Group I and group II metabotropic glutamate receptor allosteric modulators as novel potential antipsychotics

• mGlu5 PAMs treat positive, negative, and cognitive symptoms in animal models.
• Genetic mutations in mGlu1 have been identified in some schizophrenic patients.
• Early clinical data showed efficacy of mGlu2/3 agonists, but later trials did not.
• mGlu2 PAMs are now in clinical development.
• Mutations in mGlu3 have been identified in schizophrenics and may affect cognition.

Recently, there has been a shift in the schizophrenia field focusing on restoring glutamate signaling. Extensive preclinical data suggests that mGlu5 PAMs could have efficacy in all three symptom domains but there is concern of potential adverse effects. New insights into mechanisms underlying this toxicity may provide a path for discovery of safe mGlu5 PAMs. Genetic mutations in mGlu1 have been described in schizophrenics creating interest in this receptor as a therapeutic target. Preclinical data demonstrated the antipsychotic potential of mGlu2/3 agonists but clinical trials were not successful. However, studies have suggested that mGlu2 is the subtype mediating antipsychotic effects and selective mGlu2 PAMs are now in clinical development. Finally, recent genetic studies suggest mGlu3 modulators may be pro-cognitive.