Abstract Major depressive disorder (MDD) is the most burdensome psychiatric disorder characterized by remarkably heterogeneous clinical phenotypes. It remains challenging to delineate the heterogeneity of neurobiological abnormalities underlying the clinical variance and, on this basis, to identify neurophysiological subtypes of MDD patients. Here, using a large multisite resting-state functional MRI data from 1,148 MDD patients and 1,079 healthy controls, we generated lifespan normative models of functional connectivity strengths, mapped the heterogeneity of patients’ individual deviations, and identified neurobiological MDD subtypes. MDD patients showed positive deviations mainly in the default mode and subcortical areas, and negative deviations widely distributed over the cortex. However, there was a great inter-subject heterogeneity as indicated by that no more than 3.14% of patients deviated from the normative range for any brain region. Two neurophysiological MDD subtypes were identified. Subtype 1 showed severe deviations with positive deviations in the default mode, limbic, and subcortical areas, and negative deviations in the sensorimotor, dorsal and ventral attention areas, while subtype 2 showed a moderate but conversed deviation pattern. The severe-deviation subtype had older age, higher medicated proportion, and higher Suicide item score, while the moderate-deviation subtype showed higher Work and Activities and Depressed Mood item scores. Moreover, the baseline deviations in the severe-deviation subtype were predictive of 6-month antidepressant treatment effects in a subsample. To our knowledge, the current study is the largest multisite analysis of neurophysiological MDD subtyping to date and the findings shed light on our understanding of the biological mechanisms underlying the intersubject heterogeneity of clinical phenotypes, which are informative for the development of personalized treatments for this disorder.

Mapping Neurophysiological Subtypes of Major Depressive Disorder Using Normative Models of the Functional Connectome