David Popovic, Clara Weyer, Dominic Dwyer, Siân Lowri Griffiths, Paris Alexandros Lalousis, Nicholas M. Barnes, Clara Vetter, L. Neuner, Madalina-Octavia Buciuman, Elif Sarisik, Marco Paolini, Theresa Lichtenstein, Lana Kambeitz‐Ilankovic, Joseph Kambeitz, Stephan Ruhrmann, Katharine Chisholm, Frauke Schultze‐Lutter, Peter Falkai, Kolja Schiltz, Johann Steiner, Michael J. Ziller, Giulio Pergola, Giuseppe Blasi, Alessandro Bertolino, Georg Romer, Rebekka Lencer, Udo Dannlowski, Raimo K. R. Salokangas, Christos Pantelis, Paolo Brambilla, Stefan Borgwardt, Stephen J. Wood, Eva Meisenzahl, Nikolaos Koutsouleris, Rachel Upthegrove, Shalaila S. Haas, Alkomiet Hasan, Claudius Hoff, Ifrah Khanyaree, Camilla Krämer, Aylin Melo, Susanna Muckenhuber-Sternbauer, Yanis Köhler, Ömer Öztürk, Nora Penzel, Adrian Rangnick, Sebastian von Saldern, Rachele Sanfelici, Moritz Spangemacher, Ana Tupac, María Fernanda Urquijo, Johanna Weiske, Antonia Wosgien, Karsten Blume, Dennis M. Hedderich, Dominika Julkowski, Nathalie Kaiser, Theresa Lichtenstein, Ruth Milz, Alexandra Nikolaides, Tanja Pilgram, Mauro Seves, Martina Wassen, Christina Andreou, Laura Egloff, Fabienne Harrisberger, Ulrike Heitz, Claudia Lenz, Letizia Leanza, Amatya Mackintosh, Renata Smieskova, Erich Studerus, Anna Walter, Sonja Widmayer, Chris Day, Mariam Iqbal, Mirabel Pelton, Pavan Mallikarjun, Alexandra Stainton, Ashleigh Lin, Alexander Denissoff, Anu Ellilä, Tiina From, Markus Heinimaa, Tuula Ilonen, Päivi Jalo, Heikki Laurikainen, Antti Luutonen, Akseli Mäkela, Janina Paju, Henri Pesonen, Reetta-Liina Säilä, Anna Toivonen, Otto Turtonen, Sonja Botterweck, Norman Kluthausen, Gerald Antoch, Julian Caspers, Hans‐Jörg Wittsack, Grazia Caforio
Importance: 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. Objective: 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. Design, Setting, and Participants: 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). Exposures: 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. Main Outcomes and Measures: 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. Results: 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%). Conclusions and Relevance: 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.