Clozapine and rapamycin reverse behavioral abnormalities in an animal model of autoimmune schizophrenia.

Objective: Autoantibody-associated psychosis represents a distinct disease subgroup of patients with schizophrenia with a suspected autoimmune origin. Although preliminary studies have suggested adjunctive drug treatment strategies targeting the immune system, further validation of these findings is warranted. Autoantibodies against SFT2D2 have been identified in patients with schizophrenia. ApoE^-/- mice immunized with SFT2D2-peptides can be used as a model for testing immunotherapy in this subgroup of patients. We used the atypical antipsychotic drug clozapine and immunosuppressant rapamycin to test their effects in this mouse model.

Methods: The mice were evaluated for cognitive and schizophrenia-like behaviors. Following behavioral testing, brain samples were collected for analyzing specific pathological changes and dendritic spine formation.

Results: Clozapine and rapamycin reversed impaired pre-pulse inhibition, motor impairment, and improved cognitive ability in ApoE ^-/- mice exposed to anti-SFT2D2 immunoglobulin G. Immunohistochemical assays revealed that both clozapine and rapamycin significantly reduced activated microglial infiltration and restored neuronal dendritic spine density.

Conclusions: Our study results suggested that clozapine and rapamycin possess therapeutic benefits for managing autoimmune psychosis and provide mechanistic insights into immunotherapies involving immunosuppressive agents.