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Peripheral inflammatory biomarkers define biotypes of bipolar depression

Molecular Psychiatry volume 26, pages 3395–3406 (2021)Cite this article

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Abstract

We identified biologically relevant moderators of response to tumor necrosis factor (TNF)-α inhibitor, infliximab, among 60 individuals with bipolar depression. Data were derived from a 12-week, randomized, placebo-controlled clinical trial secondarily evaluating the efficacy of infliximab on a measure of anhedonia (i.e., Snaith–Hamilton Pleasure Scale). Three inflammatory biotypes were derived from peripheral cytokine measurements using an iterative, machine learning-based approach. Infliximab-randomized participants classified as biotype 3 exhibited lower baseline concentrations of pro- and anti-inflammatory cytokines and soluble TNF receptor-1 and reported greater pro-hedonic improvements, relative to those classified as biotype 1 or 2. Pretreatment biotypes also moderated changes in neuroinflammatory substrates relevant to infliximab’s hypothesized mechanism of action. Neuronal origin-enriched extracellular vesicle (NEV) protein concentrations were reduced to two factors using principal axis factoring: phosphorylated nuclear factorκB (p-NFκB), Fas-associated death domain (p-FADD), and IκB kinase (p-IKKα/β) and TNF receptor-1 (TNFR1) comprised factor “NEV1,” whereas phosphorylated insulin receptor substrate-1 (p-IRS1), p38 mitogen-activated protein kinase (p-p38), and c-Jun N-terminal kinase (p-JNK) constituted “NEV2”. Among infliximab-randomized subjects classified as biotype 3, NEV1 scores were decreased at weeks 2 and 6 and increased at week 12, relative to baseline, and NEV2 scores increased over time. Decreases in NEV1 scores and increases in NEV2 scores were associated with greater reductions in anhedonic symptoms in our classification and regression tree model (r2 = 0.22, RMSE = 0.08). Our findings provide preliminary evidence supporting the hypothesis that the pro-hedonic effects of infliximab require modulation of multiple TNF-α signaling pathways, including NF-κB, IRS1, and MAPK.

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Fig. 1: We used an iterative, machine learning-based approach to investigate peripheral markers of inflammatory activation relevant to infliximab’s hypothesized mechanism of action.
Fig. 2: Hypothesized mechanism of action of infliximab in bipolar depression.

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Acknowledgements

This study was funded by the Stanley Medical Research Institute (Grant 13T-012 to RSM and TS). This research was supported in part by the Intramural Research Program of the National Institute on Aging, NIH (authors DK, FDP, SC, CNO).

Author information

Authors and Affiliations

  1. Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada

    Yena Lee, Rodrigo B. Mansur, Joshua D. Rosenblat & Roger S. McIntyre

  2. Institute of Medical Science, University of Toronto, Toronto, ON, Canada

    Yena Lee, Benjamin I. Goldstein, Arun V. Ravindran, Valerie H. Taylor & Roger S. McIntyre

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

    Rodrigo B. Mansur, Joshua D. Rosenblat, Benjamin I. Goldstein, Arun V. Ravindran, Valerie H. Taylor & Roger S. McIntyre

  4. Department of Psychiatry, School of Medicine, Queen’s University, Kingston, ON, Canada

    Elisa Brietzke

  5. Centre for Neuroscience Studies, Queen’s University, Kingston, ON, Canada

    Elisa Brietzke

  6. Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIA/NIH), Baltimore, MD, USA

    Dimitrios Kapogiannis, Francheska Delgado-Peraza, Sahil Chawla & Carlos Nogueras-Ortiz

  7. Department of Industrial and Systems Engineering, University of Wisconsin–Madison, Madison, WI, USA

    Justin J. Boutilier

  8. Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON, Canada

    Timothy C. Y. Chan

  9. Department of Psychology, Ryerson University, Toronto, ON, Canada

    Nicole E. Carmona

  10. Department of Psychiatry, College of Medicine, Haeundae Paik Hospital, Inje University, Busan, Republic of Korea

    JungGoo Lee

  11. Paik Institute for Clinical Research, Inje University, Busan, Republic of Korea

    JungGoo Lee

  12. Department of Health Science and Technology, Graduate School, Inje University, Busan, Republic of Korea

    JungGoo Lee

  13. Department of Neuropsychiatry and Behavioral Sciences, University of South Carolina School of Medicine, Greer, SC, USA

    Vladimir Maletic

  14. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Hillerød, Denmark

    Maj Vinberg

  15. Psychiatric Research Unit, Psychiatric Centre North Zealand, Hillerød, Denmark

    Maj Vinberg

  16. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

    Trisha Suppes, Victoria E. Cosgrove & Nicole E. Kramer

  17. VA Palo Alto Health Care System, Palo Alto, CA, USA

    Trisha Suppes

  18. Centre for Youth Bipolar Disorder, Centre for Addiction and Mental Health, Toronto, ON, Canada

    Benjamin I. Goldstein

  19. Department of Pharmacology, University of Toronto, Toronto, ON, Canada

    Benjamin I. Goldstein & Roger S. McIntyre

  20. Department of Psychiatry, Foothills Medical Centre, University of Calgary, Calgary, AB, Canada

    Valerie H. Taylor

  21. Department of Psychological Medicine, National University of Singapore, Singapore, Singapore

    Roger Ho

  22. School of Human Ecology, University of Wisconsin–Madison, Madison, WI, USA

    Charles A. Raison

  23. Brain and Cognition Discovery Foundation, Toronto, ON, Canada

    Roger S. McIntyre

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Correspondence to Yena Lee.

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RSM has received research grant support from the Stanley Medical Research Institute and the Canadian Institutes of Health Research/Global Alliance for Chronic Diseases/National Natural Science Foundation of China and speaker/consultation fees from Lundbeck, Janssen, Shire, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, and Minerva within the past 36 months. EB has been supported by Faculty of Health Sciences, Queen’s University and received honoraria as speaker/member of advisory board from Daiichi-Sankyo not related to the content of this study. JDR has received research grant support from the University of Toronto, Canadian Cancer Society, Canadian Psychiatric Association, American Psychiatric Association, American Society of Psychopharmacology (New Investigator Award), University Health Network Centre for Mental Health, Joseph M. West Family Memorial Fund and Timeposters Fellowship and industry funding for speaker/consultation/research fees from Allergan, Lundbeck and COMPASS; and is the medical director of a private clinic providing off-label ketamine infusions for depression. BIG receives grant or research support from the Brain and Behavior Research Foundation (NARSAD), Brain Canada, the Canadian Institutes of Health Research, the Heart and Stroke Foundation, National Institute of Mental Health, the Ontario Ministry of Research and Innovation, and the Departments of Psychiatry of Sunnybrook Health Sciences Centre and the University of Toronto. MV has received consultancy fees from Lundbeck, Sunovion, and Janssen/Cilag within the last 3 years. All other authors declare no conflict of interest.

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Lee, Y., Mansur, R.B., Brietzke, E. et al. Peripheral inflammatory biomarkers define biotypes of bipolar depression. Mol Psychiatry 26, 3395–3406 (2021). https://doi.org/10.1038/s41380-021-01051-y

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