Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case-control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen's d=-0.232; P=3.50 × 10-7) and thalamus (d=-0.148; P=4.27 × 10-3) and enlarged lateral ventricles (d=-0.260; P=3.93 × 10-5) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.

Academic Psychiatry and Regional Affective Disorders Service Newcastle University Newcastle UK

Center for Neurobehavioral Genetics University of California Los Angeles CA USA

Center for Translational Research in Systems Neuroscience and Psychiatry Department of Psychiatry and Psychotherapy Georg August University Goettingen Goettingen Germany

Centre for Affective Disorders King's College London London UK

Clinical Neuroimaging Laboratory College of Medicine Nursing and Health Sciences National University of Ireland Galway Galway Ireland

Department of Clinical Neuroscience Section of Psychiatry Karolinska Institutet Stockholm Sweden

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

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Neurobiology Yale University School of Medicine New Haven CT USA

Department of Neurology Oslo University Hospital Oslo Norway

Department of Neuroradiology Karolinska University Hospital Stockholm Sweden

Department of Psychiatric Research Diakonhjemmet Hospital Oslo Norway

Department of Psychiatry and Biobehavioral Sciences University of California Los Angeles CA USA

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

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

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

Department of Psychiatry Brown University Providence RI USA

Department of Psychiatry Dalhousie University Halifax Canada

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

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

Department of Psychiatry University of Oxford Oxford UK

Department of Psychiatry University of Pennsylvania Perelman School of Medicine Philadelphia PA USA

Department of Psychiatry University of Pittsburgh Western Psychiatric Institute and Clinic Pittsburgh PA USA

Department of Psychiatry Yale University New Haven CT USA

Department of Psychology and Counselling Newman University Birmingham UK

Department of Psychology University of California Los Angeles CA USA

Department of Psychology University of Oslo Oslo Norway

Department of Psychosomatic Medicine Oslo University Hospital Rikshospitalet Oslo Norway

Department of Research and Education Oslo University Hospital Oslo Norway

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

Division of Psychiatry University of Edinburgh Edinburgh UK

Imaging Genetics Center University of Southern California Los Angeles CA USA

Inserm U955 Equipe 15 Psychiatrie génétique Créteil France

Institute of Clinical Medicine University of Oslo Oslo Norway

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

Karolinska MR Research Center Karolinska Institutet Stockholm Sweden

MMIL Department of Radiology University of California San Diego CA USA

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

National Institute of Mental Health Klecany Czech Republic

Neurospin Uniact I2BM CEA Saclay Saclay France

Norwegian Research Network On Mood Disorders Oslo Norway

Olin Neuropsychiatric Research Center Institute of Living Hartford CT USA

Osher Center for Integrative Medicine Karolinska Institutet Stockholm Sweden

School of Psychology University of Exeter Exeter UK

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

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

Université Paris Est UMR S955 UPEC Créteil France

University of Oxford Centre for Clinical Magnetic Resonance Research Oxford UK

UT Center of Excellence on Mood Disorders Department of Psychiatry and Behavioral Sciences UT Houston Medical School Houston TX USA

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