title: Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group.
abstract: The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.
authors.affiliation: Department of Psychiatry and Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Schmaal
authors.affiliation: Department of Psychiatry and Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: D J
authors.initials: DJ
authors.lastname: Veltman
authors.affiliation: Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA.
authors.forename: T G M
authors.initials: TG
authors.lastname: van Erp
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: P G
authors.initials: PG
authors.lastname: Sämann
authors.affiliation: Department of Psychiatry, University of Regensburg, Regensburg, Germany.|Department of Psychiatry, University of Dublin, Trinity College, Dublin, Ireland.
authors.forename: T
authors.initials: T
authors.lastname: Frodl
authors.affiliation: Imaging Genetics Center, Department of Neurology, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Jahanshad
authors.affiliation: Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Loehrer
authors.affiliation: Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.|Department of Psychiatry, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: H
authors.identifier: 0000-0002-4395-1397
authors.initials: H
authors.lastname: Tiemeier
authors.affiliation: Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Departments of Radiology and Medical Informatics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.|Imaging Science and Technology, Faculty of Applied Sciences, Delft University of Technology, Delft, The Netherlands.
authors.forename: W J
authors.initials: WJ
authors.lastname: Niessen
authors.affiliation: Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.|Departments of Radiology and Medical Informatics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: M W
authors.initials: MW
authors.lastname: Vernooij
authors.affiliation: Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.|Departments of Radiology and Medical Informatics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.|Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: M A
authors.initials: MA
authors.lastname: Ikram
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Rostock/Greifswald, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Wittfeld
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Rostock/Greifswald, Germany.|Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.|Helios Hospital Stralsund, Stralsund, Germany.
authors.forename: H J
authors.initials: HJ
authors.lastname: Grabe
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Block
authors.affiliation: Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Hegenscheid
authors.affiliation: Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Völzke
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Hoehn
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Czisch
authors.affiliation: Clinical Research Unit, Brain and Mind Research Institute, University of Sydney, Camperdown, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Lagopoulos
authors.affiliation: Clinical Research Unit, Brain and Mind Research Institute, University of Sydney, Camperdown, Australia.
authors.forename: S N
authors.initials: SN
authors.lastname: Hatton
authors.affiliation: Clinical Research Unit, Brain and Mind Research Institute, University of Sydney, Camperdown, Australia.
authors.forename: I B
authors.initials: IB
authors.lastname: Hickie
authors.affiliation: Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center, Goettingen, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Goya-Maldonado
authors.affiliation: Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center, Goettingen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Krämer
authors.affiliation: Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center, Goettingen, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Gruber
authors.affiliation: NeuroImaging Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.|School of Psychology, University of Queensland, Brisbane, QLD, Australia.|Center for Advanced Imaging, University of Queensland, Brisbane, QLD, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Couvy-Duchesne
authors.affiliation: Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: M E
authors.initials: ME
authors.lastname: Rentería
authors.affiliation: NeuroImaging Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.|School of Psychology, University of Queensland, Brisbane, QLD, Australia.|Center for Advanced Imaging, University of Queensland, Brisbane, QLD, Australia.
authors.forename: L T
authors.initials: LT
authors.lastname: Strike
authors.affiliation: Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.|Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia.
authors.forename: N T
authors.initials: NT
authors.lastname: Mills
authors.affiliation: School of Psychology, University of Queensland, Brisbane, QLD, Australia.
authors.forename: G I
authors.initials: GI
authors.lastname: de Zubicaray
authors.affiliation: Center for Advanced Imaging, University of Queensland, Brisbane, QLD, Australia.
authors.forename: K L
authors.initials: KL
authors.lastname: McMahon
authors.affiliation: Quantitative Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: S E
authors.initials: SE
authors.lastname: Medland
authors.affiliation: Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: N G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Gillespie
authors.affiliation: NeuroImaging Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Wright
authors.affiliation: Department of Psychology, Neuroscience and Behaviour, McMaster University, Hamilton, ON, Canada.
authors.forename: G B
authors.initials: GB
authors.lastname: Hall
authors.affiliation: Department of Psychiatry, Mathison Centre for Mental Health Research and Education, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: G M
authors.initials: GM
authors.lastname: MacQueen
authors.affiliation: Department of Psychiatry, University of Regensburg, Regensburg, Germany.
authors.forename: E M
authors.initials: EM
authors.lastname: Frey
authors.affiliation: Department of Psychiatry and Institute of Neuroscience, University of Dublin, Trinity College Dublin, Dublin, Ireland.
authors.forename: A
authors.initials: A
authors.lastname: Carballedo
authors.affiliation: Department of Psychiatry and Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: L S
authors.initials: LS
authors.lastname: van Velzen
authors.affiliation: University of Groningen, University Medical Center Groningen, NeuroImaging Center, Groningen, The Netherlands.
authors.forename: M J
authors.initials: MJ
authors.lastname: van Tol
authors.affiliation: Department of Psychiatry, Leiden University Medical Center, Leiden University, Leiden, The Netherlands.|Leiden Institute for Brain and Cognition, Leiden, The Netherlands.
authors.forename: N J
authors.initials: NJ
authors.lastname: van der Wee
authors.affiliation: Department of Psychiatry and Psychotherapy, Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: I M
authors.initials: IM
authors.lastname: Veer
authors.affiliation: Department of Psychiatry and Psychotherapy, Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Walter
authors.affiliation: Department of General Psychiatry, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Schnell
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center Freiburg, Freiburg im Breisgau, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Schramm
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center Freiburg, Freiburg im Breisgau, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Normann
authors.affiliation: Department of Psychiatry, University of Bonn, Bonn, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Schoepf
authors.affiliation: Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Konrad
authors.affiliation: Center for Integrative Psychiatry, University of Lübeck, Lübeck, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Zurowski
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
authors.forename: T
authors.initials: T
authors.lastname: Nickson
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, UK.|Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: McIntosh
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
authors.forename: M
authors.initials: M
authors.lastname: Papmeyer
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
authors.forename: H C
authors.initials: HC
authors.lastname: Whalley
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
authors.forename: J E
authors.initials: JE
authors.lastname: Sussmann
authors.affiliation: University Department of Psychiatry, Warneford Hospital, Oxford, UK.
authors.forename: B R
authors.initials: BR
authors.lastname: Godlewska
authors.affiliation: University Department of Psychiatry, Warneford Hospital, Oxford, UK.
authors.forename: P J
authors.initials: PJ
authors.lastname: Cowen
authors.affiliation: Department of Psychosomatic Medicine, Center for Internal Medicine and Dermatology, Charité Universitätsmedizin, Berlin, Germany.|Institute for Social Medicine, Epidemology and Health Economics, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: F H
authors.initials: FH
authors.lastname: Fischer
authors.affiliation: Department of Psychosomatic Medicine, Center for Internal Medicine and Dermatology, Charité Universitätsmedizin, Berlin, Germany.|Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Rose
authors.affiliation: Department of Psychiatry and Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: B W J H
authors.initials: BW
authors.lastname: Penninx
authors.affiliation: Imaging Genetics Center, Department of Neurology, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Thompson
authors.affiliation: Imaging Genetics Center, Department of Neurology, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
authors.forename: D P
authors.initials: DP
authors.lastname: Hibar
mesh_terms: D000328:Adult; D001921:Brain / Q000473:pathology*; D016022:Case-Control Studies; D003865:Major Depressive Disorder / Q000473:pathology*; D005260:Female; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging / Q000379:methods