Multivariate Brain-Blood Signatures in Early-Stage Depression and Psychosis.
Authors
Affiliations (33)
Affiliations (33)
- Max Planck Institute of Psychiatry, Munich, Germany.
- Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University, Munich, Germany.
- Graduate School of Systemic Neurosciences, Ludwig-Maximilian-University, Munich, Germany.
- Centre for Youth Mental Health, University of Melbourne, Melbourne, Victoria, Australia.
- Institute for Mental Health, University of Birmingham, Birmingham, United Kingdom.
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
- Neuropharmacology Research Group, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom.
- International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Munich, Germany.
- Department of Radiology, LMU University Hospital, Ludwig Maximilian University Munich, Munich, Germany.
- Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany.
- Department of Psychology, Faculty of Psychology and Educational Sciences, Ludwig-Maximilian University, Munich, Germany.
- School of Psychology, University of Sussex, Brighton, United Kingdom.
- Department of Psychiatry and Psychotherapy, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany.
- Department of Psychology, Faculty of Psychology, Airlangga University, Surabaya, Indonesia.
- University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland.
- German Center for Mental Health, partner site Munich-Augsburg, Germany.
- Department of Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
- Center for Intervention and Research on Adaptive and Maladaptive Brain Circuits Underlying Mental Health, Site Jena-Magdeburg-Halle, Magdeburg, Germany.
- German Center for Mental Health, Halle-Jena-Magdeburg, Germany.
- Institute for Translational Psychiatry, University of Münster, Münster, Germany.
- Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Bari, Italy.
- Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland.
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland.
- Department of Child and Adolescent Psychiatry, University of Münster, Münster, Germany.
- Department of Psychiatry and Psychotherapy, University of Lübeck, Germany.
- Department of Psychiatry, University of Turku, Turku, Finland.
- Melbourne Neuropsychiatry Centre, University of Melbourne & Melbourne Health, Melbourne, Victoria, Australia.
- Department of Neurosciences and Mental Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.
- Department of Transplantation and Pathophysiology, University of Milan, Milan, Italy.
- Orygen, the National Centre of Excellence for Youth Mental Health, Melbourne, Victoria, Australia.
- Department of Psychiatry, Oxford University, Warneford Hospital, Oxford, United Kingdom.
- Early Intervention Service, Birmingham Women's and Children's National Health Service Trust, Birmingham, United Kingdom.
- National Institute for Health and Care Research, Oxford Health Biomedical Research Centre, Oxford, United Kingdom.
Abstract
Inflammation is increasingly implicated in the pathophysiology of mood and psychotic disorders. Integrating blood biomarkers and brain imaging may help uncover mechanistic pathways and guide targeted interventions. To identify shared and distinct multivariate patterns of peripheral inflammation and gray matter volume (GMV) in early-stage depressive and psychotic disorders using a transdiagnostic machine learning approach. The naturalistic multicenter PRONIA study was conducted between February 2014 and May 2019 with a follow-up period of up to 36 months; baseline data were analyzed between August 2021 and April 2024. Eight sites, including inpatient and outpatient facilities, in 5 European countries (Germany, Italy, Switzerland, Finland, and the United Kingdom) were included. The study included individuals with recent-onset depression (ROD, n = 163) or psychosis (ROP, n = 177) or clinical high-risk states for psychosis (CHR-P, n = 172), all with minimal medication exposure, and healthy control (HC) individuals (n = 166). Structural magnetic resonance imaging (MRI), peripheral assays of cytokines (eg, interleukin [IL] 6, IL-1β, tumor necrosis factor [TNF] α, C-reactive protein [CRP], brain-derived neurotrophic factor [BDNF], S100 calcium-binding protein B [S100B]); clinical assessments; neurocognitive testing. After data collection, sparse partial least squares was used to identify latent brain-blood signatures. Support vector machine classification evaluated psychosocial and neurocognitive predictors of signature expression using repeated nested cross-validation. A total of 678 participants (346 [51.0%] female; median [IQR] age, 24.0 [20.9-28.9] years) were included. Four signatures were identified. A psychosis signature (ρ = 0.27; P = .002) differentiated ROP from CHR-P with elevated IL-6, TNF-α, and reduced CRP, alongside GMV shifts in corticothalamic circuits. A depression signature (ρ = 0.19; P = .02) differentiated ROD from HC individuals with elevated IL-1β, IL-2, IL-4, S100B, and BDNF and GMV reductions in limbic regions. Additional signatures reflected age (ρ = 0.67) and sex or MRI quality (ρ = 0.53). Psychosocial features, including a differential childhood trauma pattern, predicted both the psychosis (balanced accuracy [BAC] = 67.2%) and depression (BAC = 78.0%) signatures. Cognitive performance predicted only the psychosis signature (BAC = 65.1%). In this study, early-stage depression and psychosis exhibited distinct neurobiological signatures involving immune and neuroanatomical markers, challenging fully dimensional disease models. These signatures are shaped by childhood trauma and cognition and may support biologically informed early interventions.