Neuroanatomical dimensions in recent-onset depression: clinical profiles, inflammatory markers, and proteomic ageing
Year: 2026
Type: preprint
Abstract: Background Major depressive disorder (MDD) is clinically heterogeneous, hindering identification of reproducible biomarkers. Using a semi-supervised machine learning approach, HYDRA, we previously identified two neuroanatomical dimensions from structural MRI in medication-free MDD from COORDINATE-MDD consortium. These dimensions (D1, D2) showed differential responses to selective serotonin reuptake inhibitor (SSRI) antidepressants and placebo. External replication in UK Biobank linked D2, characterized by widespread subtle neuroanatomical reductions, to an immuno-metabolic profile. Here, we examined whether these dimensions are detectable early in the course of illness. Methods We applied the pre-trained model to structural MRI data from the multisite PRONIA cohort, comprising individuals with recent-onset depression (ROD; n = 377; mean age 25.8 years, SD 6.0; 51.3% female) and healthy controls (n = 267; mean age 25.5 years, SD 6.4; 61.0% female). Participants were assigned to clusters (C1, C2) corresponding to the previously identified dimensions (D1, D2). Clusters were compared on clinical symptom profiles, peripheral inflammatory markers, and in a subset (n = 107), proteomic ageing indices. Results Two neuroanatomical clusters were identified in PRONIA. C1 (n = 265) showed higher negative symptom severity and elevated interleukin-2 levels. C2 (n = 140) was associated with higher residual proteomic age. Overall depressive symptom severity did not differ significantly between clusters. Conclusions Neuroanatomical dimensions of MDD are reproducible and detectable at illness onset. Associations with negative symptom severity, inflammatory signalling, and proteomic ageing suggest these dimensions capture biologically meaningful heterogeneity early in depression. These findings support a biologically informed framework for stratified treatment approaches in MDD.
Source: medRxiv
Authors: Paris Alexandros Lalousis, Louise Moles, Mathilde Antoniades, Wenyi Xiao, Amalie C. M. Couch, Guray Erus, Pranav Thokachichu, Dhivya Srinivasan, Yong Fan, Rachel D. Woodham, Danilo Arnone, Stephen R. Arnott, Taolin Chen, Ki Sueng Choi, Cherise Chin Fatt, Benicio N. Frey, Vibe G. Frokjaer, Melanie Ganz, Beata R. Godlewska, Stefanie Hassel, Keith Ho, Andrew M. McIntosh, Kun Qin, Susan Rotzinger, Matthew D. Sacchet, Jonathan Savitz, Haochang Shou, Aleks Stolicyn, Irina Strigo, Stephen C. Strother, Duygu Tosun, Teresa A. Victor, Dongtao Wei, Toby Wise, Roland Zahn, Ian M. Anderson, J.F. William Deakin, W. Edward Craighead, Boadie W. Dunlop, Rebecca Elliott, Qiyong Gong, Ian H. Gotlib, Catherine J. Harmer, Sidney H. Kennedy, Gitte M. Knudsen, Helen S. Mayberg, Martin P. Paulus, Jiang Qiu, Madhukar H. Trivedi, Heather C. Whalley, Chao-Gan Yan, Allan H. Young, Grace Jacobs, Nora Penzel, Raimo K.R. Salokangas, Eva Meisenzahl, Jarmo Hietala, Alessandro Bertolino, Rebekka Lencer, Stephen Wood, Christos Pantelis, Georg Romer, Dominic Dwyer, Joseph Kambeitz, Lana Kambeitz-Ilankovic, Frauke Schultze-Lutter, Stephan Ruhrmann, Nicholas M. Barnes, Rachel Upthegrove, Nikolaos Koutsouleris, Christos Davatzikos, Cynthia H.Y. Fu
Institutions: King's College London, University of Pennsylvania, University of East London, University of Oxford, Imperial College London, Mohammed Bin Rashid University of Medicine and Health Sciences, Baycrest Hospital, Rotman Research Institute, Sichuan University, West China Medical Center of Sichuan University, West China Hospital of Sichuan University, Icahn School of Medicine at Mount Sinai, The University of Texas Southwestern Medical Center, St. Joseph’s Healthcare Hamilton, McMaster University, University of Copenhagen, Rigshospitalet, Oxford Health NHS Foundation Trust, University of Calgary, University Health Network, University of Edinburgh, Unity Health Toronto, Harvard University, Massachusetts General Hospital, Mass General Brigham, Laureate Institute for Brain Research, University of California, San Francisco, University of Toronto, Southwest University, South London and Maudsley NHS Foundation Trust, University of Manchester, Emory University, Stanford University, Institute of Psychology, Chinese Academy of Sciences, Ludwig-Maximilians-Universität München, University of Turku, Heinrich Heine University Düsseldorf, University of Bari Aldo Moro, University of Münster, University of Lübeck, Orygen, Swinburne University of Technology, The University of Melbourne, Western Health, Monash University, University of Cologne, University Hospital Cologne, University of Birmingham, Birmingham and Solihull Mental Health NHS Foundation Trust, Max Planck Society, Max Planck Institute of Psychiatry
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7163520168