In schizophrenia and bipolar disorder, tight junction deficits in brain microvascular endothelial cells (BMECs) lead to blood brain barrier (BBB) dysfunction. Using an in vitro model of human BBB function, we show that BMECs derived from human induced pluripotent stem cells of schizophrenia patients show reduced BBB integrity and increased small molecule permeability when compared to healthy control BMECs. Stratification based on BBB function in schizophrenia and bipolar disorder patients

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... fied a BBB-deficit subtype with reduced barrier function, increased permeability to larger molecules, and decreased claudin-5 (CLDN5) levels. BMECs from the BBB-deficit group show increased MMP1 activity, which correlated with reduced CLDN5 levels and worse BBB function, which were rescued by tumor necrosis factor α (TNFα and MMP1 inhibition. These results show intrinsic deficits in BMECs in psychotic disorders that result in BBB disruption and further identify TNFα and MMP1 as potential targets for ameliorating BBB deficits.