Dusting off old blueprints: Is it time to reconsider metabotropic glutamate receptor 2 for therapeutic drug development?

The metabotropic glutamate receptor 2 (mGlu₂) is a heavily studied therapeutic target in neuropsychiatry for which we anticipate a renewed interest in the near future. We review the rationale and the outcome of clinical trials with mGlu_2/3 receptor agonists in schizophrenia, a field of intense research since a seminal publication by Patel and colleagues (2007). We summarize evidence about selective, potent and safe agents with quantifiable CNS penetration that can be used to test hypotheses of mGlu₂ receptors involvement in neuropsychiatric diseases. We summarize lessons learned from previous programs that should be considered to maximize the probability of success when targeting orthosteric and allosteric enhancement of mGlu₂ receptor function in schizophrenia and beyond. First, we propose expanding our focus beyond presynaptic mGlu₂ receptor stimulation in schizophrenia to novel hypotheses and that the choice of a therapeutic indication no longer be dictated by commercial opportunity but following science as a driver. Second, evidence on internal validity of preclinical studies supporting efficacy claims in the mGlu₂ field is very limited. This gap will need to be closed when reviewing the rationale to re-initiate efforts in this field. Third, the pomaglumetad program was halted due to insufficient clinical efficacy, partly because of the inability to identify a treatment responder population. In preclinical studies, effects of mGlu_2/3 receptor stimulation also seemed to vary significantly between laboratories. Definition of the responsive subject population and development of response-predicting biomarkers is therefore one of the main avenues of further research in the mGlu₂ field.