Decomposing neuroanatomical heterogeneity in depression: insights from an ENIGMA major depressive disorder working group study in 5146 individuals.

Authors

Lukas Sempach, Sarah Ulrich, Stéphanie E E C Bauduin, Jochen Bauer, Francesco Benedetti, Klaus Berger, Bianca Besteher, Robin Bülow, Colm G Connolly, Emmanuelle Corruble, Baptiste Couvy-Duchesne, Kathryn R Cullen, Udo Dannlowski, Christopher G Davey, Danai Dima, Annemiek Dols, Jennifer W Evans, Cynthia Fu, Paola Fuentes-Claramonte, Ali Saffet Gonul, Ian H Gotlib, Roberto Goya-Maldonado, Hans J Grabe, Nynke A Groenewold, Dominik Grotegerd, Oliver Gruber, Tim Hahn, J Paul Hamilton, Laura K M Han, Ben J Harrison, Sean N Hatton, Marco Hermesdorf, Ian B Hickie, Tiffany C Ho, Julia M Hubbert, Neda Jahanshad, Hamidreza Jamalabadi, Alec J Jamieson, Christoph Jurischka, Antonia Jüllig, Toshiharu Kamishikiryo, Tilo Kircher, Sheri-Michelle Koopowitz, Bernd Krämer, Anna Kraus, Judith Krieger, Axel Krug, Jim Lagopoulos, Meng Li, Andrew McIntosh, Susanne Meinert, Elisa M T Melloni, Benson Mwangi, Igor Nenadic, Amar Ojha, Go Okada, Mardien L Oudega, Brenda W J H Penninx, Sara Poletti, Edith Pomarol-Clotet, Maria J Portella, Liesbeth Reneman, Elena Rodriguez-Cano, Matthew Sacchet, Raymond Salvador, Anouk Schrantee, Hotaka Shinzato, Kang Sim, Theresa M Slump, Jair C Soares, Dan J Stein, Frederike Stein, Lea Teutenberg, Florian Thomas-Odenthal, Sophia I Thomopoulos, Nic J A van der Wee, Steven J A van der Werff, Henry Völzke, Martin Walter, Heather C Whalley, Sarah Whittle, Katharina Wittfeld, Mon-Ju Wu, Tony T Yang, Carlos Zarate, Giovana B Zunta-Soares, Paul M Thompson, Dick J Veltman, Elena Pozzi, Lianne Schmaal, André Schmidt

Published in

Translational psychiatry. Jun 23, 2026. Epub Jun 23, 2026.

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.

PMID:
42337246
Bibliographic data and abstract were imported from PubMed on 24 Jun 2026.

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