Researchers discover clues to developing more effective antipsychotic drugs

Researchers from Mount Sinai School of Medicine, have identified the pattern of cell signaling induced by antipsychotic drugs in a complex composed of two brain receptors linked to schizophrenia. The discovery should allow researchers to predict the effectiveness of novel compounds for the treatment of schizophrenia and other serious mental disorders and may accelerate the development of better antipsychotic drugs. The findings are published in the November 23 issue of Cell.

Until now, the molecular mechanism through which current treatments for schizophrenia achieve their intended antipsychotic effects was unknown. Schizophrenia, which affects nearly one percent of the world's population, is a severe, chronic condition characterized by hallucinations, delusions and cognitive deficits. The most effective antipsychotic treatment, clozapine, was originally developed as an antidepressant and found to have antipsychotic properties. However, the use of clozapine has substantial undesirable effects, such as glucose abnormalities and a low white blood cell count, which severely restrict its use.

In this study, the research teams led by Javier Gonzalez-Maeso, PhD, Assistant Professor of Psychiatry and Neurology at Mount Sinai School of Medicine and Diomedes Logothetis, PhD, Professor and Chair of Physiology and Biophysics at Virginia Commonwealth University looked at the effects of antipsychotic and hallucinogenic drugs on two brain receptors linked to schizophrenia: the glutamate mGlu2 receptor and the serotonin 5-HT2A receptor. The hallucinogenic drugs were used to induce one of the main symptoms of schizophrenia.

The antipsychotic drugs significantly increased levels of activity in the glutamate receptor and decreased levels of activity in the serotonin receptor. Introducing hallucinogens had the reverse effect. Although the ideal ratio is unknown, healthy brains have higher levels of activity in the glutamate receptor and lower levels in the serotonin receptor, while in brains of schizophrenic patients this balance is reversed.

The study built on earlier research by the same team that discovered that these glutamate and serotonin receptors communicate with each other and work as a single complex switch.

"In the first two phases of our research we have made important discoveries about how the receptor complex forms and how it signals, as well as how drugs alter the signaling activity to treat or cause psychosis," said Miguel Fribourg, PhD, the first author of the study and a postdoctoral fellow in the laboratory of Stuart Sealfon, MD, a study co-author and the Glickenhaus Professor and Chairman of the Department of Neurology at Mount Sinai.

In the next phase, researchers will look for treatments that achieve the optimal balance of activity between the two receptors.

"Now that we know how current drugs affect the ratio of activity in this glutamate-serotonin receptor complex, we can try to identify or develop more effective treatments for schizophrenia that result in a healthier signaling ratio," said Dr. Gonzalez-Maeso.

This study was a joint effort between several teams at Mount Sinai School of Medicine, Virginia Commonwealth University, and University of Maryland School of Pharmacy.

"This is a clear example of collaborative, team-based research combining multidisciplinary approaches ranging from cell and molecular biology to computational biophysics, neurochemistry and behavioral pharmacology" said Marta Filizola, PhD, an Associate Professor of Structural and Chemical Biology at Mount Sinai. Dr. Filizola's team contributed a mechanistic understanding of the glutamate-serotonin signaling triggered by antipsychotic drugs through computer simulations.

About The Mount Sinai Medical Center
The Mount Sinai Medical Center encompasses both The Mount Sinai Hospital and Mount Sinai School of Medicine. Established in 1968, Mount Sinai School of Medicine is one of the leading medical schools in the United States. The Medical School is noted for innovation in education, biomedical research, clinical care delivery, and local and global community service. It has more than 3,400 faculty in 32 departments and 14 research institutes, and ranks among the top 20 medical schools both in National Institutes of Health (NIH) funding and by U.S. News & World Report.

The Mount Sinai Hospital, founded in 1852, is a 1,171-bed tertiary- and quaternary-care teaching facility and one of the nation's oldest, largest and most-respected voluntary hospitals. In 2011, U.S. News & World Report ranked The Mount Sinai Hospital 16th on its elite Honor Roll of the nation's top hospitals based on reputation, safety, and other patient-care factors. Of the top 20 hospitals in the United States, Mount Sinai is one of 12 integrated academic medical centers whose medical school ranks among the top 20 in NIH funding and US News & World Report and whose hospital is on the US News & World Report Honor Roll. Nearly 60,000 people were treated at Mount Sinai as inpatients last year, and approximately 560,000 outpatient visits took place.

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