Alterations in white matter (WM) microstructure have been implicated in the pathophysiology of major depressive disorder (MDD). However, previous findings have been inconsistent, partially due to low statistical power and the heterogeneity of depression. In the largest multi-site study to date, we examined WM anisotropy and diffusivity in 1305 MDD patients and 1602 healthy controls (age range 12-88 years) from 20 samples worldwide, which included both adults and adolescents, within the MDD Working Group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium. Processing of diffusion tensor imaging (DTI) data and statistical analyses were harmonized across sites and effects were meta-analyzed across studies. We observed subtle, but widespread, lower fractional anisotropy (FA) in adult MDD patients compared with controls in 16 out of 25 WM tracts of interest (Cohen's d between 0.12 and 0.26). The largest differences were observed in the corpus callosum and corona radiata. Widespread higher radial diffusivity (RD) was also observed (all Cohen's d between 0.12 and 0.18). Findings appeared to be driven by patients with recurrent MDD and an adult age of onset of depression. White matter microstructural differences in a smaller sample of adolescent MDD patients and controls did not survive correction for multiple testing. In this coordinated and harmonized multisite DTI study, we showed subtle, but widespread differences in WM microstructure in adult MDD, which may suggest structural disconnectivity in MDD.

Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen's d = 0.14, 95% CI: 0.08-0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.

Brain structural abnormalities in obesity: Relation to age, genetic risk, and common psychiatric disordersEvidence through univariate and multivariate mega-analysis including 6420 participants from the ENIGMA MDD working group

It has been difficult to find robust brain structural correlates of the overall severity of major depressive disorder (MDD). We hypothesized that specific symptoms may better reveal correlates and investigated this for the severity of insomnia, both a key symptom and a modifiable major risk factor of MDD. Cortical thickness, surface area and subcortical volumes were assessed from T1-weighted brain magnetic resonance imaging (MRI) scans of 1053 MDD patients (age range 13-79 years) from 15 cohorts within the ENIGMA MDD Working Group. Insomnia severity was measured by summing the insomnia items of the Hamilton Depression Rating Scale (HDRS). Symptom specificity was evaluated with correlates of overall depression severity. Disease specificity was evaluated in two independent samples comprising 2108 healthy controls, and in 260 clinical controls with bipolar disorder. Results showed that MDD patients with more severe insomnia had a smaller cortical surface area, mostly driven by the right insula, left inferior frontal gyrus pars triangularis, left frontal pole, right superior parietal cortex, right medial orbitofrontal cortex, and right supramarginal gyrus. Associations were specific for insomnia severity, and were not found for overall depression severity. Associations were also specific to MDD; healthy controls and clinical controls showed differential insomnia severity association profiles. The findings indicate that MDD patients with more severe insomnia show smaller surfaces in several frontoparietal cortical areas. While explained variance remains small, symptom-specific associations could bring us closer to clues on underlying biological phenomena of MDD.

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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...

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