Regional brain morphology and current antidepressant use: findings from 32 international cohorts from the ENIGMA major depressive disorder working group

Chaira Serrarens; Yara J. Toenders; Elena Pozzi; André Aleman; Nina Alexander; Zeynep Başgöze; Vladimir Belov; Klaus Berger; Katharina Brosch; Robin Bülow; Geraldo Filho Busatto; Liliana P. Capitão; Colm G. Connolly; Baptiste Couvy-Duchesne; Kathryn R. Cullen; Udo Dannlowski; Christopher G. Davey; Greig I. de Zubicaray; Danai Dima; Katharina Dohm; Verena Enneking; Tracy Erwin-Grabner; Ulrika Evermann; Cynthia H.Y. Fu; Paola Fuentes-Claramonte; Beata R. Godlewska; Ali Saffet Gonul; Ian H. Gotlib; Roberto Goya-Maldonado; Hans J. Grabe; Nynke A. Groenewold; Dominik Grotegerd; Oliver Gruber; Tim Hahn; Geoffrey Hall; Ben J. Harrison; Walter Heindel; Marco Hermesdorf; Tiffany C. Ho; Naho Ichikawa; Eri Itai; Neda Jahanshad; Hamidreza Jamalabadi; Alec J. Jamieson; Andreas Jansen; Tilo Kircher; Bonnie Klimes-Dougan; Bernd Krämer; Axel Krug; Thomas M. Lancaster; Elisabeth J. Leehr; Meng Li; David E.J. Linden; Frank MacMaster; Katie L. McMahon; Sarah E. Medland; David M.A. Mehler; Susanne Meinert; Benson Mwangi; Igor Nenadić; Go Okada; Yasumasa Okamoto; Nils Opel; Julia Katharina Pfarr; Edith Pomarol-Clotet; Maria J. Portella; Ronny Redlich; Liesbeth Reneman; Jonathan Repple; Kai Ringwald; Elena Rodriguez-Cano; Pedro G.P. Rosa; Matthew D. Sacchet; Philipp G. Sämann; Raymond Salvador; Anouk Schrantee; Hotaka Shinzato; Kang Sim; Egle Simulionyte; Jair C. Soares; Dan J. Stein; Frederike Stein; Benjamin Straube; Lachlan T. Strike; Florian Thomas-Odenthal; Sophia I. Thomopoulos; Paul M. Thompson; Marie Jose van Tol; Paula Usemann; Aslihan Uyar; Nic van der Wee; Steven van der Werff; Yolanda Vives-Gilabert; Henry Völzke; Martin Walter; Sarah Whittle; Katharina Wittfeld; Adrian Wroblewski; Mon Ju Wu; Tony T. Yang; Giovana B. Zunta-Soares; Dick J. Veltman; Lianne Schmaal; Laura S. van Velzen

doi:10.1038/s41380-025-03310-8

Regional brain morphology and current antidepressant use: findings from 32 international cohorts from the ENIGMA major depressive disorder working group

Chaira Serrarens, Yara J. Toenders, Elena Pozzi, André Aleman, Nina Alexander, Zeynep Başgöze, Vladimir Belov, Klaus Berger, Katharina Brosch, Robin Bülow, Geraldo Filho Busatto, Liliana P. Capitão, Colm G. Connolly, Baptiste Couvy-Duchesne, Kathryn R. Cullen, Udo Dannlowski, Christopher G. Davey, Greig I. de Zubicaray, Danai Dima, Katharina DohmVerena Enneking, Tracy Erwin-Grabner, Ulrika Evermann, Cynthia H.Y. Fu, Paola Fuentes-Claramonte, Beata R. Godlewska, Ali Saffet Gonul, Ian H. Gotlib, Roberto Goya-Maldonado, Hans J. Grabe, Nynke A. Groenewold, Dominik Grotegerd, Oliver Gruber, Tim Hahn, Geoffrey Hall, Ben J. Harrison, Walter Heindel, Marco Hermesdorf, Tiffany C. Ho, Naho Ichikawa, Eri Itai, Neda Jahanshad, Hamidreza Jamalabadi, Alec J. Jamieson, Andreas Jansen, Tilo Kircher, Bonnie Klimes-Dougan, Bernd Krämer, Axel Krug, Thomas M. Lancaster, Elisabeth J. Leehr, Meng Li, David E.J. Linden, Frank MacMaster, Katie L. McMahon, Sarah E. Medland, David M.A. Mehler, Susanne Meinert, Benson Mwangi, Igor Nenadić, Go Okada, Yasumasa Okamoto, Nils Opel, Julia Katharina Pfarr, Edith Pomarol-Clotet, Maria J. Portella, Ronny Redlich, Liesbeth Reneman, Jonathan Repple, Kai Ringwald, Elena Rodriguez-Cano, Pedro G.P. Rosa, Matthew D. Sacchet, Philipp G. Sämann, Raymond Salvador, Anouk Schrantee, Hotaka Shinzato, Kang Sim, Egle Simulionyte, Jair C. Soares, Dan J. Stein, Frederike Stein, Benjamin Straube, Lachlan T. Strike, Florian Thomas-Odenthal, Sophia I. Thomopoulos, Paul M. Thompson, Marie Jose van Tol, Paula Usemann, Aslihan Uyar, Nic van der Wee, Steven van der Werff, Yolanda Vives-Gilabert, Henry Völzke, Martin Walter, Sarah Whittle, Katharina Wittfeld, Adrian Wroblewski, Mon Ju Wu, Tony T. Yang, Giovana B. Zunta-Soares, Dick J. Veltman, Lianne Schmaal, Laura S. van Velzen

Department of Psychology

Research output: Contribution to journal › Article › peer-review

Abstract

The understanding of how antidepressant (AD) use is associated with brain structure in individuals with major depressive disorder (MDD) remains incomplete. We aimed to examine the association between AD medication use and brain morphology in relation to age and sex by pooling structural neuroimaging and clinical data from 32 cohorts within the ENIGMA-MDD working group. Interaction effects of group (2076 cases with current AD use (AD), 1495 cases not currently taking AD (nAD) and 5125 healthy controls (HC)) with age and sex, and main effects of group on regional brain structure (cortical surface area and thickness, and subcortical volume) were examined. Additionally, we examined the effect of AD type (SSRI, SNRI or mirtazapine) and duration of use on brain morphology. Younger individuals in the AD group showed lower bilateral middle temporal gyrus thickness compared to nAD and HC, but this was not seen in older individuals (crossover around 50 years). Lower hippocampal volume and thinner inferior temporal gyrus were shown in AD compared to nAD. These effects were independent of group differences in disease-course-related measures, but were driven by depressive symptom severity. Greater bilateral rostral anterior cingulate thickness was found in individuals older than approximately 40 years taking mirtazapine compared to individuals taking SSRIs or SNRIs. Evidence for subtle structural brain differences in temporal and limbic regions in individuals with MDD who currently use AD medication were found compared to those not currently taking AD medication. Future longitudinal studies are needed to determine the causality of these associations.

Original language	English
Pages (from-to)	5625-5636
Number of pages	12
Journal	Molecular Psychiatry
Volume	30
Issue number	12
Early online date	3 Nov 2025
DOIs	https://doi.org/10.1038/s41380-025-03310-8
Publication status	E-pub ahead of print - 3 Nov 2025

Data Availability Statement

The datasets generated during and/or analysed during the current study are not publicly available due to privacy restrictions.

Funding

ENIGMA MDD is supported by the National Institute of Mental Health grant numbers MH129832, MH117601 and MH129742. CS is supported by NIMH 5U01MH119740-05. LS is supported by an National Health and Medical Research Council (NHMRC) Investigator grant 2017962. The Goettingen site acknowledges funding from the University Medical Center Göttingen Starting Funds and the German Federal Ministry of Education and Research (BMBF: 01 ZX 1507, “PreNeSt - e:Med”). The work at DIP Groningen was funded by the Gratama Foundation, the Netherlands (2012/35 to Dr. Groenewold). SEM is supported by NHMRC grants APP1172917 and APP1158127. KLM is supported by funding from the National Institute of Child Health and Human Development (R01 HD050735), and the National Health and Medical Research Council (NHMRC 486682, 1009064), Australia. MDS acknowledges funding from the National Institute of Mental Health (Project Number R01MH125850), Brain and Behavior Research Foundation (Grant Number 28972). IHG is supported by the National Institute of Mental Health (R37MH101495). The University of Minnesota study is funded by the National Institute of Mental Health (K23MH090421), the National Alliance for Research on Schizophrenia and Depression, the University of Minnesota Graduate School, the Minnesota Medical Foundation, and the Biotechnology Research Center (P41 RR008079 to the Center for Magnetic Resonance Research), University of Minnesota, and the Deborah E. Powell Center for Women’s Health Seed Grant, University of Minnesota. TCH is supported in part by the National Institutes of Health (K01MH117442, R01MH127176, R21MH130817). The Melbourne site was funded by National Health and Medical Research Council of Australia (NHMRC) Project Grants 1064643 (PI Harrison) and 1024570 (PI Davey). TTY acknowledges support from the National Center for Complementary and Integrative Health Grant numbers: R21AT009173, R61AT009864, R33AT009864; University of California San Francisco Weill Institute for Neurosciences; University of California San Francisco Weill Institute for Neurosciences Grant numbers: Award for Junior Investigators in the Neurosciences Impacted by COVID-19 Setbacks; National Center for Advancing Translational Sciences Grant numbers: CTSI UL1TR001872; American Foundation for Suicide Prevention Grant numbers: SRG-1-141-18; National Institute of Mental Health Grant R01MH085734 R01MH127176, K01MH117442. YO is supported by the Japan Agency for Medical Research and Development (AMED) under grant number JP18dm0307002. SHIP is part of the Community Medicine Research Network of the University Medicine Greifswald, which is supported by the German Federal State of Mecklenburg- West Pomerania. The Cardiff sample was supported by the Medical Research Council (UK) grant G 1100629. RR acknowledges support from grants from the German Research Foundation (grant RE4458/1-1 to R.R.) and the German Center for Mental Health (DZPG; BMBF grant 01EE2305C to R.R). TH was supported by the German Research Foundation (DFG grants HA7070/2-2, HA7070/3, HA7070/4). KD acknowledges support from the Innovative Medizinische Forschung (IMF; KO121806 to K.D.). This work was funded by the German Research Foundation (DFG), Udo Dannlowski (co-speaker FOR2107, DA 1151/5-1, DA 1151/5-2, grant DA1151/9-1, DA1151/10-1 and DA1151/11-1) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/022/22 to UD); This work was funded by the German Research Foundation (SFB-TRR58, Project C09 to UD). This work was supported by the German Research Foundation (DFG), grants NE2254/1-2, NE2254/3-1, and NE2254/4-1 to Igor Nenadić and DFG grant FOR2107, KI588/14-1 and FOR2107, KI588/14-2 to Tilo Kircher (coordinator of FOR2107). This work was supported by the Hessisches Ministerium für Wissenschaft und Kunst (HMWK; project “The Adaptive Mind”) to TK and BS. BS was additionally supported by the German Research Foundation (DFG, STR1146/18-1). AW is supported by the German Research Foundation (DFG, STR1146/18-1; KI588/22-1). The FIDMAG group is grateful for support from CIBERSAM, AGAUR (2014-SGR-1573 and 2017-SGR-1271), Instituto de Salud Carlos III (Sara Borrell research contract CD19/00149). LPC was was funded by the NIHR Oxford Health Biomedical Research Centre (UK) at the University of Oxford as part of this work, and now works at the Psychology Research Centre (PSI/01662), School of Psychology, University of Minho. The centre is supported by the Foundation for Science and Technology (FCT) through the Portuguese State Budget (Ref.: UIDB/PSI/01662/2020). Liliana is also currently funded by FCT (Ref.: 2021.004515.CEECIND). The BiDirect study was funded by the German Ministry of Education and Research (01ER0816; 01ER1506). PMT and SIT are supported by NIH grants R01MH116147, P41EB015922, Milken Foundation/Baszucki Brain Research Fund, R01MH129742. NJ is supported by NIH grants R01MH117601, R01MH134004, R01MH116147 and P41EB015922. The IMH-MDD study was supported by National Healthcare Group Research Grant, Singapore (SIG/15012). BCD is supported by a CJ Martin Fellowship (NHMRC App 1161356). CHYF is supported by the Medical Research Council (G0802594), NIMH (R01MH134236). AJ was supported by DFG grants JA 1890/7-1 and JA 1890/7-2. IN was supported by DFG grants NE2255/1-2, NE2255/2-1, NE2255/3-1, NE2255/4-1. The Barcelona cohort was collected from studies funded by the Spanish Ministry of Health, Instituto Carlos III (PI10/00372; PI13/01057), by the CIBERSAM and by the CERCA programme of the Catalan Government (Generalitat de Catalunya). JCS was supported by NIMH (1R01MH085667-01A1), John S. Dunn Foundation (Houston, Texas), and Pat Rutherford Chair in Psychiatry (UTHealth Houston). Other funding source and potential conflict of interests include: ALKERMES (Advisory Board), BOEHRINGER Ingelheim (Consultant), COMPASS Pathways (Research Grant), JOHNSON & JOHNSON (Consultant), LIVANOVA (Consultant), RELMADA (Research Grant), SUNOVION (Research Grant),Mind Med (Research Grant).

ASJC Scopus subject areas

Molecular Biology
Psychiatry and Mental health
Cellular and Molecular Neuroscience

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

Serrarens, C., Toenders, Y. J., Pozzi, E., Aleman, A., Alexander, N., Başgöze, Z., Belov, V., Berger, K., Brosch, K., Bülow, R., Busatto, G. F., Capitão, L. P., Connolly, C. G., Couvy-Duchesne, B., Cullen, K. R., Dannlowski, U., Davey, C. G., de Zubicaray, G. I., Dima, D., ... van Velzen, L. S. (2025). Regional brain morphology and current antidepressant use: findings from 32 international cohorts from the ENIGMA major depressive disorder working group. Molecular Psychiatry, 30(12), 5625-5636. Advance online publication. https://doi.org/10.1038/s41380-025-03310-8

Serrarens, C, Toenders, YJ, Pozzi, E, Aleman, A, Alexander, N, Başgöze, Z, Belov, V, Berger, K, Brosch, K, Bülow, R, Busatto, GF, Capitão, LP, Connolly, CG, Couvy-Duchesne, B, Cullen, KR, Dannlowski, U, Davey, CG, de Zubicaray, GI, Dima, D, Dohm, K, Enneking, V, Erwin-Grabner, T, Evermann, U, Fu, CHY, Fuentes-Claramonte, P, Godlewska, BR, Gonul, AS, Gotlib, IH, Goya-Maldonado, R, Grabe, HJ, Groenewold, NA, Grotegerd, D, Gruber, O, Hahn, T, Hall, G, Harrison, BJ, Heindel, W, Hermesdorf, M, Ho, TC, Ichikawa, N, Itai, E, Jahanshad, N, Jamalabadi, H, Jamieson, AJ, Jansen, A, Kircher, T, Klimes-Dougan, B, Krämer, B, Krug, A, Lancaster, TM, Leehr, EJ, Li, M, Linden, DEJ, MacMaster, F, McMahon, KL, Medland, SE, Mehler, DMA, Meinert, S, Mwangi, B, Nenadić, I, Okada, G, Okamoto, Y, Opel, N, Pfarr, JK, Pomarol-Clotet, E, Portella, MJ, Redlich, R, Reneman, L, Repple, J, Ringwald, K, Rodriguez-Cano, E, Rosa, PGP, Sacchet, MD, Sämann, PG, Salvador, R, Schrantee, A, Shinzato, H, Sim, K, Simulionyte, E, Soares, JC, Stein, DJ, Stein, F, Straube, B, Strike, LT, Thomas-Odenthal, F, Thomopoulos, SI, Thompson, PM, van Tol, MJ, Usemann, P, Uyar, A, van der Wee, N, van der Werff, S, Vives-Gilabert, Y, Völzke, H, Walter, M, Whittle, S, Wittfeld, K, Wroblewski, A, Wu, MJ, Yang, TT, Zunta-Soares, GB, Veltman, DJ, Schmaal, L & van Velzen, LS 2025, 'Regional brain morphology and current antidepressant use: findings from 32 international cohorts from the ENIGMA major depressive disorder working group', Molecular Psychiatry, vol. 30, no. 12, pp. 5625-5636. https://doi.org/10.1038/s41380-025-03310-8

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title = "Regional brain morphology and current antidepressant use: findings from 32 international cohorts from the ENIGMA major depressive disorder working group",

abstract = "The understanding of how antidepressant (AD) use is associated with brain structure in individuals with major depressive disorder (MDD) remains incomplete. We aimed to examine the association between AD medication use and brain morphology in relation to age and sex by pooling structural neuroimaging and clinical data from 32 cohorts within the ENIGMA-MDD working group. Interaction effects of group (2076 cases with current AD use (AD), 1495 cases not currently taking AD (nAD) and 5125 healthy controls (HC)) with age and sex, and main effects of group on regional brain structure (cortical surface area and thickness, and subcortical volume) were examined. Additionally, we examined the effect of AD type (SSRI, SNRI or mirtazapine) and duration of use on brain morphology. Younger individuals in the AD group showed lower bilateral middle temporal gyrus thickness compared to nAD and HC, but this was not seen in older individuals (crossover around 50 years). Lower hippocampal volume and thinner inferior temporal gyrus were shown in AD compared to nAD. These effects were independent of group differences in disease-course-related measures, but were driven by depressive symptom severity. Greater bilateral rostral anterior cingulate thickness was found in individuals older than approximately 40 years taking mirtazapine compared to individuals taking SSRIs or SNRIs. Evidence for subtle structural brain differences in temporal and limbic regions in individuals with MDD who currently use AD medication were found compared to those not currently taking AD medication. Future longitudinal studies are needed to determine the causality of these associations.",

author = "Chaira Serrarens and Toenders, \{Yara J.\} and Elena Pozzi and Andr{\'e} Aleman and Nina Alexander and Zeynep Ba{\c s}g{\"o}ze and Vladimir Belov and Klaus Berger and Katharina Brosch and Robin B{\"u}low and Busatto, \{Geraldo Filho\} and Capit{\~a}o, \{Liliana P.\} and Connolly, \{Colm G.\} and Baptiste Couvy-Duchesne and Cullen, \{Kathryn R.\} and Udo Dannlowski and Davey, \{Christopher G.\} and \{de Zubicaray\}, \{Greig I.\} and Danai Dima and Katharina Dohm and Verena Enneking and Tracy Erwin-Grabner and Ulrika Evermann and Fu, \{Cynthia H.Y.\} and Paola Fuentes-Claramonte and Godlewska, \{Beata R.\} and Gonul, \{Ali Saffet\} and Gotlib, \{Ian H.\} and Roberto Goya-Maldonado and Grabe, \{Hans J.\} and Groenewold, \{Nynke A.\} and Dominik Grotegerd and Oliver Gruber and Tim Hahn and Geoffrey Hall and Harrison, \{Ben J.\} and Walter Heindel and Marco Hermesdorf and Ho, \{Tiffany C.\} and Naho Ichikawa and Eri Itai and Neda Jahanshad and Hamidreza Jamalabadi and Jamieson, \{Alec J.\} and Andreas Jansen and Tilo Kircher and Bonnie Klimes-Dougan and Bernd Kr{\"a}mer and Axel Krug and Lancaster, \{Thomas M.\} and Leehr, \{Elisabeth J.\} and Meng Li and Linden, \{David E.J.\} and Frank MacMaster and McMahon, \{Katie L.\} and Medland, \{Sarah E.\} and Mehler, \{David M.A.\} and Susanne Meinert and Benson Mwangi and Igor Nenadi{\'c} and Go Okada and Yasumasa Okamoto and Nils Opel and Pfarr, \{Julia Katharina\} and Edith Pomarol-Clotet and Portella, \{Maria J.\} and Ronny Redlich and Liesbeth Reneman and Jonathan Repple and Kai Ringwald and Elena Rodriguez-Cano and Rosa, \{Pedro G.P.\} and Sacchet, \{Matthew D.\} and S{\"a}mann, \{Philipp G.\} and Raymond Salvador and Anouk Schrantee and Hotaka Shinzato and Kang Sim and Egle Simulionyte and Soares, \{Jair C.\} and Stein, \{Dan J.\} and Frederike Stein and Benjamin Straube and Strike, \{Lachlan T.\} and Florian Thomas-Odenthal and Thomopoulos, \{Sophia I.\} and Thompson, \{Paul M.\} and \{van Tol\}, \{Marie Jose\} and Paula Usemann and Aslihan Uyar and \{van der Wee\}, Nic and \{van der Werff\}, Steven and Yolanda Vives-Gilabert and Henry V{\"o}lzke and Martin Walter and Sarah Whittle and Katharina Wittfeld and Adrian Wroblewski and Wu, \{Mon Ju\} and Yang, \{Tony T.\} and Zunta-Soares, \{Giovana B.\} and Veltman, \{Dick J.\} and Lianne Schmaal and \{van Velzen\}, \{Laura S.\}",

year = "2025",

month = nov,

day = "3",

doi = "10.1038/s41380-025-03310-8",

language = "English",

volume = "30",

pages = "5625--5636",

journal = "Molecular Psychiatry",

issn = "1359-4184",

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number = "12",

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TY - JOUR

T1 - Regional brain morphology and current antidepressant use

T2 - findings from 32 international cohorts from the ENIGMA major depressive disorder working group

AU - Serrarens, Chaira

AU - Toenders, Yara J.

AU - Pozzi, Elena

AU - Aleman, André

AU - Alexander, Nina

AU - Başgöze, Zeynep

AU - Belov, Vladimir

AU - Berger, Klaus

AU - Brosch, Katharina

AU - Bülow, Robin

AU - Busatto, Geraldo Filho

AU - Capitão, Liliana P.

AU - Connolly, Colm G.

AU - Couvy-Duchesne, Baptiste

AU - Cullen, Kathryn R.

AU - Dannlowski, Udo

AU - Davey, Christopher G.

AU - de Zubicaray, Greig I.

AU - Dima, Danai

AU - Dohm, Katharina

AU - Enneking, Verena

AU - Erwin-Grabner, Tracy

AU - Evermann, Ulrika

AU - Fu, Cynthia H.Y.

AU - Fuentes-Claramonte, Paola

AU - Godlewska, Beata R.

AU - Gonul, Ali Saffet

AU - Gotlib, Ian H.

AU - Goya-Maldonado, Roberto

AU - Grabe, Hans J.

AU - Groenewold, Nynke A.

AU - Grotegerd, Dominik

AU - Gruber, Oliver

AU - Hahn, Tim

AU - Hall, Geoffrey

AU - Harrison, Ben J.

AU - Heindel, Walter

AU - Hermesdorf, Marco

AU - Ho, Tiffany C.

AU - Ichikawa, Naho

AU - Itai, Eri

AU - Jahanshad, Neda

AU - Jamalabadi, Hamidreza

AU - Jamieson, Alec J.

AU - Jansen, Andreas

AU - Kircher, Tilo

AU - Klimes-Dougan, Bonnie

AU - Krämer, Bernd

AU - Krug, Axel

AU - Lancaster, Thomas M.

AU - Leehr, Elisabeth J.

AU - Li, Meng

AU - Linden, David E.J.

AU - MacMaster, Frank

AU - McMahon, Katie L.

AU - Medland, Sarah E.

AU - Mehler, David M.A.

AU - Meinert, Susanne

AU - Mwangi, Benson

AU - Nenadić, Igor

AU - Okada, Go

AU - Okamoto, Yasumasa

AU - Opel, Nils

AU - Pfarr, Julia Katharina

AU - Pomarol-Clotet, Edith

AU - Portella, Maria J.

AU - Redlich, Ronny

AU - Reneman, Liesbeth

AU - Repple, Jonathan

AU - Ringwald, Kai

AU - Rodriguez-Cano, Elena

AU - Rosa, Pedro G.P.

AU - Sacchet, Matthew D.

AU - Sämann, Philipp G.

AU - Salvador, Raymond

AU - Schrantee, Anouk

AU - Shinzato, Hotaka

AU - Sim, Kang

AU - Simulionyte, Egle

AU - Soares, Jair C.

AU - Stein, Dan J.

AU - Stein, Frederike

AU - Straube, Benjamin

AU - Strike, Lachlan T.

AU - Thomas-Odenthal, Florian

AU - Thomopoulos, Sophia I.

AU - Thompson, Paul M.

AU - van Tol, Marie Jose

AU - Usemann, Paula

AU - Uyar, Aslihan

AU - van der Wee, Nic

AU - van der Werff, Steven

AU - Vives-Gilabert, Yolanda

AU - Völzke, Henry

AU - Walter, Martin

AU - Whittle, Sarah

AU - Wittfeld, Katharina

AU - Wroblewski, Adrian

AU - Wu, Mon Ju

AU - Yang, Tony T.

AU - Zunta-Soares, Giovana B.

AU - Veltman, Dick J.

AU - Schmaal, Lianne

AU - van Velzen, Laura S.

PY - 2025/11/3

Y1 - 2025/11/3

N2 - The understanding of how antidepressant (AD) use is associated with brain structure in individuals with major depressive disorder (MDD) remains incomplete. We aimed to examine the association between AD medication use and brain morphology in relation to age and sex by pooling structural neuroimaging and clinical data from 32 cohorts within the ENIGMA-MDD working group. Interaction effects of group (2076 cases with current AD use (AD), 1495 cases not currently taking AD (nAD) and 5125 healthy controls (HC)) with age and sex, and main effects of group on regional brain structure (cortical surface area and thickness, and subcortical volume) were examined. Additionally, we examined the effect of AD type (SSRI, SNRI or mirtazapine) and duration of use on brain morphology. Younger individuals in the AD group showed lower bilateral middle temporal gyrus thickness compared to nAD and HC, but this was not seen in older individuals (crossover around 50 years). Lower hippocampal volume and thinner inferior temporal gyrus were shown in AD compared to nAD. These effects were independent of group differences in disease-course-related measures, but were driven by depressive symptom severity. Greater bilateral rostral anterior cingulate thickness was found in individuals older than approximately 40 years taking mirtazapine compared to individuals taking SSRIs or SNRIs. Evidence for subtle structural brain differences in temporal and limbic regions in individuals with MDD who currently use AD medication were found compared to those not currently taking AD medication. Future longitudinal studies are needed to determine the causality of these associations.

AB - The understanding of how antidepressant (AD) use is associated with brain structure in individuals with major depressive disorder (MDD) remains incomplete. We aimed to examine the association between AD medication use and brain morphology in relation to age and sex by pooling structural neuroimaging and clinical data from 32 cohorts within the ENIGMA-MDD working group. Interaction effects of group (2076 cases with current AD use (AD), 1495 cases not currently taking AD (nAD) and 5125 healthy controls (HC)) with age and sex, and main effects of group on regional brain structure (cortical surface area and thickness, and subcortical volume) were examined. Additionally, we examined the effect of AD type (SSRI, SNRI or mirtazapine) and duration of use on brain morphology. Younger individuals in the AD group showed lower bilateral middle temporal gyrus thickness compared to nAD and HC, but this was not seen in older individuals (crossover around 50 years). Lower hippocampal volume and thinner inferior temporal gyrus were shown in AD compared to nAD. These effects were independent of group differences in disease-course-related measures, but were driven by depressive symptom severity. Greater bilateral rostral anterior cingulate thickness was found in individuals older than approximately 40 years taking mirtazapine compared to individuals taking SSRIs or SNRIs. Evidence for subtle structural brain differences in temporal and limbic regions in individuals with MDD who currently use AD medication were found compared to those not currently taking AD medication. Future longitudinal studies are needed to determine the causality of these associations.

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U2 - 10.1038/s41380-025-03310-8

DO - 10.1038/s41380-025-03310-8

M3 - Article

C2 - 41184571

AN - SCOPUS:105020874724

SN - 1359-4184

VL - 30

SP - 5625

EP - 5636

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 12

ER -

Regional brain morphology and current antidepressant use: findings from 32 international cohorts from the ENIGMA major depressive disorder working group

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