ArticlemedRxiv : the preprint server for health sciences2026
Brain Ageing in Social Anxiety Disorder: An ENIGMA-Anxiety Mega-Analysis Across 26 International Cohorts.
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97 authors.
Kimberly V BlakeDepartment of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa.ORCID 0000-0002-4376-5658
Jonathan C IpserDepartment of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa.ORCID 0000-0003-1272-0032
Alyssa R AmodDepartment of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa.ORCID 0000-0001-5190-9597
Tobias KaufmannDepartment of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany.ORCID 0000-0002-4003-1018
Yair Bar-HaimTel Aviv University, Tel Aviv, Israel.
Jochen BauerUniversity Clinic for Radiology, University of Münster, Münster, Germany.ORCID 0000-0001-9345-2126
Ali BayramIstanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Neuroscience, Turkey.ORCID 0000-0002-6588-3479
Katja Beesdo-BaumBehavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, TUD - Dresden University of Technology, Germany.ORCID 0000-0002-9687-5527
Laura Blanco-HinojoMRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain.
Tiana BorgersInstitute for Translational Psychiatry, University of Münster, Münster, Germany.ORCID 0000-0003-2309-6079
Robin BülowInstitute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
Marta CanoSant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain.
Narcís CardonerSant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain.ORCID 0000-0001-9633-0888
Christopher R K ChingImaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA.ORCID 0000-0003-2921-3408
Soo-Hee ChoiDepartment of Psychiatry, Seoul National University College of Medicine and Institute of Human Behavioral Medicine, SNU-MRC, Seoul, Republic of Korea.
Udo DannlowskiInstitute for Translational Psychiatry, University of Münster, Münster, Germany.ORCID 0000-0002-0623-3759
Christopher G DaveyDepartment of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia.ORCID 0000-0003-1431-3852
Alexander G G DoruyterDivision of Nuclear Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa.
Kira FlinkenflügelInstitute for Translational Psychiatry, University of Münster, Münster, Germany.
Gregory A FonzoDepartment of Psychiatry and Behavioral Sciences, The University of Texas at Austin Dell Medical School, Austin, TX, USA.ORCID 0000-0002-0213-1034
Tomas FurmarkDepartment of Psychology, Uppsala University, Uppsala, Sweden.ORCID 0000-0001-6821-9058
Dominik GrotegerdInstitute for Translational Psychiatry, University of Münster, Münster, Germany.ORCID 0000-0001-8718-0128
Hans J GrabeDepartment of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.ORCID 0000-0003-3684-4208
Tim HahnInstitute for Translational Psychiatry, University of Münster, Münster, Germany.
Ben J HarrisonDepartment of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia.ORCID 0000-0002-2226-2074
Alexandre HeerenPsychological Science Research Institute, Université Catholique de Louvain, Louvain-la-Neuve, Belgium.ORCID 0000-0003-0553-6149
Kevin HilbertDepartment of Psychology, HMU Health and Medical University Erfurt, Germany.ORCID 0000-0002-7986-4113
Yoshiyuki HiranoResearch Center for Child Mental Development, Chiba University, Chiba, Japan.ORCID 0000-0003-3844-3061
Joy HirschDepartments of Psychiatry, Comparative Medicine, & Neuroscience, Yale School of Medicine, New Haven, CT, USA.ORCID 0000-0002-1418-6489
David HofmannInstitute of Medical Psychology and Systems Neuroscience, University of Münster, Münster, Germany.ORCID 0000-0003-3494-634X
Yuko IsobeDepartment of Cognitive Behavioral Physiology, Graduate School of Medicine, Chiba University, Chiba, Japan.ORCID 0009-0004-2811-6977
Neda JahanshadImaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA.ORCID 0000-0003-4401-8950
Hamidreza JamalabadiDepartment of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.ORCID 0000-0003-2485-2374
Alec J JamiesonDepartment of Psychiatry, The University of Melbourne, Parkville, Victoria, 3010, Australia.ORCID 0000-0002-5598-0240
Andreas JansenDepartment of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.ORCID 0000-0002-3140-8207
Jaehyun Edmund KimSeoul National University, Seoul, Republic of Korea.
Tilo KircherDepartment of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.
Hitomi KitagawaResearch Center for Child Mental Development, Chiba University, Chiba, Japan.
Anna Luisa KlahnDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Saskia B J KochDonders Center for Cognitive Neuroimaging (DCCN), Radboud University Nijmegen, Nijmegen, the Netherlands.ORCID 0000-0002-3628-6712
Axel KrugDepartment of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany.ORCID 0000-0002-0564-2497
Harald KugelUniversity Clinic for Radiology, University of Münster, Münster, Germany.ORCID 0000-0002-4349-1984
Dasom LeeDepartment of Psychiatry, Seoul National University Hospital, Seoul, Republic of Korea.ORCID 0000-0003-3776-2263
Elisabeth J LeehrInstitute for Translational Psychiatry, University of Münster, Münster, Germany.ORCID 0000-0002-9264-5003
Christine LochnerSAMRC Unit on Risk and Resilience in Mental Disorders, Stellenbosch University, Stellenbosch, South Africa.ORCID 0000-0002-4766-3704
Ulrike LuekenDepartment of Psychology, Humboldt-Universität zu Berlin, German Center for Mental Health (DZPG), partner site Berlin-Potsdam, Germany.ORCID 0000-0003-1564-4012
Amirhossein ManzouriDepartment of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.ORCID 0000-0001-5127-9855
Kristoffer N T MånssonDepartment of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Koji MatsumotoDepartment of Radiology, Chiba University Hospital, Chiba, Japan.
Susanne MeinertInstitute for Translational Psychiatry, University of Münster, Münster, Germany.ORCID 0000-0003-2177-7161
Alicia MenzeMedical Faculty Münster, University Hospital Münster, Münster, Germany.ORCID 0009-0002-8275-8167
Markus MuehlhanDepartment of Psychology, Faculty of Human Sciences, MSH Medical School Hamburg, Hamburg, Germany.ORCID 0000-0002-8855-8724
Benson MwangiDepartment of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.ORCID 0000-0002-1717-4395
Igor NenadićDepartment of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.
Ziphozihle NtwatwaDepartment of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa.ORCID 0000-0002-4953-2695
Hyuntaek OhThe Menninger Clinic, Houston, TX, USA.ORCID 0000-0002-6410-6360
Spiro P PantazatosDepartment of Psychiatry, Columbia University Medical Center, New York, NY, USA.ORCID 0000-0002-9572-8816
Martin P PaulusLaureate Institute for Brain Research, Tulsa, OK, USA.ORCID 0000-0002-0825-3606
Jutta PeterbursInstitute of Systems Medicine and Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg, Germany.ORCID 0000-0003-3571-126X
Jesus PujolMRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain.
Karin RoelofsDonders Center for Cognitive Neuroimaging (DCCN), Radboud University Nijmegen, Nijmegen, the Netherlands.ORCID 0000-0002-8863-8978
Ramiro SalasThe Menninger Clinic, Houston, TX, USA.
Franklin R SchneierNew York State Psychiatric Institute, New York, NY, USA.ORCID 0000-0002-2938-2693
Elisabeth SchrammenInstitute for Translational Psychiatry, University of Münster, Münster, Germany.ORCID 0000-0001-8710-1274
Eiji ShimizuResearch Center for Child Mental Development, Chiba University, Chiba, Japan.ORCID 0000-0002-6741-9338
Lisa SindermannDepartment of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany.ORCID 0000-0002-3186-2100
Theresa M SlumpInstitute for Translational Psychiatry, University of Münster, Münster, Germany.ORCID 0009-0008-2114-187X
Jair C SoaresDepartment of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Benjamin StraubeDepartment of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.ORCID 0000-0002-9837-0944
Thomas StraubeInstitute of Medical Psychology and Systems Neuroscience, University of Münster, Münster, Germany.
Murray B SteinDepartment of Psychiatry & School of Public Health, University of California, San Diego, La Jolla, CA, USA.
Ardesheer TalatiDepartment of Psychiatry, Columbia University Medical Center, New York, NY, USA.ORCID 0000-0001-5708-1372
Florian Thomas-OdenthalDepartment of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.ORCID 0000-0003-4912-8307
Sophia I ThomopoulosImaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA.ORCID 0000-0002-0046-4070
Raşit TükelIstanbul University, Istanbul Faculty of Medicine, Department of Psychiatry, Istanbul, Turkey.
Anna TyborowskaDonders Center for Cognitive Neuroimaging (DCCN), Radboud University Nijmegen, Nijmegen, the Netherlands.ORCID 0000-0002-7621-3497
Marie-José Van TolCenter for Clinical Neuroscience and Cognition, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Dick J VeltmanDepartment of Psychiatry, Amsterdam University Medical Center, Amsterdam, the Netherlands.
Roman A VoglerInstitute for Translational Psychiatry, University of Münster, Münster, Germany.ORCID 0009-0004-9382-5470
Inge VolmanNational Education Lab for AI, Radboud University Nijmegen, Nijmegen, the Netherlands.
Henry VölzkeInstitute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
P Michiel WestenbergDepartment of Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, the Netherlands.ORCID 0000-0001-9138-7703
Katharina WittfeldDepartment of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.ORCID 0000-0003-4383-5043
Mon-Ju WuDepartment of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.ORCID 0000-0002-0540-8027
Noga YairTel Aviv University, Tel Aviv, Israel.ORCID 0009-0001-8797-6377
Tokiko YoshidaResearch Center for Child Mental Development, Chiba University, Chiba, Japan.ORCID 0000-0002-4410-7163
Chen ZhangThe University of Texas at Arlington, Arlington, USA.
Xi ZhuThe University of Texas at Arlington, Arlington, USA.
Giovana B Zunta-SoaresDepartment of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Peter ZwanzgerDepartment of Psychiatry and Psychotherapy, Ludwig-Maximilian University of Munich, Germany.ORCID 0009-0006-8290-9702
Daniel S PineNational Institute of Mental Health, Emotion and Development Branch, USA.ORCID 0000-0002-4301-9516
Moji AghajaniInstitute of Education & Child Studies, Section Forensic Family & Youth Care, Leiden University, Leiden, the Netherlands.ORCID 0000-0003-2040-4881
Paul M ThompsonImaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, CA, USA.
Nic J A Van der WeeLeiden Institute for Brain and Cognition, Leiden, the Netherlands.ORCID 0000-0003-3235-1633
Dan J SteinDepartment of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa.ORCID 0000-0001-7218-7810
Janna Marie Bas-HoogendamDepartment of Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, the Netherlands.ORCID 0000-0001-8982-1670
Nynke A GroenewoldDepartment of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, South Africa.ORCID 0000-0002-0865-8427
Funding
fMRI Studies Of Pediatric Mood And Anxiety DisordersZIAMH002781 · NIMH · NATIONAL INSTITUTE OF MENTAL HEALTH · PI PINE, DANIEL · 2009 to 2025
$41.5MFmri Studies Of Risk For Mood And Anxiety Disorders In ChildrenZIAMH002782 · NIMH · NATIONAL INSTITUTE OF MENTAL HEALTH · PI PINE, DANIEL · 2009 to 2025
$28.3MTraining U54EB020403 · NIBIB · UNIVERSITY OF SOUTHERN CALIFORNIA · PI THOMPSON, PAUL M · 2014 to 2018
$10.1M1/2 Neurodevelopmental and clinical trajectories of youth at risk for bipolar I disorderR01MH125886 · NIMH · UNIVERSITY OF TEXAS AT AUSTIN · PI ALMEIDA, JORGE R C, STRAKOWSKI, STEPHEN M · 2021 to 2025
$4.3MLifespan Epilepsy Network Signatures (LENS): Leveraging ENIGMA-Epilepsy to Predict Cognitive Aging and Surgical OutcomesR01NS122827 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI CARRIE R MCDONALD · 2021 to 2026
$3.8MENIGMA World Aging CenterR01AG058854 · NIA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI THOMPSON, PAUL M · 2021 to 2025
$3.3MENIGMA Bipolar Initiative: A Global Study of Imaging Genomics & Clinical OutcomesR01MH129742 · NIMH · UNIVERSITY OF SOUTHERN CALIFORNIA · PI Christopher Ching, PAUL M THOMPSON · 2022 to 2026
$3.0MSearching for Endophenotypes of Bipolar DisorderR01MH085667 · NIMH · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI SOARES, JAIR C · 2012 to 2016
$3.0MEstablishing Multimodal Brain Biomarkers Using Data-driven Analyticsfor Treatment Selection in DepressionR01MH129694 · NIMH · STANFORD UNIVERSITY · PI Yu Zhang · 2023 to 2026
$2.8MGlobal Deep Learning Initiative to Understand Outcomes in Major DepressionR01MH131806 · NIMH · UNIVERSITY OF SOUTHERN CALIFORNIA · PI Roberto Goya-Maldonado, PAUL M THOMPSON · 2023 to 2026
$2.6MThe effects of trauma-focused psychotherapy on reward circuitry function and information encodingR01MH132784 · NIMH · UNIVERSITY OF TEXAS AT AUSTIN · PI Gregory Fonzo · 2024 to 2026
$2.3MHigh Capacity, High Performance Storage System for NeuroscienceS10OD032285 · OD · UNIVERSITY OF SOUTHERN CALIFORNIA · PI TOGA, ARTHUR W · 2022 to 2022
$1.7MCSRD VA I01 CX001937Intramural NIH HHS ZIA MH002781Intramural NIH HHS ZIA MH002782NIA NIH HHS R01 AG058854NIBIB NIH HHS U54 EB020403NIH HHS S10 OD032285NIMH NIH HHS K01 MH122774NIMH NIH HHS R01 MH085667NIMH NIH HHS R01 MH125886NIMH NIH HHS R01 MH129694NIMH NIH HHS R01 MH129742NIMH NIH HHS R01 MH131806NIMH NIH HHS R01 MH132784NIMH NIH HHS R01 MH134962NIMH NIH HHS R01 MH138569NIMH NIH HHS R21 MH139001NINDS NIH HHS R01 NS122827
Abstract
Social anxiety disorder (SAD) is among the most prevalent anxiety disorders, and it has been associated with signs of advanced biological ageing. Despite this, brain age research on anxiety disorders remains limited. This mega-analysis investigated brain ageing in adults with SAD within the ENIGMA-Anxiety Working Group. Structural MRI scans from 576 participants with SAD and 1 355 non-affected healthy controls (HCs) across 26 international samples were included. Brain age was estimated from 77 cortical and subcortical regions using a publicly available ENIGMA brain age model. The brain-predicted age difference (brain-PAD) was calculated as the difference between brain age and chronological age. Group and subgroup differences (comorbidity, medication) were assessed using linear mixed-effect models. In the full sample, there was no group difference in brain-PAD (diagnosis (SE)=0.70 (0.37) years,
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