Researchers identify new drug target for schizophrenia

(Medical Xpress) -- Researchers at Mount Sinai School of Medicine may have discovered why certain drugs to treat schizophrenia are ineffective in some patients. Published online in Nature Neuroscience, the research will pave the way for a new class of drugs to help treat this devastating mental illness, which impacts one percent of the world's population, 30 percent of whom do not respond to currently available treatments.

A team of researchers at Mount Sinai School of Medicine set out to discover what epigenetic factors, or external factors that influence , are involved in this treatment-resistance to atypical antipsychotic drugs, the standard of care for schizophrenia. They discovered that, over time, an enzyme in the brains of schizophrenic patients analyzed at autopsy begins to compensate for the prolonged caused by antipsychotics, resulting in reduced efficacy of the drugs.

"These results are groundbreaking because they show that may be caused by the very medications prescribed to treat schizophrenia, when administered chronically," said Javier Gonzalez-Maeso, PhD, Assistant Professor of Psychiatry and Neurology at Mount Sinai School of Medicine and lead investigator on the study.

They 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 . A similar finding was observed in the postmortem brains of . The research team 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 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, PhD, a postdoctoral fellow at Mount Sinai and the lead author of the study, said, "We found that 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," said

Dr. 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.

Related Stories

Recommended for you

New research supporting stroke rehabilitation

8 hours ago

Using world-leading research methods, the team of Dr David Wright and Prof Paul Holmes, working with Dr Jacqueline Williams from the Victoria University in Melbourne, studied activity in an area of the brain ...

Team finds an off switch for pain

13 hours ago

In research published in the medical journal Brain, Saint Louis University researcher Daniela Salvemini, Ph.D. and colleagues within SLU, the National Institutes of Health (NIH) and other academic institutions have d ...

Brain researchers pinpoint gateway to human memory

15 hours ago

An international team led by researchers of the University of Magdeburg and the DZNE has successfully determined the location, where memories are generated with a level of precision never achieved before. ...

User comments

Adjust slider to filter visible comments by rank

Display comments: newest first

tadchem
5 / 5 (1) Aug 13, 2012
Many schizophrenics develop an apparent resistance to the treatments, and increased dosage does little to help. My late brother found that after a while only ethanol would mute the interminable chatter of the internal voices. He traded his health and a large portion of his life expectancy for peace *within* his mind.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.