BACKGROUND: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. METHODS: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide. RESULTS: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. CONCLUSIONS: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.

Athinoula A Martinos Center for Biomedical Imaging Charlestown Massachusetts; Division of Psychological and Social Medicine and Developmental Neurosciences Faculty of Medicine Technische Universität Dresden Dresden Germany

Beth K and Stuart C Yudofsky Division of Neuropsychiatry Menninger Department of Psychiatry and Behavioral Sciences Baylor College of Medicine Houston Texas; Laboratory of Neuropsychiatry Department of Clinical and Behavioral Neurology IRCCS Santa Lucia Foundation Rome Italy

Brain Imaging and Analysis Center Duke University Medical Center Durham North Carolina

Center for Translational Imaging and Precision Medicine San Diego California; Department of Neurosciences University of California San Diego La Jolla California; Department of Radiology University of California San Diego La Jolla California; Department of Psychiatry University of California San Diego La Jolla California; Department of Cognitive Science University of California San Diego La Jolla California

Center for Translational Research in Systems Neuroscience and Psychiatry Department of Psychiatry Georg August University Göttingen Germany; Department of Psychiatry University Medical Center Göttingen Göttingen Germany

Centre for Addiction and Mental Health Toronto Canada

Centre for Cognitive Ageing and Cognitive Epidemiology University of Edinburgh Edinburgh United Kingdom; Department of Psychology University of Edinburgh Edinburgh United Kingdom

Centre for Neuroimaging and Cognitive Genomics Clinical Neuroimaging Laboratory National Centre for Biomedical Engineering Galway Neuroscience Centre College of Medicine Nursing and Health Sciences National University of Ireland Galway Galway Ireland

Centre for Neuroimaging and Cognitive Genomics Clinical Neuroimaging Laboratory National Centre for Biomedical Engineering Galway Neuroscience Centre College of Medicine Nursing and Health Sciences National University of Ireland Galway Galway Ireland; School of Psychology and Department of Biochemistry National University of Ireland Galway Galway Ireland; Neuropsychiatric Genetics Research Group Department of Psychiatry and Trinity College Institute of Neuroscience Trinity College Dublin Ireland

Centre for Psychiatry Research Karolinska Institutet Stockholm Sweden; Stockholm Health Services Stockholm County Council Stockholm Sweden

Children's Clinical and Research Institute of Emergency Surgery and Trauma Moscow Russia

Chongqing Three Gorges Central Hospital Chongqing China

Department of Basic Medical Science Neuroscience and Sense Organs University of Bari Aldo Moro Bari Italy

Department of Biomedical Engineering Illinois Institute of Technology Chicago Illinois

Department of Child and Adolescent Psychiatry Psychology Erasmus Medical Centre Rotterdam The Netherlands; Department of Psychiatry and Brain Center Rudolf Magnus University Medical Center Utrecht Utrecht The Netherlands

Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden; Fundación para la Investigación y Docencia Maria Angustias Giménez Germanes Hospitalaries Research Foundation Barcelona Spain; Centro Investigación Biomédica en Red de Salud Mental Barcelona Spain; Department of Psychosis Studies Institute of Psychiatry Psychology and Neuroscience King's College London London United Kingdom

Department of Neuroimaging Institute of Psychiatry Psychology and Neuroscience King's College London London United Kingdom; Department of Psychology City University of London London United Kingdom

Department of Neuropsychiatry Graduate School of Medicine University of Tokyo Bunkyo ku Tokyo Japan

Department of Neuroscience University Medical Center Groningen Rijks Universiteit Groningen Groningen The Netherlands; Department of Psychiatry University Medical Center Groningen Rijks Universiteit Groningen Groningen The Netherlands

Department of Psychiatry Academic Medical Center University of Amsterdam Amsterdam The Netherlands

Department of Psychiatry and Behavioral Sciences Northwestern University Feinberg School of Medicine Chicago Illinois

Department of Psychiatry and Behavioral Sciences Northwestern University Feinberg School of Medicine Chicago Illinois; Department of Radiology Northwestern University Feinberg School of Medicine Chicago Illinois

Department of Psychiatry and Biobehavioral Sciences University of California Los Angeles Los Angeles California

Department of Psychiatry and Brain Center Rudolf Magnus University Medical Center Utrecht Utrecht The Netherlands

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

Department of Psychiatry and Psychology Maastricht University Maastricht The Netherlands

Department of Psychiatry Beth Israel Deaconess Medical Center Harvard Medical School Boston Massachusetts; Psychiatry Neuroimaging Laboratory Brigham and Women's Hospital Harvard Medical School Boston Massachusetts

Department of Psychiatry Groote Schuur Hospital University of Cape Town Cape Town South Africa

Department of Psychiatry Groote Schuur Hospital University of Cape Town Cape Town South Africa; Medical Research Council Unit on Risk and Resilience in Mental Disorders Department of Psychiatry Stellenbosch University Cape Town South Africa

Department of Psychiatry Groote Schuur Hospital University of Cape Town Cape Town South Africa; Medical Research Council Unit on Risk and Resilience in Mental Disorders Department of Psychiatry University of Cape Town Cape Town South Africa

Department of Psychiatry Monash University Melbourne Victoria Australia; School of Psychiatry University of New South Wales New South Wales Australia

Department of Psychiatry Osaka University Graduate School of Medicine Suita Osaka Japan

Department of Psychiatry Psychosomatic Medicine and Psychotherapy University Hospital Frankfurt Goethe University Frankfurt Frankfurt Germany

Department of Psychiatry Seoul National University College of Medicine Seoul Republic of Korea; Department of Brain and Cognitive Sciences College of Natural Sciences Seoul National University Seoul Republic of Korea

Department of Psychiatry University Hospital Marqués de Valdecilla School of Medicine Marqués de Valdecilla Research Institute University of Cantabria Santander Spain; Centro Investigación Biomédica en Red de Salud Mental Santander Spain

Department of Psychiatry University of California San Diego La Jolla California

Department of Psychiatry University of Iowa Iowa City Iowa

Department of Psychiatry University of Minnesota Minneapolis Minnesota

Department of Psychiatry University of Minnesota Minneapolis Minnesota; Minneapolis VA Health Care System Minneapolis Minnesota

Department of Psychiatry University of New Mexico Albuquerque New Mexico

Department of Psychiatry University of New Mexico Albuquerque New Mexico; Mind Research Network Albuquerque New Mexico

Department of Psychiatry University of North Carolina at Chapel Hill Chapel Hill North Carolina; Brain Imaging and Analysis Center Duke University Medical Center Durham North Carolina

Department of Psychiatry University of Pennsylvania Philadelphia Pennsylvania

Department of Psychiatry Vrije Universiteit Medical Center Amsterdam The Netherlands

Department of Psychiatry Weill Institute for Neurosciences University of California San Francisco California; San Francisco Veterans Affairs Medical Center San Francisco California

Department of Psychiatry Yale University New Haven Connecticut; Olin Neuropsychiatric Research Center Institute of Living Hartford Hospital Hartford Connecticut

Department of Psychology Georgia State University Atlanta Georgia

Department of Psychology University of Oslo Oslo Norway; Division of Mental Health and Addiction NORMENT K G Jebsen Centre for Psychosis Research Oslo University Hospital Oslo Norway

Department of Psychosis Studies Institute of Psychiatry Psychology and Neuroscience King's College London London United Kingdom

Department of Psychosis Studies Institute of Psychiatry Psychology and Neuroscience King's College London London United Kingdom; National Institute for Health Research Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust London United Kingdom

Discipline of Psychiatry School of Medicine University of Queensland Brisbane Queensland Australia

Division of Cerebral Integration National Institute for Physiological Sciences Okazaki Aichi Japan

Division of Mental Health and Addiction NORMENT K G Jebsen Centre for Psychosis Research Oslo University Hospital Oslo Norway

Division of Psychiatry University of Edinburgh Edinburgh United Kingdom

Division of Psychiatry University of Edinburgh Edinburgh United Kingdom; Centre for Cognitive Ageing and Cognitive Epidemiology University of Edinburgh Edinburgh United Kingdom

Fundación para la Investigación y Docencia Maria Angustias Giménez Germanes Hospitalaries Research Foundation Barcelona Spain; Centro Investigación Biomédica en Red de Salud Mental Barcelona Spain

Imaging Genetics and Neuroinformatics Lab Georgia State University Atlanta Georgia

Imaging Genetics and Neuroinformatics Lab Georgia State University Atlanta Georgia; Mind Research Network Albuquerque New Mexico

Imaging Genetics Center Mark and Mary Stevens Neuroimaging and Informatics Institute Keck School of Medicine of the University of Southern California Marina del Rey California

Imaging Genetics Center Mark and Mary Stevens Neuroimaging and Informatics Institute Keck School of Medicine of the University of Southern California Marina del Rey California; Janssen Research and Development San Diego California

Institute of Clinical Medicine Norwegian Centre for Mental Disorders Research K G Jebsen Centre for Psychosis Research University of Oslo Oslo Norway

Institute of Clinical Medicine Norwegian Centre for Mental Disorders Research K G Jebsen Centre for Psychosis Research University of Oslo Oslo Norway; Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden

Institute of Clinical Medicine Norwegian Centre for Mental Disorders Research K G Jebsen Centre for Psychosis Research University of Oslo Oslo Norway; Department of Psychiatric Research Diakonhjemmet Hospital Oslo Norway

Institute of Clinical Medicine Norwegian Centre for Mental Disorders Research K G Jebsen Centre for Psychosis Research University of Oslo Oslo Norway; Department of Psychiatric Research Diakonhjemmet Hospital Oslo Norway; Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden

Institute of Clinical Medicine Norwegian Centre for Mental Disorders Research K G Jebsen Centre for Psychosis Research University of Oslo Oslo Norway; Division of Mental Health and Addiction NORMENT K G Jebsen Centre for Psychosis Research Oslo University Hospital Oslo Norway

Istituto Di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza San Giovanni Rotondo Italy

Laboratory of Neuropsychiatry Department of Clinical and Behavioral Neurology IRCCS Santa Lucia Foundation Rome Italy

Laboratory of Neuropsychiatry Department of Clinical and Behavioral Neurology IRCCS Santa Lucia Foundation Rome Italy; Centro Fermi Museo Storico della Fisica e Centro Studi e Ricerche Enrico Fermi Rome Italy

Laboratory of Neuropsychiatry Department of Clinical and Behavioral Neurology IRCCS Santa Lucia Foundation Rome Italy; Dipartimento di Neuroscienze Salute Mentale e Organi di Senso Faculty of Medicine and Psychology and Department of Neurology and Psychiatry Sapienza University of Rome Rome Italy

Laboratory of Psychiatric Neuroimaging Laboratórios de Investigação Médica 21 Department of Psychiatry Faculty of Medicine and Center for Interdisciplinary Research on Applied Neurosciences University of São Paulo São Paulo Brazil

Luoyang 5th People's Hospital Henan Province Luoyang China

Maryland Psychiatric Research Center University of Maryland School of Medicine Baltimore Maryland

Mental Health Research Center Moscow Russia

Mind Research Network Albuquerque New Mexico

Mind Research Network Albuquerque New Mexico; Department of Psychiatry University of Iowa Iowa City Iowa; Advanced Biomedical Informatics Group LLC Iowa City Iowa

Molecular Research Center for Children's Mental Development United Graduate School of Child Development Osaka University Suita Osaka Japan; Department of Psychiatry Osaka University Graduate School of Medicine Suita Osaka Japan

Murdoch Children's Research Institute Melbourne Victoria Australia

National Institute of Mental Health Klecany Czech Republic

National Institute of Mental Health Klecany Czech Republic; Institute of Computer Science Czech Academy of Sciences Czech Technical University Prague Prague Czech Republic; Faculty of Electrical Engineering Czech Technical University Prague Prague Czech Republic

National Institute of Mental Health Klecany Czech Republic; MR Unit Department of Diagnostic and Interventional Radiology Institute for Clinical and Experimental Medicine Prague Czech Republic

Neuropsychiatric Genetics Research Group Department of Psychiatry and Trinity College Institute of Neuroscience Trinity College Dublin Ireland

Neuropsychiatry Centre University of Melbourne Melbourne Victoria Australia

Neuropsychiatry Centre University of Melbourne Melbourne Victoria Australia; Florey Institute of Neuroscience and Mental Health University of Melbourne Melbourne Victoria Australia

Orygen The National Centre of Excellence in Youth Mental Health Melbourne Victoria Australia; Centre for Youth Mental Health University of Melbourne Melbourne Victoria Australia; Department of Psychiatry and Neuroscience VU University Medical Center Amsterdam The Netherlands

Priority Research Centre for Brain and Mental Health University of Newcastle Newcastle New South Wales Australia

Priority Research Centre for Brain and Mental Health University of Newcastle Newcastle New South Wales Australia; Grow Up Well University of Newcastle Newcastle New South Wales Australia; Hunter Medical Research Institute Newcastle New South Wales Australia

Priority Research Centre for Brain and Mental Health University of Newcastle Newcastle New South Wales Australia; Hunter Medical Research Institute Newcastle New South Wales Australia; Hunter New England Local Health District Newcastle New South Wales Australia

Priority Research Centre for Health Behaviour University of Newcastle Newcastle New South Wales Australia; School of Medicine and Public Health University of Newcastle Newcastle New South Wales Australia; Hunter Medical Research Institute Newcastle New South Wales Australia

Psychiatry Research Center Beijing Huilongguan Hospital Beijing China

Queensland Brain Institute University of Queensland Brisbane Queensland Australia; Queensland Centre for Mental Health Research University of Queensland Brisbane Queensland Australia

Research Group in Psychiatry Department of Psychiatry Faculty of Medicine Universidad de Antioquia Medellin Colombia

School of Biomedical Sciences and Pharmacy University of Newcastle Newcastle New South Wales Australia; Hunter Medical Research Institute Newcastle New South Wales Australia

School of Biomedical Sciences and Pharmacy University of Newcastle Newcastle New South Wales Australia; Priority Research Centre for Brain and Mental Health University of Newcastle Newcastle New South Wales Australia; Hunter Medical Research Institute Newcastle New South Wales Australia

School of Medical Sciences University of New South Wales New South Wales Australia; Neuroscience Research Australia Sydney New South Wales Australia

School of Psychiatry and Clinical Neurosciences University of Western Australia Perth Western Australia Australia

School of Psychiatry University of New South Wales New South Wales Australia; Neuroscience Research Australia Sydney New South Wales Australia

School of Psychology University of Newcastle Newcastle New South Wales Australia

Section for Experimental Psychopathology and Neuroimaging Department of General Psychiatry Heidelberg University Hospital Heidelberg Germany; Center for Translational Research in Systems Neuroscience and Psychiatry Department of Psychiatry Georg August University Göttingen Germany

Semel Institute for Neuroscience and Human Behavior University of California Los Angeles Los Angeles California; Department of Psychiatry and Brain Center Rudolf Magnus University Medical Center Utrecht Utrecht The Netherlands

Social Neuroscience Laboratory Charlestown Massachusetts; Psychiatric Neuroimaging Research Program Massachusetts General Hospital Harvard Medical School Boston Massachusetts; Department of Psychiatry Massachusetts General Hospital Harvard Medical School Boston Massachusetts; Division of Psychological and Social Medicine and Developmental Neurosciences Faculty of Medicine Technische Universität Dresden Dresden Germany

University of Basel Psychiatric Hospital Basel Switzerland

Yeongeon Student Support Center Seoul National University College of Medicine Seoul Republic of Korea; Seoul National University Hospital Seoul Republic of Korea

Zhumadian Psychiatry Hospital Henan Province Zhumadian China

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Neurostructural subgroup in 4291 individuals with schizophrenia identified using the subtype and stage inference algorithm

Principal component analysis as an efficient method for capturing multivariate brain signatures of complex disorders-ENIGMA study in people with bipolar disorders and obesity

Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study

Structural brain abnormalities and aggressive behaviour in schizophrenia: Mega-analysis of data from 2095 patients and 2861 healthy controls via the ENIGMA consortium

Two neurostructural subtypes: results of machine learning on brain images from 4,291 individuals with schizophrenia

Cortical morphology in patients with the deficit and non-deficit syndrome of schizophrenia: a worldwide meta- and mega-analyses

Mega-analysis of association between obesity and cortical morphology in bipolar disorders: ENIGMA study in 2832 participants

Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium

Obesity and brain structure in schizophrenia - ENIGMA study in 3021 individuals

Virtual Ontogeny of Cortical Growth Preceding Mental Illness

Clozapine Reverses Dysfunction of Glutamatergic Neurons Derived From Clozapine-Responsive Schizophrenia Patients

Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder

What we learn about bipolar disorder from large-scale neuroimaging: Findings and future directions from the ENIGMA Bipolar Disorder Working Group

Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders

Higher Body-Mass Index and Lower Gray Matter Volumes in First Episode of Psychosis

Increased power by harmonizing structural MRI site differences with the ComBat batch adjustment method in ENIGMA

The Relationship Between White Matter Microstructure and General Cognitive Ability in Patients With Schizophrenia and Healthy Participants in the ENIGMA Consortium

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder