Heterogeneity of brain functional connectivity, transcriptome, and neurotransmitter profiles in major depressive disorder

Background Major depressive disorder (MDD) is a heterogeneous with underlying mechanisms that are insufficiently studied. We aimed to identify functional connectivity (FC)-based subtypes of MDD and investigate their biological mechanisms. Methods Consensus clustering of FC patterns was applied to a population of 829 MDD patients from the REST-Meta-MDD database, with validity assessed across multiple dimensions, including atlas replication, cross-validated classification, and drug-naïve subgroup analysis. Regression models were used to quantify FC alterations in each MDD subgroup compared with 770 healthy controls, and to analyze spatial associations between FC alterations and publicly available gene transcriptomic and neurotransmitter receptor/transporter density databases. Results Two stable MDD subtypes emerged: hypoconnectivity ( n = 527) and hyperconnectivity ( n = 299), which had both shared and distinct regions with remarkable FC alterations (i.e. epicenters) in the default mode network. There were several common enriched genes (e.g. axon/brain development, synaptic transmission/organization, etc.) related to FC alterations in both subtypes. However, glial cell and neuronal differentiation genes were specifically enriched in the hypoconnectivity and hyperconnectivity subtypes, respectively. Both subtypes showed spatial associations between FC alterations and serotonin receptor/transporter density. In the hypoconnectivity subtype, FC alterations correlated with GABA and acetylcholine receptor densities, while norepinephrine transporter and glutamate receptor densities were linked to the hyperconnectivity subtype. Conclusions Our findings suggested the presence of two neuroimaging subtypes of MDD characterized by hypoconnectivity or hyperconnectivity, demonstrating robust reproducibility. The two subtypes had both shared and distinct genetic mechanisms and neurotransmitter receptor/transporter profiles, suggesting potential clinical implications for this heterogeneous disorder.