Major depressive disorder (MDD) is one of the most common mental health conditions that has been intensively investigated for its association with brain atrophy and mortality. Recent studies suggest that the deviation between the predicted and the chronological age can be a marker of accelerated brain aging to characterize MDD. However, current conclusions are usually drawn based on structural MRI information collected from Caucasian participants. The universality of this biomarker needs to be further validated by subjects with different ethnic/racial backgrounds and by different types of data. Here we make use of the REST-meta-MDD, a large scale resting-state fMRI dataset collected from multiple cohort participants in China. We develop a stacking machine learning model based on 1101 healthy controls, which estimates a subject’s chronological age from fMRI with promising accuracy. The trained model is then applied to 1276 MDD patients from 24 sites. We observe that MDD patients exhibit a +4.43 years (p < 0.0001, Cohen’s d = 0.31, 95% CI: 2.23–3.88) higher brain-predicted age difference (brain-PAD) compared to controls. In the MDD subgroup, we observe a statistically significant +2.09 years (p < 0.05, Cohen’s d = 0.134525) brain-PAD in antidepressant users compared to medication-free patients. The statistical relationship observed is further checked by three different machine learning algorithms. The positive brain-PAD observed in participants in China confirms the presence of accelerated brain aging in MDD patients. The utilization of functional brain connectivity for age estimation verifies existing findings from a new dimension.

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