Distance-Dependent Functional Dysconnectivity and Neurotransmitter Correlates in Major Depressive Disorder

Motivation: The differences between first-episode drug-naïve (FEDN) and recurrent major depressive disorder (RMDD) patients in the functional dysconnectivity and their association with neurotransmitter systems remain poorly understood. Goal(s): To investigate distance-specific alterations of functional connectivity (FC) and the relationship between functional dysconnectivity and neurotransmitter systems in MDD subtypes. Approach: We examined distance-dependent FC differences in a large cohort of 848 MDD patients and 794 controls, and integrated them with neurotransmitter density from a public PET dataset. Results: FEDN and RMDD showed distinct patterns of distance-dependent FC disruption, particularly in long-range connections, with specific correlations with serotonergic, GABAergic, and opioid systems. Impact: Functional dysconnectivity in MDD subtypes shows distinct distance-dependent patterns and specific correlations with neurotransmitter systems. These findings advance our understanding of subtype-specific pathophysiology and may guide the development of more precise therapeutic strategies for MDD.