MRI studies in bipolar disorder (BD) have yielded inconsistent findings, partly due to the varied use of psychotropic medications. This study utilised a mega-analysis approach, accounting for concurrent medication status (syndrome-based and Neuroscience-based Nomenclature (NbN) classifications), in order to assess the association of medication status with subcortical brain volumes in BD. Data from 2,664 BD patients and 4,065 controls (CN) were pooled from 34 research groups as part of the ENIGMA Bipolar Disorder Working Group. Standardized ENIGMA protocols were used to measure subcortical brain volumes. Linear-mixed-effects regression evaluated the association between psychotropic medications and subcortical volumes, and moderation analyses explored interactions. Medication-free patients (n = 410) showed mild ventricular enlargement (d = 0.07) and increased putamen volume (d = 0.06) compared to CN. Patients taking psychotropic medications exhibited smaller subcortical volumes (d = -0.06 to -0.11) and larger ventricles (d = 0.11 to 0.19). Use of antiepileptic and antipsychotic medications was associated with smaller hippocampal and thalamic volumes (d = -0.07 to -0.14), while NbN classification indicated that the categories of 'valproate' and 'dopamine and other monoamine receptor antagonists' are key variables when considering volume differences between BD and CN. Concurrent lithium use weakened the negative association between antiepileptic use and hippocampal volume (β = 0.19, q = 0.038) in patients. Medication status is associated with altered subcortical brain volumes in BD. The NbN classification provides a useful framework for future studies, emphasizing the need for comprehensive longitudinal research to further unravel complex clinical-pharmacological-neurobiological interactions in BD.

APHP Mondor University Hospitals DMU IMPACT Créteil France

Bipolar and Depressive Disorders Unit Department of Psychiatry and Psychology Hospital Clínic de Barcelona Barcelona Spain

Center of Excellence on Mood Disorders UTHealth Houston Houston TX USA

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

Centre for Precision Psychiatry University of Oslo Oslo Norway

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

CIBERSAM ISCIII Madrid Spain

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

Clinical Psychology and Translational Psychotherapy Department of Psychology University of Münster Münster Germany

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

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 Canada

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Medicine Faculty of Medicine and Health Sciences Institute of Neurosciences University of Barcelona Barcelona Spain

Department of Mental Health and Addictions ASST Papa Giovanni XXIII Bergamo Italy

Department of Neurology Oslo University Hospital Oslo Norway

Department of Neuroscience University of Padova Padova Italy

Department of Pharmacology and Toxicology University of Toronto Toronto Canada

Department of Psychiatry and Behavioral Sciences Medical University of South Carolina Charleston SC USA

Department of Psychiatry and Behavioral Sciences University of Minnesota Minneapolis MN USA

Department of Psychiatry and Behavioral Sciences UTHealth Houston Houston TX USA

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 Boston Children's Hospital Boston MA USA

Department of Psychiatry Dalhousie University Halifax Nova Scotia Canada

Department of Psychiatry Harvard Medical School Boston MA Boston USA

Department of Psychiatry Medical School and University Medical Center OWL Protestant Hospital of the Bethel Foundation Bielefeld University Bielefeld Germany

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

Department of Psychiatry University of British Columbia Vancouver British Columbia Canada

Department of Psychiatry University of Melbourne Melbourne Victoria Australia

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

Department of Psychiatry University of Toronto Toronto Canada

Department of Psychology Stanford University Stanford CA USA

Department of Psychology University of Minnesota Minneapolis MN USA

Department of Psychology University of Oslo Oslo Norway

Department of Psychosomatic Medicine Oslo University Hospital Oslo Norway

Department of Radiology Centre Hospitalier Universitaire Vaudois Lausanne Switzerland

Department of Radiology University of Münster Münster Germany

Departments of Neurology Psychiatry Radiology Engineering Pediatrics and Ophthalmology University of Southern California Los Angeles CA USA

Departments of Psychiatry and Neuroscience Yale University School of Medicine New Haven CT USA

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

Division of Mental Health and Addiction Oslo University Hospital Oslo Norway

Division of Neuroscience Psychiatry and Psychobiology Unit IRCCS Ospedale San Raffaele Milan Italy

FIDMAG Germanes Hospitalàries Research Foundation Barcelona Spain

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

Imaging Genetics Center Mark and Mary Stevens Neuroimaging and Informatics Institute Keck School of Medicine University of Southern California Los Angeles California USA

Institut d'Investigacions Biomèdiques August Pi i Sunyer Barcelona Spain

Institute for Translational Neuroscience University of Münster Münster Germany

Institute for Translational Psychiatry University of Münster Münster Germany

Institute of Clinical Medicine University of Oslo Oslo Norway

Institute of Epidemiology and Social Medicine University of Münster Münster Germany

KG Jebsen Centre for Neurodevelopmental Disorders University of Oslo Oslo Norway

Laboratory of Systems Neuroscience and Imaging in Psychiatry Department of Psychiatry and Psychotherapy University Medical Center Goettingen Goettingen Germany

Laureate Institute for Brain Research Tulsa Oklahoma USA

Meditation Research Program Department of Psychiatry Massachusetts General Hospital Harvard Medical School Boston MA USA

Minneapolis VA Health Care System Minneapolis MN USA

Mood Disorders Unit Hospital das Clinicas HCFMUSP Faculdade de Medicina Universidade de São Paulo São Paulo SP Brazil

National Institute of Mental Health Klecany Czech Republic

NeuroRecovery Research Hub School of Psychology University of New South Wales Sydney Sydney New South Wales Australia

Neuroscience Institute University of Cape Town Cape Town South Africa

Neuroscience Research Australia Randwick New South Wales Australia

Neurospin CEA Paris Saclay team UNIACT Gif sur Yvette France

Northern Hospital Mental Health Services Epping Victoria Australia

Oslo University Hospital Department of Acute Psychiatry Unit of Psychosomatic and CL Adult Psychiatry Oslo Norway

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

Philipps Universität Marburg Faculty of Medicine Department of Psychiatry and Psychotherapy Rudolf Bultmann Str 8 D 35039 Marburg Germany

Psychiatry Mental Health and Addictions Group Vall d'Hebron Research Institute Centro de Investigación Biomédica en Red de Salud Mental Instituto de Salud Carlos 3 Barcelona Catalonia Spain

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

Research Ireland Futureneuro Centre for Translation Brain Science Royal College of Surgeons Dublin Ireland

School of Behavioral Health Sciences UTHealth Houston Houston TX USA

School of Biomedical Sciences Faculty of Medicine and Health University of New South Wales Sydney Australia

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

Section for Precision Psychiatry Division of Mental Health and Addiction Oslo University Hospital Oslo Norway Oslo Norway

Signal Processing Lab École Polytechnique Fédérale de Lausanne Lausanne Switzerland

South African Medical Research Council Unit on Risk and Resilience in Mental Disorders South African Medical Research Council Cape Town South Africa

St Vincent's Mental Health St Vincent's Hospital Melbourne VIC Australia

Université Paris Est Créteil INSERM Unit 955 Team Translational NeuroPsychiatry Créteil France

Valkenburg Hospital Cape Town South Africa

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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