Resolving Heterogeneity in Major Depression: Overcoupling and Undercoupling Subtypes Exhibit Differential Treatment Response and Molecular Pathways

Major depressive disorder (MDD) exhibits significant heterogeneity whose neurobiological mechanisms remain elusive. Alterations in morphological-functional coupling (MFC) have been observed in MDD. This study aims to investigate MDD subtypes based on MFC alterations and their associations with clinical symptoms and molecular basis. We identified two clinically distinct MDD subtypes in multi-center neuroimaging data (Discovery: 828 MDD/776 healthy controls; Validation: 236 MDD/86 healthy controls) by using a semi-supervised machine learning approach based on MFC changes, which were validated and robustly repeated in the validation dataset. Differences among subtypes were then examined in relation to clinical assessments, gene expression patterns, neurotransmitter and cell density, and treatment response. Subtype I (overcoupling) showed elevated MFC in high-order association cortices, linking to synaptic transmission activity and severe symptoms. Subtype II (undercoupling) demonstrated reduced MFC in primary cortices, associated with cell cycle regulation and treatment resistance. Both subtypes shared molecular signatures (cell types: astrocytes and oligodendrocytes; neurotransmitter systems: serotonergic and GABAergic receptors). Crucially, longitudinal data (33 MDD undergoing Escitalopram monotherapy) revealed that undercoupling subtype exhibited better response, implying a potential mechanism of the drug via increasing the MFC. Our work deciphers MFC-driven MDD phenotypes with distinct molecular profiles and differential treatment outcomes, suggesting potential pathways for personalized diagnosis and treatment strategies in MDD, advancing precision psychiatry.