Major depressive disorder (MDD) is associated with brain structural abnormalities, yet how these abnormalities vary across age and sex remain incompletely understood. Here, we aimed to characterize sex-stratified age-related brain morphological patterns in patients with MDD across a broad age range. Using large multisite datasets, we modeled sex-stratified age-related patterns of gray-matter morphometrics in patients with MDD (n = 1,982) and healthy controls (HCs, n = 5,160) aged 12–75 years.
Then, we examined the biological relevance of age-related group differences in morphometric features by linking them to brain metabolic, neurotransmitter, and transcriptomic profiles. Here we show that males with MDD exhibit decreased brain volume and cortical thickness during adolescence, which correlate with the cerebral metabolic rate of glucose use (CMRglc) and cerebral blood flow (CBF). Females with MDD exhibit prominent differences in late adulthood, colocalizing with oxygen consumption, CMRglc, and CBF.
These sex-stratified age-related morphological patterns are associated with genes enriched in metabolic processes and neurotransmitter signaling. Collectively, sexually divergent brain morphology alterations in adolescence and late adulthood highlight a sex-specific vulnerability window in the pathology of MDD. Major depressive disorder (MDD) can affect the brain, but these effects may differ between males and females and may also change with age.
We investigated brain morphometric features in more than 7,000 individuals aged 12 to 75 years, including patients with MDD and healthy individuals. We found that males with MDD show more noticeable brain differences during adolescence, whereas females with MDD show more differences in late adulthood. These changes are linked to how the brain uses energy, receives blood, and communicates through chemical signals.
Our findings suggest that males and females may have different periods of greater brain vulnerability to MDD. Understanding these differences may support the development of more age- and sex-specific approaches to depression. We thank all participants for their contributions to this study.
We also thank the investigators and staff at all participating sites for their efforts in participant recruitment, data collection, and data management. W.L. discloses support for the research of this work from the National Natural Science Foundation of China [grant number 62571105] and the Sichuan Science and Technology Program [grant number 2026NSFSCZY0055]. J.L. discloses support for the research of this work from the National Natural Science Foundation of China [grant number 62473082], the Sichuan Science and Technology Program [grant number 2026NSFSC0377], and the Fundamental Research Funds for the Central Universities [grant number ZYGX2024XJ054].
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