title: Peripheral Immune Cell Populations Associated with Cognitive Deficits and Negative Symptoms of Treatment-Resistant Schizophrenia.
abstract: Hypothetically, psychotic disorders could be caused or conditioned by immunological mechanisms. If so, one might expect there to be peripheral immune system phenotypes that are measurable in blood cells as biomarkers of psychotic states.
  
  
  
  We used multi-parameter flow cytometry of venous blood to quantify and determine the activation state of 73 immune cell subsets for 18 patients with chronic schizophrenia (17 treated with clozapine), and 18 healthy volunteers matched for age, sex, BMI and smoking. We used multivariate methods (partial least squares) to reduce dimensionality and define populations of differentially co-expressed cell counts in the cases compared to controls.
  
  
  
  Schizophrenia cases had increased relative numbers of NK cells, naïve B cells, CXCR5+ memory T cells and classical monocytes; and decreased numbers of dendritic cells (DC), HLA-DR+ regulatory T-cells (Tregs), and CD4+ memory T cells. Likewise, within the patient group, more severe negative and cognitive symptoms were associated with decreased relative numbers of dendritic cells, HLA-DR+ Tregs, and CD4+ memory T cells. Motivated by the importance of central nervous system dopamine signalling for psychosis, we measured dopamine receptor gene expression in separated CD4+ cells. Expression of the dopamine D3 (DRD3) receptor was significantly increased in clozapine-treated schizophrenia and covaried significantly with differentiated T cell classes in the CD4+ lineage.
  
  
  
  Peripheral immune cell populations and dopaminergic signalling are disrupted in clozapine-treated schizophrenia. Immuno-phenotypes may provide peripherally accessible and mechanistically specific biomarkers of residual cognitive and negative symptoms in this treatment-resistant subgroup of patients.
authors.affiliation: NIHR Cambridge Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, Cambridge, United Kingdom.|University of Cambridge, Behavioural & Clinical Neuroscience Institute, Department of Psychiatry, Cambridge, United Kingdom.|Centro de Investigación Biomedica en Red de Salud Mental (CIBERSAM), G04, Barcelona, Spain.|Cambridgeshire & Peterborough NHS Foundation Trust, Cambridge, United Kingdom.
authors.forename: Emilio
authors.identifier: 0000-0003-4128-8955
authors.initials: E
authors.lastname: Fernandez-Egea
authors.affiliation: University of Cambridge, Behavioural & Clinical Neuroscience Institute, Department of Psychiatry, Cambridge, United Kingdom.
authors.forename: Petra E
authors.initials: PE
authors.lastname: Vértes
authors.affiliation: Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge, School of Clinical Medicine, Cambridge, United Kingdom.
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Flint
authors.affiliation: NIHR Cambridge Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, Cambridge, United Kingdom.|Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge, School of Clinical Medicine, Cambridge, United Kingdom.
authors.forename: Lorinda
authors.initials: L
authors.lastname: Turner
authors.affiliation: University of Cambridge, Behavioural & Clinical Neuroscience Institute, Department of Psychiatry, Cambridge, United Kingdom.
authors.forename: Syed
authors.initials: S
authors.lastname: Mustafa
authors.affiliation: Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge, School of Clinical Medicine, Cambridge, United Kingdom.
authors.forename: Alex
authors.initials: A
authors.lastname: Hatton
authors.affiliation: NIHR Cambridge Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, Cambridge, United Kingdom.|Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge, School of Clinical Medicine, Cambridge, United Kingdom.
authors.forename: Kenneth G C
authors.initials: KG
authors.lastname: Smith
authors.affiliation: Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge, School of Clinical Medicine, Cambridge, United Kingdom.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Lyons
authors.affiliation: NIHR Cambridge Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, Cambridge, United Kingdom.|University of Cambridge, Behavioural & Clinical Neuroscience Institute, Department of Psychiatry, Cambridge, United Kingdom.|Cambridgeshire & Peterborough NHS Foundation Trust, Cambridge, United Kingdom.|GlaxoSmithKline, ImmunoPsychiatry, Alternative Discovery & Development, Pharmaceutical R&D, Cambridge, United Kingdom.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Bullmore
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D018791:CD4 Lymphocyte Count; D016022:Case-Control Studies; D003024:Clozapine / Q000627:therapeutic use*; D060825:Cognitive Dysfunction / Q000175:diagnosis / Q000188:drug therapy; D003430:Cross-Sectional Studies; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D050637:Receptors, Dopamine D3 / Q000096:biosynthesis / Q000235:genetics; D012559:Schizophrenia / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D015415:Biomarkers; C493593:DRD3 protein, human; D006684:HLA-DR Antigens; D050637:Receptors, Dopamine D3; D003024:Clozapine