Although specific risk factors for brain alterations in bipolar disorders (BD) are currently unknown, obesity impacts the brain and is highly prevalent in BD. Gray matter correlates of obesity in BD have been well documented, but we know much less about brain white matter abnormalities in people who have both obesity and BD. We obtained body mass index (BMI) and diffusion tensor imaging derived fractional anisotropy (FA) from 22 white matter tracts in 899 individuals with BD, and 1287 control individuals from 20 cohorts in the ENIGMA-BD working group. In a mega-analysis, we investigated the associations between BMI, diagnosis or medication and FA. Lower FA was associated with both BD and BMI in six white matter tracts, including the corpus callosum and thalamic radiation. Higher BMI or BD were uniquely associated with lower FA in three and six white matter tracts, respectively. People not receiving lithium treatment had a greater negative association between FA and BMI than people treated with lithium in the posterior thalamic radiation and sagittal stratum. In three tracts BMI accounted for 10.5 to 17% of the negative association between the number of medication classes other than lithium and FA. Both overweight/obesity and BD demonstrated lower FA in some of the same regions. People prescribed lithium had a weaker association between BMI and FA than people not on lithium. In contrast, greater weight contributed to the negative associations between medications and FA. Obesity may add to brain alterations in BD and may play a role in effects of medications on the brain.

Assistance Publique Hôpitaux de Paris CHU Mondor Psychiatry Department Créteil France

Bipolar Disorders Unit Clinical Institute of Neurosciences Hospital Clínic Barcelona Spain

Black Dog Institute Sydney Sydney NSW Australia

Center for Brain Resilience and Recovery Hurvitz Brain Sciences Program Physical Sciences Platform Sunnybrook Research Institute Toronto ON Canada

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

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

Centre for Youth Bipolar Disorder Centre for Addiction and Mental Health Toronto ON Canada

Core Facility Brainimaging Faculty of Medicine University of Marburg Marburg Germany

Department of Behavioural Medicine Institute of Basic Medical Sciences University of Oslo Oslo Norway

Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden

Department of Medical Biophysics University of Toronto Toronto ON Canada

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Medical Neuroscience Dalhousie University Halifax NS Canada

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

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

Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology University of Gothenburg Gothenburg Sweden

Department of Psychiatry and Psychotherapy Philipps Universität Marburg Marburg Germany

Department of Psychiatry and Psychotherapy University Hospital Jena Jena Germany

Department of Psychiatry Dalhousie University Halifax NS Canada

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

Department of Psychiatry Royal Edinburgh Hospital Edinburgh UK

Department of Psychiatry St Vincent's Hospital Melbourne Australia

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

Discipline of Psychiatry and Mental Health School of Clinical Medicine University of New South Wales Sydney NSW Australia

Division of Mental Health and Addiction Oslo University Hospital Oslo Norway

Division of Neuroscience IRCCS San Raffaele Scientific Institute Milano Italy

Faculté de Médecine Université Paris Est Créteil Créteil France

FIDMAG Germanes Hospitalàries Research Foundation Barcelona Spain

Generation Scotland Institute for Genetics and Cancer University of Edinburgh Edinburgh UK

German Center for Mental Health Jena Germany

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

INSERM Unit U955 Team Translational Neuropsychiatry Créteil France

Institut d'Investigacions Biomèdiques August Pi i Sunyer University of Barcelona Barcelona Spain

Institute for Mental and Physical Health and Clinical Translation School of Medicine Deakin University Geelong VIC Australia

Institute for Translational Neuroscience University of Münster Münster Germany

Institute for Translational Psychiatry University of Münster Münster Germany

Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore

Louis A Faillace MD Department of Psychiatry and Behavioral Sciences University of Texas Health Science Center at Houston Houston TX USA

Melbourne Neuropsychiatry Centre Department of Psychiatry University of Melbourne Melbourne VIC Australia

Mental Health Research Networking Center ISC 3 Barcelona Spain

National Institute of Mental Health Klecany Czech Republic

Neuroscience Institute University of Cape Town Cape Town South Africa

Neurospin CEA Université Paris Saclay Gif sur Yvette France

NORMENT Centre University of Oslo Oslo Norway

Norwegian Centre for Mental Disorders Research Institute of Clinical Medicine University of Oslo Oslo Norway

Quantify Research Stockholm Sweden Stockholm Sweden

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

Synapsy Center Department of Psychiatry Faculty of Medicine University of Geneva Geneva Switzerland

Unit for Psychosomatics and C L psychiatry for adults Oslo University Hospital Oslo Norway

Univ Grenoble Alpes Inserm U1216 CHU Grenoble Alpes Grenoble Institut Neurosciences Grenoble France

University of Pittsburgh Medical Center Pittsburgh PA USA

University Vita Salute San Raffaele Milano 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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