222Background: Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, 223 aging-related diseases, and mortality. We examined potential advanced brain aging in MDD patients, and 224 whether this process is associated with clinical characteristics in a large multi-center international dataset.
225Methods: We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI 226 scans from 29 samples worldwide. Normative brain aging was estimated by predicting chronological age 227 (10-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and 228 total intracranial volume measures separately in 1,147 male and 1,386 female controls from the ENIGMA 229 MDD working group. The learned model parameters were applied to 1,089 male controls and 1,167 230 depressed males, and 1,326 female controls and 2,044 depressed females to obtain independent 231 unbiased brain-based age predictions. The difference between predicted "brain age" and chronological 232 age was calculated to indicate brain predicted age difference (brain-PAD).
233Findings: On average, MDD patients showed a higher brain-PAD of +0.90 (SE 0.21) years (Cohen's 234 d=0.12, 95% CI 0.06-0.17) compared to controls. Relative to controls, first-episode and currently 235 depressed patients showed higher brain-PAD (+1.2 [0.3] years), and the largest effect was observed in 236 those with late-onset depression (+1.7 [0.7] years). In addition, higher brain-PAD was associated with 237 higher self-reported depressive symptomatology (b=0.05, p=0.004).
238Interpretation: This highly powered collaborative effort showed subtle patterns of abnormal structural 239 brain aging in MDD. Substantial within-group variance and overlap between groups were observed.
240Longitudinal studies of MDD and somatic health outcomes are needed to further assess the predictive 241 value of these brain-PAD estimates. 242 Funding: This work was supported, in part, by NIH grants U54 EB020403 and R01 MH116147.243 244 245 246 247248 . 29 Alternatively, brain age may be more sensitive to subjective (BDI) than to objectively 595 (HDRS-17) rated experiences, consistent with the finding of Kwak and colleagues (2018) that the 596 subjective experience of aging was closely related to predicted brain age. 30 However, it is important to 597 20 bear in mind the small effect size (b=0.05). Nonetheless, positive associations with current depressive 598 symptom severity have been previously reported with more advanced levels of biological aging, as 599 indicated by shorter telomere length 31 and increased epigenetic aging. 19
601This study showed relatively largest effect size of advanced brain aging in patients with a late-life onset of 602 depression (>55 years old) compared to controls. However, we did not find significant differences 603 between early vs. adult vs. late onset of depression groups. Additionally, no differences between remitted 604 (N=344) and acute patients (N=2,179) were found, leading to the speculatio...