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. Duran; Verena 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

doi:10.1038/s41380-020-0754-0

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 journal › Article › peer-review

159 Scopus citations

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.

Original language	English (US)
Pages (from-to)	5124-5139
Number of pages	16
Journal	Molecular psychiatry
Volume	26
Issue number	9
Early online date	May 18 2020
DOIs	https://doi.org/10.1038/s41380-020-0754-0
State	Published - 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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Han, L. K. M., Dinga, R., Hahn, T., Ching, C. R. K., Eyler, L. T., Aftanas, L., Aghajani, M., Aleman, A., Baune, B. T., Berger, K., Brak, I., Filho, G. B., Carballedo, A., Connolly, C. G., Couvy-Duchesne, B., Cullen, K. R., Dannlowski, U., Davey, C. G., Dima, D., ... Schmaal, L. (2021). Brain aging in major depressive disorder: results from the ENIGMA major depressive disorder working group. Molecular psychiatry, 26(9), 5124-5139. https://doi.org/10.1038/s41380-020-0754-0

Han, LKM, Dinga, R, Hahn, T, Ching, CRK, Eyler, LT, Aftanas, L, Aghajani, M, Aleman, A, Baune, BT, Berger, K, Brak, I, Filho, GB, Carballedo, A, Connolly, CG, Couvy-Duchesne, B, Cullen, KR, Dannlowski, U, Davey, CG, Dima, D, Duran, FLS, Enneking, V, Filimonova, E, Frenzel, S, Frodl, T, Fu, CHY, Godlewska, BR, Gotlib, IH, Grabe, HJ, Groenewold, NA, Grotegerd, D, Gruber, O, Hall, GB, Harrison, BJ, Hatton, SN, Hermesdorf, M, Hickie, IB, Ho, TC, Hosten, N, Jansen, A, Kähler, C, Kircher, T, Klimes-Dougan, B, Krämer, B, Krug, A, Lagopoulos, J, Leenings, R, MacMaster, FP, MacQueen, G, McIntosh, A, McLellan, Q, McMahon, KL, Medland, SE, Mueller, BA, Mwangi, B, Osipov, E, Portella, MJ, Pozzi, E, Reneman, L, Repple, J, Rosa, PGP, Sacchet, MD, Sämann, PG, Schnell, K, Schrantee, A, Simulionyte, E, Soares, JC, Sommer, J, Stein, DJ, Steinsträter, O, Strike, LT, Thomopoulos, SI, van Tol, MJ, Veer, IM, Vermeiren, RRJM, Walter, H, van der Wee, NJA, van der Werff, SJA, Whalley, H, Winter, NR, Wittfeld, K, Wright, MJ, Wu, MJ, Völzke, H, Yang, TT, Zannias, V, de Zubicaray, GI, Zunta-Soares, GB, Abé, C, Alda, M, Andreassen, OA, Bøen, E, Bonnin, CM, Canales-Rodriguez, EJ, Cannon, D, Caseras, X, Chaim-Avancini, TM, Elvsåshagen, T, Favre, P, Foley, SF, Fullerton, JM, Goikolea, JM, Haarman, BCM, Hajek, T, Henry, C, Houenou, J, Howells, FM, Ingvar, M, Kuplicki, R, Lafer, B, Landén, M, Machado-Vieira, R, Malt, UF, McDonald, C, Mitchell, PB, Nabulsi, L, Otaduy, MCG, Overs, BJ, Polosan, M, Pomarol-Clotet, E, Radua, J, Rive, MM, Roberts, G, Ruhe, HG, Salvador, R, Sarró, S, Satterthwaite, TD, Savitz, J, Schene, AH, Schofield, PR, Serpa, MH, Sim, K, Soeiro-de-Souza, MG, Sutherland, AN, Temmingh, HS, Timmons, GM, Uhlmann, A, Vieta, E, Wolf, DH, Zanetti, MV, Jahanshad, N, Thompson, PM, Veltman, DJ, Penninx, BWJH, Marquand, AF, Cole, JH & Schmaal, L 2021, 'Brain aging in major depressive disorder: results from the ENIGMA major depressive disorder working group', Molecular psychiatry, vol. 26, no. 9, pp. 5124-5139. https://doi.org/10.1038/s41380-020-0754-0

@article{a3c790f2f2ee4d95b792532671a854fb,

title = "Brain aging in major depressive disorder: results from the ENIGMA major depressive disorder working group",

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{\textquoteright}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.",

author = "Han, {Laura K.M.} and Richard Dinga and Tim Hahn and Ching, {Christopher R.K.} and Eyler, {Lisa T.} and Lyubomir Aftanas and Moji Aghajani and Andr{\'e} Aleman and Baune, {Bernhard T.} and Klaus Berger and Ivan Brak and Filho, {Geraldo Busatto} and Angela Carballedo and Connolly, {Colm G.} and Baptiste Couvy-Duchesne and Cullen, {Kathryn R.} and Udo Dannlowski and Davey, {Christopher G.} and Danai Dima and Duran, {Fabio L.S.} and Verena Enneking and Elena Filimonova and Stefan Frenzel and Thomas Frodl and Fu, {Cynthia H.Y.} and Godlewska, {Beata R.} and Gotlib, {Ian H.} and Grabe, {Hans J.} and Groenewold, {Nynke A.} and Dominik Grotegerd and Oliver Gruber and Hall, {Geoffrey B.} and Harrison, {Ben J.} and Hatton, {Sean N.} and Marco Hermesdorf and Hickie, {Ian B.} and Ho, {Tiffany C.} and Norbert Hosten and Andreas Jansen and Claas K{\"a}hler and Tilo Kircher and Bonnie Klimes-Dougan and Bernd Kr{\"a}mer and Axel Krug and Jim Lagopoulos and Ramona Leenings and MacMaster, {Frank P.} and Glenda MacQueen and Andrew McIntosh and Quinn McLellan and McMahon, {Katie L.} and Medland, {Sarah E.} and Mueller, {Bryon A.} and Benson Mwangi and Evgeny Osipov and Portella, {Maria J.} and Elena Pozzi and Liesbeth Reneman and Jonathan Repple and Rosa, {Pedro G.P.} and Sacchet, {Matthew D.} and S{\"a}mann, {Philipp G.} and Knut Schnell and Anouk Schrantee and Egle Simulionyte and Soares, {Jair C.} and Jens Sommer and Stein, {Dan J.} and Olaf Steinstr{\"a}ter and Strike, {Lachlan T.} and Thomopoulos, {Sophia I.} and {van Tol}, {Marie Jos{\'e}} and Veer, {Ilya M.} and Vermeiren, {Robert R.J.M.} and Henrik Walter and {van der Wee}, {Nic J.A.} and {van der Werff}, {Steven J.A.} and Heather Whalley and Winter, {Nils R.} and Katharina Wittfeld and Wright, {Margaret J.} and Wu, {Mon Ju} and Henry V{\"o}lzke and Yang, {Tony T.} and Vasileios Zannias and {de Zubicaray}, {Greig I.} and Zunta-Soares, {Giovana B.} and Christoph Ab{\'e} and Martin Alda and Andreassen, {Ole A.} and Erlend B{\o}en and Bonnin, {Caterina M.} and Canales-Rodriguez, {Erick J.} and Dara Cannon and Xavier Caseras and Chaim-Avancini, {Tiffany M.} and Torbj{\o}rn Elvs{\aa}shagen and Pauline Favre and Foley, {Sonya F.} and Fullerton, {Janice M.} and Goikolea, {Jose M.} and Haarman, {Bartholomeus C.M.} and Tomas Hajek and Chantal Henry and Josselin Houenou and Howells, {Fleur M.} and Martin Ingvar and Rayus Kuplicki and Beny Lafer and Mikael Land{\'e}n and Rodrigo Machado-Vieira and Malt, {Ulrik F.} and Colm McDonald and Mitchell, {Philip B.} and Leila Nabulsi and Otaduy, {Maria Concepcion Garcia} and Overs, {Bronwyn J.} and Mircea Polosan and Edith Pomarol-Clotet and Joaquim Radua and Rive, {Maria M.} and Gloria Roberts and Ruhe, {Henricus G.} and Raymond Salvador and Salvador Sarr{\'o} and Satterthwaite, {Theodore D.} and Jonathan Savitz and Schene, {Aart H.} and Schofield, {Peter R.} and Serpa, {Mauricio H.} and Kang Sim and Soeiro-de-Souza, {Marcio Gerhardt} and Sutherland, {Ashley N.} and Temmingh, {Henk S.} and Timmons, {Garrett M.} and Anne Uhlmann and Eduard Vieta and Wolf, {Daniel H.} and Zanetti, {Marcus V.} and Neda Jahanshad and Thompson, {Paul M.} and Veltman, {Dick J.} and Penninx, {Brenda W.J.H.} and Marquand, {Andre F.} and Cole, {James H.} and Lianne Schmaal",

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{\textquoteright} 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{\textquoteright}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{\textquoteright} 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{\textquoteright}s website. CRKC has received (nonrelated) research funding from Biogen, Inc. (Boston). Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2021",

month = sep,

doi = "10.1038/s41380-020-0754-0",

language = "English (US)",

volume = "26",

pages = "5124--5139",

journal = "Molecular psychiatry",

issn = "1359-4184",

publisher = "Springer Nature",

number = "9",

}

TY - JOUR

T1 - Brain aging in major depressive disorder

T2 - results from the ENIGMA major depressive disorder working group

AU - Han, Laura K.M.

AU - Dinga, Richard

AU - Hahn, Tim

AU - Ching, Christopher R.K.

AU - Eyler, Lisa T.

AU - Aftanas, Lyubomir

AU - Aghajani, Moji

AU - Aleman, André

AU - Baune, Bernhard T.

AU - Berger, Klaus

AU - Brak, Ivan

AU - Filho, Geraldo Busatto

AU - Carballedo, Angela

AU - Connolly, Colm G.

AU - Couvy-Duchesne, Baptiste

AU - Cullen, Kathryn R.

AU - Dannlowski, Udo

AU - Davey, Christopher G.

AU - Dima, Danai

AU - Duran, Fabio L.S.

AU - Enneking, Verena

AU - Filimonova, Elena

AU - Frenzel, Stefan

AU - Frodl, Thomas

AU - Fu, Cynthia H.Y.

AU - Godlewska, Beata R.

AU - Gotlib, Ian H.

AU - Grabe, Hans J.

AU - Groenewold, Nynke A.

AU - Grotegerd, Dominik

AU - Gruber, Oliver

AU - Hall, Geoffrey B.

AU - Harrison, Ben J.

AU - Hatton, Sean N.

AU - Hermesdorf, Marco

AU - Hickie, Ian B.

AU - Ho, Tiffany C.

AU - Hosten, Norbert

AU - Jansen, Andreas

AU - Kähler, Claas

AU - Kircher, Tilo

AU - Klimes-Dougan, Bonnie

AU - Krämer, Bernd

AU - Krug, Axel

AU - Lagopoulos, Jim

AU - Leenings, Ramona

AU - MacMaster, Frank P.

AU - MacQueen, Glenda

AU - McIntosh, Andrew

AU - McLellan, Quinn

AU - McMahon, Katie L.

AU - Medland, Sarah E.

AU - Mueller, Bryon A.

AU - Mwangi, Benson

AU - Osipov, Evgeny

AU - Portella, Maria J.

AU - Pozzi, Elena

AU - Reneman, Liesbeth

AU - Repple, Jonathan

AU - Rosa, Pedro G.P.

AU - Sacchet, Matthew D.

AU - Sämann, Philipp G.

AU - Schnell, Knut

AU - Schrantee, Anouk

AU - Simulionyte, Egle

AU - Soares, Jair C.

AU - Sommer, Jens

AU - Stein, Dan J.

AU - Steinsträter, Olaf

AU - Strike, Lachlan T.

AU - Thomopoulos, Sophia I.

AU - van Tol, Marie José

AU - Veer, Ilya M.

AU - Vermeiren, Robert R.J.M.

AU - Walter, Henrik

AU - van der Wee, Nic J.A.

AU - van der Werff, Steven J.A.

AU - Whalley, Heather

AU - Winter, Nils R.

AU - Wittfeld, Katharina

AU - Wright, Margaret J.

AU - Wu, Mon Ju

AU - Völzke, Henry

AU - Yang, Tony T.

AU - Zannias, Vasileios

AU - de Zubicaray, Greig I.

AU - Zunta-Soares, Giovana B.

AU - Abé, Christoph

AU - Alda, Martin

AU - Andreassen, Ole A.

AU - Bøen, Erlend

AU - Bonnin, Caterina M.

AU - Canales-Rodriguez, Erick J.

AU - Cannon, Dara

AU - Caseras, Xavier

AU - Chaim-Avancini, Tiffany M.

AU - Elvsåshagen, Torbjørn

AU - Favre, Pauline

AU - Foley, Sonya F.

AU - Fullerton, Janice M.

AU - Goikolea, Jose M.

AU - Haarman, Bartholomeus C.M.

AU - Hajek, Tomas

AU - Henry, Chantal

AU - Houenou, Josselin

AU - Howells, Fleur M.

AU - Ingvar, Martin

AU - Kuplicki, Rayus

AU - Lafer, Beny

AU - Landén, Mikael

AU - Machado-Vieira, Rodrigo

AU - Malt, Ulrik F.

AU - McDonald, Colm

AU - Mitchell, Philip B.

AU - Nabulsi, Leila

AU - Otaduy, Maria Concepcion Garcia

AU - Overs, Bronwyn J.

AU - Polosan, Mircea

AU - Pomarol-Clotet, Edith

AU - Radua, Joaquim

AU - Rive, Maria M.

AU - Roberts, Gloria

AU - Ruhe, Henricus G.

AU - Salvador, Raymond

AU - Sarró, Salvador

AU - Satterthwaite, Theodore D.

AU - Savitz, Jonathan

AU - Schene, Aart H.

AU - Schofield, Peter R.

AU - Serpa, Mauricio H.

AU - Sim, Kang

AU - Soeiro-de-Souza, Marcio Gerhardt

AU - Sutherland, Ashley N.

AU - Temmingh, Henk S.

AU - Timmons, Garrett M.

AU - Uhlmann, Anne

AU - Vieta, Eduard

AU - Wolf, Daniel H.

AU - Zanetti, Marcus V.

AU - Jahanshad, Neda

AU - Thompson, Paul M.

AU - Veltman, Dick J.

AU - Penninx, Brenda W.J.H.

AU - Marquand, Andre F.

AU - Cole, James H.

AU - Schmaal, Lianne

N1 - 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). Publisher Copyright: © 2020, The Author(s).

PY - 2021/9

Y1 - 2021/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85085208849&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85085208849&partnerID=8YFLogxK

U2 - 10.1038/s41380-020-0754-0

DO - 10.1038/s41380-020-0754-0

M3 - Article

C2 - 32424236

AN - SCOPUS:85085208849

SN - 1359-4184

VL - 26

SP - 5124

EP - 5139

JO - Molecular psychiatry

JF - Molecular psychiatry

IS - 9

ER -

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

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