes, Gerwyn Morris & Brisa S. Fernandes

  5. Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Michael Maes

  6. Department of Psychiatry, Faculty of Medicine, State University of Londrina, Londrina, PR, Brazil

    Michael Maes

  7. Department of Psychiatry, Medical University Plovdiv, Plovdiv, Bulgaria

    Michael Maes

  8. Revitalis, Waalre, The Netherlands

    Michael Maes

  9. Department of Neurosciences, University of Padova, Padova, Italy

    Marco Solmi

  10. Institute of Clinical Research and Education in Medicine (IREM), Padua, Italy

    Marco Solmi & Nicola Veronese

  11. National Research Council, Neuroscience Institute, Aging Branch, Via Giustiniani 2, 35128, Padova, Italy

    Nicola Veronese

  12. Laboratory of Calcium Binding Proteins in the Central Nervous System, Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil

    Brisa S. Fernandes

  13. Center for Clinical and Epidemiological Research & Interdisciplinary Center for Applied Neuromodulation (CINA), University Hospital, University of São Paulo, São Paulo, Brazil

    André R. Brunoni

  14. Service of Interdisciplinary Neuromodulation (SIN), Department and Institute of Psychiatry, Faculty of Medicine of University of São Paulo, São Paulo, Brazil

    André R. Brunoni

  15. Laboratory of Neuroscience (LIM27), Department and Institute of Psychiatry, University of São Paulo, São Paulo, Brazil

    André R. Brunoni

  16. Neuropsychopharmacology Research Group, Hurvitz Brain Sciences Program Sunnybrook Research Institute, Toronto, ON, Canada

    Nathan Herrmann & Krista L. Lanctôt

  17. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Nathan Herrmann & Krista L. Lanctôt

  18. Department of Human Development and Family Studies, School of Human Ecology, University of Wisconsin-Madison, 1300 Linden Drive, Room 4174, Madison, WI, 53705, USA

    Charles L. Raison

  19. Department of Psychiatry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53705, USA

    Charles L. Raison

  20. Department of Psychiatry & Health Behavior, Georgia Regents University, Augusta, GA, USA

    Brian J. Miller

  21. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada

    Krista L. Lanctôt

  22. Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Rua Prof. Costa Mendes, 1608, 4° andar, Fortaleza, CE, 60430-040, Brazil

    André F. Carvalho

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  1. Cristiano A. Köhler
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  2. Thiago H. Freitas
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Correspondence to André F. Carvalho.

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In the past 12 months, CLR has served on the scientific advisory board for Usona Institute. All other authors report no conflicts of interest.

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Köhler, C.A., Freitas, T.H., Stubbs, B. et al. Peripheral Alterations in Cytokine and Chemokine Levels After Antidepressant Drug Treatment for Major Depressive Disorder: Systematic Review and Meta-Analysis. Mol Neurobiol 55, 4195–4206 (2018). https://doi.org/10.1007/s12035-017-0632-1

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