Invited reviewMetabotropic glutamate receptors as therapeutic targets for schizophrenia

Treatment options for schizophrenia that address all symptom categories (positive, negative, and cognitive) are lacking in current therapies for this disorder. Compounds targeting the metabotropic glutamate (mGlu) receptors hold promise as a more comprehensive therapeutic alternative to typical and atypical antipsychotics and may avoid the occurrence of extrapyramidal side effects that accompany these treatments. Activation of the group II mGlu receptors (mGlu2 and mGlu3) and the group I mGlu5 are hypothesized to normalize the disruption of thalamocortical glutamatergic circuitry that results in abnormal glutamaterigic signaling in the prefrontal cortex (PFC). Agonists of mGlu2 and mGlu3 have demonstrated efficacy for the positive symptom group in both animal models and clinical trials with mGlu2 being the subtype most likely responsible for the therapeutic effect. Limitations in the chemical space tolerated by the orthosteric site of the mGlu receptors has led to the pursuit of compounds that potentiate the receptor's response to glutamate by acting at less highly conserved allosteric sites. Several series of selective positive allosteric modulators (PAMs) for mGlu2 and mGlu5 have demonstrated efficacy in animal models used for the evaluation of antipsychotic agents. In addition, evidence from animal studies indicates that mGlu5 PAMs hold promise for the treatment of cognitive deficits that occur in schizophrenia. Hopefully, further optimization of allosteric modulators of mGlu receptors will yield clinical candidates that will allow full evaluation of the potential efficacy of these compounds in the treatment of multiple symptom domains in schizophrenia patients in the near future.This article is part of a Special Issue entitled 'Schizophrenia'.

► Disruption of glutamatergic circuitry is implicated in the pathology of schizophrenia. ► Agonists of mGlu2 and mGlu3 show efficacy in animal models and clinical trials for schizophrenia. ► Positive allosteric modulators (PAMs) of mGlu2 and mGlu5 are promising alternatives to agonists. ► Evidence shows that mGlu5 PAMs may be effective in treating cognitive deficits in schizophrenia.