Toward Reproducible, Generalizable, and Clinically Useful Neurophysiological Subtypes of Major Depressive Disorder

Major depressive disorder (MDD) is a severe mental disorder that contributes significantly to the global health and economic burden ( 1 Vos T. Lim S.S. Abbafati C. Abbas K.M. Abbasi M. Abbasifard M. et al. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020; 396: 1204-1222 Abstract Full Text Full Text PDF PubMed Scopus (5930) Google Scholar ). It is characterized by a persistent depressed mood or the loss of interest or pleasure in nearly all activities and the presence of a range of other symptoms, including disturbances in sleep or psychomotor activity; appetite or weight change; decreased energy; feelings of worthlessness or guilt; difficulty in thinking, concentrating, or making decisions; or recurrent thoughts of death, suicidal ideation, or suicide plans or attempts ( 2 American Psychiatric AssociationDiagostic and Statistical Manual of Mental Disorder. 5th ed. American Psychiatric Association Publishing, Arlington2013 Crossref Google Scholar ). Yet the clinical manifestation of individuals diagnosed with MDD is highly heterogeneous, with a varied presence of symptoms, illness trajectories, and responses to treatment ( 3 Malhi G.S. Mann J.J. Depression. Lancet. 2018; 392: 2299-2312 Abstract Full Text Full Text PDF PubMed Scopus (1621) Google Scholar ). The neurobiological substrates associated with MDD also appear highly heterogeneous, with little consensus in the literature about which brain regions and neural circuits are associated with the disorder ( 4 Kaiser R.H. Andrews-Hanna J.R. Wager T.D. Pizzagalli D.A. Large-scale network dysfunction in major depressive disorder: A meta-analysis of resting-state functional connectivity. JAMA Psychiatry. 2015; 72: 603-611 Crossref PubMed Scopus (1260) Google Scholar ). To date, there is no biomarker with sufficient sensitivity and specificity to be used as a diagnostic or prognostic tool for MDD. The diagnosis of MDD is solely based on clinical observations of symptoms, and the treatment of MDD still relies on a sequential, trial-and-error approach, which can take months to find the right antidepressant. The biologically informed diagnosis and prognosis of MDD remains challenging. SEE CORRESPONDING ARTICLE ON PAGE 936 SEE CORRESPONDING ARTICLE ON PAGE 936 Mapping Neurophysiological Subtypes of Major Depressive Disorder Using Normative Models of the Functional ConnectomeBiological PsychiatryVol. 94Issue 12PreviewMajor depressive disorder (MDD) is a highly heterogeneous disorder that typically emerges in adolescence and can occur throughout adulthood. Studies aimed at quantitatively uncovering the heterogeneity of individual functional connectome abnormalities in MDD and identifying reproducibly distinct neurophysiological MDD subtypes across the lifespan, which could provide promising insights for precise diagnosis and treatment prediction, are still lacking. Full-Text PDF