Psychotropic medications and their interactions with subcortical brain volume in bipolar disorder: An ENIGMA mega-analysis

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.

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Journal
Molecular Psychiatry
Published
2026-01-15
DOI
https://doi.org/10.1038/s41380-025-03432-z
Primary Topic
Bipolar Disorder and Treatment
Type
article
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0.00

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article

Psychotropic medications and their interactions with subcortical brain volume in bipolar disorder: An ENIGMA mega-analysis

Christopher R. K. Ching, Anna Luisa Klahn, Josselin Houenou, Carlos A. Lopez-Jaramillo et al.
Molecular Psychiatry
Bipolar Disorder and Treatment
article

Psychotropic medications and their interactions with subcortical brain volume in bipolar disorder: An ENIGMA mega-analysis

Christopher R. K. Ching, Anna Luisa Klahn, Josselin Houenou, Carlos A. Lopez-Jaramillo, Elijah Lahud, Bartholomeus C. M. Haarman, Giulia Tronchin, Bradley J. MacIntosh, Brian P. Hallahan, Sílvia Alonso-Lana, Lisa S. Furlong, Benson Mwangi, Caroline Demro, Emma Corley, Scott R. Sponheim, Elena Rodríguez‐Cano, L. Teutenberg, Sinéad King, María Florencia Forte, James J. Prisciandaro, Ian H. Gotlib, Oliver Gruber, MJ Green, Leonie Hater, Ana M. Díaz‐Zuluaga, James A. Karantonis, Fleur M. Howells, Amanda Rodrigue, Tracy Erwin-Grabner, T. Hahn, Susan Lee Rossell, Pauline Favre, Tamsyn E. Van Rheenen, Nadine Parker, Lisa Rauer, Snežana Urošević, Salvador Raymond, Susanne Meinert, Beatrice Bravi, Maximilian Konowski, Eduard Vieta, Erlend Bøen, Yann Quide, Marcio Gerhardt Soeiro-de-Souza, Dag Alnæs, Mon-Ju Wu, Martin Alda, John O’Connor, Jair C. Soares, Jochen Bauer, Giovana B. Zunta-Soares, Sophia I. Thomopoulos, Elisa M. T. Melloni, Dara M. Cannon, Udo Dannlowski, Edith Pomarol-Clotet, Leila Nabulsi, Daniel H. Wolf, Navid Schürmeyer, Tilo Kircher, Elisa Fontana, Theodore D. Satterthwaite, Ole A. Andreassen, Gloria Roberts, Janice M. Fullerton, Francesco Benedetti, Fabio Sambataro, Jonathan Savitz, Joaquim Radua, Tomas Hajek, for the ENIGMA Bipolar Disorder Working Group, Silvia Amoretti, Roberto Goya-Maldonado, Hannah Meinert, Chen Shen, Matthew D. Sacchet, Frederike Stein, Kody G. Kennedy, Lars T. Westlye, Torbjørn Elvsåshagen, Bernd Krämer, Birgitte Boye, Dominik Grotegerd, Godfrey Pearlson, Benjamin I. Goldstein, Rayus Kuplicki, Lakshmi N. Yatham, Kang Sim, Henk S. Temmingh, Joscha Böhnlein, Freda Scheffler, Philip B. Mitchell, Christoph Abé, Aleix Solanes, David C. Glahn, Klaus Berger, Michael Berk, Mikael Landén, Paul M. Thompson, Igor Nenadić, Colm McDonald, Melody J. Y. Kang, Dan J. Stein
article en

Abstract

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.

Molecular Psychiatry
South African Medical Research Council (ZA), University of Southern California (US), Oslo University Hospital (NO), Boston Medical Center (US), Boston Children's Hospital (US), Dalhousie University (CA), University of Minnesota (US), Barwon Health (AU), University Medical Center Groningen (NL), Centre for Addiction and Mental Health (CA), Harvard University (US), University of Padua (IT), University of British Columbia (CA), Royal College of Surgeons in Ireland (IE), Medical University of South Carolina (US), Vita-Salute San Raffaele University (IT), Inserm (FR), University of Cape Town (ZA), Philipps University of Marburg (DE), The University of Melbourne (AU), National University of Singapore (SG), University of Groningen (NL), University of Oslo (NO), University of Toronto (CA), Université Paris-Est Créteil (FR), Heidelberg University (DE), University of Münster (DE), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Instituto de Salud Carlos III (ES), Centre Hospitalier Universitaire Vaudois (CH), Northern Hospital (AU), Valkenberg Hospital (ZA), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Karolinska Institutet (SE), UNSW Sydney (AU), Yale University (US), Universidad de Antioquia (CO), St Vincent's Hospital Melbourne (AU), Ospedale Maggiore (IT), Massachusetts General Hospital (US), Centro de Investigación Biomédica en Red de Salud Mental (ES), Vall d'Hebron Institut de Recerca (ES), Ospedale Papa Giovanni XXIII (IT), Hospital Clínic de Barcelona (ES), Minneapolis VA Health Care System (US), Fidmag Sisters Hospitallers (ES), CEA Paris-Saclay (FR), IRCCS Ospedale San Raffaele (IT), Institute of Mental Health (SG), Cognitive Neuroimaging Lab (FR), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR), The University of Texas Health Science Center (US), Institut Mondor de Recherche Biomédicale (FR), Laureate Institute for Brain Research (US), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), National Institute of Mental Health (CZ), École Polytechnique Fédérale de Lausanne (CH), Swinburne University of Technology (AU), FH Münster University of Applied Sciences (DE), Universitat de Barcelona (ES), University of Göttingen (DE), University of Pennsylvania (US), Neuroscience Research Australia (AU), University of Tulsa (US), University of Gothenburg (SE), Bethel University (US), The University of Texas Health Science Center at Houston (US), Stanford University (US)
U.S. Department of Veterans Affairs, Sanofi, Yale University, Biogen, Teva Pharmaceutical Industries, Medical University of South Carolina, Fondation de l'Avenir pour la Recherche Médicale Appliquée, Sunovion, LivaNova, Centre for Addiction and Mental Health Foundation, National Imaging Facility, Irish Research eLibrary, Vistagen Therapeutics, European Commission, Macquarie University, National Research Foundation, South African Medical Research Council, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, University of New South Wales, Swinburne University of Technology, Bundesministerium für Bildung und Forschung, Dainippon Sumitomo Pharma, Gedeon Richter, University of Toronto, Centre of Excellence in Cognition and its Disorders, Australian Research Council, Eisai, Hjärnfonden, Novo Nordisk, Vetenskapsrådet, NordForsk, Westfälische Wilhelms-Universität Münster, Universidad de Antioquia, Norges Forskningsråd, University of Cape Town, Novo Nordisk Fonden, Servier, H. Lundbeck A/S, Neuraxpharm, Idorsia Pharmaceuticals, National Institutes of Health, Canadian Institutes of Health Research, Medical Research Council, National Health and Medical Research Council, National Institute of Mental Health, Cilag
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