Bridging molecules and connectome: network biomarkers guided by neurotransmitter architecture in major depressive...

Major depressive disorder (MDD) involves multiscale alterations ranging from molecular signaling to large-scale brain network dysfunction. However, how molecular topography constrains system-level connectome reorganization remains inadequately understood, limiting the development of biologically grounded diagnostic markers. We established a biologically grounded framework by integrating molecular organization with systems-level connectome analysis to characterize and classify MDD. Using resting-state functional magnetic resonance imaging data from a discovery cohort of 237 first-episode, medication-naïve MDD patients and 305 healthy controls (HC), as well as an independent multi-site validation cohort comprising 243 MDD patients and 340 HCs, we systematically mapped connectome-wide reconfigurations onto 14 normative neurotransmitter receptor and transporter density distributions. Our findings revealed widespread connectivity alterations (6.38% of edges). These alterations spatially correlated with normative densities of serotonin 1A (5-HT_1A; ρ = -0.217) and dopaminergic markers, including the dopamine transporter (DAT) and dopamine receptors (D1 and D2; ρ range: -0.204 to -0.227). To translate these mechanistic insights into individual-level predictions, we developed the Neurotransmitter Transporter/Receptor-Annotated Connectome Classification Model (NTR-CCM), which incorporates molecular maps as biological priors to guide feature selection. The NTR-CCM achieved superior diagnostic performance in the discovery cohort (area under the curve [AUC] = 0.83-0.86) and maintained robust generalization in the external validation cohort (AUC = 0.73-0.75). These results indicate that macroscale connectome reorganization in MDD is spatially constrained by the brain's underlying neurochemical architecture. By bridging molecular and systems scales, the NTR-CCM provides a high-performing and mechanistically interpretable framework for precision psychiatry.