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

Change history

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.

References

  1. Andreasen, N.C. & Carpenter, W.T., Jr. Diagnosis and classification of schizophrenia. Schizophr. Bull. 19, 199–214 (1993).
    Article CAS Google Scholar
  2. Tamminga, C.A. & Lahti, A.C. The new generation of antipsychotic drugs. Int. Clin. Psychopharmacol. 11, 73–76 (1996).
    Article Google Scholar
  3. Rorick-Kehn, L.M. 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).
    Article CAS Google Scholar
  4. Moghaddam, B. & Adams, B.W. Reversal of phenylcyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281, 1349–1352.
  5. Schoepp, D.D. Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system. J. Pharmacol. Exp. Ther. 299, 12–20 (2001).
    CAS PubMed Google Scholar
  6. Large, C.H., Webster, E.L. & Goff, D.C. The potential role of lamotrigine in schizophrenia. Psychopharmacology (Berl.) 181, 415–436 (2005).
    Article CAS Google Scholar
  7. Kremer, I. et al. Placebo-controlled trial of lamotrigine added to conventional and atypical antipsychotics in schizophrenia. Biol. Psychiatry 56, 441–446 (2004).
    Article CAS Google Scholar
  8. Tuominen, H.J., Tiihonen, J. & Wahlbeck, K. Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis. Schizophr. Res. 72, 225–234 (2005).
    Article Google Scholar
  9. Goff, D.C. 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).
    Article CAS Google Scholar
  10. Heresco-Levy, U. et al. D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biol. Psychiatry 57, 577–585 (2005).
    Article CAS Google Scholar
  11. Schoepp, D.D. & Marek, G.J. Preclinical pharmacology of mGlu2/3 receptor agonists: novel agents for schizophrenia? Current Drug Targets. CNS & Neurological Disorders. 1, 215–225 (2002).
    Article CAS Google Scholar
  12. Swanson, C.J. & Schoepp, D.D. 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).
    Article CAS Google Scholar
  13. Aghajanian, G.K. & Marek, G.J. Serotonin model of schizophrenia: emerging role of glutamate mechanisms. Brain Research. Brain Res. Brain Res. Rev. 31, 302–312 (2000).
    Article CAS Google Scholar
  14. Meltzer, H.Y. Neuropsychopharmacology: The Fifth Generation of Progress (eds. Davis, K.L., Charney, D., Coyle, J.T. & Nemeroff, C.) 819–831 (Lippincott Williams & Wilkins, 2002).
    Google Scholar
  15. Marek, G.J., Wright, R.A., Schoepp, D.D., Monn, J.A. & Aghajanian, G.K. Physiological antagonism between 5-hydroxytryptamine(2A) and group II metabotropic glutamate receptors in prefrontal cortex. J. Pharmacol. Exp. Ther. 292, 76–87 (2000).
    CAS PubMed Google Scholar
  16. Aghajanian, G.K. & Marek, G.J. Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells. Neuropharmacology 36, 589–599 (1997).
    Article CAS Google Scholar
  17. Marek, G.J., Wright, R.A., Gewirtz, J.C. & Schoepp, D.D. A major role for thalamocortical afferents in serotonergic hallucinogen receptor function in the rat neocortex. Neuroscience 105, 379–392 (2001).
    Article CAS Google Scholar
  18. Gewirtz, J.C. & Marek, G.J. Behavioral evidence for interactions between a hallucinogenic drug and group II metabotropic glutamate receptors. Neuropsychopharmacology 23, 569–576 (2000).
    Article CAS Google Scholar
  19. Zhai, Y. 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).
    Article CAS Google Scholar
  20. Ellenbroek, B.A. Treatment of schizophrenia: a clinical and preclinical evaluation of neuroleptic drugs. Pharmacol. Ther. 57, 1–78 (1993).
    Article CAS Google Scholar
  21. Svensson, L., Zhang, J., Johannessen, K. & Engel, J.A. Effect of local infusion of glutamate analogues into the nucleus accumbens of rats: an electrochemical and behavioural study. Brain Res. 643, 155–161 (1994).
    Article CAS Google Scholar
  22. Xi, Z.X. et al. Modulation of group II metabotropic glutamate receptor signaling by chronic cocaine. J. Pharmacol. Exp. Ther. 303, 608–615 (2002).
    Article CAS Google Scholar
  23. Hu, G., Duffy, P., Swanson, C., Ghasemzadeh, M.B. & Kalivas, P.W. The regulation of dopamine transmission by metabotropic glutamate receptors. J. Pharmacol. Exp. Ther. 289, 412–416 (1999).
    CAS PubMed Google Scholar
  24. Cartmell, J., Monn, J.A. & Schoepp, D.D. 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).
    CAS PubMed Google Scholar
  25. Flor, P.J., Battaglia, G., Nicoletti, F., Gasparini, F. & Bruno, V. Neuroprotective activity of metabotropic glutamate receptor ligands. Adv. Exp. Med. Biol. 513, 197–223 (2002).
    Article CAS Google Scholar
  26. Fleischhacker, W.W., Meise, U., Gunther, V. & Kurz, M. Compliance with antipsychotic drug treatment: influence of side effects. Acta Psychiatr. Scand. Suppl. 382, 11–15 (1994).
    CAS PubMed Google Scholar
  27. Crawford, A.M., Beasley, C.M., Jr. & Tollefson, G.D. The acute and long-term effect of olanzapine compared with placebo and haloperidol on serum prolactin concentrations. Schizophr. Res. 26, 41–54 (1997).
    Article CAS Google Scholar
  28. Johnson, M.P. & Chamberlain, M. Modulation of stress-induced and stimulated hyperprolactinemia with the group II metabotropic glutamate receptor selective agonist, LY379268. Neuropharmacology 43, 799–808 (2002).
    Article CAS Google Scholar
  29. Kay, S.R., Opler, L.A. & Fiszbein, A. Positive and negative syndrome scale (PANSS) manual. (Multi-Health Systems, North Tonawanda, New York, USA, 1986).
    Google Scholar
  30. Guy, W. ECDEU assessment manual for psychopharmacology, revised version. (US Department of Health, Education and Welfare, Bethesda, Maryland, USA, 1976).
    Google Scholar

Download references

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

Authors

  1. Sandeep T Patil
    You can also search for this author inPubMed Google Scholar
  2. Lu Zhang
    You can also search for this author inPubMed Google Scholar
  3. Ferenc Martenyi
    You can also search for this author inPubMed Google Scholar
  4. Stephen L Lowe
    You can also search for this author inPubMed Google Scholar
  5. Kimberley A Jackson
    You can also search for this author inPubMed Google Scholar
  6. Boris V Andreev
    You can also search for this author inPubMed Google Scholar
  7. Alla S Avedisova
    You can also search for this author inPubMed Google Scholar
  8. Leonid M Bardenstein
    You can also search for this author inPubMed Google Scholar
  9. Issak Y Gurovich
    You can also search for this author inPubMed Google Scholar
  10. Margarita A Morozova
    You can also search for this author inPubMed Google Scholar
  11. Sergey N Mosolov
    You can also search for this author inPubMed Google Scholar
  12. Nikolai G Neznanov
    You can also search for this author inPubMed Google Scholar
  13. Alexander M Reznik
    You can also search for this author inPubMed Google Scholar
  14. Anatoly B Smulevich
    You can also search for this author inPubMed Google Scholar
  15. Vladimir A Tochilov
    You can also search for this author inPubMed Google Scholar
  16. Bryan G Johnson
    You can also search for this author inPubMed Google Scholar
  17. James A Monn
    You can also search for this author inPubMed Google Scholar
  18. Darryle D Schoepp
    You can also search for this author inPubMed Google Scholar

Corresponding authors

Correspondence toFerenc Martenyi or James A Monn.

Ethics declarations

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.

Supplementary information

Rights and permissions

About this article

Cite this article

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

Download citation