Exploratory Analysis for a Targeted Patient Population Responsive to the Metabotropic Glutamate 2/3 Receptor Agonist Pomaglumetad Methionil in Schizophrenia

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

“…Consistent with this hypothesis, a new, exploratory meta-analysis of the clinical trials showed that the low dose, but not the high dose, of LY2140023 improved patients who were early in the disease. 5 Our data suggest that these low, beneficial doses may have engaged postsynaptic receptors on dendritic spines, and that patients with more long-standing illness may have lost these spines and thus lost the substrate for the drug's therapeutic actions. It is hoped that future research can better isolate the beneficial effects of mGluR2/3 agonists at postsynaptic receptors, for example, by dissecting mGluR2 vs mGluR3 actions in primate dlPFC.…”

“…20 mGluR2/3 agonists have been a focus of drug development for schizophrenia, based on findings that NMDAR antagonists increase, whereas mGluR2/3 agonists decrease, glutamate release in rodent medial PFC. 23,27,49 However, the results of clinical trials have been mixed, [3][4][5][6][7] emphasizing the need for understanding mGluR2/3 actions in primate dlPFC. Here we examined mGluR2/3 mechanisms in the dlPFC of rhesus macaque monkeys.…”

“…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.…”

Juvenile treatment with a novel mGluR2 agonist/mGluR3 antagonist compound, LY395756, reverses learning deficits and cognitive flexibility impairments in adults in a neurodevelopmental model of schizophrenia

“…Pharmacologically targeting metabotropic glutamate receptor 2/3 (mGluR2/3) offers promising therapeutic effects to patients with SCZ (Moghaddam and Adams, 1998; Patil et al, 2007; Conn et al, 2009; Mezler et al, 2010; Kinon et al, 2011; Fell et al, 2012; Kinon et al, 2015). Recent studies have shown that compounds targeting mGluR2/3 are well-tolerated, exhibit few side-effects, and demonstrate a strong potential for alleviating cognitive impairments in both animal models and human subjects with SCZ (Helton et al, 1998; Spooren et al, 2002; Swanson et al, 2005; Fell et al, 2012; Harvey and Shahid, 2012).…”

Positive allosteric modulators of metabotropic glutamate 2 receptors in schizophrenia treatment

“…However, subsequent clinical trials with pomaglumetad showed either inconclusive results [99], or results that are no different from placebo [100]. Importantly, results form a recent post-hoc analysis suggest that the therapeutic effects of pomaglumetad depend on previous exposure to either typical or atypical antipsychotic drugs [101]. These findings and their basic mechanism based on previous preclinical findings [102] are discussed in Box 1…”