Role of the Blood-Brain Barrier in the Pathophysiology of Major Depressive Disorder, Bipolar Disorder, and Schizophrenia: A Comparative Review.

The blood-brain barrier (BBB) is a unique neurovascular interface essential for central nervous system homeostasis. Beyond its classical protective role, accumulating evidence points to the BBB as a dynamic structure actively involved in brain function in health and disease. The present review synthesizes clinical, molecular, and neuroimaging evidence implicating BBB dysfunction in major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia. The paper was prepared in accordance with the recommendations of the Scale for the Assessment of Narrative Review Articles and was based on a PubMed search of publications published between 2000 and 2026. We summarize BBB architecture and regulation within the neurovascular unit and examine how neuroinflammation, oxidative stress, mitochondrial dysfunction, vascular-metabolic disturbances, and glucocorticoid signaling compromise tight junction, endothelial, pericyte, and astrocytic function, thereby facilitating peripheral immune signaling and sustaining central inflammation. Disorder-specific findings highlight shared and distinct mechanisms: In MDD, EZH2-mediated downregulation of claudin-5 and VEGF-driven barrier disruption are associated with increased permeability in the prefrontal cortex and hippocampus; in BD, elevated cerebrospinal fluid/serum albumin ratios and levels of S100B and matrix metalloproteinase-9-mediated tight junction degradation are associated with illness duration and neuroprogression; and in schizophrenia, reduced expression of claudin-5 and claudin-11, diminished pericyte coverage, and dysregulation of transforming growth factor-α/platelet-derived growth factor signaling are associated with neuroinflammation and treatment resistance. Therapeutic implications are discussed, including anti-inflammatory and antioxidant strategies, endothelial stabilization, and BBB-targeted delivery, as well as methodological limitations and future directions for biomarker development and neurovascular modeling.