The Role of Blood-Brain Barrier Integrity in the Pathophysiology and Progression of Psychiatric Disorders

Neuroprogression, marked by clinical deterioration and neural restructuring in psychiatric disorders, involves mechanisms contributing to disease chronicity and severity. Central to this is the blood-brain barrier (BBB), crucial for central nervous system (CNS) homeostasis. BBB disruption significantly affects the pathogenesis and progression of brain disorders. This review examines the role of BBB impairment in psychiatric disorders and possible contributions to illness neuroprogression. Oxidative and nitrosative stress, due to imbalances in reactive oxygen and nitrogen species and antioxidant defenses, lead to cellular damage and BBB impairment. Mitochondrial dysfunction can exacerbate these effects, causing energy deficits and impaired neuronal function. Neuroinflammation perpetuates neurotoxicity and BBB disruption by releasing cytokines and chemokines from activated immune cells. Additionally, metabolic dysfunction, including insulin resistance and lipid abnormalities, can compromise BBB integrity, increase permeability and facilitate neurodegeneration. Genetic and epigenetic factors, including mutations in genes encoding BBB structural proteins and transporters, also contribute to CNS disease pathology and possibly progression. Advances in neuroimaging, such as dynamic contrast-enhanced MRI (DCE-MRI), enable in vivo assessment of BBB integrity, revealing permeability changes linked to psychiatric morbidity. Also, highlighted are therapeutic strategies targeting BBB integrity which may mitigate disease processes and progression, and inform stage-specific therapeutic developments in psychiatric disorders. • BBB disruption links systemic stress to neuroinflammation in psychiatric illness. • Peripheral and CSF biomarkers implicate BBB leakage in psychiatric disorders. • Neuroimaging methods permit in vivo assessment of subtle BBB permeability changes. • Metabolic dysfunction and inflammation converge on neurovascular integrity. • Therapeutic agents targeting the BBB may prevent psychiatric neuroprogression.