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

Laura K.M. Han, Richard Dinga, Tim Hahn, Christopher R.K. Ching, Lisa T. Eyler, Lyubomir Aftanas, Moji Aghajani, André Aleman, Bernhard T. Baune, Klaus Berger, Ivan Brak, Geraldo Busatto Filho, Angela Carballedo, Colm G. Connolly, Baptiste Couvy-Duchesne, Kathryn R. Cullen, Udo Dannlowski, Christopher G. Davey, Danai Dima, Fabio L.S. DuranVerena Enneking, Elena Filimonova, Stefan Frenzel, Thomas Frodl, Cynthia H.Y. Fu, Beata R. Godlewska, Ian H. Gotlib, Hans J. Grabe, Nynke A. Groenewold, Dominik Grotegerd, Oliver Gruber, Geoffrey B. Hall, Ben J. Harrison, Sean N. Hatton, Marco Hermesdorf, Ian B. Hickie, Tiffany C. Ho, Norbert Hosten, Andreas Jansen, Claas Kähler, Tilo Kircher, Bonnie Klimes-Dougan, Bernd Krämer, Axel Krug, Jim Lagopoulos, Ramona Leenings, Frank P. MacMaster, Glenda MacQueen, Andrew McIntosh, Quinn McLellan, Katie L. McMahon, Sarah E. Medland, Bryon A. Mueller, Benson Mwangi, Evgeny Osipov, Maria J. Portella, Elena Pozzi, Liesbeth Reneman, Jonathan Repple, Pedro G.P. Rosa, Matthew D. Sacchet, Philipp G. Sämann, Knut Schnell, Anouk Schrantee, Egle Simulionyte, Jair C. Soares, Jens Sommer, Dan J. Stein, Olaf Steinsträter, Lachlan T. Strike, Sophia I. Thomopoulos, Marie José van Tol, Ilya M. Veer, Robert R.J.M. Vermeiren, Henrik Walter, Nic J.A. van der Wee, Steven J.A. van der Werff, Heather Whalley, Nils R. Winter, Katharina Wittfeld, Margaret J. Wright, Mon Ju Wu, Henry Völzke, Tony T. Yang, Vasileios Zannias, Greig I. de Zubicaray, Giovana B. Zunta-Soares, Christoph Abé, Martin Alda, Ole A. Andreassen, Erlend Bøen, Caterina M. Bonnin, Erick J. Canales-Rodriguez, Dara Cannon, Xavier Caseras, Tiffany M. Chaim-Avancini, Torbjørn Elvsåshagen, Pauline Favre, Sonya F. Foley, Janice M. Fullerton, Jose M. Goikolea, Bartholomeus C.M. Haarman, Tomas Hajek, Chantal Henry, Josselin Houenou, Fleur M. Howells, Martin Ingvar, Rayus Kuplicki, Beny Lafer, Mikael Landén, Rodrigo Machado-Vieira, Ulrik F. Malt, Colm McDonald, Philip B. Mitchell, Leila Nabulsi, Maria Concepcion Garcia Otaduy, Bronwyn J. Overs, Mircea Polosan, Edith Pomarol-Clotet, Joaquim Radua, Maria M. Rive, Gloria Roberts, Henricus G. Ruhe, Raymond Salvador, Salvador Sarró, Theodore D. Satterthwaite, Jonathan Savitz, Aart H. Schene, Peter R. Schofield, Mauricio H. Serpa, Kang Sim, Marcio Gerhardt Soeiro-de-Souza, Ashley N. Sutherland, Henk S. Temmingh, Garrett M. Timmons, Anne Uhlmann, Eduard Vieta, Daniel H. Wolf, Marcus V. Zanetti, Neda Jahanshad, Paul M. Thompson, Dick J. Veltman, Brenda W.J.H. Penninx, Andre F. Marquand, James H. Cole, Lianne Schmaal

Research output: Contribution to journalArticlepeer-review

104 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)5124-5139
Number of pages16
JournalMolecular psychiatry
Issue number9
Early online dateMay 18 2020
StatePublished - Sep 2021

Bibliographical note

Funding Information:
Conflict of interest 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, Jans-sen, 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).

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