BACKGROUND: Obesity is highly prevalent and disabling, especially in individuals with severe mental illness including bipolar disorders (BD). The brain is a target organ for both obesity and BD. Yet, we do not understand how cortical brain alterations in BD and obesity interact. METHODS: We obtained body mass index (BMI) and MRI-derived regional cortical thickness, surface area from 1231 BD and 1601 control individuals from 13 countries within the ENIGMA-BD Working Group. We jointly modeled the statistical effects of BD and BMI on brain structure using mixed effects and tested for interaction and mediation. We also investigated the impact of medications on the BMI-related associations. RESULTS: BMI and BD additively impacted the structure of many of the same brain regions. Both BMI and BD were negatively associated with cortical thickness, but not surface area. In most regions the number of jointly used psychiatric medication classes remained associated with lower cortical thickness when controlling for BMI. In a single region, fusiform gyrus, about a third of the negative association between number of jointly used psychiatric medications and cortical thickness was mediated by association between the number of medications and higher BMI. CONCLUSIONS: We confirmed consistent associations between higher BMI and lower cortical thickness, but not surface area, across the cerebral mantle, in regions which were also associated with BD. Higher BMI in people with BD indicated more pronounced brain alterations. BMI is important for understanding the neuroanatomical changes in BD and the effects of psychiatric medications on the brain.

Center for Mind Brain and Behavior University of Marburg and Justus Liebig University Giessen Marburg Germany

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

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

Department of Child and Adolescents Psychiatry Psychology Erasmus MC Sophia Children's Hospital Erasmus University Medical Center Rotterdam The Netherlands

Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Neurology Division of Clinical Neuroscience Oslo University Hospital Oslo Norway

Department of Neurology Institute of Clinical Medicine University of Oslo Oslo Norway

Department of Neuroscience and Physiology Sahlgrenska Academy at Gothenburg University Gothenburg Sweden

Department of Psychiatry and Mental Health University of Cape Town Cape Town South Africa

Department of Psychiatry and Psychotherapy Philipps University Marburg Marburg Germany

Department of Psychiatry and Psychotherapy University Hospital Bonn Bonn Germany

Department of Psychiatry Dalhousie University Halifax NS Canada

Department of Psychiatry Erasmus University Medical Center Rotterdam The Netherlands

Department of Psychiatry Jena University Hospital Friedrich Schiller University Jena Jena Germany

Department of Psychiatry University Medical Center Groningen University of Groningen Groningen The Netherlands

Department of Psychiatry University Medical Center Utrecht Brain Center University Medical Center Utrecht Utrecht University Utrecht The Netherlands

Department of Psychiatry University of California San Diego La Jolla CA USA

Department of Psychiatry University of Münster Münster Germany

Desert Pacific MIRECC VA San Diego Healthcare San Diego CA USA

Division of Neuroscience Psychiatry and Psychobiology Unit IRCCS San Raffaele Scientific Institute Milan Italy

Erasmus School of Social and Behavioural Sciences Department of Psychology Education and Child Studies Erasmus University Rotterdam The Netherlands

FIDMAG Germanes Hospitalàries Research Foundation Barcelona Spain

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

Institut d'Investigacions Biomèdiques August Pi i Sunyer Barcelona Spain

Institute for Translational Neuroscience University of Münster Münster Germany

Institute of Clinical Medicine University of Oslo Oslo Norway

Institute of Psychiartry King's College Londen London UK

Laureate Institute for Brain Research Tulsa OK USA

National Institute of Mental Health Klecany Czech Republic

Neuroscience Institute University of Cape Town Cape Town South Africa

Neuroscience Research Australia Randwick NSW Australia

Norwegian Centre for Mental Disorders Research Institute of Clinical Medicine University of Oslo and Division of Mental Health and Addiction Oslo University Hospital Oslo Norway

Oxley College of Health Sciences The University of Tulsa Tulsa OK USA

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

Research Group Instituto de Alta Tecnología Médica Ayudas diagnósticas SURA Medellin Colombia

School of Medical Sciences University of New South Wales Sydney NSW Australia

School of Psychiatry University of New South Wales Sydney NSW Australia

South African MRC Unit on Risk and Resilience in Mental Disorders University of Cape Town Cape Town South Africa

UCLA Center for Neurobehavioral Genetics Los Angeles CA USA

Unit for Psychosomatics CL Outpatient Clinic for Adults Division of Mental Health and Addiction Oslo University Hospital Oslo Norway

University of British Columbia Vancouver BC Canada

Vita Salute San Raffaele University Milan Italy

West Region Institute of Mental Health Singapore Singapore

Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore

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