Biotypes of major depressive disorder identified by a multiview clustering framework.

Background: The advances in resting-state functional magnetic resonance imaging techniques motivate parsing heterogeneity in major depressive disorder (MDD) through neurophysiological subtypes (i.e., biotypes). Based on graph theories, researchers have observed the functional organization of the human brain as a complex system with modular structures and have found wide-spread but variable MDD-related abnormality regarding the modules. The evidence implies the possibility of identifying biotypes using high-dimensional functional connectivity (FC) data in ways that suit the potentially multifaceted biotypes taxonomy.

Methods: We proposed a multiview biotype discovery framework that involves theory-driven feature subspace partition (i.e., "view") and independent subspace clustering. Six views were defined using intra- and intermodule FC regarding three MDD focal modules (i.e., the sensory-motor system, default mode network, and subcortical network). For robust biotypes, the framework was applied to a large multisite sample (805 MDD participants and 738 healthy controls).

Results: Two biotypes were stably obtained in each view, respectively characterized by significantly increased and decreased FC compared to healthy controls. These view-specific biotypes promoted the diagnosis of MDD and showed different symptom profiles. By integrating the view-specific biotypes into biotype profiles, a broad spectrum in the neural heterogeneity of MDD and its separation from symptom-based subtypes was further revealed.

Limitations: The power of clinical effects is limited and the cross-sectional nature cannot predict the treatment effects of the biotypes.

Conclusions: Our findings not only contribute to the understanding of heterogeneity in MDD, but also provide a novel subtyping framework that could transcend current diagnostic boundaries and data modality.