Multimodal brain-derived subtypes of Major depressive disorder differentiate patients for anergic symptoms, immune-inflammatory markers, history of childhood trauma and treatment-resistance.

An estimated 30 % of Major Depressive Disorder (MDD) patients exhibit resistance to conventional antidepressant treatments. Identifying reliable biomarkers of treatment-resistant depression (TRD) represents a major goal of precision psychiatry, which is hampered by the clinical and biological heterogeneity. To uncover biologically-driven subtypes of MDD, we applied an unsupervised data-driven framework to stratify 102 MDD patients on their neuroimaging signature, including extracted measures of cortical thickness, grey matter volumes, and white matter fractional anisotropy. Our novel analytical pipeline integrated different machine learning algorithms to harmonize data, perform data dimensionality reduction, and provide a stability-based relative clustering validation. The obtained clusters were characterized for immune-inflammatory peripheral biomarkers, TRD, history of childhood trauma and depressive symptoms. Our results indicated two different clusters of patients, differentiable with 67 % of accuracy: one cluster (n = 59) was associated with a higher proportion of TRD, and higher scores of energy-related depressive symptoms, history of childhood abuse and emotional neglect; this cluster showed a widespread reduction in cortical thickness (d = 0.43-1.80) and volumes (d = 0.45-1.05), along with fractional anisotropy in the fronto-occipital fasciculus, stria terminalis, and corpus callosum (d = 0.46-0.52); the second cluster (n = 43) was associated with cognitive and affective depressive symptoms, thicker cortices and wider volumes. Multivariate analyses revealed distinct brain-inflammation relationships between the two clusters, with increase in pro-inflammatory markers being associated with decreased cortical thickness and volumes. Our stratification of MDD patients based on structural neuroimaging identified clinically-relevant subgroups of MDD with specific symptomatic and immune-inflammatory profiles, which can contribute to the development of tailored personalized interventions for MDD.