Distinct and Shared Molecular Mechanisms Underlie Morphological-Functional Overcoupling and Undercoupling in Major Depressive Disorder.

BACKGROUND: Major depressive disorder (MDD) exhibits significant heterogeneity in alterations of brain morphology and function, however, the potential neurobiological mechanisms remain elusive. This study aims to investigate MDD subtypes based on morphological-functional coupling (MFC) and their associations with clinical symptoms and molecular basis. METHODS: We employed a semi-supervised machine learning approach on multi-center neuroimaging data (Discovery: 828 MDD/776 healthy controls; Validation: 236 MDD/86 healthy controls) to identify subtypes based on morphological-functional coupling (MFC). Subtypes were characterized clinically and linked to spatial gene expression, neurotransmitter maps, and cell-type-specific density. Treatment response was assessed in a longitudinal cohort (n = 33) receiving escitalopram. RESULTS: We identified two highly replicable MDD subtypes. The Subtype I (overcoupling), with elevated MFC in association cortices, was associated with synaptic transmission pathways and more severe symptoms, especially psychomotor retardation, agitation, and hypochondriasis. In contrast, the Subtype II (undercoupling), with reduced MFC in primary cortices, was linked to cell cycle-related pathways. Crucially, both subtypes shared common enrichment for astrocyte and oligodendrocyte gene expression and convergent dysregulation in serotonergic and GABAergic receptor systems. Preliminary longitudinal data suggested that the undercoupling subtype showed a more favorable response to escitalopram, concomitant with a normalization of MFC. CONCLUSIONS: Our findings move beyond descriptive subtyping by showing that clinically distinct subtypes of MDD spatially correlate with divergent glial and synaptic molecular signatures. This MFC-based framework provides a neurobiologically informed classification of MDD, linking macroscale brain organization with microscale cellular and molecular features.