• 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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  • 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.


  1. 1.

    & Diagnosis and classification of schizophrenia. Schizophr. Bull. 19, 199–214 (1993).

  2. 2.

    & The new generation of antipsychotic drugs. Int. Clin. Psychopharmacol. 11, 73–76 (1996).

  3. 3.

    et al. Pharmacological and pharmacokinetic properties of a structurally-novel, potent, selective mGlu2/3 receptor agonist: in vitro characterization of LY404039. J. Pharmacol. Exp. Ther. 321, 308–317 (2007).

  4. 4.

    & Reversal of phenylcyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281, 1349–1352.

  5. 5.

    Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J. Pharmacol. Exp. Ther. 299, 12–20 (2001).

  6. 6.

    , & The potential role of lamotrigine in schizophrenia. Psychopharmacology (Berl.) 181, 415–436 (2005).

  7. 7.

    et al. Placebo-controlled trial of lamotrigine added to conventional and atypical antipsychotics in schizophrenia. Biol. Psychiatry 56, 441–446 (2004).

  8. 8.

    , & Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis. Schizophr. Res. 72, 225–234 (2005).

  9. 9.

    et al. A six-month, placebo-controlled trial of D-cycloserine co-administered with conventional antipsychotics in schizophrenia patients. Psychopharmacology (Berl.) 179, 144–150 (2005).

  10. 10.

    et al. D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biol. Psychiatry 57, 577–585 (2005).

  11. 11.

    & Preclinical pharmacology of mGlu2/3 receptor agonists: novel agents for schizophrenia? Current Drug Targets. CNS & Neurological Disorders. 1, 215–225 (2002).

  12. 12.

    & The group II metabotropic glutamate agonist LY379268 and clozapine reverse phencyclidine-induced behaviors in monoamine-depleted rats. J. Pharmacol. Exp. Ther. 303, 919–927 (2002).

  13. 13.

    & Serotonin model of schizophrenia: emerging role of glutamate mechanisms. Brain Research. Brain Res. Brain Res. Rev. 31, 302–312 (2000).

  14. 14.

    Neuropsychopharmacology: The Fifth Generation of Progress (eds. Davis, K.L., Charney, D., Coyle, J.T. & Nemeroff, C.) 819–831 (Lippincott Williams & Wilkins, 2002).

  15. 15.

    , , , & Physiological antagonism between 5-hydroxytryptamine(2A) and group II metabotropic glutamate receptors in prefrontal cortex. J. Pharmacol. Exp. Ther. 292, 76–87 (2000).

  16. 16.

    & Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells. Neuropharmacology 36, 589–599 (1997).

  17. 17.

    , , & A major role for thalamocortical afferents in serotonergic hallucinogen receptor function in the rat neocortex. Neuroscience 105, 379–392 (2001).

  18. 18.

    & Behavioral evidence for interactions between a hallucinogenic drug and group II metabotropic glutamate receptors. Neuropsychopharmacology 23, 569–576 (2000).

  19. 19.

    et al. Group II metabotropic glutamate receptor modulation of DOI-induced c-fos mRNA and excitatory responses in the cerebral cortex. Neuropsychopharmacology 28, 45–52 (2003).

  20. 20.

    Treatment of schizophrenia: a clinical and preclinical evaluation of neuroleptic drugs. Pharmacol. Ther. 57, 1–78 (1993).

  21. 21.

    , , & Effect of local infusion of glutamate analogues into the nucleus accumbens of rats: an electrochemical and behavioural study. Brain Res. 643, 155–161 (1994).

  22. 22.

    et al. Modulation of group II metabotropic glutamate receptor signaling by chronic cocaine. J. Pharmacol. Exp. Ther. 303, 608–615 (2002).

  23. 23.

    , , , & The regulation of dopamine transmission by metabotropic glutamate receptors. J. Pharmacol. Exp. Ther. 289, 412–416 (1999).

  24. 24.

    , & The metabotropic glutamate 2/3 receptor agonists LY354740 and LY379268 selectively attenuate phencyclidine versus D-amphetamine motor behaviors in rats. J. Pharmacol. Exp. Ther. 291, 161–170 (1999).

  25. 25.

    , , , & Neuroprotective activity of metabotropic glutamate receptor ligands. Adv. Exp. Med. Biol. 513, 197–223 (2002).

  26. 26.

    , , & Compliance with antipsychotic drug treatment: influence of side effects. Acta Psychiatr. Scand. Suppl. 382, 11–15 (1994).

  27. 27.

    , & The acute and long-term effect of olanzapine compared with placebo and haloperidol on serum prolactin concentrations. Schizophr. Res. 26, 41–54 (1997).

  28. 28.

    & Modulation of stress-induced and stimulated hyperprolactinemia with the group II metabotropic glutamate receptor selective agonist, LY379268. Neuropharmacology 43, 799–808 (2002).

  29. 29.

    , & Positive and negative syndrome scale (PANSS) manual. (Multi-Health Systems, North Tonawanda, New York, USA, 1986).

  30. 30.

    ECDEU assessment manual for psychopharmacology, revised version. (US Department of Health, Education and Welfare, Bethesda, Maryland, USA, 1976).

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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.

Author information

Author notes

    • Sandeep T Patil
    •  & Darryle D Schoepp

    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.).


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

    • Sandeep T Patil
    • , Lu Zhang
    • , Bryan G Johnson
    • , James A Monn
    •  & Darryle D Schoepp
  2. Lilly Medical Center, Kolblgasse 8-10, A-1030 Vienna, 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, Surrey GU20 6PH, 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, Moscow region 142601, Russia.

    • Alexander M Reznik
  12. Mechnikov State Medical Academy, Naberezhnaya reki Mojki, 126, St. Petersburg 190121, Russia.

    • Vladimir A Tochilov


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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.

Corresponding authors

Correspondence to Ferenc Martenyi or James A Monn.

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    Supplementary Tables 1–4, Supplementary Figs. 1–3, Supplementary Methods

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