Around 1% of the world's population suffers from schizophrenia. However, around 30% of patients do not respond to current drugs for treating schizophrenia. In a study published online in Nature Neuroscience, researchers of the Mount Sinai School of Medicine may now have discovered the reasons for this. The discovery opens the door for a new class of drugs that can help in treating this devastating mental illness.
Researchers from Mount Sinai School of Medicine decided to investigate what epigenetic factors, or external factors that influence gene expression, are involved in the treatment-resistance to commonly used atypical antipsychotic drugs. They conducted an autopsy on the brains of schizophrenic patients, discovering that over time, an enzyme starts compensating for the prolonged chemical changes caused by antipsychotics, which leads to a reduced efficacy of the drugs.
Leading researcher Javier Gonzalez-Maeso, PhD, Assistant Professor of Psychiatry and Neurology at Mount Sinai School of Medicine, said: "These results are groundbreaking because they show that drug resistance may be caused by the very medications prescribed to treat schizophrenia, when administered chronically."
The team discovered that the brain of mice chronically treated with antipsychotic drugs showed a highly expressed enzyme called HDAC2. This led to a lower expression of the mGlu2 receptor, meaning that the psychotic symptoms recurred. The team discovered made a similar finding in the postmortem brains of schizophrenic patients. By administering a chemical called suberoylanilide hydroxamic acid (SAHA), which inhibits the entire family of HDACs, the team observed that the detrimental effect of the antipsychotic named clopine on mGlu2 expression was prevented and also that it improved the therapeutic effects of atypical antipsychotics in mouse models.
The team's earlier studies demonstrated that chronic treatment with clozapine causes repression of mGlu2 expression in the frontal cortex of mice, a brain area key to cognition and perception. They believed that clozapine's effect on mGlu2 may have a vital impact on restraining the therapeutic effects of antipsychotic drugs.
Dr. Gonzalez-Maeso said:
"We had previously found that chronic antipsychotic drug administration causes biochemical changes in the brain that may limit the therapeutic effects of these drugs. 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."
Leading researcher of the study, Mitsumasa Kurita, PhD, a postdoctoral fellow at Mount Sinai, added: "We 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."
The team is currently developing compounds that specifically inhibit HDAC2 as adjunctive treatments to antipsychotics.
Written by Petra Rattue