Multicenter Study

. 2021 Sep;26(9):5124-5139.

doi: 10.1038/s41380-020-0754-0. Epub 2020 May 18.

Brain aging in major depressive disorder: results from the ENIGMA major depressive disorder working group

Laura K M Han¹, Richard Dinga^{2

3}, Tim Hahn⁴, Christopher R K Ching⁵, Lisa T Eyler^{6

7}, Lyubomir Aftanas^{8

9}, Moji Aghajani², André Aleman^{10

11}, Bernhard T Baune^{4

12

13}, Klaus Berger¹⁴, Ivan Brak^{8

15}, Geraldo Busatto Filho¹⁶, Angela Carballedo^{17

18}, Colm G Connolly¹⁹, Baptiste Couvy-Duchesne²⁰, Kathryn R Cullen²¹, Udo Dannlowski⁴, Christopher G Davey^{22

23}, Danai Dima^{24

25}, Fabio L S Duran¹⁶, Verena Enneking⁴, Elena Filimonova⁸, Stefan Frenzel²⁶, Thomas Frodl^{17

27

28}, Cynthia H Y Fu^{29

30}, Beata R Godlewska³¹, Ian H Gotlib³², Hans J Grabe^{26

33}, Nynke A Groenewold^{34

35}, Dominik Grotegerd⁴, Oliver Gruber³⁶, Geoffrey B Hall³⁷, Ben J Harrison³⁸, Sean N Hatton^{39

40}, Marco Hermesdorf¹⁴, Ian B Hickie³⁹, Tiffany C Ho^{32

41}, Norbert Hosten⁴², Andreas Jansen⁴³, Claas Kähler⁴, Tilo Kircher⁴³, Bonnie Klimes-Dougan⁴⁴, Bernd Krämer³⁶, Axel Krug^{43

45}, Jim Lagopoulos^{39

46}, Ramona Leenings⁴, Frank P MacMaster^{47

48}, Glenda MacQueen⁴⁹, Andrew McIntosh⁵⁰, Quinn McLellan^{47

51}, Katie L McMahon^{52

53}, Sarah E Medland⁵⁴, Bryon A Mueller²¹, Benson Mwangi⁵⁵, Evgeny Osipov¹⁵, Maria J Portella^{56

57}, Elena Pozzi^{21

38}, Liesbeth Reneman⁵⁸, Jonathan Repple⁴, Pedro G P Rosa¹⁶, Matthew D Sacchet⁵⁹, Philipp G Sämann⁶⁰, Knut Schnell^{61

62}, Anouk Schrantee⁵⁸, Egle Simulionyte³⁷, Jair C Soares⁵⁵, Jens Sommer⁴⁴, Dan J Stein^{35

63}, Olaf Steinsträter⁴², Lachlan T Strike⁶⁴, Sophia I Thomopoulos⁵, Marie-José van Tol⁶⁵, Ilya M Veer⁶⁶, Robert R J M Vermeiren^{67

68}, Henrik Walter⁶⁶, Nic J A van der Wee^{68

69}, Steven J A van der Werff^{68

69}, Heather Whalley⁵⁰, Nils R Winter⁴, Katharina Wittfeld^{26

33}, Margaret J Wright^{64

70}, Mon-Ju Wu⁵⁵, Henry Völzke⁷¹, Tony T Yang⁷², Vasileios Zannias⁵⁰, Greig I de Zubicaray^{53

73}, Giovana B Zunta-Soares⁵⁵, Christoph Abé⁷⁴, Martin Alda⁷⁵, Ole A Andreassen^{76

77}, Erlend Bøen⁷⁸, Caterina M Bonnin⁷⁹, Erick J Canales-Rodriguez⁸⁰, Dara Cannon⁸¹, Xavier Caseras⁸², Tiffany M Chaim-Avancini¹⁶, Torbjørn Elvsåshagen^{83

84}, Pauline Favre^{85

86}, Sonya F Foley⁸⁷, Janice M Fullerton^{88

89}, Jose M Goikolea⁷⁹, Bartholomeus C M Haarman⁹⁰, Tomas Hajek⁷⁵, Chantal Henry⁹¹, Josselin Houenou^{85

86}, Fleur M Howells^{35

92}, Martin Ingvar⁷⁴, Rayus Kuplicki⁹³, Beny Lafer⁹⁴, Mikael Landén^{74

95

96}, Rodrigo Machado-Vieira⁹⁴, Ulrik F Malt^{97

98}, Colm McDonald⁸¹, Philip B Mitchell^{99

100}, Leila Nabulsi⁸¹, Maria Concepcion Garcia Otaduy¹⁰¹, Bronwyn J Overs⁸⁸, Mircea Polosan^{102

103}, Edith Pomarol-Clotet⁸⁰, Joaquim Radua⁷⁹, Maria M Rive¹⁰⁴, Gloria Roberts^{99

100}, Henricus G Ruhe^{3

104

105}, Raymond Salvador⁸⁰, Salvador Sarró⁸⁰, Theodore D Satterthwaite¹⁰⁶, Jonathan Savitz^{93

107}, Aart H Schene^{3

105}, Peter R Schofield^{88

89}, Mauricio H Serpa¹⁶, Kang Sim^{108

109}, Marcio Gerhardt Soeiro-de-Souza⁹⁴, Ashley N Sutherland⁷, Henk S Temmingh^{36

110}, Garrett M Timmons⁷, Anne Uhlmann³⁵, Eduard Vieta⁷⁹, Daniel H Wolf¹⁰⁶, Marcus V Zanetti^{16

111}, Neda Jahanshad⁵, Paul M Thompson⁵, Dick J Veltman², Brenda W J H Penninx^#², Andre F Marquand^#^{3

112}, James H Cole^#^{25

113

114}, Lianne Schmaal^#^{22

23}

Affiliations

¹ Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit & GGZinGeest, Amsterdam, The Netherlands. l.han@amsterdamumc.nl.
² Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit & GGZinGeest, Amsterdam, The Netherlands.
³ Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, The Netherlands.
⁴ Department of Psychiatry, University of Münster, Münster, Germany.
⁵ Imaging Genetics Center, Mark & Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ Desert-Pacific Mental Illness Research Education and Clinical Center, VA San Diego Healthcare, San Diego, CA, USA.
⁷ Department of Psychiatry, University of California San Diego, Los Angeles, CA, USA.
⁸ FSSBI "Scientific Research Institute of Physiology & Basic Medicine", Laboratory of Affective, Cognitive & Translational Neuroscience, Novosibirsk, Russia.
⁹ Department of Neuroscience, Novosibirsk State University, Novosibirsk, Russia.
¹⁰ Department of Neuroscience, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
¹¹ Department of Clinical and Developmental Neuropsychology, University of Groningen, Groningen, The Netherlands.
¹² Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, VIC, Australia.
¹³ The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia.
¹⁴ Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
¹⁵ Laboratory of Experimental & Translational Neuroscience, Novosibirsk State University, Novosibirsk, Russia.
¹⁶ Laboratory of Psychiatric Neuroimaging (LIM-21), Instituto de Psiquiatria, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.
¹⁷ Department for Psychiatry, Trinity College Dublin, Dublin, Ireland.
¹⁸ North Dublin Mental Health Services, Dublin, Ireland.
¹⁹ Department of Biomedical Sciences, Florida State University, Tallahassee, FL, USA.
²⁰ Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
²¹ Department of Psychiatry and Behavioral Sciences, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
²² Orygen, The National Centre of Excellence in Youth Mental Health, Parkville, VIC, Australia.
²³ Centre for Youth Mental Health, The University of Melbourne, Melbourne, VIC, Australia.
²⁴ Department of Psychology, School of Arts and Social Sciences, City, University of London, London, UK.
²⁵ Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College, London, UK.
²⁶ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
²⁷ Department of Psychiatry and Psychotherapy, Otto von Guericke University (OVGU), Magdeburg, Germany.
²⁸ German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
²⁹ Centre for Affective Disorders, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
³⁰ School of Psychology, University of East London, London, UK.
³¹ Department of Psychiatry, University of Oxford, Oxford, UK.
³² Department of Psychology, Stanford University, Stanford, CA, USA.
³³ German Center of Neurodegenerative Diseases (DZNE) Site Rostock/Greifswald, Greifswald, Germany.
³⁴ Interdisciplinary Center Psychopathology and Emotion regulation (ICPE), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
³⁵ Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
³⁶ Section for Experimental Psychopathology and Neuroimaging, Department of Psychiatry, University of Heidelberg, Heidelberg, Germany.
³⁷ Department of Psychology, Neuroscience & Behaviour, McMaster University, Hamilton, ON, Canada.
³⁸ Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne & Melbourne Health, Melbourne, VIC, Australia.
³⁹ Youth Mental Health Team, Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.
⁴⁰ Department of Neuroscience, University of California San Diego, San Diego, CA, USA.
⁴¹ Department of Psychiatry & Behavioral Sciences, Standord University, Stanford, CA, USA.
⁴² Department of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
⁴³ Department of Psychiatry, Philipps-University Marburg, Marburg, Germany.
⁴⁴ Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
⁴⁵ Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
⁴⁶ Sunshine Coast Mind and Neuroscience Institute, University of the Sunshine Coast QLD, Sippy Downs, QLD, Australia.
⁴⁷ Departments of Psychiatry and Pediatrics, University of Calgary, Calgary, AB, Canada.
⁴⁸ Addictions and Mental Health Strategic Clinical Network, Calgary, AB, Canada.
⁴⁹ Department of Psychiatry, University of Calgary, Calgary, AB, Canada.
⁵⁰ Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
⁵¹ Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
⁵² School of Clinical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
⁵³ Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.
⁵⁴ QIMR Berghofer Medical Research Instititute, Brisbane, QLD, Australia.
⁵⁵ Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁵⁶ Institut d'Investigació Biomèdica Sant Pau, Barcelona, Catalonia, Spain.
⁵⁷ Centro de Investigación Biomédica en Red de Salud Mental, Cibersam, Spain.
⁵⁸ Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, AMC, Amsterdam, The Netherlands.
⁵⁹ Center for Depression, Anxiety, and Stress Research, McLean Hospital, Harvard Medical School, Belmont, MA, USA.
⁶⁰ Max Planck Institute of Psychiatry, Munich, Germany.
⁶¹ Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.
⁶² Department of Psychiatry and Psychotherapy, Asklepios Fachklinikum Göttingen, Göttingen, Germany.
⁶³ SA MRC Unit on Risk and Resilience, University of Cape Town, Cape Town, South Africa.
⁶⁴ Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia.
⁶⁵ Cognitive Neuroscience Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁶⁶ Division of Mind and Brain Research, Department of Psychiatry and Psychotherapy CCM, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
⁶⁷ Department of Child Psychiatry, University Medical Center, Leiden, The Netherlands.
⁶⁸ Leiden Institute for Brain and Cognition, Leiden University, Leiden, The Netherlands.
⁶⁹ Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.
⁷⁰ Centre for Advanced Imaging, University of Queensland, Brisbane, QLD, Australia.
⁷¹ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
⁷² Department of Psychiatry, Division of Child and Adolescent Psychiatry, UCSF School of Medicine, UCSF, San Francisco, CA, USA.
⁷³ Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.
⁷⁴ Department of Clinical Neuroscience, Osher Center, Karolinska Institutet, Stockholm, Sweden.
⁷⁵ Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
⁷⁶ NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁷⁷ Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
⁷⁸ Clinic for Mental Health and Dependency, C-L psychiatry and Psychosomatic Unit, Oslo University Hospital, Oslo, Norway.
⁷⁹ Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
⁸⁰ FIDMAG Germanes Hospitalàries Research Foundation, CIBERSAM, Barcelona, Catalonia, Spain.
⁸¹ Centre for Neuroimaging & Cognitive Genomics (NICOG), Clinical Neuroimaging Laboratory, NCBES Galway Neuroscience Centre, College of Medicine Nursing and Health Sciences, National University of Ireland Galway, H91 TK33, Galway, Ireland.
⁸² MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
⁸³ Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁸⁴ Department of Neurology, Oslo University Hospital, Oslo, Norway.
⁸⁵ UNIACT, Psychiatry Team, Neurospin, Atomic Energy Commission, Gif-Sur-Yvette, France.
⁸⁶ Translational Psychiatry Team, Pôle de psychiatrie, Faculté de Médecine, APHP, Hôpitaux Universitaires Mondor, INSERM, U955, Créteil, France.
⁸⁷ Cardiff University Brain Research Imaging Centre, Cardiff University, Cardiff, UK.
⁸⁸ Neuroscience Research Australia, Randwick, Sydney, NSW, Australia.
⁸⁹ School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
⁹⁰ Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁹¹ Université de Paris, Service Hospitalo-Universitaire, GHU Paris Psychiatrie & Neuroscience, F-75014, Paris, France.
⁹² Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
⁹³ Laureate Institute for Brain Research, Tulsa, OK, USA.
⁹⁴ Department of Psychiatry, School of Medicine, University of Sao Paulo (FMUSP), Sao Paulo, Brazil.
⁹⁵ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
⁹⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁹⁷ Department of Clinical Neuroscience, University of Oslo, Oslo, Norway.
⁹⁸ Clinic for Psychiatry and Dependency, C-L psychiatry and Psychosomatic Unit, Oslo University Hospital, Oslo, Norway.
⁹⁹ School of Psychiatry, University of New South Wales, Kingsford, Sydney, NSW, Australia.
¹⁰⁰ Black Dog Institute, Prince of Wales Hospital, Randwick, Sydney, NSW, Australia.
¹⁰¹ Instituto de Radiologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.
¹⁰² Department of Psychiatry and Neurology, CHU Grenoble Alpes, Université Grenoble Alpes, F-38000, Grenoble, France.
¹⁰³ Inserm 1216, Grenoble Institut des Neurosciences, GIN, F-38000, Grenoble, France.
¹⁰⁴ Department of Psychiatry, Amsterdam University Medical Centers, AMC, Amsterdam, The Netherlands.
¹⁰⁵ Department of Psychiatry, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁰⁶ Department of Psychiatry, University of Pennsylvannia Perelman School of Medicine, Philadelphia, PA, USA.
¹⁰⁷ Oxley College of Health Sciences, The University of Tulsa, Tulsa, OK, USA.
¹⁰⁸ West Region and Research Division, Institute of Mental Health, Singapore, Singapore.
¹⁰⁹ Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
¹¹⁰ Valkenberg Psychiatric Hospital, Cape Town, South Africa.
¹¹¹ Instituto de Ensino e Pesquisa, Hospital Sírio-Libanês, Sao Paulo, SP, Brazil.
¹¹² Department of Cognitive Neuroscience, Radboud University Medical Centre, Nijmegen, The Netherlands.
¹¹³ Centre for Medical Image Computing, Department of Computer Science, University College London, London, UK.
¹¹⁴ Dementia Research Centre, Institute of Neurology, University College London, London, UK.

^# Contributed equally.

PMID: 32424236
PMCID: PMC8589647
DOI: 10.1038/s41380-020-0754-0

Multicenter Study

Brain aging in major depressive disorder: results from the ENIGMA major depressive disorder working group

Laura K M Han et al. Mol Psychiatry. 2021 Sep.

. 2021 Sep;26(9):5124-5139.

doi: 10.1038/s41380-020-0754-0. Epub 2020 May 18.

Authors

Affiliations

¹ Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit & GGZinGeest, Amsterdam, The Netherlands. l.han@amsterdamumc.nl.
² Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit & GGZinGeest, Amsterdam, The Netherlands.
³ Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, The Netherlands.
⁴ Department of Psychiatry, University of Münster, Münster, Germany.
⁵ Imaging Genetics Center, Mark & Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ Desert-Pacific Mental Illness Research Education and Clinical Center, VA San Diego Healthcare, San Diego, CA, USA.
⁷ Department of Psychiatry, University of California San Diego, Los Angeles, CA, USA.
⁸ FSSBI "Scientific Research Institute of Physiology & Basic Medicine", Laboratory of Affective, Cognitive & Translational Neuroscience, Novosibirsk, Russia.
⁹ Department of Neuroscience, Novosibirsk State University, Novosibirsk, Russia.
¹⁰ Department of Neuroscience, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
¹¹ Department of Clinical and Developmental Neuropsychology, University of Groningen, Groningen, The Netherlands.
¹² Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, VIC, Australia.
¹³ The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia.
¹⁴ Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
¹⁵ Laboratory of Experimental & Translational Neuroscience, Novosibirsk State University, Novosibirsk, Russia.
¹⁶ Laboratory of Psychiatric Neuroimaging (LIM-21), Instituto de Psiquiatria, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.
¹⁷ Department for Psychiatry, Trinity College Dublin, Dublin, Ireland.
¹⁸ North Dublin Mental Health Services, Dublin, Ireland.
¹⁹ Department of Biomedical Sciences, Florida State University, Tallahassee, FL, USA.
²⁰ Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
²¹ Department of Psychiatry and Behavioral Sciences, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
²² Orygen, The National Centre of Excellence in Youth Mental Health, Parkville, VIC, Australia.
²³ Centre for Youth Mental Health, The University of Melbourne, Melbourne, VIC, Australia.
²⁴ Department of Psychology, School of Arts and Social Sciences, City, University of London, London, UK.
²⁵ Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College, London, UK.
²⁶ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
²⁷ Department of Psychiatry and Psychotherapy, Otto von Guericke University (OVGU), Magdeburg, Germany.
²⁸ German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
²⁹ Centre for Affective Disorders, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
³⁰ School of Psychology, University of East London, London, UK.
³¹ Department of Psychiatry, University of Oxford, Oxford, UK.
³² Department of Psychology, Stanford University, Stanford, CA, USA.
³³ German Center of Neurodegenerative Diseases (DZNE) Site Rostock/Greifswald, Greifswald, Germany.
³⁴ Interdisciplinary Center Psychopathology and Emotion regulation (ICPE), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
³⁵ Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
³⁶ Section for Experimental Psychopathology and Neuroimaging, Department of Psychiatry, University of Heidelberg, Heidelberg, Germany.
³⁷ Department of Psychology, Neuroscience & Behaviour, McMaster University, Hamilton, ON, Canada.
³⁸ Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne & Melbourne Health, Melbourne, VIC, Australia.
³⁹ Youth Mental Health Team, Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.
⁴⁰ Department of Neuroscience, University of California San Diego, San Diego, CA, USA.
⁴¹ Department of Psychiatry & Behavioral Sciences, Standord University, Stanford, CA, USA.
⁴² Department of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
⁴³ Department of Psychiatry, Philipps-University Marburg, Marburg, Germany.
⁴⁴ Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
⁴⁵ Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
⁴⁶ Sunshine Coast Mind and Neuroscience Institute, University of the Sunshine Coast QLD, Sippy Downs, QLD, Australia.
⁴⁷ Departments of Psychiatry and Pediatrics, University of Calgary, Calgary, AB, Canada.
⁴⁸ Addictions and Mental Health Strategic Clinical Network, Calgary, AB, Canada.
⁴⁹ Department of Psychiatry, University of Calgary, Calgary, AB, Canada.
⁵⁰ Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
⁵¹ Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
⁵² School of Clinical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
⁵³ Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.
⁵⁴ QIMR Berghofer Medical Research Instititute, Brisbane, QLD, Australia.
⁵⁵ Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁵⁶ Institut d'Investigació Biomèdica Sant Pau, Barcelona, Catalonia, Spain.
⁵⁷ Centro de Investigación Biomédica en Red de Salud Mental, Cibersam, Spain.
⁵⁸ Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, AMC, Amsterdam, The Netherlands.
⁵⁹ Center for Depression, Anxiety, and Stress Research, McLean Hospital, Harvard Medical School, Belmont, MA, USA.
⁶⁰ Max Planck Institute of Psychiatry, Munich, Germany.
⁶¹ Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.
⁶² Department of Psychiatry and Psychotherapy, Asklepios Fachklinikum Göttingen, Göttingen, Germany.
⁶³ SA MRC Unit on Risk and Resilience, University of Cape Town, Cape Town, South Africa.
⁶⁴ Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia.
⁶⁵ Cognitive Neuroscience Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁶⁶ Division of Mind and Brain Research, Department of Psychiatry and Psychotherapy CCM, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
⁶⁷ Department of Child Psychiatry, University Medical Center, Leiden, The Netherlands.
⁶⁸ Leiden Institute for Brain and Cognition, Leiden University, Leiden, The Netherlands.
⁶⁹ Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.
⁷⁰ Centre for Advanced Imaging, University of Queensland, Brisbane, QLD, Australia.
⁷¹ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
⁷² Department of Psychiatry, Division of Child and Adolescent Psychiatry, UCSF School of Medicine, UCSF, San Francisco, CA, USA.
⁷³ Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.
⁷⁴ Department of Clinical Neuroscience, Osher Center, Karolinska Institutet, Stockholm, Sweden.
⁷⁵ Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
⁷⁶ NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁷⁷ Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
⁷⁸ Clinic for Mental Health and Dependency, C-L psychiatry and Psychosomatic Unit, Oslo University Hospital, Oslo, Norway.
⁷⁹ Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
⁸⁰ FIDMAG Germanes Hospitalàries Research Foundation, CIBERSAM, Barcelona, Catalonia, Spain.
⁸¹ Centre for Neuroimaging & Cognitive Genomics (NICOG), Clinical Neuroimaging Laboratory, NCBES Galway Neuroscience Centre, College of Medicine Nursing and Health Sciences, National University of Ireland Galway, H91 TK33, Galway, Ireland.
⁸² MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
⁸³ Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁸⁴ Department of Neurology, Oslo University Hospital, Oslo, Norway.
⁸⁵ UNIACT, Psychiatry Team, Neurospin, Atomic Energy Commission, Gif-Sur-Yvette, France.
⁸⁶ Translational Psychiatry Team, Pôle de psychiatrie, Faculté de Médecine, APHP, Hôpitaux Universitaires Mondor, INSERM, U955, Créteil, France.
⁸⁷ Cardiff University Brain Research Imaging Centre, Cardiff University, Cardiff, UK.
⁸⁸ Neuroscience Research Australia, Randwick, Sydney, NSW, Australia.
⁸⁹ School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
⁹⁰ Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁹¹ Université de Paris, Service Hospitalo-Universitaire, GHU Paris Psychiatrie & Neuroscience, F-75014, Paris, France.
⁹² Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
⁹³ Laureate Institute for Brain Research, Tulsa, OK, USA.
⁹⁴ Department of Psychiatry, School of Medicine, University of Sao Paulo (FMUSP), Sao Paulo, Brazil.
⁹⁵ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
⁹⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁹⁷ Department of Clinical Neuroscience, University of Oslo, Oslo, Norway.
⁹⁸ Clinic for Psychiatry and Dependency, C-L psychiatry and Psychosomatic Unit, Oslo University Hospital, Oslo, Norway.
⁹⁹ School of Psychiatry, University of New South Wales, Kingsford, Sydney, NSW, Australia.
¹⁰⁰ Black Dog Institute, Prince of Wales Hospital, Randwick, Sydney, NSW, Australia.
¹⁰¹ Instituto de Radiologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.
¹⁰² Department of Psychiatry and Neurology, CHU Grenoble Alpes, Université Grenoble Alpes, F-38000, Grenoble, France.
¹⁰³ Inserm 1216, Grenoble Institut des Neurosciences, GIN, F-38000, Grenoble, France.
¹⁰⁴ Department of Psychiatry, Amsterdam University Medical Centers, AMC, Amsterdam, The Netherlands.
¹⁰⁵ Department of Psychiatry, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁰⁶ Department of Psychiatry, University of Pennsylvannia Perelman School of Medicine, Philadelphia, PA, USA.
¹⁰⁷ Oxley College of Health Sciences, The University of Tulsa, Tulsa, OK, USA.
¹⁰⁸ West Region and Research Division, Institute of Mental Health, Singapore, Singapore.
¹⁰⁹ Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
¹¹⁰ Valkenberg Psychiatric Hospital, Cape Town, South Africa.
¹¹¹ Instituto de Ensino e Pesquisa, Hospital Sírio-Libanês, Sao Paulo, SP, Brazil.
¹¹² Department of Cognitive Neuroscience, Radboud University Medical Centre, Nijmegen, The Netherlands.
¹¹³ Centre for Medical Image Computing, Department of Computer Science, University College London, London, UK.
¹¹⁴ Dementia Research Centre, Institute of Neurology, University College London, London, UK.

^# Contributed equally.

PMID: 32424236
PMCID: PMC8589647
DOI: 10.1038/s41380-020-0754-0

Abstract

Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen's d = 0.14, 95% CI: 0.08-0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.

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Conflict of interest statement

LA, MA, AA, BTB, KB, IB, GBF, AC, CRKC, JHC, CGC, BC-D, KC, UD, CGD, DD, RD, FLSD, VE, LTE, EF, SF, TF, CHYF, BRG, IHG, NAG, DG, OG, TH, GBH, LKMH, BJH, SNH, MH, TCH, NH, NJ, AJ, CK, TK, BK-D, BK, AK, JL, RL, FPM, GM, AFM, AM, KLM, SEM, PBM, BAM, BM, EO, MJP, EP, LR, JR, PGPR, MDS, PGS, LS, AS, ES, JS, DJS, OS, LTS, SIT, M-JvT, IMV, RRJMV, HW, NJAvdW, SJAvdW, HW, NRW, KW, MJW, M-JW, DJV, HV, TTY, VZ, GIdZ, GBZ-S, CA, MA, OAA, EB, CMB, EJC-R, DC, XC, TMC-A, PF, SFF, JMF, JMG, BCMH, TH, CH, JH, FMH, MI, RK, BL, RM-V, UFM, CM, PBM, LN, MCGO, BJO, MP, EP-C, JR, MMR, GR, HGR, RS, SS, TDS, JS, AHS, PRS, MHS, KS, MGS-d-S, ANS, HST, GMT, AU, DHW, MVZ: these authors received the following funding; however, all unrelated to the current manuscript: BRG has received a (nonrelated) travel grant from Janssen UK. HJG has received travel grants and speakers’ honoraria from Servier, Fresenius Medical Care and Janssen Cilag. He has received research funding from the German Research Foundation (DFG), the German Ministry of Education and Research (BMBF), the DAMP Foundation, Fresenius Medical Care, the EU “Joint Programme Neurodegenerative Disorders (JPND) and the European Social Fund (ESF)”. IBH was an inaugural Commissioner on Australia’s National Mental Health Commission (2012-2018). He is the Co-Director, Health and Policy at the Brain and Mind Centre (BMC) University of Sydney. The BMC operates an early-intervention youth services at Camperdown under contract to headspace. IBH has previously led community-based and pharmaceutical industry-supported (Wyeth, Eli Lily, Servier, Pfizer, AstraZeneca) projects focused on the identification and better management of anxiety and depression. He was a member of the Medical Advisory Panel for Medibank Private until October 2017, a Board Member of Psychosis Australia Trust and a member of Veterans Mental Health Clinical Reference group. He is the Chief Scientific Advisor to, and an equity shareholder in, Innowell. Innowell has been formed by the University of Sydney and PwC to deliver the $30 million Australian Government-funded “Project Synergy.” Project Synergy is a 3-year program for the transformation of mental health services through the use of innovative technologies. BWJHP has received (nonrelated) research funding from Boehringer Ingelheim and Jansen Research. KS has consulted for Roche Pharmaceuticals and Servier Pharmaceuticals. JCS has received research support from BMS, Forest, Merck, Elan, Johnson & Johnson and COMPASS in the form of grants and clinical trials. He is a member of the speakers’ bureaus for Pfizer, Abbott and Sonify and he is a consultant for Astellas. TE has served as a speaker for Lundbeck. ML declares that, over the past 36 months, he has received lecture honoraria from Lundbeck pharmaceutical. No other equity ownership, profit-sharing agreements, royalties, or patent. PMT has received (nonrelated) research funding from Biogen, Inc. (Boston). EV has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbott, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, SAGE, Sanofi-Aventis, Servier, Shire, Sunovion, and Takeda. Supplementary information is available at MP’s website. CRKC has received (nonrelated) research funding from Biogen, Inc. (Boston).

Figures

**Fig. 1. Data partition approach.**
a Schematic illustration of features used and data partition into training and test samples, separately for males and females. A full list of features can be found in the Supplementary Material. b Data from control groups (blue) were partitioned into balanced 50:50 splits within each scanning site following random sampling but preserving the overall chronological age distribution. Major depressive disorder (MDD) groups are shown in red. The top panel illustrates the male (left) and female (right) training samples. The middle and bottom panels show the male (controls: mean [SD] in years, 43.1 [15.3]; MDD: 42.8 [13.1]) and female test samples (controls: 39.4 [15.7]; MDD: 43.2 [14.0]). ICV intracranial volume.

**Fig. 2. Brain age prediction based on 7 FreeSurfer subcortical volumes, lateral ventricles, 34 cortical thickness and 34 surface area measures, and total intracranial volume.**
The plots show the correlation between chronological age and predicted brain age in the tenfold cross-validation of the ridge regression in the control train sample, the out-of-sample validation of the test samples (controls and MDD patients) from the ENIGMA MDD working group, and generalizability to completely independent test samples (controls only) from the ENIGMA BD working group (top to bottom). The colors indicate scanning sites and each circle represents an individual subject. Diagonal dashed line reflects the line of identity (x = y).

**Fig. 3. Case–control differences in brain aging.**
Brain-PAD (predicted brain age—chronological age) in patients with major depressive disorder (MDD) and controls. Group level analyses showed that MDD patients exhibited significantly higher brain-PAD than controls (b = 1.08, p < 0.0001), although large within-group variation and between-group overlap are observed as visualized in a the density plot and b the Engelmann–Hecker plot. The brain-PAD estimates are adjusted for chronological age, age², sex, and scanning site.

**Fig. 4. Structure coefficients of predicted brain age and FreeSurfer features across control and major depressive disorder (MDD) groups.**
Bivariate correlations are shown for illustrative purposes and to provide a sense of importance of features in the brain age prediction. The figure shows Pearson correlations between predicted brain age and cortical thickness features (top row), cortical surface areas (middle row), and subcortical volumes (bottom row). The negative correlation with ICV was excluded from this figure for display purposes.

See this image and copyright information in PMC

References

1. John A, Patel U, Rusted J, Richards M, Gaysina D. Affective problems and decline in cognitive state in older adults: a systematic review and meta-analysis. Psychol Med. 2018;49:353–65. - PMC - PubMed
1. Vancampfort D, Correll CU, Wampers M, Sienaert P, Mitchell AJ, De Herdt A, et al. Metabolic syndrome and metabolic abnormalities in patients with major depressive disorder: a meta-analysis of prevalences and moderating variables. Psychol Med. 2014;44:2017–28. - PubMed
1. Verhoeven JE, Révész D, Epel ES, Lin J, Wolkowitz OM, Penninx BWJH. Major depressive disorder and accelerated cellular aging: results from a large psychiatric cohort study. Mol Psychiatry. 2014;19:895–901. - PubMed
1. Verhoeven JE, Révész D, Picard M, Epel EE, Wolkowitz OM, Matthews KA, et al. Depression, telomeres and mitochondrial DNA: Between- and within-person associations from a 10-year longitudinal study. Mol Psychiatry. 2018;23:850–7. - PubMed
1. Evans DL, Charney DS, Lewis L, Golden RN, Gorman JM, Krishnan KRR, et al. Mood disorders in the medically ill: scientific review and recommendations. Biol Psychiatry. 2005;58:175–89. - PubMed

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Brain aging in major depressive disorder: results from the ENIGMA major depressive disorder working group

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Brain aging in major depressive disorder: results from the ENIGMA major depressive disorder working group

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