New Discovery Raises Hope for Drug-Resistant Schizophrenia

Megan Brooks

August 16, 2012

August 16, 2012 — Scientists have discovered a molecular mechanism for resistance to antipsychotic medications, a finding that may pave the way for the development of new drugs to treat a significant proportion of schizophrenia patients who do not respond to these medications.

Investigators led by Javier González-Maeso, PhD, assistant professor of psychiatry and neurology, Mount Sinai School of Medicine in New York City, found that long-term administration of atypical antipsychotic drugs selectively upregulates expression of the enzyme histone deacetylase 2 (HDAC2) in both mouse and human frontal cortex.

This epigenetic change, which is dependent on serotonin 5-hydroxytryptamine 2A (5-HT2A) upregulation, leads to lower expression of the metabotropic glutamate 2 receptor (mGlu2), thereby limiting the therapeutic effects of atypical antipsychotic therapy, often leading to a recurrence of psychotic symptoms.

According to investigators, blocking this cascade of events with HDAC inhibitors may improve responses to atypical antipsychotic drug therapy.

"Together, these data suggest that HDAC2 may be a new therapeutic target to augment the treatment of schizophrenia.... Specifically, our findings encourage the development and testing of HDAC2-selective inhibitors for schizophrenia," the investigators write.

The research was published online August 5 in Nature Neuroscience.

"Exciting" Findings

Commenting on the findings for Medscape Medical News, David P. Gavin, MD, of the Department of Psychiatry, University of Illinois at Chicago, described the findings as "very exciting."

"Antipsychotic resistance is a major problem in treating schizophrenia patients, especially those who have been afflicted with the illness for many years. Clearly, the ability to reverse a histone modification that would otherwise lead to long-term treatment resistance would be a major breakthrough in treating schizophrenia," he said.

Dr. Gavin was not involved in the study.

In prior studies, the study team found that long-term antipsychotic drug administration causes biochemical changes in the brain that may limit the therapeutic effects of these drugs, Dr. González-Maeso told Medscape Medical News.

"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," he added in a statement.

The scientists found that HDAC2 was upregulated in the brain of mice treated on a long-term basis with antipsychotic drugs. It was also upregulated in postmortem frontal cortex tissue of schizophrenic patients who had been treated with antipsychotics, but it was not found to be upregulated in untreated patients with schizophrenia.

"As we detected no alteration in untreated subjects with schizophrenia, these results suggest that dysregulation of HDAC2 expression represents a consequence of antipsychotic drug medication, and not a biochemical marker of schizophrenia in post-mortem human brain," they write.

They also found that treatment with suberoylanilide hydroxamic acid (SAHA), which inhibits the entire family of HDACs, prevented the detrimental effect of the antipsychotic clozapine on mGlu2 expression. It also improved the therapeutic effects of atypical antipsychotics in mouse models.

Dr. González-Maeso said his team is now developing compounds that specifically inhibit HDAC2 as adjunct treatments to antipsychotics.

Outstanding Issues

Dr. Gavin pointed out that "HDAC inhibitors, such as valproic acid, when used as adjuncts to antipsychotics have not been shown to lead to dramatic improvements in the core symptoms of schizophrenia (there is a documented improvement in aggression, however)."

He said there are several possible explanations for this lack of clinical efficacy, "which could include the heterogeneous nature of the illness, the lack of specificity of valproic acid as an HDAC inhibitor, or the ephemeral nature of histone acetylation."

"Regardless of which of these possibilities will ultimately lead to improved treatments for schizophrenia, the data presented in this paper are very exciting in terms of providing both a possible mechanism of, and treatment for, treatment-resistant schizophrenia," he added.

The study was funded by the National Institutes of Health. The authors and Dr. Gavin have disclosed no relevant financial relationships.

Nature Neurosci. Published online August 5, 2012. Abstract