A new mechanism of action for the antipsychotics of tomorrow

[Press release] - Published on January 29, 2024 in Press Room, Science-Society

In a groundbreaking scientific article published in Science Advances, Franck Vandermoere, a biologist at the CNRS, together with three teams from the Institute of Functional Genomics (University of Montpellier, CNRS, INSERM) and a team from Huazhong University in Wuhan (China) worked to decipher the mode of action of a new class of antipsychotics targeting the_mGlu2 glutamate receptor, in order to understand how they reduce the so-called "negative" and "cognitive" symptoms of several diseases, including schizophrenia.

Schizophrenia is a highly debilitating mental illness affecting more than 1% of the world's population. It is characterized by positive symptoms (hallucinations, delusions), negative symptoms (lack of energy, difficulty performing actions, concentrating, emotional blunting, difficulty forming relationships) and cognitive disorders (difficulty memorizing, disorganized thinking, vague or even incomprehensible speech, aimless behavior). While the antipsychotics currently used in clinical practice effectively control the positive symptoms of the disease, they are not very effective against the negative symptoms and cognitive disorders, which cause great difficulty in social integration and suffering for patients and their families.

To meet this therapeutic need, a new class of antipsychotics targeting the_mGlu2 glutamate receptor is currently undergoing clinical trials. Although interference with certain current antipsychotics has been detected, they remain candidates for first-line treatment, with efficacy on positive symptoms but also, and above all, on the negative and cognitive symptoms of the disease. The mechanisms by which stimulation of the_mGlu2 receptor acts on symptoms that are resistant to current antipsychotics remain unknown to date.

A surprising discovery

Using a technologically innovative approach based on a nanobody (a tiny antibody from llamas) and high-resolution mass spectrometry analysis, the authors discovered an interaction between the_mGlu2 receptor and the TrkB receptor for neurotrophins, which are essential factors for neuron survival and differentiation. They then demonstrated in a preclinical model of schizophrenia that the TrkB receptor plays a key role in the response to antipsychotics targeting the_mGlu2 receptor, particularly with regard to behavioral disturbances that are resistant to current antipsychotics.

This work has therefore identified an important mechanism of action for future antipsychotics on resistant symptoms of schizophrenia.

Keywords: Research, schizophrenia, Science, Company