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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\u2009=\u20095146; age range: 9\u201382 years; 64% female). Analyses of global neurostrucutral variability revealed greater cortical thickness heterogeneity in MDD compared with healthy controls (Cohen\u2019s d = \u20130.26). 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\u2019s d = \u20130.39). Patient-specific analyses further showed that individuals with markedly increased cortical thickness variability (&lt;5\n                    <jats:sup>th<\/jats:sup>\n                    percentile relative to the normative range) exhibited greater depressive symptom severity than those within the normative range (5\n                    <jats:sup>th<\/jats:sup>\n                    \u201395\n                    <jats:sup>th<\/jats:sup>\n                    percentile; Cohen\u2019s d\u2009=\u20090.19\u20130.36). 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.\n                  <\/jats:p>","DOI":"10.1038\/s41398-026-04189-x","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T13:47:13Z","timestamp":1782222433000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Decomposing neuroanatomical heterogeneity in depression: insights from an ENIGMA major depressive disorder working group study in 5146 individuals"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7785-0052","authenticated-orcid":false,"given":"Lukas","family":"Sempach","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1516-8362","authenticated-orcid":false,"given":"Sarah","family":"Ulrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1253-7377","authenticated-orcid":false,"given":"St\u00e9phanie E. 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KG. HJG has received travel grants and speaker\u2019s honoraria from Neuraxpharm, Servier, Indorsia and Janssen Cilag. IBH 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. He is the Chief Scientific Advisor to, and a 3.2% equity shareholder in, InnoWell Pty Ltd. which aims to transform mental health services through the use of innovative technologies. JCS: 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). TTY: UCSF and NeuroQore have a clinical trials agreement that provides funds to UCSF, and a portion of these funds to UCSF supported TTY\u2019s effort on papers with NeuroQore. NeuroQore did not support any of the current MDD ENIGMA paper. TTY is a professor and full-time UCSF faculty member, and he is paid by UCSF.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"452"}}