Sex-specific neurodevelopmental pathways to depressive symptoms

Sex-specific neurodevelopmental pathways to depressive symptoms

Molecular Psychiatry

10.1038/s41380-026-03576-6

https://doi.org/10.1038/s41380-026-03576-6

Shi Yu Chan, Pei Huang, Zhen Ming Ngoh, Joanne S. M. Chia, Janice Lee, Aisleen M. A. Manahan, Jasmine S. M. Chuah, Marielle V. Fortier, Fabian Yap, Yap-Seng Chong, Peter Gluckman, Johan Eriksson, Michael J. Meaney, Ai Peng Tan

01 April 2026

Chan, S. Y., Huang, P., Ngoh, Z. M., Chia, J. S. M., Lee, J., Manahan, A. M. A., Chuah, J. S. M., Fortier, M. V., Yap, F., Chong, Y.-S., Gluckman, P., Eriksson, J., Meaney, M. J., & Tan, A. P. (2026). Sex-specific neurodevelopmental pathways to depressive symptoms. Molecular Psychiatry. https://doi.org/10.1038/s41380-026-03576-6

While sex differences in the prevalence of depression are consistently observed in adolescence, sex-specific endophenotypes associated with depression appear earlier in childhood. Our study examined whether neurodevelopmental changes in childhood associated with depressive symptoms in adolescence show sex-specificity. Longitudinal multi-modal neuroimaging data were collected at ages 4.5, 6.0, and 7.5 years. Neurodevelopment was measured by structure-function coupling (SC-FC), the correlation between structural and functional connectivity, derived for 114 cortical regions and averaged across the whole cortex. Depressive symptoms were self-reported at age 13 years with the Child Depression Inventory (CDI), Youth Self Report (YSR), and Multidimensional Anxiety Scale for Children. Partial least squares correlation was used to identify latent variables that maximized covariance between the 28 CDI items and 114 cortical regions. Females reported significantly higher depressive symptoms than males at age 13 years (N = 636, p < 0.001). Whole cortex SC-FC showed sex-specific trajectories across childhood (N = 549, 917 scans). Females showed a steeper decrease in SC-FC relative to males in the pre-school phase (ages 4.5 to 6.0, p = 0.019) but not during mid-childhood (ages 6.0 to 7.5, p = 0.340). For both childhood phases (Pre-school: N = 97, Mid-childhood: N = 162), sex-specific models better explained the data than full cohort (“All”) models. Items/regions with significant contributions to their respective latent variables were distinct in males and females and between childhood phases. Sex-specific cortical changes improved regression models predicting YSR Depressive Problems. We provide evidence for sex-specific childhood neurodevelopmental pathways to depressive symptoms in adolescence that could guide the timing for more effective intervention programs.

Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

This research / project is supported by the National Medical Research Council - Open Fund - Young Individual Research Grant
Grant Reference no. : MOH-001149-00

This research / project is supported by the National Medical Research Council - TCR
Grant Reference no. : NMRC/TCR/004-NUS/2008 and NMRC/TCR/012-NUHS/2014

This research / project is supported by the National Medical Research Council - Open Fund Large Collaborative Grant
Grant Reference no. : OFLCG/MOH-000504

This research / project is supported by the A*STAR - Prenatal/Early Childhood Grant
Grant Reference no. : H22P0M0001

https://oar.a-star.edu.sg/communities-collections/articles/23421

1359-4184
1476-5578

Institute for Human Development and Potential

https://doi.org/10.1038/s41380-026-03576-6