Perspectives on the mGluR2/3 agonists as a therapeutic target for schizophrenia: Still promising or a dead end?

Abstract

Group II metabotropic glutamate receptor (mGluR2/3) agonists once showed promise as non-dopaminergic antipsychotic drugs because of their efficacy in alleviating symptoms of schizophrenia (SZ) in both animal models and human patients. However, the recent failure of Phase III clinical trials dealt a huge blow to the scientific community and the aftershock of the setback in mGluR2/3 research can be felt everywhere from grant support and laboratory studies to paper publication. An immediate question raised is whether mGluR2/3 is still a promising therapeutic target for schizophrenia. Answering this question is not easy, but apparently a new strategy is needed. This article provides a focused review of literature on the study of mGluR2/3 agonists, especially on mGluR2/3 agonists’ mechanism of action and efficacy in both normal conditions and animal models of SZ, as well as clinical studies in human patients with the disease. We argue that the cellular and molecular actions of mGluR2/3 agonists, the distinct roles between mGluR2 and mGluR3, as well as their effects on different stages of the disease and different subpopulations of patients, remain incompletely studied. Until the mechanisms associated with mGluR2/3 are clearly elucidated and all treatment options are tested, it would be a great mistake to terminate the study of mGluR2/3 as a therapeutic target for schizophrenia. This review will thus shed light on the comprehensive features of the translational potential mGluR2/3 agonists as well as the need for further research into the more selective activation of mGluR2.

mGluR2/3 mechanisms in primate dorsolateral prefrontal cortex: evidence for both presynaptic and postsynaptic actions

“…1,2 Although initial trials with mGluR2/3 agonists have had mixed results, [3][4][5][6][7] data increasingly indicate that changes in mGluR3 are associated with schizophrenia and aging, [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] encouraging this treatment strategy. Clinical trials were originally based on data from rodent models.…”

mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia

“…In accordance, increasing the activity of mGluR2/3 receptors might therefore be a viable treatment strategy. The upregulation of mGluR2/3 signaling using agonists or modulators of mGluR2/3 has been shown to have therapeutic potential in schizophrenia relevant behavioral paradigms (Li et al, 2015). However, none of these studies have assessed the potential of these agents to correct core NMDA-R and GABAA-R deficits and/or imbalances.…”

“…While the mGluR2/3 agonist LY2140023 has been discontinued during the clinical trial phase III due to a lack of significant improvement above placebo, more selective agonists, including LY379268, have been hypothesized to exert a stronger therapeutic action (Li et al, 2015).…”

Targeting glutamate to treat schizophrenia: lessons from recent clinical studies

“…Similar problems occurred in the development of mGluR2/3 agonists, which act by inhibiting glutamate release (Li et al 2015). Despite a promising proof of concept study finding improved positive and negative symptoms after treatment with LY2140023 compared with placebo (Patil et al 2007), later trials were unsuccessful.…”

“…Despite a promising proof of concept study finding improved positive and negative symptoms after treatment with LY2140023 compared with placebo (Patil et al 2007), later trials were unsuccessful. One follow-up multi-centre phase II trial was inconclusive, with a high placebo response rate (Kinon et al 2011), and another phase II open-label study found LY2140023 was inferior to a comparison atypical antipsychotic (Li et al 2015). In August 2012, Eli Lilly announced their decision to stop phase III trials as one of the trials, closest to completion, failed to meet its primary endpoint (Li et al 2015).…”