Machine learning can be used to define subtypes of psychiatric conditions based on shared clinical and biological foundations, presenting a crucial step toward establishing biologically based subtypes of mental disorders. With the goal of identifying subtypes of disease progression in schizophrenia, here we analyzed cross-sectional brain structural magnetic resonance imaging (MRI) data from 4,291 individuals with schizophrenia (1,709 females, age=32.5 years±11.9) and 7,078 healthy controls (3,461 females, age=33.0 years±12.7) pooled across 41 international cohorts from the ENIGMA Schizophrenia Working Group, non-ENIGMA cohorts and public datasets. Using a machine learning approach known as Subtype and Stage Inference (SuStaIn), we implemented a brain imaging-driven classification that identifies two distinct neurostructural subgroups by mapping the spatial and temporal trajectory of gray matter (GM) loss in schizophrenia. Subgroup 1 (n=2,622) was characterized by an early cortical-predominant loss (ECL) with enlarged striatum, whereas subgroup 2 (n=1,600) displayed an early subcortical-predominant loss (ESL) in the hippocampus, amygdala, thalamus, brain stem and striatum. These reconstructed trajectories suggest that the GM volume reduction originates in the Broca's area/adjacent fronto-insular cortex for ECL and in the hippocampus/adjacent medial temporal structures for ESL. With longer disease duration, the ECL subtype exhibited a gradual worsening of negative symptoms and depression/anxiety, and less of a decline in positive symptoms. We confirmed the reproducibility of these imaging-based subtypes across various sample sites, independent of macroeconomic and ethnic factors that differed across these geographic locations, which include Europe, North America and East Asia. These findings underscore the presence of distinct pathobiological foundations underlying schizophrenia. This new imaging-based taxonomy holds the potential to identify a more homogeneous sub-population of individuals with shared neurobiological attributes, thereby suggesting the viability of redefining existing disorder constructs based on biological factors.

Center for the Neurobiology of Learning and Memory University of California Irvine 309 Qureshey Research Lab Irvine CA 92697 USA

Centre for Addiction and Mental Health Toronto Canada

Centre for Mental Health and Brain Sciences School of Health Sciences Swinburne University Melbourne Australia

Centro de Investigación Biomédica en Red de Salud Mental Instituto de Salud Carlos 3 Spain

Chinese Institute for Brain Research Beijing PR China

Clinical Translational Neuroscience Laboratory Department of Psychiatry and Human Behavior University of California Irvine Irvine Hall room 109 Irvine CA 92697 3950 USA

Department of Advanced Biomedical Sciences University Federico 2 Naples Italy

Department of Clinical Psychology 4th Military Medical University Xi'an PR China

Department of Computer Science University of Warwick Coventry CV4 7AL UK

Department of Human Genetics and South Texas Diabetes and Obesity Institute School of Medicine University of Texas of the Rio Grande Valley Brownsville TX USA

Department of MRI The 1st Affiliated Hospital of Zhengzhou University Zhengzhou China

Department of Neurology Huashan Hospital Fudan University Shanghai China

Department of Neurology Jena University Hospital Jena Germany

Department of Pathology of Mental Diseases National Institute of Mental Health National Center of Neurology and Psychiatry Kodaira 187 8553 Japan

Department of Pediatrics University of California Irvine Irvine California USA

Department of Psychiatry and Behavioral Sciences University of Minnesota Minneapolis MN USA

Department of Psychiatry and Human Behavior University of California Irvine Irvine California USA

Department of Psychiatry and Psychotherapie and Center for Brain Behavior and Metabolism Lübeck University Lübeck Germany

Department of Psychiatry and Psychotherapy Jena University Hospital Jena Germany

Department of Psychiatry and Psychotherapy Philipps Universität Marburg Rudolf Bultmann Str 8 35039 Marburg Germany

Department of Psychiatry Boston Children's Hospital Harvard Medical School Boston MA USA

Department of Psychiatry Division of Clinical Medicine Institute of Medicine University of Tsukuba Tsukuba 305 8575 Japan

Department of Psychiatry Jeonbuk National University Hospital Jeonju Korea

Department of Psychiatry Jeonbuk National University Medical School Jeonju Korea

Department of Psychiatry Psychotherapy and Psychosomatics Psychiatric Hospital University of Zurich Switzerland

Department of Psychiatry Psychotherapy and Psychosomatics Psychiatric University Hospital Zurich Switzerland

Department of Psychiatry Taipei Veterans General Hospital Taipei Taiwan

Department of Psychiatry Temerty Faculty of Medicine University of Toronto Toronto Canada

Department of Psychology University of Minnesota Minneapolis MN USA

Department of Psychology University of Oslo Oslo Norway

Division of Adult Psychiatry Department of Psychiatry University Hospitals of Geneva Switzerland

Douglas Mental Health University Institute Department of Psychiatry McGill University Montréal Canada

Ege University Institute of Health Sciences Department of Neuroscience Izmir Turkey

Ege University School of Medicine Department of Psychiatry SoCAT Lab Izmir Turkey

Experimental Psychopathology and Psychotherapy Department of Psychology University of Zurich Switzerland

Faculty of Electrical Engineering Czech Technical University Prague Prague Czech Republic

FIDMAG Germanes Hospitalàries Research Foundation Barcelona 08035 Spain

Fudan ISTBI ZJNU Algorithm Centre for Brain Inspired Intelligence Zhejiang Normal University Jinhua China

German Center for Mental Health Site Jena Magdeburg Halle Germany

High Field Magnetic Resonance Brain Imaging Key Laboratory of Sichuan Province Center for Information in Medicine University of Electronic Science and Technology of China Chengdu China

Imaging Genetics Center Stevens Neuroimaging and Informatics Institute Keck School of Medicine University of Southern California Los Angeles CA USA

Institute for Translational Psychiatry University of Münster Münster Germany

Institute for Transnational Psychiatry and Otto Creutzfeldt Center for Behavioral and Cognitive Neuroscience University of Münster Münster Germany

Institute of Computer Science Czech Academy of Sciences Prague Czech Republic

Institute of Neuroscience National Yang Ming Chiao Tung University Taipei Taiwan

Institute of Science and Technology for Brain Inspired Intelligence Fudan University Shanghai China

Key Laboratory of Computational Neuroscience and Brain Inspired Intelligence Ministry of Education Shanghai China

KG Jebsen Centre for Neurodevelopmental Disorders University of Oslo and Oslo University Hospital Oslo Norway

Lee Kong Chian School of Medicine Nanyang Technological University Singapore

Melbourne Neuropsychiatry Centre Department of Psychiatry University of Melbourne Melbourne Australia

Minneapolis VA Medical Center University of Minnesota Minneapolis MN USA

MOE Frontiers Center for Brain Science Fudan University Shanghai China

MR Unit Department of Diagnostic and Interventional Radiology Institute for Clinical and Experimental Medicine Prague Czech Republic

National Clinical Research Center for Mental Disorders Department of Psychiatry The 2nd Xiangya Hospital of Central South University Changsha Hunan PR China

National Institute of Mental Health Klecany Czech Republic

Neuropsychiatry Laboratory Department of Clinical Neuroscience and Neurorehabilitation IRCCS Santa Lucia Foundation Rome Italy

Neuroscience Center Zurich University of Zurich and Swiss Federal Institute of Technology Zurich Zurich Switzerland

NORMENT Centre Division of Mental Health and Addiction Oslo University Hospital and Institute of Clinical Medicine University of Oslo Oslo Norway

Olin Neuropsychiatry Research Center Institute of Living Hartford CT USA

Peking University Sixth Hospital Peking University Institute of Mental Health NHC Key Laboratory of Mental Health Beijing PR China

PKU IDG McGovern Institute for Brain Research Peking University Beijing PR China

Psychiatric Hospital University of Zurich Zurich Switzerland

Psychiatry and Behavioral Health Ohio State Wexner Medical Center Columbus OH USA

Research Institute of Clinical Medicine of Jeonbuk National University Biomedical Research Institute of Jeonbuk National University Hospital Jeonju Korea

Research Unit of NeuroInformation Chinese Academy of Medical Sciences Chengdu China

School of Clinical Medicine University of New South Wales Sydney Australia

School of Data Science Fudan University Shanghai China

School of Psychology University of New South Wales Sydney Australia

Section of Psychiatry Department of Neuroscience University Federico 2 Naples Italy

Shanghai Key Laboratory of Psychotic Disorders Shanghai Mental Health Center Shanghai Jiao Tong University School of Medicine Shanghai China

Shanghai Medical College and Zhongshan Hospital Immunotherapy Technology Transfer Center Shanghai China

The Clinical Hospital of Chengdu Brain Science Institute MOE Key Lab for Neuroinformation School of life Science and technology University of Electronic Science and Technology of China Chengdu China

Tri institutional Center for Translational Research in Neuroimaging and Data Science [Georgia State University Georgia Institute of Technology Emory University] Atlanta GA USA

West Region Institute of Mental Health Singapore

Yong Loo Lin School of Medicine National University of Singapore Singapore

Zhangjiang Fudan International Innovation Center Shanghai China

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