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Pro-inflammatory cytokines as predictors of antidepressant effects of exercise in major depressive disorder

Molecular Psychiatry volume 18, pages 1119–1124 (2013)Cite this article

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Abstract

Exercise is an efficacious treatment for major depressive disorder (MDD) and has independently been shown to have anti-inflammatory effects in non-depressed subjects. Patients with MDD have elevated inflammatory cytokines but it is not known if exercise affects inflammation in MDD patients and whether these changes are clinically relevant. In the TReatment with Exercise Augmentation for Depression (TREAD) study, participants who were partial responders to a selective serotonin reuptake inhibitor were randomized to receive one of two doses of exercise: 16 kilocalories per kilogram of body weight per week (KKW), or 4 KKW for 12 weeks. Blood samples were collected before initiation and again at the end of the 12-week exercise intervention. Serum was analyzed using a multiplexed ELISA for interferon-γ (IFN-γ), interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Higher baseline levels of TNF-α were associated with greater decrease in depression symptoms over the 12-week exercise period (P<0.0001). In addition, a significant positive correlation between change in IL-1β and change in depression symptom scores was observed (P=0.04). There were no significant changes in mean level of any cytokine following the 12-week intervention, and no significant relationship between exercise dose and change in mean cytokine level. Results suggest that high TNF-α may differentially predict better outcomes with exercise treatment as opposed to antidepressant medications for which high TNF-α is linked to poor response. Our results also confirm findings from studies of antidepressant medications that tie decreasing IL-1β to positive depression treatment outcomes.

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Acknowledgements

We thank the following individuals for their contributions to this project: several persons assisted with trial implementation, including Tyson M Bain; Heather O Chambliss; Alexander N Jordan; Heather Kitzman-Ulrich; Jennifer Kupper; Lucille Marcoux; Erin L Sinclair (all affiliated with The Cooper Institute, Dallas, TX, at the time of their participation); Ella Daly (Dr Daly is currently a full-time employee of Johnson and Johnson Pharmaceutical Research and Development and completed work on this study while she was on the faculty at the University of Texas Southwestern Medical Center at Dallas); Mariam Andersen; Shailesh Jain; Beverly Kleiber; David W Morris; Anne Marie Jones; and Michelle Rivas (all affiliated with the University of Texas Southwestern Medical Center at Dallas at the time of their participation). For assistance with database management, we thank Bradley Witte (the University of Texas Southwestern Medical Center at Dallas), and Beth Wright; Carrie E Finley; Mei Sui; and Carolyn E Barlow (all affiliated with the Cooper Institute, Dallas, TX). For assistance with statistical analyses (development of moderator selection methodology), we thank Richard M Golden (University of Texas at Dallas) and T Michael Kashner (the University of Texas Southwestern Medical Center at Dallas). We thank A John Rush, for providing comments on the study design (Dr Rush was affiliated with the University of Texas Southwestern Medical Center at Dallas at the time of his contribution to the study; he has received consulting fees from the University of Michigan and Brain Resource; has received speaker fees from Otsuka Pharmaceuticals; has received author royalties from Guilford Publications and the University of Texas Southwestern Medical Center at Dallas; and has received research support from the National Institute of Mental Health). We are very grateful to all of the study participants who contributed to this project. We also thank Eric Nestler and Carol A Tamminga, both of the Department of Psychiatry, the University of Texas Southwestern Medical Center, Dallas, for administrative support. None of the acknowledged individuals have potential conflict of interests or disclosures to report except as noted above. TREAD was supported by NIMH grant #5-R01-MH067692 (PI: Dr Trivedi) and by a NARSAD Independent Investigator Award (PI: Dr Trivedi). Funding for the brain-derived neurotrophic factor ELISAs was provided by the Sara M and Charles E Seay Center for Basic and Applied Research. Neither NIMH, NARSAD, nor the Seay Center had further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

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  1. Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA

    C D Rethorst, M S Toups, T L Greer, P A Nakonezny, T J Carmody, B D Grannemann, R M Huebinger, R C Barber & M H Trivedi

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  1. C D Rethorst
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Correspondence to M H Trivedi.

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Competing interests

TLG has received research funding from NARSAD. TJC has received a consulting fee from Cyberonics. MHT has received research support from the Agency for Healthcare Research and Quality (AHRQ), Corcept Therapeutics, Cyberonics, Merck, National Alliance for Research in Schizophrenia and Depression, National Institute of Mental Health, National Institute on Drug Abuse, Naurex, Novartis, Pharmacia and Upjohn, Predix Pharmaceuticals (Epix), Solvay Pharmaceuticals, Targacept and Valient. He has received consulting and speaker fees from Abbott Laboratories, Abdi Ibrahim, Akzo (Organon Pharmaceuticals), Alkermes, AstraZeneca, Axon Advisors, Bristol-Myers Squibb Company, Cephalon, Evotec, Fabre Kramer Pharmaceuticals, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica Products, Johnson and Johnson PRD, Libby, LP, Eli Lilly and Company, Lundbeck, Meade Johnson, MedAvante, Medtronic, Neuronetics, Otsuka Pharmaceuticals, Pamlab, Parke-Davis Pharmaceuticals, Pfizer, PgxHealth, Rexahn Pharmaceuticals, Sepracor, SHIRE Development, Sierra, Takeda,Tal Medical/Puretech, Transcept, VantagePoint and Wyeth-Ayerst Laboratories. The remaining authors declare no conflict of interest.

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Rethorst, C., Toups, M., Greer, T. et al. Pro-inflammatory cytokines as predictors of antidepressant effects of exercise in major depressive disorder. Mol Psychiatry 18, 1119–1124 (2013). https://doi.org/10.1038/mp.2012.125

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