Age-dependent structural brain aging in medication-free major depressive disorder: A multi-site analysis from COORDINATE-MDD consortium.
Abstract
Background
Major depressive disorder (MDD) is associated with altered brain structure and accelerated brain aging. However, previous studies have been limited by clinical samples with mixed medication status and multiple mood states, modest sample sizes, underrepresentation of older adults with MDD, and/or reliance on summary-level data.
Methods
Harmonized T1-weighted MRI from MDD (n = 645), all medication-free and in a current depressive episode, and matched healthy controls (n = 645), segmented into 145 regional volumes, from 11 sites in COORDINATE-MDD consortium. Brain age gap (BAG) was estimated cross-sectionally using gradient boosting regression with nested cross-validation. Group differences in BAG (and age-corrected BAG [cBAG]) were examined across age strata. Regional contributions were evaluated using SHAP values.
Results
MDD was associated with significantly elevated cBAG compared with healthy controls (mean difference + 2.0 years [95% CI 1.251, 2.774], Cohen's d -0.289 [95% CI -0.399, -0.179]). Age-stratified analyses showed no differences before mid-30s, with progressively larger gaps thereafter, reaching +6.8 years in MDD aged 55 and older in unadjusted analyses (4.3 years after accounting for site). cBAG differed across neuroanatomical phenotypes previously identified using COORDINATE-MDD data. Key contributing regions included lateral and medial prefrontal regions, middle temporal gyrus, putamen, supplementary motor cortex, central operculum, and cerebellum.
Conclusions
Structural brain aging in MDD is age-dependent and most pronounced in a neuroanatomical phenotype associated with poorer key clinical outcomes. The findings are consistent with, but do not establish, neuroprogression models of MDD and demonstrate that cBAG is not a uniform feature of MDD, being more strongly expressed in a specifically clinically vulnerable disease phenotype.