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

Nature Medicine volume 13, pages 1102–1107 (2007)Cite this article

A Corrigendum to this article was published on 01 October 2007

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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)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.

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  • 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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Acknowledgements

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.

Author information

Author notes

  1. Sandeep T Patil & Darryle D Schoepp

    Present address: Present addresses: Takeda Global Research and Development Center, Inc., One Takeda Parkway, Deerfield, Illinois 60015, USA (S.T.P.); Merck and Company, Inc., 351 Sumneytown Pike, UG/4CDS013, North Wales, Pennsylvania 19454, USA (D.D.S.).,

Authors and Affiliations

  1. Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, 46285, Indiana, USA

    Sandeep T Patil, Lu Zhang, Bryan G Johnson, James A Monn & Darryle D Schoepp

  2. Lilly Medical Center, Kolblgasse 8-10, Vienna, A-1030, Austria

    Ferenc Martenyi

  3. Lilly-National University of Singapore Centre for Clinical Pharmacology, Level 6 Clinical Research Centre (MD11), 10 Medical Drive, 117597, Singapore

    Stephen L Lowe

  4. Lilly-Erl Wood Manor, Windlesham, GU20 6PH, Surrey, UK

    Kimberley A Jackson

  5. St. Petersburg State University, St. Petersburg and Gatchinskiy Regional Psychiatric Hospital, Nikolskoe, 188357, Russia

    Boris V Andreev

  6. Serbsky State Scientific Center of Social and Forensic Psychiatry, 23, Kropotkinskiy per, Moscow, 123367, Russia

    Alla S Avedisova

  7. Moscow State University of Medicine and Dentistry based at Moscow Psychiatry Hospital no. 15, Moscvorechie ul. 7, Moscow, 115522, Russia

    Leonid M Bardenstein

  8. Moscow Research Institute of Psychiatry, Poteshnaya ul. 3, Moscow, 107076, Russia

    Issak Y Gurovich & Sergey N Mosolov

  9. State Institution “Mental Health Scientific Research Center of the Russian Academy of Medical Sciences”, Kashyrskoye sh. 34, Moscow, 115522, Russia

    Margarita A Morozova & Anatoly B Smulevich

  10. Bekhterev Research Psychoneurological Institute, Bekhtereva ul. 3, St. Petersburg, 192019, Russia

    Nikolai G Neznanov

  11. Moscow Regional Psychiatry Hospital #5, Abramtsevskoye sh. 1a, Khotkovo, 142601, Moscow region, Russia

    Alexander M Reznik

  12. Mechnikov State Medical Academy, Naberezhnaya reki Mojki, 126, St. Petersburg, 190121, Russia

    Vladimir A Tochilov

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  1. Sandeep T Patil
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Correspondence to Ferenc Martenyi or James A Monn.

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Competing interests

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). https://doi.org/10.1038/nm1632

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