Researchers discover clues to developing more effective 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.