BACKGROUND: Schizophrenia is associated with an increased risk of aggressive behaviour, which may partly be explained by illness-related changes in brain structure. However, previous studies have been limited by group-level analyses, small and selective samples of inpatients and long time lags between exposure and outcome. METHODS: This cross-sectional study pooled data from 20 sites participating in the international ENIGMA-Schizophrenia Working Group. Sites acquired T1-weighted and diffusion-weighted magnetic resonance imaging scans in a total of 2095 patients with schizophrenia and 2861 healthy controls. Measures of grey matter volume and white matter microstructural integrity were extracted from the scans using harmonised protocols. For each measure, normative modelling was used to calculate how much patients deviated (in z-scores) from healthy controls at the individual level. Ordinal regression models were used to estimate the associations of these deviations with concurrent aggressive behaviour (as odds ratios [ORs] with 99% confidence intervals [CIs]). Mediation analyses were performed for positive symptoms (i.e., delusions, hallucinations and disorganised thinking), impulse control and illness insight. Aggression and potential mediators were assessed with the Positive and Negative Syndrome Scale, Scale for the Assessment of Positive Symptoms or Brief Psychiatric Rating Scale. RESULTS: Aggressive behaviour was significantly associated with reductions in total cortical volume (OR [99% CI] = 0.88 [0.78, 0.98], p = .003) and global white matter integrity (OR [99% CI] = 0.72 [0.59, 0.88], p = 3.50 × 10-5) and additional reductions in dorsolateral prefrontal cortex volume (OR [99% CI] = 0.85 [0.74, 0.97], p =.002), inferior parietal lobule volume (OR [99% CI] = 0.76 [0.66, 0.87], p = 2.20 × 10-7) and internal capsule integrity (OR [99% CI] = 0.76 [0.63, 0.92], p = 2.90 × 10-4). Except for inferior parietal lobule volume, these associations were largely mediated by increased severity of positive symptoms and reduced impulse control. CONCLUSIONS: This study provides evidence that the co-occurrence of positive symptoms, poor impulse control and aggressive behaviour in schizophrenia has a neurobiological basis, which may inform the development of therapeutic interventions.

Center for the Neurobiology of Learning and Memory University of California Irvine Irvine USA

Centre de Recherche de l'Institut Universitaire en Santé Mentale de Montréal Montreal Canada

Centro de Investigación Biomédica en Red de Salud Mental Carlos 3 Health Institute Barcelona Spain

Department of Advanced Biomedical Sciences University of Naples Federico 2 Naples Italy

Department of Brain and Cognitive Sciences Seoul National University College of Natural Sciences Seoul South Korea

Department of Child and Adolescent Psychiatry and Psychology Erasmus MC Sophia Rotterdam the Netherlands

Department of Child and Adolescent Psychiatry and Psychotherapy TU Dresden Germany

Department of Cognitive Science and Artificial Intelligence Tilburg University Tilburg the Netherlands

Department of Complex Trait Genetics Vrije Universiteit Amsterdam Amsterdam the Netherlands

Department of Criminology University of Pennsylvania Philadelphia USA

Department of Criminology Vrije Universiteit Amsterdam Amsterdam the Netherlands

Department of Electrical Engineering and Information Technology University of Naples Federico 2 Naples Italy

Department of Neuropsychiatry Seoul National University Hospital Seoul South Korea

Department of Neurosciences Reproductive Sciences and Dentistry University of Naples Federico 2 Naples Italy

Department of Psychiatry and Addictology University of Montreal Montreal Canada

Department of Psychiatry and Behavioral Science UTHealth Houston Houston USA

Department of Psychiatry and Behavioral Sciences Northwestern University Chicago USA

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

Department of Psychiatry and Neuropsychology Maastricht University Medical Center Maastricht the Netherlands

Department of Psychiatry and Psychotherapy Philipps University Marburg Marburg Germany

Department of Psychiatry and Psychotherapy University of Lübeck Germany

Department of Psychiatry Harvard Medical School Harvard USA

Department of Psychiatry Jeonbuk National University Hospital Jeonju South Korea

Department of Psychiatry Jeonbuk National University Jeonju South Korea

Department of Psychiatry Psychotherapy and Psychosomatics University of Zürich Switzerland

Department of Psychiatry Seoul National University College of Medicine Seoul South Korea

Department of Psychiatry University Hospitals of Geneva Geneva Switzerland

Department of Psychiatry University Medical Center Utrecht Utrecht the Netherlands

Department of Psychiatry University of Iowa Iowa City USA

Department of Psychiatry University of Pennsylvania Philadelphia USA

Department of Psychology and Neuroscience Center Brigham Young University Provo USA

Department of Psychology Georgia State University Atlanta USA

Department of Psychology University of Pennsylvania Philadelphia USA

Department of Psychology Utrecht University Utrecht the Netherlands

Department of Research Institute of Mental Health Singapore

Department of Youth Psychiatry Mental Health Research Center Moscow Russia

Division of Psychological and Social Medicine and Developmental Neurosciences TU Dresden Germany

Donders Institute for Brain Cognition and Behaviour Radboud University Nijmegen the Netherlands

Faculty of Electrical Engineering Czech Technical University Prague Prague Czech Republic

FIDMAG Germanes Hospitalaries Research Foundation Barcelona Spain

Hospital Benito Menni CASM Barcelona Spain

Institut Philippe Pinel Montreal Canada

Institute for Translational Neuroscience University of Münster Münster Germany

Institute for Translational Psychiatry University of Münster Münster Germany

Institute of Behavioral Science Feinstein Institutes for Medical Research Manhasset USA

Institute of Clinical Sciences Imperial College London London UK

Institute of Computer Science Czech Academy of Sciences Prague Czech Republic

Institute of Psychiatry Psychology and Neuroscience King's College London London UK

Iowa Neuroscience Institute University of Iowa Iowa City USA

Laboratory of Neuroimaging and Multimodal Analysis Mental Health Research Center Moscow Russia

Laboratory of Neuropsychiatry Santa Lucia Foundation IRCCS Rome Italy

Montreal Neurological Institute Hospital McGill University Montreal Canada

MRC London Institute of Medical Sciences Imperial College London London UK

National Institute of Mental Health Klecany Czech Republic

Neuroscience Research Australia Randwick Australia

Olin Neuropsychiatry Research Center Institute of Living Hartford USA

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

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

School of Clinical Medicine University of New South Wales Sydney Australia

School of Psychology University of New South Wales Sydney Australia

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

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