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

AI Summary

Blood-brain barrier dysfunction is implicated in MDD, bipolar disorder and schizophrenia through disrupted tight junctions, endothelial, pericyte and astrocyte dysfunction.
Shared mechanisms include neuroinflammation, oxidative stress, mitochondrial and vascular metabolic disturbances, and glucocorticoid signalling compromising barrier integrity.
Disease-specific signatures: MDD shows claudin-5 downregulation and VEGF-driven permeability; BD shows elevated CSF/serum albumin ratio, S100B, MMP-9; schizophrenia shows claudin loss and pericyte deficits.

TL;DR (AI Generated)

The present review synthesizes clinical, molecular, and neuroimaging evidence implicating BBB dysfunction in major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia.

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.

Basic summary

Pharmaceuticals (Basel). 2026 Sep 17;19(9):1483. doi: 10.3390/ph19091483.

ABSTRACT

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.

PMID:42797527 | DOI:10.3390/ph19091483

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