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.
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Deletion of subunits of metabotropic glutamate receptors induces glutamatergic function deficits and schizophrenia-like symptoms.
“Deletion of subunits of metabotropic glutamate receptors induce glutamatergic function deficits 82,83 and schizophrenia-like symptoms.84,85”
From Glutamate in Schizophrenia: A Focused Review and Meta-Analysis of 1H-MRS Studies (2013) · cites this paper as [84]
A mGluR2/3 agonist, which by acting on presynaptic receptors reduces glutamate release, showed efficacy in a clinical trial.
“A promising initial observation is the efficacy of a mGluR2/3 agonist, which by acting on presynaptic receptors reduces glutamate release, in a clinical trial.79”
From Adolescent Onset of Cortical Disinhibition in Schizophrenia: Insights From Animal Models (2011) · cites this paper as [79]
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- Authors
- Patil, S. T., Zhang, L., Martenyi, F., Lowe, S. L., Jackson, K. A., Andreev, B. V., Avedisova, A. S., Bardenstein, L. M., Gurovich, I. Y., Morozova, M. A., Mosolov, S. N., Neznanov, N. G., Reznik, A. M., Smulevich, A. B., Tochilov, V. A., Johnson, B. G., Monn, J. A., & Schoepp, D. D.
- Affiliations
- Eli Lilly (United States) (US)
- National University of Singapore (SG)
- St Petersburg University (RU)
- Moscow Regional Psychiatry Hospital No.5 (RU)
- North-Western State Medical University named after I.I. Mechnikov (RU)
- Corresponding author
- Monn, James A
- Venue
- Nature Medicine
- Published
- 2007-09
- Volume
- 13
- Issue
- 9
- Pages
- 1102-1107
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2116386279
- Cited by
- 1,040
- References
- 30
- Citations by year
- 2026: 14 · 2025: 9 · 2024: 13 · 2023: 18 · 2022: 31 · 2021: 20 · 2020: 19 · 2019: 24 · 2018: 34 · 2017: 41 · 2016: 51 · 2015: 58 · 2014: 64 · 2013: 69 · 2012: 114
- FWCI
- 72.14
- Type
- journal article
- Language
- en
- Update notices
- erratum (2007-10-01)
- Open access
- closed
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- schizophrenia, mGlu2/3 receptor agonists, metabotropic glutamate receptors, antipsychotic drugs, olanzapine, positive symptoms, negative symptoms, prolactin elevation, extrapyramidal symptoms, weight gain, glutamatergic neurotransmission
- MeSH terms
- Olanzapine, Animals, Benzodiazepines, Cyclic S-Oxides, Disease Models, Animal, Double-Blind Method, Humans, Placebos, Schizophrenia, Antipsychotic Agents, Receptors, Metabotropic Glutamate, Bridged Bicyclo Compounds, Heterocyclic
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