Functional connectivity-based classification and subtyping of major depression for precision mental health: An...

Major depressive disorder (MDD) remains clinically diagnosed based on subjective symptoms rather than objective neurobiological markers, which limits diagnostic accuracy and the ability to tailor treatment. We present an ensemble hybrid framework that integrates graph neural networks (GNN) with unsupervised clustering to classify and subtype MDD using resting-state functional connectivity (rs-fMRI) profiles. A GNN was trained to distinguish MDD from healthy controls using functional connectivity derived brain graphs, and the resulting subject level embeddings were clustered to uncover subtype structure. We evaluated the approach on two public multisite cohorts, REST-meta-MDD (China; N = 1,604; 17 sites) and SRPBS (Japan; N = 446; 4 sites), using leave-one-site-out cross-validation and cross-national transfer. The classifier achieved 0.73 leave-one-site-out accuracy on REST-meta-MDD and retained 0.78 sensitivity when transferred from the Chinese to the Japanese cohort, outperforming BrainIB and CI GNN under the same protocol. To mitigate site related confounds, we applied a standardized preprocessing pipeline and ComBat harmonization. Clustering consistently identified three MDD subtypes with distinct connectivity signatures involving the default mode network and cerebellum, the insula-cingulum temporal circuit, and frontostriatal circuitry. These findings provide a reproducible and biologically interpretable stratification of MDD. Prospective studies will be needed to link these subtypes to treatment response and other clinically meaningful outcomes.