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

A Corrigendum to this article was published on 01 October 2007

This article has been updated


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)1. Altered glutamate neurotransmission has for decades been linked to schizophrenia, but all commonly prescribed antipsychotics act on dopamine receptors2. LY404039 is a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors3 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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Figure 1: Blockade of phencyclidine-induced hyperlocomotion by LY404039, but not by olanzapine, is dependent on expression of Grm2 and Grm3 in mice.
Figure 2: Weekly change in efficacy measures from baseline determined using MMRM analysis.

Change history

  • 17 September 2007

    Nat. Med. 13, 1102-1107 (2007); published online 2 September; corrected after print 17 September 2007. In the version of this article initially published, the affiliation of the name of one person acknowledged was misspelled, and reference 4 should have been: Moghaddam, B. & Adams, B.W. Reversal of phenylcyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281, 1349–1352. These errors have been corrected in the HTML and PDF versions of the article.


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We thank the Lilly Russian Affiliate Team (E. Faustova, N. Jarkova, O. Orlova, O. Larionova, M. Ipatov, M. Putilovsky), the Lilly mGlu2/3 Program Team, R.C. Mohs, X. Peng, P. Cana, S. Marrero, A. Delvaux, J. Ryner, B. Moser, D. Michelson, B. Kinon, A. Stepanov, E. Roberts, I. Pavo, B. Gaydos, D. Manner, F. Wilhite, W.Z. Potter, C.M. Beasley and S.M. Paul.

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Correspondence to Ferenc Martenyi or James A Monn.

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S.T.P., L.Z., F.M., S.L.L., K.A.J., J.A.M., B.G.J., & D.D.S. are/were employees of Eli Lilly and Company at the time of this clinical study. Several of them own Lilly stock.

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Supplementary Tables 1–4, Supplementary Figs. 1–3, Supplementary Methods (PDF 141 kb)

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Patil, S., Zhang, L., Martenyi, F. et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med 13, 1102–1107 (2007).

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