Chapter 4 - Neurovascular Dysfunction With BBB Hyperpermeability Related to the Pathophysiology of Major Depressive Disorder

Abstract

For decades, standard treatment of major depressive disorder (MDD) has been antidepressants based on the monoaminergic dysregulation hypothesis. However, one-third of patients with MDD fail at least two antidepressants within the first year of treatment. Clinical and experimental evidence suggests a multifactorial etiology, emphasizing the need for important paradigm shifts in the neurobiology of depression extending beyond a “chemical imbalance.” The mechanistic link between neurovascular unit dysfunction with blood-brain barrier (BBB) hyperpermeability to neuroinflammation and oxidative stress is well documented in many neurological disorders associated with depression, such as multiple sclerosis, stroke, brain injury, and epilepsy. Although neuroinflammation and oxidative stress are implicated in the neurobiology of MDD, evidence of associated neurovascular dysfunction with BBB hyperpermeability is less conclusive. We provide a theoretical integration of human and experimental data suggesting that neurovascular unit dysfunction with BBB hyperpermeability may occur in MDD and development of novel treatments aimed at reversing these abnormalities may prove to be effective.