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; Marie Jose van Tol; 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 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, Marie Jose van Tol, Lianne Schmaal^*, Laura S. van Velzen

^*Corresponding author for this work

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

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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
DOIs	https://doi.org/10.1038/s41380-025-03310-8
Publication status	Published - Dec-2025

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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. https://doi.org/10.1038/s41380-025-03310-8

@article{e25d9e444cdc44bb9427b311f4b6533b,

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 \{van Tol\}, \{Marie Jose\} and Lianne Schmaal and \{van Velzen\}, \{Laura S.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

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

language = "English",

volume = "30",

pages = "5625--5636",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

number = "12",

}

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, van Tol, MJ, 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

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 - van Tol, Marie Jose

AU - Schmaal, Lianne

AU - van Velzen, Laura S.

PY - 2025/12

Y1 - 2025/12

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.

UR - https://www.scopus.com/pages/publications/105020874724

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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