Neuroanatomical dimensions in major depression linked to cognition, adverse life events, self-harm, metabolomics and genetics.
Xiao W., Woodham RD., Cui Y., Wen J., Antoniades M., Srinivasan D., Fan Y., Erus G., Garcia JA., Arnott SR., Chen T., Choi KS., Chin Fatt C., Frey BN., Frokjaer VG., Ganz M., Godlewska BR., Hassel S., Ho K., McIntosh AM., Qin K., Rotzinger S., Sacchet MD., Savitz J., Shou H., Singh A., Stolicyn A., Strigo I., Strother SC., Tosun D., Wei D., Anderson IM., Craighead WE., Deakin JFW., Dunlop BW., Elliott R., Gong Q., Gotlib IH., Harmer CJ., Kennedy SH., Knudsen GM., Mayberg HS., Paulus MP., Qiu J., Trivedi MH., Whalley HC., Yan C-G., Young AH., Davatzikos C., Fu CHY.
BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability worldwide, yet its diagnosis relies on clinical symptoms alone. METHODS: Using the semi-supervised machine learning algorithm, Heterogeneity through Discriminative Analysis (HYDRA), we had identified two neuroanatomical dimensions in deeply phenotyped (i.e., comprehensively assessed across neuroimaging, clinical, and behavioural domains), medication-free participants with MDD from the COORDINATE-MDD consortium. In the present study, we apply this pre-trained HYDRA model to the UK Biobank (UKB) to validate these dimensions in a large general population and a subsample with current depressive symptoms. RESULTS: Dimension 2 (D2), compared to Dimension 1 (D1), is characterized by reduced grey and white matter volumes and limited treatment response to antidepressant and placebo medications. Out-of-sample validation in the UKB general population (n = 37,235) confirms these neuroanatomical features and reveals D2 associations with cognitive impairments, adverse life events, self-harm and suicide attempts, a pro-atherogenic lipid profile, and genetic links to neurodegenerative traits. Similar profiles are observed in the UKB subsample with current depressive symptoms (n = 1455). CONCLUSIONS: D1 and D2 represent distinct neurobiological mechanisms underlying MDD. The validation in a general population-based cohort and in a cohort sample with depressive symptoms delineates mechanisms underlying heterogeneity in MDD.