Faulty fences: Blood-brain barrier dysfunction in schizophrenia

Caveats about this research

There are 3 important points to note about the current research concerning abnormal BBB permeability:

1. BBB dysfunction may exist only in a subset of people diagnosed with schizophrenia. In most human studies, only some patients with schizophrenia demonstrated alterations that suggested pathological BBB permeability. In addition, even when there is BBB dysfunction, it could be a secondary phenomenon, rather than a primary etiologic process.

2. Patient demographics across studies have not always been adequately described. Potential confounds such as obesity, smoking, or antipsychotic use were not consistently recorded or examined as a possible factor.

3. Currently available biomarkers are not perfect. Cytokine elevation, S100B, and Q-Alb are indirect measures of BBB disruption and are found in other disorders. Therefore, they only support the theory of BBB dysfunction in schizophrenia, rather than prove it. They are also not reliable markers for schizophrenia alone. Researchers have pointed out that these markers and proteins work in concert, which necessitates a network analy­sis approach.¹⁶ More research regarding the details of permeability is required to establish more reliable biomarkers and tailored treatment.

Treatment implications

One of the first treatment directions that comes to mind is managing the gaps in the BBB via tight junctions. Presently, there are no FDA-approved medications for altering tight junction proteins, but researchers are exploring potential agents that can induce claudin-5 and reduce inflammation.¹⁴ While we wait for such a medication, patients may benefit from existing anti-inflammatory treatments to control immune infiltration and its products. Various anti-inflammatory agents—including cyclooxygenase inhibitors, minocycline, neurosteroids, N-acetylcysteine, statins, and estrogen—show replicable improvement in symptoms of schizophrenia,^16,19 but we know these abnormalities are not universal and currently there is no marker for determining which individuals might benefit from one of these treatments over another. Antipsychotics have also been found to alter adhesion molecules,²² claudin-5,⁷ and cytokine levels,²⁰ but more research must be conducted to tease out the differential effects of first- vs second-generation antipsychotics.

Bottom Line

Recent research has revealed that the blood-brain barrier (BBB) is pathologically permeable in several disease states, including schizophrenia. Better characterization of the leaky BBB in schizophrenia has enormous potential in helping us understand how current theories fit together and could serve as a missing puzzle piece in treating schizophrenia.

Related Resources

• Levine A, Strawn JR. The brain’s Twitter system: neuronal extracellular vesicles. Current Psychiatry. 2022;21(6):9-11, 17-19,27. doi:10.12788/cp.0257

Drug Brand Names

Minocycline • Dynacin, Minocin