Biological subtypes of cognitive impairment in first-episode medication-naïve MDD linking individualized functional connectome, cognition, and symptom.

BACKGROUND

Major depressive disorder (MDD) is a leading cause of disability worldwide and exhibits high heterogeneity, particularly in cognitive impairments. Understanding the biological mechanisms underlying cognitive impairment in MDD is crucial for developing individualized treatment.

METHODS

This study included 80 first-episode medication-naïve (FEDN) MDD patients and 40 healthy controls (HC). Sparse multiple canonical correlation analysis (smCCA) and K-means clustering were used to identify MDD subtypes based on individualized functional connectivity (FC), cognitive performance, and clinical symptoms.

RESULTS

Two data-driven MDD subtypes were identified: the global impairment subtype (giMDD), characterized by widespread cognitive deficits across memory, processing speed, and executive function; and the memory-specific impairment subtype (miMDD), showing memory-specific impairments. giMDD exhibited unique hyperconnectivity between the dorsal attention network (DAN) and frontoparietal network (FN), and between the ventral attention network (VAN) and FN.

CONCLUSIONS

This study highlights the heterogeneity of cognitive impairment in MDD and identifies two data-driven MDD subtypes associated with distinct brain network connectivity patterns. These findings provide insights into the biological mechanisms underlying MDD heterogeneity and offer a potential framework for personalized treatment strategies. Future studies are needed to evaluate the clinical utility of these subtypes in improving individualized care for MDD.