Blood-brain barrier dysfunction in bipolar disorder: Molecular mechanisms and clinical implications

Abstract

Bipolar disorder (BD) is a severe psychiatric disorder affecting approximately 1–3% of the population and characterized by a chronic and recurrent course of debilitating symptoms. An increasing focus has been directed to discover and explain the function of Blood-Brain Barrier (BBB) integrity and its association with a number of psychiatric disorders; however, there has been limited research in the role of BBB integrity in BD. Multiple pathways may play crucial roles in modulating BBB integrity in BD, such as inflammation, insulin resistance, and alterations of neuronal plasticity. In turn, BBB impairment is hypothesized to have a significant clinical impact in BD patients. Based on the high prevalence of medical and psychiatric comorbidities in BD and a growing body of evidence linking inflammatory and neuroinflammatory mechanisms to the disorder, recent studies have suggested that BBB dysfunction may play a key role in BD's pathophysiology. In this comprehensive narrative review, we aim to discuss studies investigating biological markers of BBB in patients with BD, mechanisms that modulate BBB integrity, their clinical implications on patients, and key targets for future development of novel therapies.

Highlights

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  Bipolar disorder (BD) is associated with a blood-brain barrier (BBB) dysfunction.

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  Postmortem studies have reported altered levels of tight junction proteins in BD.

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  Extensive BBB dysfunction is associated with worse clinical outcomes in patients.

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  BBB dysfunction may relate to gut microbiome, substance abuse, insulin resistance.

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  Lithium and valproate have protective effects on BBB function and integrity.