Decomposing neuroanatomical heterogeneity in depression: insights from an ENIGMA major depressive disorder working group study in 5146 individuals
Sempach, L., Ulrich, S., Bauduin, S. E. E. C. , Bauer, J., Benedetti, F., Berger, K., Besteher, B., Bülow, R., Connolly, C. G., Corruble, E., Couvy-Duchesne, B., Cullen, K. R., Dannlowski, U., Davey, C. G., Dima, D. 
ORCID: 0000-0002-2598-0952, Dols, A., Evans, J. W., Fu, C., Fuentes-Claramonte, P., Gonul, A. S., Gotlib, I. H., Goya-Maldonado, R., Grabe, H. J., Groenewold, N. A., Grotegerd, D., Gruber, O., Hahn, T., Hamilton, J. P., Han, L. K. M., Harrison, B. J., Hatton, S. N., Hermesdorf, M., Hickie, I. B., Ho, T. C., Hubbert, J. M., Jahanshad, N., Jamalabadi, H., Jamieson, A. J., Jurischka, C., Jüllig, A., Kamishikiryo, T., Kircher, T., Koopowitz, S-M., Krämer, B., Kraus, A., Krieger, J., Krug, A., Lagopoulos, J., Li, M., McIntosh, A., Meinert, S., Melloni, E. M. T., Mwangi, B., Nenadic, I., Ojha, A., Okada, G., Oudega, M. L., Penninx, B. W. J. H., Poletti, S., Pomarol-Clotet, E., Portella, M. J., Reneman, L., Rodriguez-Cano, E., Sacchet, M., Salvador, R., Schrantee, A., Shinzato, H., Sim, K., Slump, T. M., Soares, J. C., Stein, D. J., Stein, F., Teutenberg, L., Thomas-Odenthal, F., Thomopoulos, S. I., van der Wee, N. J. A., van der Werff, S. J. A., Völzke, H., Walter, M., Whalley, H. C., Whittle, S., Wittfeld, K., Wu, M-J., Yang, T. T., Zarate, C., Zunta-Soares, G. B., Thompson, P. M., Veltman, D. J., Pozzi, E., Schmaal, L. & Schmidt, A. (2026).
Decomposing neuroanatomical heterogeneity in depression: insights from an ENIGMA major depressive disorder working group study in 5146 individuals.
Translational Psychiatry,
doi: 10.1038/s41398-026-04189-x
Abstract
The clinical and biological heterogeneity of major depressive disorder (MDD) may reflect the aggregation of different conditions with distinct pathologies under a single diagnostic label. Neuroanatomical heterogeneity in MDD was examined using a harmonized, age- and sex-matched sample from the ENIGMA MDD consortium (N = 5146; age range: 9–82 years; 64% female). Analyses of global neurostrucutral variability revealed greater cortical thickness heterogeneity in MDD compared with healthy controls (Cohen’s d = –0.26). Regionally, increased variability in cortical thickness was most prominent in the cingulate (+6.1 to +6.6% more variation in MDD) and insular (+5.8%) cortices, as well as in the frontal (+5.7 to +6.8%) and temporal (+6.1 to +6.8%) lobes. Heterogeneity in cortical thickness was more pronounced among patients using antidepressant medication (Cohen’s d = –0.39). Patient-specific analyses further showed that individuals with markedly increased cortical thickness variability (<5
th
percentile relative to the normative range) exhibited greater depressive symptom severity than those within the normative range (5
th
–95
th
percentile; Cohen’s d = 0.19–0.36). Overall, the results indicate that neuroanatomical heterogeneity in MDD is primarily expressed in cortical thickness, offering refined insights into the neurobiological complexity of structural alterations associated with depression. These findings could guide future stratification efforts examining whether regionally confined changes in cortical thickness within areas of pronounced variability reflect clinically meaningful patient subgroups.
| Publication Type: | Article |
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| Additional Information: | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
| Publisher Keywords: | Biomarkers, Depression, Neuroscience |
| Subjects: | R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry |
| Departments: | School of Health & Medical Sciences School of Health & Medical Sciences > Department of Psychology & Neuroscience |
| SWORD Depositor: |
Available under License Creative Commons Attribution.
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