Vascular depression: A comprehensive exploration of the definition, mechanisms, and clinical challenges.

Vascular depression (VaDep), which was proposed over two decades ago, is a distinct subtype of depression primarily observed in patients with stroke and cerebral small-vessel disease and is characterized by white matter hyperintensities; however, the lack of standardized diagnostic criteria and consensus limits its clinical application. This review explores the pathological conditions and vascular risk factors that may precipitate VaDep, particularly in relation to stroke and cerebral small-vessel disease. VaDep is distinguished by unique pathophysiological mechanisms and treatment responses. We categorize these mechanisms into three groups: 1) macroscopic mechanisms, including vascular aging, cerebral hypoperfusion, blood-brain barrier disruption, and neural circuit dysfunction; 2) microscopic mechanisms, involving the inflammatory response, hypothalamic-pituitary-adrenal axis dysregulation, impaired monoamine synthesis, and mitochondrial dysfunction; and 3) undetermined mechanisms, such as microbiota-gut-brain axis dysbiosis. These insights support VaDep as a distinct depression subtype, differentiating it from late-life depression and major depressive disorder. Treatment is challenging, as patients with VaDep often exhibit resistance to conventional antidepressants. Addressing vascular risk factors and protecting vascular integrity are essential for effective management. Future research should validate these mechanisms and develop novel diagnostic and therapeutic approaches to improve VaDep outcomes.