TY - JOUR
T1 - Whole-blood expression of inflammasome- and glucocorticoid-related mRNAs correctly separates treatment-resistant depressed patients from drug-free and responsive patients in the BIODEP study
AU - Cattaneo, Annamaria
AU - Ferrari, Clarissa
AU - Turner, Lorinda
AU - Mariani, Nicole
AU - Enache, Daniela
AU - Hastings, Caitlin
AU - Kose, Melisa
AU - Lombardo, Giulia
AU - McLaughlin, Anna P.
AU - Nettis, Maria A.
AU - Nikkheslat, Naghmeh
AU - Sforzini, Luca
AU - Worrell, Courtney
AU - Zajkowska, Zuzanna
AU - Cattane, Nadia
AU - Lopizzo, Nicola
AU - Mazzelli, Monica
AU - Pointon, Linda
AU - Cowen, Philip J.
AU - Cavanagh, Jonathan
AU - Harrison, Neil A.
AU - de Boer, Peter
AU - Jones, Declan
AU - Drevets, Wayne C.
AU - Mondelli, Valeria
AU - Bullmore, Edward T.
AU - Pariante, Carmine M.
AU - the Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) Consortium,
N1 - Funding Information:
This work was supported by the Wellcome Trust strategy award to the Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) Consortium (104025), which is also funded by Janssen, GlaxoSmithKline, Lundbeck and Pfizer; the full list of consortium members is presented in the Supplementary Material. As part of the Wellcome Trust strategy award to the Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) Consortium, the authors will be conducting a clinical trial testing a CNS-penetrant P2RX7 antagonist by Johnson & Johnson, JNJ-54175446, in TRD patients (EudraCT Number:2018-001884-21). C.M.P. and E.T.B. are each supported by a NIHR Senior Investigator award. This work was also supported by the NIHR Biomedical Research Centre (BRC) at the South London and Maudsley NHS Foundation Trust and King’s College London, London, the NIHR Cambridge Biomedical Research Centre (Mental Health) and the Cambridge NIHR BRC Cell Phenotyping Hub. C.M.P. and V.M. are in receipt of research funding from J&J. E.T.B. consults for Sosei Heptares. L.T. is supported by the NIHR Cambridge BRC. N.H. consults for GlaxoSmithKline and is in receipt of research funding from J&J. P.B., D.J. and W.D. are employees of Janssen Research & Development, LLC, of Johnson & Johnson, and hold stock in Johnson & Johnson. All the other authors have no disclosures to declare. Study data were collected and managed using REDCap electronic data capture tools hosted at the University of Cambridge. For the members of the NIMA Consortium (as detailed in the Supplementary Material): Khan, Murphy, Parker, Patel and Richardson are employees of GSK; Acton, Austin, Bhattacharya, Carruthers, Isaac, Kemp, Kolb, Nye (deceased) and Wittenberg are employee of Janssen; Campbell, Egebjerg, Eriksson, Gastambide, Adams, Jeggo, Moeller, Nelson, Plath, Thomsen, Pederson and Zorn are employees of Lundbeck; Balice-Gordon, Binneman, Duerr, Fullerton, Goli, Hughes, Piro, Samad and Sporn are employees of Pfizer; all other consortium members have no disclosures to declare. The sharing of data used in this study is restricted by the informed consent process. Our data cannot be made available on public repositories but will be shared with other scientifically accredited research groups on request.
Publisher Copyright:
© 2020, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - The mRNA expression signatures associated with the ‘pro-inflammatory’ phenotype of depression, and the differential signatures associated with depression subtypes and the effects of antidepressants, are still unknown. We examined 130 depressed patients (58 treatment-resistant, 36 antidepressant-responsive and 36 currently untreated) and 40 healthy controls from the BIODEP study, and used whole-blood mRNA qPCR to measure the expression of 16 candidate mRNAs, some never measured before: interleukin (IL)-1-beta, IL-6, TNF-alpha, macrophage inhibiting factor (MIF), glucocorticoid receptor (GR), SGK1, FKBP5, the purinergic receptor P2RX7, CCL2, CXCL12, c-reactive protein (CRP), alpha-2-macroglobulin (A2M), acquaporin-4 (AQP4), ISG15, STAT1 and USP-18. All genes but AQP4, ISG15 and USP-18 were differentially regulated. Treatment-resistant and drug-free depressed patients had both increased inflammasome activation (higher P2RX7 and proinflammatory cytokines/chemokines mRNAs expression) and glucocorticoid resistance (lower GR and higher FKBP5 mRNAs expression), while responsive patients had an intermediate phenotype with, additionally, lower CXCL12. Most interestingly, using binomial logistics models we found that a signature of six mRNAs (P2RX7, IL-1-beta, IL-6, TNF-alpha, CXCL12 and GR) distinguished treatment-resistant from responsive patients, even after adjusting for other variables that were different between groups, such as a trait- and state-anxiety, history of childhood maltreatment and serum CRP. Future studies should replicate these findings in larger, longitudinal cohorts, and test whether this mRNA signature can identify patients that are more likely to respond to adjuvant strategies for treatment-resistant depression, including combinations with anti-inflammatory medications.
AB - The mRNA expression signatures associated with the ‘pro-inflammatory’ phenotype of depression, and the differential signatures associated with depression subtypes and the effects of antidepressants, are still unknown. We examined 130 depressed patients (58 treatment-resistant, 36 antidepressant-responsive and 36 currently untreated) and 40 healthy controls from the BIODEP study, and used whole-blood mRNA qPCR to measure the expression of 16 candidate mRNAs, some never measured before: interleukin (IL)-1-beta, IL-6, TNF-alpha, macrophage inhibiting factor (MIF), glucocorticoid receptor (GR), SGK1, FKBP5, the purinergic receptor P2RX7, CCL2, CXCL12, c-reactive protein (CRP), alpha-2-macroglobulin (A2M), acquaporin-4 (AQP4), ISG15, STAT1 and USP-18. All genes but AQP4, ISG15 and USP-18 were differentially regulated. Treatment-resistant and drug-free depressed patients had both increased inflammasome activation (higher P2RX7 and proinflammatory cytokines/chemokines mRNAs expression) and glucocorticoid resistance (lower GR and higher FKBP5 mRNAs expression), while responsive patients had an intermediate phenotype with, additionally, lower CXCL12. Most interestingly, using binomial logistics models we found that a signature of six mRNAs (P2RX7, IL-1-beta, IL-6, TNF-alpha, CXCL12 and GR) distinguished treatment-resistant from responsive patients, even after adjusting for other variables that were different between groups, such as a trait- and state-anxiety, history of childhood maltreatment and serum CRP. Future studies should replicate these findings in larger, longitudinal cohorts, and test whether this mRNA signature can identify patients that are more likely to respond to adjuvant strategies for treatment-resistant depression, including combinations with anti-inflammatory medications.
KW - depression
KW - inflammation in depression
UR - http://www.scopus.com/inward/record.url?scp=85088368060&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85088368060&partnerID=8YFLogxK
U2 - 10.1038/s41398-020-00874-7
DO - 10.1038/s41398-020-00874-7
M3 - Article
C2 - 32699209
AN - SCOPUS:85088368060
VL - 10
JO - Translational Psychiatry
JF - Translational Psychiatry
SN - 2158-3188
IS - 1
M1 - 232
ER -