Multidimensional characterization of structure aberrations for biotypes of major depressive disorder

Major depressive disorder (MDD) is a heterogeneous clinical syndrome associated with brain structural abnormalities, yet the neurobiological heterogeneity and consistent neuroimaging findings underlying these alterations remain unclear. Multilevel and multidimensional analyses are therefore needed to identify reliable structural signatures of MDD biotypes.

K-means clustering was applied to identify biotypes in 387 drug-naive MDD patients, with gray matter volume (GMV) compared to 1104 healthy controls. Causal structural covariance network (CaSCN), individual differential structural covariance network (IDSCN), and graph theory-based single-subject morphological network analyses were performed to characterize subtype-specific causal influences, individual-level covariance, and network topology. Transcriptomic and neurotransmitter association analyses were further conducted to probe the biological mechanisms underlying each subtype.

Subtype 1 showed predominant GMV alterations in the visual network, subtype 2 in somatomotor, default mode, and limbic networks, and subtype 3 in cerebellar-limbic regions. CaSCN revealed subtype-specific directed influences, indicating differential propagation of structural abnormalities. IDSCN identified distinct altered covariance patterns, highlighting subtype-dependent thalamo-cerebellar changes and selective links to depressive severity. Graph theory showed divergent global topology, with subtype 1 exhibiting higher network integration, whereas subtypes 2 and 3 showed reduced integration and efficiency. Each biotype showed distinct neurobiological profiles, with subtype 1 enriched in cellular functions, subtype 2 in metabolic regulation, and subtype 3 in neurodevelopmental genes, alongside distinct neurotransmitter associations.

These findings advance the understanding of structural and individual-level network alterations underlying MDD biotypes and provide novel insights into the neurobiological mechanisms of MDD heterogeneity.