Of potential importance to the development and testing of novel and more effective antidepressant therapies is the noninvasive characterization of requisite brain changes mediating depression remission. A further clinical goal is the identification of pretreatment markers that might eventually inform optimal treatment selection. Toward these objectives, functional neuroimaging studies have described resting-state glucose metabolic and blood flow abnormalities in cortical, subcortical, and limbic regions, including changes with various antidepressant treatments. There is, however, variability in both site and direction of changes across published reports. In this article, a cortical-limbic network model of depression is used to explain this variability. In this approach, network dysfunction combined with ongoing intrinsic compensatory processes is seen to explain the heterogeneity of depressive symptoms observed clinically, as well as variations in pretreatment scan patterns. Furthermore, the synchronized modulation of these dysfunctional cortical-limbic pathways is considered critical for illness remission, regardless of treatment modality. Formal testing of disease-specific and response-specific functional interactions among regions in this depression network using multivariate approaches are discussed, with a perspective aimed at future studies examining treatment nonresponse, relapse risk, and disease vulnerability.
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