A new mechanism of action for the antipsychotics of the future

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

In a groundbreaking scientific article published in Science Advances, Franck Vandermoere, a biologist at the CNRS, along 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 mechanism 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 that affects more than 1% of the world’s population. It is characterized by positive symptoms (hallucinations, delusions), negative symptoms (lack of energy, difficulty performing tasks, difficulty concentrating, blunted emotions, difficulty forming relationships), and cognitive impairments (difficulty remembering, disorganized thinking, vague or even incomprehensible speech, aimless behavior). While the antipsychotics currently used in clinical practice effectively control the positive symptoms of the illness, they show little efficacy against negative symptoms and cognitive impairments, which are sources of significant difficulty in social integration and suffering for patients and their families.

To address this unmet clinical need, a new class of antipsychotics targeting the_mGlu2 glutamate receptor is currently undergoing clinical trials. Although interactions with certain existing antipsychotics have been identified, these drugs remain candidates for first-line treatment, demonstrating efficacy not only against positive symptoms but also, and most importantly, against the negative and cognitive symptoms of the disease. The mechanisms by which stimulation of the_mGlu2 receptor acts on symptoms resistant to current antipsychotics remain unknown to date.

A surprising discovery

Using a technologically innovative approach based on a nanobody (a tiny llama antibody) and high-resolution mass spectrometry analysis, the authors discovered an interaction between the_mGlu2 receptor and the TrkB receptor of neurotrophins, factors essential for neuronal 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 resistant to current antipsychotics.

This study has thus identified an important mechanism of action for next-generation antipsychotics in treating treatment-resistant symptoms of schizophrenia.

Keywords: Research, schizophrenia, Science, Company