Neurophysiological stratification of major depressive disorder by distinct trajectories

Major depressive disorder (MDD) has been characterized by structural abnormalities of multiple brain regions. Nevertheless, little is known about the underlying neuropathological origin of MDD, particularly based on distinct trajectories of brain atrophy. Here, using the data-driven subtype and stage inference algorithm on large case–control magnetic resonance imaging data from 3,940 individuals (1,789 patients with MDD; 2,151 healthy controls), we demonstrated three highly robust spatiotemporal MDD subtypes: subtype 1 initiates from the subgenual anterior cingulate cortex, subtype 2 starts at the hippocampus and subtype 3 begins in the superior frontal gyrus and then the orbitofrontal cortex. These subtypes also exhibited distinct clinical profiles and differing transcriptomic gene expressions. Specifically, we identified suicide risk as the characteristic symptom for the ‘anterior cingulate cortex-led’ subtype, as well as low motivation (for example, work interests) for the ‘frontal-led’ and somatic anxiety for the ‘hippocampus-led’. Distinguishable cell type-specific transcriptional signatures further indicate distinct origins of MDD subtypes. Together, our data-driven findings demonstrate different spatiotemporal trajectories of MDD subtypes, which may contribute to the potential for individualized diagnostics, suicide risk alerts and optimizing therapeutic targeting.