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Depression Heterogeneity and Its Biological Underpinnings: Toward Immunometabolic Depression

  • Yuri Milaneschi
    Correspondence
    Address correspondence to Yuri Milaneschi, Ph.D., Department of Psychiatry, Amsterdam UMC, Vrije Universiteit/GGZ inGeest, Oldenaller 1, Amsterdam 1081 HJ, Netherlands.
    Affiliations
    Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam University Medical Center/Vrije Universiteit & GGZinGeest, Amsterdam, The Netherlands
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  • Femke Lamers
    Affiliations
    Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam University Medical Center/Vrije Universiteit & GGZinGeest, Amsterdam, The Netherlands
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  • Michael Berk
    Affiliations
    Institute for Mental and Physical Health and Clinical Treatment, School of Medicine, Deakin University and Barwon Health, Geelong, Victoria, Australia

    Orygen, The National Centre of Excellence in Youth Mental Health, Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia

    Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia
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  • Brenda W.J.H. Penninx
    Affiliations
    Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam University Medical Center/Vrije Universiteit & GGZinGeest, Amsterdam, The Netherlands
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      Abstract

      Epidemiological evidence indicates the presence of dysregulated homeostatic biological pathways in depressed patients, such as increased inflammation and disrupted energy-regulating neuroendocrine signaling (e.g., leptin, insulin). Alterations in these biological pathways may explain the considerable comorbidity between depression and cardiometabolic conditions (e.g., obesity, metabolic syndrome, diabetes) and represent a promising target for intervention. This review describes how immunometabolic dysregulations vary as a function of depression heterogeneity by illustrating that such biological dysregulations map more consistently to atypical behavioral symptoms reflecting altered energy intake/expenditure balance (hyperphagia, weight gain, hypersomnia, fatigue, and leaden paralysis) and may moderate the antidepressant effects of standard or novel (e.g., anti-inflammatory) therapeutic approaches. These lines of evidence are integrated in a conceptual model of immunometabolic depression emerging from the clustering of immunometabolic biological dysregulations and specific behavioral symptoms. The review finally elicits questions to be answered by future research and describes how the immunometabolic depression dimension could be used to dissect the heterogeneity of depression and potentially to match subgroups of patients to specific treatments with higher likelihood of clinical success.

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