Metabotropic glutamate receptors as targets for new antipsychotic drugs: Historical perspective and critical comparative assessment

In this review, we aim to present, discuss and clarify our current understanding regarding the prediction of possible antipsychotic effects of metabotropic glutamate (mGlu) receptor ligands. The number of preclinical trials clearly indicates, that this group of compounds constitutes an excellent alternative to presently used antipsychotic therapy, being effective not only to positive, but also negative and cognitive symptoms of schizophrenia. Although the results of clinical trials that were performed for the group of mGlu2/3 agonists were not so enthusiastic as in animal studies, they still showed that mGlu ligands do not induced variety of side effects typical for presently used antipsychotics, and were generally well tolerated. The lack of satisfactory effectiveness towards schizophrenia symptoms of mGlu2/3 activators in humans could be a result of variety of uncontrolled factors and unidentified biomarkers different for each schizophrenia patient, that should be taken into consideration in the future set of clinical trials. The subject is still open for further research, and the novel classes of mGlu5 or mGlu2/3 agonists/PAMs were recently introduced, including the large group of compounds from the third group of mGlu receptors, especially of mGlu4 subtype. Finally, more precise treatment based on simultaneous administration of minimal doses of the ligands for two or more receptors, seems to be promising in the context of symptoms-specific schizophrenia treatment.