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Schizophrenia is a chronic, severe, and disabling mental disorder and affects about 24 million people worldwide. According to the World Health Organization, more than 50 percent of persons with schizophrenia are not receiving appropriate care.

A team of researchers at Mount Sinai School of Medicine found that, over time, an enzyme in the brains of schizophrenic patients analyzed at autopsy begins to compensate for the prolonged chemical changes caused by antipsychotics, resulting in reduced efficacy of the drugs.

Javier Gonzalez-Maeso, lead investigator on the study, said that the results are groundbreaking because they show that drug resistance may be caused by the very medications prescribed to treat schizophrenia, when administered chronically.

Gonzalez-Maeso and his team found that an enzyme called HDAC2 was highly expressed in the brain of mice chronically treated with antipsychotic drugs, resulting in lower expression of the receptor called mGlu2, and a recurrence of psychotic symptoms. A similar finding was observed in the postmortem brains of schizophrenic patients. 

The researchers administered a chemical called suberoylanilide hydroxamic acid (SAHA), which inhibits the entire family of HDACs. They found that this treatment prevented the detrimental effect of the antipsychotic called clozapine on mGlu2 expression, and also improved the therapeutic effects of atypical antipsychotics in mouse models.

Previous research conducted by the team showed that chronic treatment with the antipsychotic clozapine causes repression of mGlu2 expression in the frontal cortex of mice, a brain area key to cognition and perception. The researchers hypothesized that this effect of clozapine on mGlu2 may play a crucial role in restraining the therapeutic effects of antipsychotic drugs.

"We had previously found that chronic antipsychotic drug administration causes biochemical changes in the brain that may limit the therapeutic effects of these drugs,"said Dr. Gonzalez-Maeso. "We wanted to identify the molecular mechanism responsible for this biochemical change, and explore it as a new target for new drugs that enhance the therapeutic efficacy of antipsychotic drugs."

Mitsumasa Kurita, lead author of the study, said that they found that atypical antipsychotic drugs trigger an increase of HDAC2 in frontal cortex of individuals with schizophrenia, which then reduces the presence of mGlu2, and thereby limits the efficacy of these drugs. 

Gonzalez-Maeso's team is now developing compounds that specifically inhibit HDAC2 as adjunctive treatments to antipsychotics. The study was funded by the National Institutes of Health.