The current approach to psychiatric diagnoses involves identifying symptom clusters that fit a specific syndrome. Although this approach has facilitated the field's development, advances in genetics and neuroimaging raise the question of how causality may fit into the diagnostic process. One approach would be a two-axial system, wherein clinical presentation is on one axis and putative risk factors are on the other. This approach applies to subcortical ischemic depression (SID), a diagnosis corresponding to the "vascular depression" hypothesis. Subcortical ischemic depression affects clinical presentation, long-term outcomes, and response to antidepressant therapy, arguing that it is a valid diagnostic entity worth further study.