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Peripheral blood cell immunophenotyping reveals distinct subgroups of inflamed depression

View ORCID ProfileMary-Ellen Lynall, View ORCID ProfileLorinda Turner, Junaid Bhatti, View ORCID ProfileJonathan Cavanagh, View ORCID ProfilePeter de Boer, View ORCID ProfileValeria Mondelli, View ORCID ProfileDeclan Jones, View ORCID ProfileWayne C. Drevets, View ORCID ProfilePhilip Cowen, View ORCID ProfileNeil A. Harrison, View ORCID ProfileCarmine M. Pariante, View ORCID ProfileLinda Pointon, NIMA Consortium, View ORCID ProfileMenna R. Clatworthy, View ORCID ProfileEd Bullmore
doi: https://doi.org/10.1101/706309
Mary-Ellen Lynall
1Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0SZ, UK
2Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, CB21 5EF, UK
3Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK
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  • For correspondence: mel41@cam.ac.uk
Lorinda Turner
1Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0SZ, UK
3Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK
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Junaid Bhatti
1Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0SZ, UK
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Jonathan Cavanagh
4Centre for Immunobiology, University of Glasgow and Sackler Institute of Psychobiological Research, Queen Elizabeth University Hospital, Glasgow, G51 4TF, UK
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Peter de Boer
5Neuroscience, Janssen Research & Development, Janssen Pharmaceutica NV, 2340 Beerse, Belgium
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Valeria Mondelli
6King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, London, UK and National Institute for Health Research Mental Health Biomedical Research Centre, South London and Maudsley NHS Foundation Trust and King’s College London, London, UK
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Declan Jones
7Neuroscience External Innovation, Janssen Pharmaceuticals, J&J Innovation Centre, London, W1G 0BG
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Wayne C. Drevets
8Janssen Research & Development, Neuroscience Therapeutic Area, 3210 Merryfield Row, San Diego, CA 92121
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Philip Cowen
9University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, OX3 7JX, UK
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Neil A. Harrison
10School of Medicine, School of Psychology, Cardiff University Brain Research Imaging Centre, Maindy Road, Cardiff, CF24 4HQ
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Carmine M. Pariante
11Stress, Psychiatry and Immunology Laboratory & Perinatal Psychiatry, Maurice Wohl Clinical Neuroscience Institute, Kings College London, SE5 9RT, UK
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Linda Pointon
1Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0SZ, UK
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Menna R. Clatworthy
3Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK
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Ed Bullmore
1Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0SZ, UK
2Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, CB21 5EF, UK
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Abstract

Depression has been associated with increased inflammatory proteins but changes in circulating immune cells are less well defined. We used multi-parametric flow cytometry to investigate 14 subsets of peripheral blood cells in 206 cases of major depressive disorder (MDD) and 77 age- and sex-matched controls. There were significant case-control differences, by univariate and multivariate analysis: cases showed increased immune cell counts, especially neutrophils, CD4+ T cells and monocytes, and increased inflammatory proteins (C-reactive protein and interleukin-6). Within-group analysis demonstrated significant association between the severity of depressive symptoms and increased myeloid and CD4+ cell counts. MDD cases could be partitioned into two groups by forced binary clustering of cell counts: the inflamed depression group (N=81 out of 206; 39%) had increased monocyte, CD4+ and neutrophil counts, increased C-reactive protein (CRP) and interleukin 6 (IL-6), and was more depressed than the uninflamed majority of cases. Relaxing the presumption of a binary classification, data-driven clustering identified four subgroups of MDD cases: two of these subgroups (N=38 and N=100; 67% collectively) were associated with increased inflammatory proteins and more severe depression, but differed from each other in the relative weighting of myeloid and lymphoid cell counts. Case-control and within-group results were robust to statistical control for the potentially confounding effects of age, sex, BMI, recent infection status, and tobacco use. Peripheral blood immunophenotyping can be used to identify a candidate cellular biomarker of inflamed depression, and to further decompose that binary partition, suggesting that there is more than one mechanistic pathway underlying inflamed depression.

One Sentence Summary Two subgroups of depressed cases (about two-thirds of all 206 cases) were identified by peripheral blood biomarker evidence of distinctive cellular immunophenotypes, biased towards the myeloid or lymphoid lineages in different subgroups, but consistently associated with increased blood concentrations of inflammatory proteins and greater severity of depressive symptoms.

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Posted July 18, 2019.
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Peripheral blood cell immunophenotyping reveals distinct subgroups of inflamed depression
Mary-Ellen Lynall, Lorinda Turner, Junaid Bhatti, Jonathan Cavanagh, Peter de Boer, Valeria Mondelli, Declan Jones, Wayne C. Drevets, Philip Cowen, Neil A. Harrison, Carmine M. Pariante, Linda Pointon, NIMA Consortium, Menna R. Clatworthy, Ed Bullmore
bioRxiv 706309; doi: https://doi.org/10.1101/706309
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Peripheral blood cell immunophenotyping reveals distinct subgroups of inflamed depression
Mary-Ellen Lynall, Lorinda Turner, Junaid Bhatti, Jonathan Cavanagh, Peter de Boer, Valeria Mondelli, Declan Jones, Wayne C. Drevets, Philip Cowen, Neil A. Harrison, Carmine M. Pariante, Linda Pointon, NIMA Consortium, Menna R. Clatworthy, Ed Bullmore
bioRxiv 706309; doi: https://doi.org/10.1101/706309

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