Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 × 10-21), left fusiform gyrus (d=-0.288; P=8.25 × 10-21) and left rostral middle frontal cortex (d=-0.276; P=2.99 × 10-19). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

Academic Psychiatry and Northern Centre for Mood Disorders Newcastle University Northumberland Tyne and Wear NHS Foundation Trust Newcastle UK

Bipolar Center Wiener Neustadt Wiener Neustadt Austria

Center for Interdisciplinary Research on Applied Neurosciences University of São Paulo São Paulo Brazil

Center for Neurobehavioral Genetics Semel Institute for Neuroscience and Human Behavior University of California Los Angeles Los Angeles CA USA

Centre for Affective Disorders King's College London London UK

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

Centro de Investigación Biomédica en Red de Salud Mental Madrid Spain

Department of Adult Psychiatry Poznan University of Medical Sciences Poznan Poland

Department of Adult Psychiatry University of Oslo Oslo Norway

Department of Clinical Neuroscience Osher Centre Karolinska Institutet Stockholm Sweden

Department of Clinical Radiology University of Münster Münster Germany

Department of Cognitive Science Neurosciences and Psychiatry University of California San Diego San Diego CA USA

Department of Neurology Oslo University Hospital Oslo Norway

Department of Neuroradiology Karolinska University Hospital Stockholm Sweden

Department of Neurosurgery Medical College of Wisconsin Milwaukee WI USA

Department of Psychiatric Research Diakonhjemmet Hospital Oslo Norway

Department of Psychiatry and Behavioral Neuroscience University of Cincinnati College of Medicine Cincinnati OH USA

Department of Psychiatry and Biobehavioral Sciences Semel Institute for Neuroscience and Human Behavior University of California Los Angeles Los Angeles CA USA

Department of Psychiatry and Human Behavior Alpert Medical School of Brown University Providence RI USA

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

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

Department of Psychiatry and Psychotherapy University Hospital Carl Gustav Carus Technische Universität Dresden Dresden Germany

Department of Psychiatry and Psychotherapy University Medical Center Göttingen Göttingen Germany

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

Department of Psychiatry Dalhousie University Halifax NS Canada

Department of Psychiatry Faculty of Medicine University of São Paulo São Paulo Brazil

Department of Psychiatry Icahn School of Medicine at Mount Sinai New York NY USA

Department of Psychiatry Radboud University Medical Center Nijmegen The Netherlands

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

Department of Psychiatry University of Adelaide Adelaide SA Australia

Department of Psychiatry University of California Los Angeles Los Angeles CA USA

Department of Psychiatry University of Münster Münster Germany

Department of Psychiatry University of Pennsylvania Philadelphia PA USA

Department of Psychiatry University of Pittsburgh School of Medicine Pittsburgh PA USA

Department of Psychiatry VU University Medical Center Amsterdam The Netherlands

Department of Psychiatry Yale University New Haven CT USA

Department of Psychology and Counselling Newman University Birmingham UK

Department of Psychology City University London London UK

Department of Psychology University of California Los Angeles Los Angeles CA USA

Department of Psychology University of Exeter Exeter UK

Department of Psychology University of Oslo Oslo Norway

Department of Radiology University of São Paulo São Paulo Brazil

Division of Clinical Neuroscience Department of Research and Education Oslo University Hospital Oslo Norway

Division of Mental Health and Addiction Oslo University Hospital Oslo Norway

Division of Psychiatry University of Edinburgh Edinburgh UK

Donders Institute for Brain Cognition and Behavior Radboud University Nijmegen The Netherlands

Experimental Therapeutics and Pathophysiology Branch National Institute of Mental Health Bethesda MD USA

Faculty of Community Medicine The University of Tulsa Tulsa OK USA

FIDMAG Germanes Hospitalàries Research Foundation Barcelona Spain

Hospital Clinic IDIBAPS University of Barcelona CIBERSAM Barcelona Spain

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

INSERM U955 Team 15 'Translational Psychiatry' University Paris East APHP CHU Mondor Fondation FondaMental Créteil France

Institut Pasteur Unité Perception et Mémoire Paris France

Institute of Clinical Medicine University of Oslo Oslo Norway

Institute of Neuroscience and Physiology The Sahlgrenska Academy at the Gothenburg University Goteborg Sweden

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

IRCCS E Medea Scientific Institute San Vito al Tagliamento Italy

Janssen Research and Development San Diego CA USA

Janssen Research and Development Titusville NJ USA

Laureate Institute for Brain Research Tulsa OK USA

LIM44 Laboratory of Magnetic Resonance in Neuroradiology University of São Paulo São Paulo Brazil

MMIL Department of Radiology University of California San Diego San Diego CA USA

MRC Centre for Neuropsychiatric Genetics and Genomics Cardiff University Cardiff UK

MRC Unit on Anxiety and Stress Disorders Groote Schuur Hospital University of Cape Town Cape Town South Africa

National Institute of Mental Health Klecany Czech Republic

National Institute of Mental Health National Institutes of Health Bethesda MD USA

Neuroscience Interdepartmental Graduate Program University of California Los Angeles Los Angeles CA USA

Neuroscience Research Australia Sydney NSW Australia

NeuroSpin UNIACT Lab Psychiatry Team CEA Saclay Gif Sur Yvette France

NORMENT KG Jebsen Centre for Psychosis Research Institute of Clinical Medicine University of Oslo Oslo Norway

Olin Neuropsychiatric Research Center Institute of Living Hartford Hospital Hartford CT USA

Program for Mood Disorders Department of Psychiatry Academic Medical Center University of Amsterdam Amsterdam The Netherlands

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

School of Psychiatry and Black Dog Institute University of New South Wales Sydney NSW Australia

School of Psychiatry University of New South Wales Sydney NSW Australia

Section for Experimental Psychopathology and Neuroimaging Department of General Psychiatry Heidelberg University Heidelberg Germany

University Department of Psychiatry and Oxford Health NHS Foundation Trust University of Oxford Oxford UK

UT Center of Excellence on Mood Disorders Department of Psychiatry and Behavioral Sciences The University of Texas Health Science Center at Houston Houston TX USA

West Los Angeles Veterans Administration Los Angeles CA USA

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