Individuals with bipolar disorders (BD) frequently suffer from obesity, which is often associated with neurostructural alterations. Yet, the effects of obesity on brain structure in BD are under-researched. We obtained MRI-derived brain subcortical volumes and body mass index (BMI) from 1134 BD and 1601 control individuals from 17 independent research sites within the ENIGMA-BD Working Group. We jointly modeled the effects of BD and BMI on subcortical volumes using mixed-effects modeling and tested for mediation of group differences by obesity using nonparametric bootstrapping. All models controlled for age, sex, hemisphere, total intracranial volume, and data collection site. Relative to controls, individuals with BD had significantly higher BMI, larger lateral ventricular volume, and smaller volumes of amygdala, hippocampus, pallidum, caudate, and thalamus. BMI was positively associated with ventricular and amygdala and negatively with pallidal volumes. When analyzed jointly, both BD and BMI remained associated with volumes of lateral ventricles and amygdala. Adjusting for BMI decreased the BD vs control differences in ventricular volume. Specifically, 18.41% of the association between BD and ventricular volume was mediated by BMI (Z = 2.73, p = 0.006). BMI was associated with similar regional brain volumes as BD, including lateral ventricles, amygdala, and pallidum. Higher BMI may in part account for larger ventricles, one of the most replicated findings in BD. Comorbidity with obesity could explain why neurostructural alterations are more pronounced in some individuals with BD. Future prospective brain imaging studies should investigate whether obesity could be a modifiable risk factor for neuroprogression.

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 National University of Ireland Galway Galway Ireland

Department of Child and Adolescent Psychiatry and Psychology Erasmus University 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 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 of Bonn Bonn Germany

Department of Psychiatry Dalhousie University Halifax NS Canada

Department of Psychiatry Erasmus University Medical Center Rotterdam The Netherlands

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

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 Bipolar Disorders and Depressive Unit Hospital Clinic Institute of Neurosciences University of Barcelona Barcelona Spain

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

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 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 Medellín 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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