The therapeutic potential of metabotropic glutamate receptor modulation for schizophrenia

Accumulating evidence suggests that a dysregulation of the glutamatergic system exists in the brains of schizophrenia patients. The metabotropic glutamate (mGlu) receptors are being investigated as novel drug targets for this disease, and have shown promise in both preclinical and clinical studies. Activation of mGlu₅ receptors may be efficacious for several symptom domains (positive, negative, and cognitive) and the potential for targeting mGlu₅ receptors has been bolstered by recent research on mitigating toxicity profiles associated with mGlu₅ activation. Additionally, genetic profiling of schizophrenia patients suggests that genes encoding for mGlu₁ and mGlu₃ receptors are altered, prompting preclinical studies that have demonstrated potential antipsychotic and cognitive enhancing effects of agents that activate mGlu₁ and mGlu₃ receptors, respectively. Development of subtype-specific drugs for the mGlu receptors, such as allosteric modulators, could provide a path forward for more efficacious and tolerable therapeutics for schizophrenia.