Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial

Abstract

Schizophrenia is a chronic, complex and heterogeneous mental disorder, with pathological features of disrupted neuronal excitability and plasticity within limbic structures of the brain. These pathological features manifest behaviorally as positive symptoms (including hallucinations, delusions and thought disorder), negative symptoms (such as social withdrawal, apathy and emotional blunting) and other psychopathological symptoms (such as psychomotor retardation, lack of insight, poor attention and impulse control). Altered glutamate neurotransmission has for decades been linked to schizophrenia, but all commonly prescribed antipsychotics act on dopamine receptors. LY404039 is a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors and has shown antipsychotic potential in animal studies. With data from rodents, we provide new evidence that mGlu2/3 receptor agonists work by a distinct mechanism different from that of olanzapine. To clinically test this mechanism, an oral prodrug of LY404039 (LY2140023) was evaluated in schizophrenic patients with olanzapine as an active control in a randomized, three-armed, double-blind, placebo-controlled study. Treatment with LY2140023, like treatment with olanzapine, was safe and well-tolerated; treated patients showed statistically significant improvements in both positive and negative symptoms of schizophrenia compared to placebo (P < 0.001 at week 4). Notably, patients treated with LY2140023 did not differ from placebo-treated patients with respect to prolactin elevation, extrapyramidal symptoms or weight gain. These data suggest that mGlu2/3 receptor agonists have antipsychotic properties and may provide a new alternative for the treatment of schizophrenia.

Intermediate phenotypes in schizophrenia genetics redux: is it a no brainer?

“…Of note, even while we anticipate the fruits of modern psychiatric genetics in terms of future medicines to be far off, it is encouraging that there has been some convergence between candidate gene, cognitive and intermediate phenotype findings in GRM3, 47 and independent early findings of efficacy in a new treatment for schizophrenia targeting this same receptor. 58 This bodes well for the possibility that integrated genetic, cognitive and brain imaging strategies of intermediate phenotypes could be further developed to potentially enhance human models of pharmacological efficacy prediction so needed in the treatment of psychosis.…”

Glutamatergic and Neuronal Dysfunction in Gray and White Matter: A Spectroscopic Imaging Study in a Large Schizophrenia Sample

“…8 Longitudinal studies examining whole brain 1 H-MRSI early in the illness will further clarify the mechanism by which increased glutamatergic metabolism contributes to the pathophysiology of schizophrenia. This line of translational investigation may identify subgroups of patients, for whom drugs, such as metabotropic MGluR2-3 agonists 65 may be particularly helpful to prevent cognitive decline.…”

Expression of a GRM3 Splice Variant is Increased in the Dorsolateral Prefrontal Cortex of Individuals Carrying a Schizophrenia Risk SNP

“…Mechanistically, it has been proposed that GRM2/3 agonists reverse the cortical glutamate efflux that is induced by NMDA antagonist administration, and which has been linked to the cognitive dysfunction. Furthermore, there is preliminary evidence in humans that group II agonists are effective in improving cognitive deficits induced by ketamine (Krystal et al, 2005) and that they possess antipsychotic activity (Patil et al, 2007).…”