How Drugs for Schizophrenia Sow Seeds of Resistance

A new study has identified why certain drugs have mixed success in treating schizophrenia; effective at first, but with chronic administration becoming less and less so.

In the study, reported online in the journal Nature Neuroscience, scientists investigated the external genetic reasons (called epigenetic factors) that cause treatment-resistance to atypical antipsychotic drugs.

Use of antipsychotic drugs is the standard of care for schizophrenia. Researchers at Mount Sinai School of Medicine report that 30 percent of individuals with schizophrenia do not respond to currently available treatments.

Researchers discovered 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.

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

Researchers 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.

In response, the research team administered a chemical called suberoylanilide hydroxamic acid (SAHA), which inhibits the entire family of HDACs. 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 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, Ph.D., a postdoctoral fellow at Mount Sinai and the lead author of the study, said, “We found that atypical antipsychotic drugs trigger an increase of HDAC2 in the frontal cortex of individuals with schizophrenia, which then reduces the presence of mGlu2, and thereby limits the efficacy of these drugs.”

As a result of these findings, Gonzalez-Maeso’s team is now developing compounds that specifically inhibit HDAC2 as adjunctive treatments to antipsychotics.

Source:The Mount Sinai Hospital/Mount Sinai School of Medicine

Face in the Mirror More Distorted in Schizophrenia

Individuals with schizophrenia experience more intense perceptual illusions while gazing into a mirror than do healthy people, according to a new study.

The new research also showed that patients with schizophrenia were more likely to believe the illusions they see in the mirror were real.

The research highlights the underlying ego dysfunction and body dysmorphic disorder found in schizophrenia.

According to the researchers, gazing at one’s own reflected face under low light can lead to ghostly experiences called “strange-face in the mirror” illusions. No study has previously focused on mirror gazing in schizophrenic patients, who already experience delirium, hallucination and self mis-attribution.

Stefano Zago of the University of Milan conducted the study to compare strange-face apparitions in response to mirror gazing in 16 patients with schizophrenia and 21 mentally healthy controls.

Subjects took a 7-minute mirror-gazing test, after which they filled out a specially designed questionnaire asking them to describe their strange-face perceptions.

The results show a number of differences between patients with schizophrenia and mentally healthy controls.  Patients on average reported a greater total number of strange faces than controls, at 2.8 versus 1.5.

The types of strange faces also differed between patients and controls. Hugely deformed features were seen by all schizophrenia patients and 71% of controls, archetypal faces by 50% of patients and 19% of controls, and monstrous faces by 88% of patients and 29% of controls. Patients’ archetypical and monster faces were typically described as satanic beings.

Furthermore, patients tended to report greater intensity in the strange faces and were more likely to say that they felt real than controls.

Of note, mentally healthy participants felt dissociative experiences during the strange-face illusions and never identified with them.

Overall, the research suggests that strange-face illusions in schizophrenia can be caused by ego dysfunction, body dysmorphic disorder, or by misattribution of self-agency, said Zago.

The research is published in Schizophrenia Research.

Source:  Schizophrenia Research