The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta-Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1-weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed-effects models and mega-analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen's d = -0.20), cornu ammonis (CA)1 (d = -0.18), CA2/3 (d = -0.11), CA4 (d = -0.19), molecular layer (d = -0.21), granule cell layer of dentate gyrus (d = -0.21), hippocampal tail (d = -0.10), subiculum (d = -0.15), presubiculum (d = -0.18), and hippocampal amygdala transition area (d = -0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non-users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD.

Amsterdam Neuroscience Amsterdam UMC Amsterdam The Netherlands

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

Black Dog Institute Sydney New South Wales Australia

Brain Mind and Society Research Hub Turner Institute for Brain and Mental Health School of Psychological Sciences Monash University Clayton Victoria Australia

Cardiff University Brain Research Imaging Centre Cardiff University Cardiff UK

Center for Mind Brain and Behavior Marburg Germany

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

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

Clinical Translational Neuroscience Laboratory Department of Psychiatry and Human Behavior University of California Irvine Irvine California USA

Deakin University IMPACT the Institute for Mental and Physical Health and Clinical Translation School of Medicine Barwon Health Geelong Victoria Australia

Department of Adult Mental Health Institute of Clinical Medicine University of Oslo Oslo Norway

Department of Clinical Neuroscience Centre for Psychiatric Research Karolinska Institutet Stockholm Sweden

Department of Clinical Neuroscience Centre for Psychiatry Research Karolinska Institutet Stockholm Sweden

Department of Neurology Oslo University Hospital Oslo Norway

Department of Neurosciences and Mental Health Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan Italy

Department of Pathophysiology and Transplantation University of Milan Milan Italy

Department of Psychiatric Research Diakonhjemmet Hospital Oslo Norway

Department of Psychiatry Amsterdam UMC Location VUMC Amsterdam The Netherlands

Department of Psychiatry and Mental Health University of Cape Town Cape Town Western Cape 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 Nova Scotia Canada

Department of Psychiatry Melbourne Medical School The University of Melbourne Melbourne Australia

Department of Psychiatry Psychosomatic Medicine and Psychotherapy University Hospital Frankfurt Frankfurt am Main Germany

Department of Psychiatry Radboudumc Nijmegen The Netherlands

Department of Psychiatry Universidade de São Paulo São Paulo Brazil

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

Department of Psychiatry University of Münster Münster Germany

Department of Psychology University of Oslo Oslo Norway

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

Division of Psychiatry University of Edinburgh Edinburgh UK

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

FIDMAG Germanes Hospitalàries Research Foundation CIBERSAM Barcelona Spain

General Adult Psychiatry Division Valkenberg Hospital Cape Town Western Cape South Africa

Hospital Clinic University of Barcelona IDIBAPS CIBERSAM Barcelona Catalonia Spain

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

Institut d'Investigacions Biomèdiques August Pi i Sunyer CIBERSAM Barcelona Spain

Institute of Clinical Medicine University of Oslo Oslo Norway

Institute of Clinical Radiology University of Münster Münster Germany

Institute of Medical Imaging and Visualisation Faculty of Health and Social Sciences Bournemouth University Bournemouth UK

Laureate Institute for Brain Research Tulsa Oklahoma USA

Lee Kong Chian School of Medicine Nanyang Technological University Singapore Singapore

LIM44 Department of Radiology and Oncology University of São Paulo São Paulo Brazil

Max Planck Institute of Psychiatry Munich Germany

Melbourne Neuropsychiatry Centre Department of Psychiatry University of Melbourne and Melbourne Health Melbourne Victoria Australia

Mood Disorders Program Hospital Universitario San Vicente Fundación Medellín Antioquia Colombia

MRC Centre for Neuropsychiatric Genetics and Genomics Department of Psychological Medicine and Clinical Neurosciences Cardiff University Cardiff UK

National Institute of Mental Health Klecany Czech Republic

Neuroscience Institute University of Cape Town Cape Town Western Cape South Africa

Neuroscience Research Australia Randwick New South Wales Australia

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

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

Orygen The National Centre of Excellence in Youth Mental Health and Centre for Youth Mental Health the Department of Psychiatry and the Florey Institute for Neuroscience and Mental Health The University of Melbourne Melbourne Victoria Australia

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

PROMENTA Research Center Department of Psychology University of Oslo Oslo Norway

Psychiatry Amsterdam UMC Location AMC Amsterdam The Netherlands

Psychiatry and Clinical Psychobiology Scientific Institute Ospedale San Raffaele Milan Italy

Psychosomatic and CL Psychiatry Division of Mental Health and Addiction Oslo University Hospital Oslo Norway

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

Research Group Instituto de Alta Tecnología Médica Medellín Antioquia Colombia

SA MRC Unit on Risk and Resilience in Mental Disorders Department of Psychiatry and Neuroscience Institute University of Cape Town Cape Town Western Cape South Africa

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

School of Mental Health and Neuroscience Faculty of Health Medicine and Life Sciences Maastricht University Maastricht The Netherlands

School of Psychiatry University of New South Wales Sydney New South Wales Australia

School of Psychology Bath University Bath UK

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

The Florey Institute of Neuroscience and Mental Health The University of Melbourne Parkville Australia

University of New Mexico Albuquerque New Mexico USA

University Vita Salute San Raffaele 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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What we learn about bipolar disorder from large-scale neuroimaging: Findings and future directions from the ENIGMA Bipolar Disorder Working Group