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Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders

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European Archives of Psychiatry and Clinical Neuroscience Aims and scope Submit manuscript

Abstract

Severe psychiatric disorders such as schizophrenia are related to cognitive and negative symptoms, which often are resistant to current treatment approaches. The glutamatergic system has been implicated in the pathophysiology of schizophrenia and affective disorders. A key component is the dysfunction of the glutamatergic N-methyl-d-aspartate (NMDA) receptor. Substances regulating activation/inhibition of the NMDA receptor have been investigated in schizophrenia and major depression and are promising in therapeutic approaches of negative symptoms, cognition, and mood. In schizophrenia, add-on treatments with glycine, d-serine, d-alanine, d-cycloserine, d-amino acid oxidase inhibitors, glycine transporter-1 (GlyT-1) inhibitors (e.g., sarcosine, bitopertin) and agonists (e.g., LY2140023) or positive allosteric modulator (e.g., ADX71149) of group II metabotropic glutamate receptors (mGluRs) have been studied. In major depression, the NMDA receptor antagonists (e.g., ketamine, AZD6765), GluN2B subtype antagonists (e.g., traxoprodil, MK-0657), and partial agonists (e.g., d-cycloserine, GLYX-13) at the glycine site of the NMDA receptor have been proven to be effective in animal studies and first clinical trials. In addition, clinical studies of mGluR2/3 antagonist BCI-838 (a prodrug of BCI-632 (MGS0039)), mGluR2/3-negative allosteric modulators (NMAs) (e.g., RO499819, RO4432717), and mGluR5 NAMs (e.g., AZD2066, RO4917523) are in progress. Future investigations should include effects on brain structure and activation to elucidate neural mechanisms underlying efficacy of these drugs.

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References

  1. Kim JS, Kornhuber HH, Holzmüller B, Schmid-Burgk W, Mergner T, Krzepinski G (1980) Reduction of cerebrospinal fluid glutamic acid in Huntigton’s chorea and in schizophrenic patients. Arch Psychiatry Nervenkr 228(1):7–10

    Article  CAS  Google Scholar 

  2. Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148(10):1301–1308

    PubMed  CAS  Google Scholar 

  3. Olney JW, Farber NB (1995) Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 52(12):998–1007

    Article  PubMed  CAS  Google Scholar 

  4. Coyle JT (1996) The glutamatergic dysfunction hypothesis for schizophrenia. Harv Rev Psychiatry 3(5):241–253

    Article  PubMed  CAS  Google Scholar 

  5. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51(3):199–214

    Article  PubMed  CAS  Google Scholar 

  6. Jentsch JD, Roth RH (1999) The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 20(3):201–225

    Article  PubMed  CAS  Google Scholar 

  7. Krystal JH, D’Souza DC, Petrakis IL, Belger A, Berman RM, Charney DS, Abi-Saab W, Madonick S (1999) NMDA agonists and antagonists as probes of glutamatergic dysfunction and pharmacotherapies in neuropsychiatric disorders. Harv Rev Psychiatry 7(3):125–143

    PubMed  CAS  Google Scholar 

  8. Lieberman JA, Kane JM, Alvir J (1987) Provocative tests with psychostimulant drugs in schizophrenia. Psychopharmacology 91(4):415–433

    Article  PubMed  CAS  Google Scholar 

  9. Preskorn SH, Baker B, Kolluri S, Menniti FS, Krams M, Landen JW (2008) An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J Clin Psychopharmacol 28(6):631–637

    Article  PubMed  CAS  Google Scholar 

  10. Moghaddam B, Javitt D (2012) From revolution to evolution: the gluatamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 37(1):4–15

    Article  PubMed  CAS  Google Scholar 

  11. Harrison PJ, Weinberger DR (2005) Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 10(1):40–68

    Article  PubMed  CAS  Google Scholar 

  12. Falkai P, Schmitt A, Cannon TD (2011) Pathophysiology of schizophrenia. In: Gaebel W (ed) Schizophrenia: current science and clinical practice. Wiley-Blackwell, Oxford, pp 31–65

    Chapter  Google Scholar 

  13. Gielen M, Retchless BS, Mony L, Johnson JW, Paoletti P (2009) Mechanism of differential control of NMDA receptor activity by NR2 subunits. Nature 459(7247):703–707

    Article  PubMed  CAS  Google Scholar 

  14. Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R (2010) Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev 62(3):405–496

    Article  PubMed  CAS  Google Scholar 

  15. Paoletti P, Neyton J (2007) NMDA receptor subunits: function and pharmacology. Curr Opin Pharmacol 7(1):39–47

    Article  PubMed  CAS  Google Scholar 

  16. Chatterton JE, Awobuluyi M, Premkumar LS, Takahashi H, Talantova M, Shin Y, Cui J, Tu S, Sevarino KA, Nakanishi N, Tong G, Lipton SA, Zhang D (2002) Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature 413(6783):793–798

    Article  CAS  Google Scholar 

  17. Millan MJ (2005) N-Methyl-D-aspartate receptors as a target for improved antipsychotic agents: nove, insights and clinical perspectives. Psychopharmacology 179(1):30–53

    Article  PubMed  CAS  Google Scholar 

  18. Moghaddam B, Adams B, Verma A, Daly D (1997) Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 17(8):2921–2927

    PubMed  CAS  Google Scholar 

  19. Niswender CM, Conn PJ (2010) Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol 50:295–322

    Article  PubMed  CAS  Google Scholar 

  20. Vinson PN, Conn PJ (2012) Metabotropic glutamate receptors as therapeutic targets for schizophrenia. Neuropharmacology 62(3):1461–1472

    Article  PubMed  CAS  Google Scholar 

  21. Krystal JH, Abi-Saab W, Perry E, D’Souza DC, Liu N, Gueorguieva R, McDougall L, Hunsberger T, Belger A, Levine L, Breier A (2005) Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects. Psychopharmacology 179(1):303–309

    Article  PubMed  CAS  Google Scholar 

  22. Coyle JT, Tsai G (2004) The NMDA receptor glycine modulatory site: a therapeutic target for improving cognition and reducing negative symptoms in schizophrenia. Psychopharmacol 174(1):32–38

    CAS  Google Scholar 

  23. Hashimoto K, Okamura N, Shimizu E, Iyo M (2004) Glutamate hypothesis of schizophrenia and approach for possible therapeutic drugs. Curr Med Chem CNS Agents 4(2):147–154

    CAS  Google Scholar 

  24. Hashimoto K, Shimizu E, Iyo M (2005) Dysfunction of glia-neuron communication in pathophysiology of schizophrenia. Curr Psychiatry Rev 1(2):151–163

    Article  CAS  Google Scholar 

  25. Hashimoto K (2006) The NMDA receptor hypofunction hypothesis for schizophrenia and glycine modulatory sites on the NMDA receptors as potential therapeutic drugs. Clin Psychopharmacol Neurosci 4(1):3–10

    CAS  Google Scholar 

  26. Javitt DC, Schoepp D, Kalivas PW, Volkow ND, Zarate C, Merchant K, Bear MF, Umbricht D, Hajos M, Potter WZ, Lee CM (2011) Translating glutamate: from pathophysiology to treatment. Sci Transl Med 3(102):102mr2

    Google Scholar 

  27. Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Thibaut F, Möller HJ, World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Treatment Guidelines for Schizophrenia (2012) World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry 13(5):318–378

    Article  PubMed  Google Scholar 

  28. Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Thibaut F, Möller HJ, WFSBP Task force on Treatment Guidelines for Schizophrenia (2013) World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for biological treatment of schizophrenia, part 2: update 2012 on the long-term treatment of schizophrenia and management of antipsychotic-induced side effects. World J Biol Psychiatry 14(1):2–44

    Article  PubMed  Google Scholar 

  29. Gao SF, Bao AM (2011) Corticotropin-releasing hormone, glutamate, and gamma-aminobutyric acid in depression. Neuroscientist 17(1):124–144

    Article  PubMed  CAS  Google Scholar 

  30. Ongur D, Jensen JE, Prescot AP, Stork C, Lundy M, Cohen BM, Renshaw PF (2008) Abnormal glutamatergic neurotransmission and neuronal-glial interactions in acute mania. Biol Psychiatry 64(8):718–726

    Article  PubMed  CAS  Google Scholar 

  31. Maeng S, Zarate CA Jr (2007) The role of glutamate in mood disorders: results from the ketamine in major depression study and the presumed cellular mechanism underlying its antidepressant effects. Current Psychiatry Rep 9(6):467–474

    Article  Google Scholar 

  32. Kugaya A, Sanacora G (2005) Beyond monoamines: glutamatergic function in mood disorders. CNS Spectr 10(10):808–819

    PubMed  Google Scholar 

  33. Hashimoto K (2009) Emerging role of glutamate in the pathophysiology of major depressive disorder. Brain Res Rev 61(2):105–123

    Article  PubMed  CAS  Google Scholar 

  34. Skolnick P, Popik P, Trullas R (2009) Glutamate-based antidepressants: 20 years on. Trends Pharmacol Sci 30(11):563–569

    Article  PubMed  CAS  Google Scholar 

  35. Heresco-Levy U, Javitt DC (2004) Comparative effects of glycine and D-cycloserine on persistent negative symptoms in schizophrenia: a retrospective analysis. Schizophr Res 66(2–3):89–96

    Article  PubMed  Google Scholar 

  36. Tsai GE, Lin PY (2010) Strategies to enhance N-methyl-D-aspartate receptor-mediated neurotransmission in schizophrenia. A critical review and meta-analysis. Curr Pham Des 16(5):522–537

    Article  CAS  Google Scholar 

  37. Tuominen HJ, Tiihonen J, Wahlbeck K (2005) Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis. Schizophr Res 72(2–3):225–234

    Article  PubMed  Google Scholar 

  38. Horio M, Mori H, Hashimoto K (in press) Is D-cycloserine a prodrug for d-serine in the brain?. Biol Psychiatry doi:10.1016/j.biopsych.2012.07.013

  39. Wolosker H (2011) Serine racemase and the serine shuttle between neurons and astrocytes. Biochem Biophys Acta 1814(11):1558–15566

    Article  PubMed  CAS  Google Scholar 

  40. Inoue R, Hashimoto K, Harai T, Mori H (2008) NMDA- and β-amyloid1-42-induced neurotoxicity is attenuated in serine racemase knock-out mice. J Neurosci 28(53):14486–144891

    Article  PubMed  CAS  Google Scholar 

  41. Horio M, Kohno M, Fujita Y, Ishima T, Inoue R, Mori H, Hashimoto K (2011) Levels of d-serine in the brain and peripheral organs of serine racemase (Srr) knock-out mice. Neurochem Int 59(6):853–859

    Article  PubMed  CAS  Google Scholar 

  42. Horio M, Kohno M, Fujita Y, Ishima T, Inoue R, Mori H, Hashimoto K (2012) Role of serine racemase in behavioral sensitization in mice after repeated administration of methamphetamine. PLoS ONE 7(4):e35494

    Article  PubMed  CAS  Google Scholar 

  43. Hashimoto K, Fukushima T, Shimizu E, Komatsu N, Watanabe H, Shinoda N, Nakazato M, Kumakiri C, Okada S, Hasegawa H, Imai K, Iyo M (2003) Decreased serum levels of d-serine in patients with schizophrenia: evidence in support of the NMDA receptor hypofunction hypothesis of schizophrenia. Arch Gen Psychiatry 60(6):572–576

    Article  PubMed  CAS  Google Scholar 

  44. Hashimoto K, Engberg G, Shimizu E, Nordin C, Lindström LH, Iyo M (2005) Reduced d-serine to total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 29(5):767–769

    Article  PubMed  CAS  Google Scholar 

  45. Yamada K, Ohnishi T, Hashimoto K, Ohba H, Iwayama-Shigeno Y, Toyoshima M, Okuno A, Takao H, Toyota T, Minabe Y, Nakamura K, Shimizu E, Itokawa M, Mori N, Iyo M, Yoshikawa T (2005) Identification of multiple serine racemase (SRR) mRNA isoforms and genetic analyses of SRR and DAO in schizophrenia and d-serine levels. Biol Psychiatry 57(12):1493–1503

    Article  PubMed  CAS  Google Scholar 

  46. Bendikov I, Nadri C, Amar S, Panizzutti R, De Miranda J, Wolosker H, Agam G (2007) A CSF and postmortem brain study of d-serine metabolic parameters in schizophrenia. Schizophr Res 90(1–3):41–51

    Article  PubMed  Google Scholar 

  47. Calcia MA, Madeira C, Alheira FV, Silva TC, Tannos FM, Vargas-Lopes C, Goldenstein N, Brasil MA, Ferreira ST, Panizzutti R (2012) Plasma levels of d-serine in Brazilian individuals with schizophrenia. Schizophr Res 142(1–3):83–87

    Article  PubMed  Google Scholar 

  48. Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H, Bougueleret L, Barry C, Tanaka H, La Rosa P, Puech A, Tahri N, Cohen-Akenine A, Delabrosse S, Lissarrague S, Picard FP, Maurice K, Essioux L, Millasseau P, Grel P, Debailleul V, Simon AM, Caterina D, Dufaure I, Malekzadeh K, Belova M, Luan JJ, Bouillot M, Sambucy JL, Primas G, Saumier M, Boubkiri N, Martin-Saumier S, Nasroune M, Peixoto H, Delaye A, Pinchot V, Bastucci M, Guillou S, Chevillon M, Sainz-Fuertes R, Meguenni S, Aurich-Costa J, Cherif D, Gimalac A, Van Duijn C, Gauvreau D, Ouellette G, Fortier I, Raelson J, Sherbatich T, Riazanskaia N, Rogaev E, Raeymaekers P, Aerssens J, Konings F, Luyten W, Macciardi F, Sham PC, Straub RE, Weinberger DR, Cohen N, Cohen D (2002) Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc Natl Acad Sci USA 99(21):13675–13680

    Article  PubMed  CAS  Google Scholar 

  49. Shinkai T, De Luca V, Hwang R, Müller DJ, Lanktree M, Zai G, Shaikh S, Wong G, Sicard T, Potapova N, Trakalo J, King N, Matsumoto C, Hori H, Wong AH, Ohmori O, Macciardi F, Nakamura J, Kennedy JL (2007) Association analyses of the DAOA/G30 and D-amino-acid oxidase genes in schizophrenia: further evidence for a role in schizophrenia. Neuromolecular Med 9(2):169–177

    Article  PubMed  CAS  Google Scholar 

  50. Verrall L, Burnet PW, Betts JF, Harrison PJ (2010) The neurobiology of D-amino acid oxidase and its involvement in schizophrenia. Mol Psychiatry 15(2):122–137

    Article  PubMed  CAS  Google Scholar 

  51. Tsai G, Yang P, Chung LC, Lange N, Coyle JT (1998) d-serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 44(11):1081–1089

    Article  PubMed  CAS  Google Scholar 

  52. Heresco-Levy U, Javitt DC, Ebstein R, Vass A, Lichtenberg P, Bar G, Catinari S, Ermilov M (2005) d-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biol Psychiatry 57(6):577–585

    Article  PubMed  CAS  Google Scholar 

  53. Lane HY, Chang YC, Liu YC, Chiu CC, Tsai GE (2005) Sarcosine or d-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study. Arch Gen Psychiatry 62(11):1196–1204

    Article  PubMed  CAS  Google Scholar 

  54. Kantrowitz JT, Malhotra AK, Cornblatt B, Silipo G, Balla A, Suckow RF, D’Souza C, Saksa J, Woods SW, Javitt DC (2010) High dose d-serine in the treatment of schizophrenia. Schizophr Res 121(1–3):125–130

    Article  PubMed  Google Scholar 

  55. Tsai GE, Yang P, Chang YC, Chong MY (2006) d-alanine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 59(3):230–234

    Article  PubMed  CAS  Google Scholar 

  56. Javitt DC, Zukin SR, Heresco-levy U, Umbricht D (2012) Has an angel shown the way? Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia. Schizophr Bull 38(5):958–966

    Article  PubMed  Google Scholar 

  57. Ferraris D, Duvall B, Ko YS, Thomas AG, Rojas C, Majer P, Hashimoto K, Tsukamoto T (2008) Synthesis and biological evaluation of D-amino acid oxidase inhibitors. J Med Chem 51(12):3357–3359

    Article  PubMed  CAS  Google Scholar 

  58. Hashimoto K, Fujita Y, Horio M, Kunitachi S, Iyo M, Ferraris D, Tsukamoto T (2009) Co-administration of D-amino acid oxidase inhibitor potentiates the efficacy of d-serine on prepulse inhibition deficits after administration of dizocilpine. Biol Psychiatry 65(12):1103–1106

    Article  PubMed  CAS  Google Scholar 

  59. Horio M, Fujita Y, Ishima T, Iyo M, Ferraris D, Tsukamoto T, Hashimoto K (2009) Effects of D-amino acid oxidase inhibitor on the extracellular d-alanine levels and the efficacy of d-alanine on dizocilpine-induced prepulse inhibition deficits in mice. Open Clin Chem J 2(1):16–21

    Article  CAS  Google Scholar 

  60. Ferraris DV, Tsukamoto T (2011) Recent advances in the discovery of D-amino acid oxidase inhibitors and their therapeutic utility in schizophrenia. Curr Pham Des 17(2):103–111

    Article  CAS  Google Scholar 

  61. Hashimoto K (2007) Glycine transporter-1 inhibitors as novel therapeutic drugs for schizophrenia. Cent Nerv Syst Agents Med Chem 7(3):177–182

    Article  CAS  Google Scholar 

  62. Hashimoto K (2011) Glycine transportor-1: a potential therapeutic target for schizophrenia. Curr Pharm Des 17(2):112–120

    Article  PubMed  CAS  Google Scholar 

  63. Sur C, Kinney GG (2004) Therapeutic potential of glycine transporter-1 inhibitors. Expert Opin Investig Drugs 13(5):515–521

    Article  PubMed  CAS  Google Scholar 

  64. Javitt DC (2012) Glycine transport inhibitors in the treatment of schizophrenia. Handb Exp Pharmacol 213:367–399

    Article  PubMed  CAS  Google Scholar 

  65. Tsai G, Lane HY, Yang P, Chong MY, Lange N (2004) Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 55(5):452–456

    Article  PubMed  CAS  Google Scholar 

  66. Lane HY, Huang CL, Wu PL, Liu YC, Chang YC, Lin PY, Chen PW, Tsai G (2006) Glycine transporter 1 inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia. Biol Psychiatry 60(6):645–649

    Article  PubMed  CAS  Google Scholar 

  67. Lane HY, Liu YC, Huang CL, Chang YC, Liau CH, Perng CH, Tsai G (2008) Sarcosine (N-methylglycine) treatment for acute schizophrenia: a randomized, double-blind study. Biol Psychiatry 63(1):9–12

    Article  PubMed  CAS  Google Scholar 

  68. Lane HY, Lin CH, Huang YJ, Liao CH, Chang YC, Tsai GE (2010) A randomized, double-blind, placebo-controlled comparison study of sarcosine (N-methylglycine) and d-serine add-on treatment for schizophrenia. Int J Neuropsychopharmacol 13(4):451–460

    Article  PubMed  CAS  Google Scholar 

  69. Pinard E, Alanine A, Alberati D, Bender M, Borroni E, Bourdeaux P, Brom V, Burner S, Fischer H, Hainzl D, Halm R, Hauser N, Jolidon S, Lengyel J, Marty HP, Meyer T, Moreau JL, Mory R, Narquizian R, Nettekoven M, Norcross RD, Puellmann B, Schmid P, Schmitt S, Stalder H, Wermuth R, Wettstein JG, Zimmerli D (2010) Selective GlyT1 inhibitors: discovery of [4-(3-fluoro-5-trifluoromethylpyridin-2- yl)piperazin-1-yl][5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methylethoxy)phenyl]methanone (RG1678), a promising novel medicine to treat schizophrenia. J Med Chem 53(12):4603–4614

    Article  PubMed  CAS  Google Scholar 

  70. Alberati D, Moreau JL, Lengyel J, Hauser N, Mory R, Borroni E, Pinard E, Knoflach F, Schlotterbeck G, Hainzl D, Wettstein JG (2012) Glycine reuptake inhibitor RG1678: a pharmacologic characterization of an investigational agent for the treatment of schizophrenia. Neuropharmacology 62(2):1152–1161

    Article  PubMed  CAS  Google Scholar 

  71. Pizzagalli F, Martin-Faklam M, Hofmann C, Boetsch C, Ereshefsy L, Patat A, Boutouyrie-Dumont B, Wettstein JG, Alberati D (2012) Central glycine increase in rats, monkeys and healthy volunteers after two glycine reuptake inhibitors, bitopertin and RG7117. Abstract of 3rd Schizophrenia International Research Society Conference, Florence, April 14–18

  72. Martin-Faklam M, Patat A, Hofmann C, Boetsch C, Banken L, Biedinger U, Boutouyrie-Dumont B (2012) Safety, tolerability and pharmacokinetics of RG1678, a novel glycine reuptake inhibitor, after multiple doses in healthy volunteers. Abstract of 3rd Schizophrenia International Research Society Conference, Florence, April 14–18

  73. Hofmann C, Banken L, Hahn M, Swearingen D, Nagel S, Martin-Facklam M (2012) Evaluation of the effects of bitopertin (RG1678) on cardiac repolarization: a thorough corrected QT study in healthy male volunteers. Clin Ther 34(10):2061–2071

    Article  PubMed  CAS  Google Scholar 

  74. Roche Global Web Site [Homepage on the Internet]. Phase II study with first-in-class investigational drug demonstrates improvement in negative symptoms in patients with schizophrenia. [Basel, December 6, 2010]. http://www.roche.com/investors/ir_update/inv-update-2010-12-06b.htm

  75. Chaki S, Hikichi H (2011) Targeting of metabotropic glutamate receptors for the treatment of schizophrenia. Curr Pharm Des 17(2):94–102

    Article  PubMed  CAS  Google Scholar 

  76. Lin CH, Lane HY, Tsai GE (2012) Glutamate signaling in the pathophysiology and therapy of schizophrenia. Pharmacol Biochem Behav 100(4):665–677

    Article  PubMed  CAS  Google Scholar 

  77. Fell MJ, Svensson KA, Johnson BG, Schoepp DD (2008) Evidence for the role of metabotropic glutamate (mGlu)2 not mGlu3 receptors in the preclinical antipsychotic pharmacology of the mGlu2/3 receptor agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404039). J Pharmacol Exp Ther 326(1):209–217

    Article  PubMed  CAS  Google Scholar 

  78. Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova AS, Bardenstein LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA, Schoepp DD (2007) Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med 13(9):1102–1107

    Article  PubMed  CAS  Google Scholar 

  79. Eli Lilly Web Site [Homepage on the Internet]. Lilly stops phase III development of pomaglumetad methionil for the treatment of schizophrenia based on efficacy results. [Indianapolis, August 29, 2012]. https://investor.lilly.com/releaseDetail.cfm?ReleaseID=703018

  80. Addex Therapeutics Web Site [Homepage on the Internet]. Addex Reports Top-line Data from a Successful Phase 2a Clinical Study with ADX71149 in Schizophrenia Patients [Geneva, Switzerland, November 5, 2012]. http://www.addextherapeutics.com/about/about-addex/

  81. Gastambide F, Cotel MC, Gilmour G, O’Neill MJ, Robbins TW, Tricklebank MD (2012) Selective remediation of reversal learning deficits in the neurodevelopmental MAM model of schizophrenia by a novel mGlu5 positive allosteric modulator. J Pharmacol Exp Ther 37(4):1057–1066

    CAS  Google Scholar 

  82. Horio M, Fujita Y, Hashimoto K (in press) Therapeutic effects of metabotropic glutamate receptor 5 positive allosteric modulator CDPPB on phencyclidine-induced cognitive deficits in mice. Fundam Clin Pharmacol 2012 May 2. doi:10.1111/j.1472-8206.2012.01045.x. [Epub ahead of print]

  83. Hashimoto K, Sawa A, Iyo M (2007) Increased levels of glutamate in brains from patients with mood disorders. Biol Psychiatry 62(11):1310–1316

    Article  PubMed  CAS  Google Scholar 

  84. Sanacora G, Zarate CA, Krystal JH, Manji HK (2008) Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov 7(5):426–437

    Article  PubMed  CAS  Google Scholar 

  85. Hashimoto K (2011) The role of glutamate on the action of antidepressants. Prog Neuropsychopharmacol Biol Psychiatry 35(7):1558–15568

    Article  PubMed  CAS  Google Scholar 

  86. Zarate C Jr, Machado-Vieira R, Henter I, Ibrahim L, Diazgranados N, Salvadore G (2010) Glutamatergic modulators: the future of treating mood disorders? Harv Rev Psychiatry 18(5):293–303

    Article  PubMed  Google Scholar 

  87. Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63(8):856–864

    Article  PubMed  CAS  Google Scholar 

  88. Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, Kammerer WA, Quezado Z, Luckenbaugh DA, Salvadore G, Machado-Vieira R, Manji HK, Zarate CA Jr (2010) A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 67(8):793–802

    Article  PubMed  CAS  Google Scholar 

  89. Zarate CA Jr, Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A, Selter J, Marquardt CA, Liberty V, Luckenbaugh DA (2012) Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry 71(11):939–946

    Article  PubMed  CAS  Google Scholar 

  90. Krystal JH (2010) N-methyl-D-aspartate glutamate antagonists and the promise of rapid-acting antidepressants. Arch Gen Psychiatry 67(11):1110–1111

    Article  PubMed  Google Scholar 

  91. Aan Het Rot M, Zarate CA Jr, Charney DS, Mathew SJ (2012) Ketamine for depression: where do we go from here? Biol Psychiatry 72(7):537–547

    Article  PubMed  CAS  Google Scholar 

  92. Zarate CA Jr, Singh JB, Quiroz JA, De Jesus G, Denicoff KK, Luckenbaugh DA, Manji HK, Charney DS (2006) A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am J Psychiatry 163(1):153–155

    Article  PubMed  Google Scholar 

  93. Boeijinga P, Danjou P, Patroneva A, Smith MA, Quirk M (2012) Low-trapping NMDA channel blocker AZD6765 increases gamma-band EEG without dissociative side effects: comparison with ketamine in healthy volunteers. 29th CINP World Congress of Neuropsychopharmacology P-09-006

  94. Zarate CA Jr, Mathews D, Ibrahim L, Chaves JF, Marquardt C, Ukoh I, Jolkovsky L, Brutsche NE, Smith MA, Luckenbaugh DA (in press) A randomized trial of a low-trapping nonselective N-methyl-D-aspartate channel blocker in major depression. Biol Psychiatry 2012 Nov 30. doi:10.1016/j.biopsych.2012.10.019. [Epub ahead of print]

  95. Maeng S, Zarate CA Jr, Du J, Schloesser RJ, McCammon J, Chen G, Manji HK (2008) Cellular mechanisms underlying the antidepressant effects of ketamine: role of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry 63(4):349–352

    Article  PubMed  CAS  Google Scholar 

  96. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329(5994):959–964

    Article  PubMed  CAS  Google Scholar 

  97. Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, Li XY, Aghajanian G, Duman RS (2011) Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 69(8):754–761

    Article  PubMed  CAS  Google Scholar 

  98. Ibrahim L, Diaz Granados N, Jolkovsky L, Brutsche N, Luckenbaugh DA, Herring WJ, Potter WZ, Zarate CA Jr (2012) A randomized, placebo-controlled, crossover pilot trial of the oral selective NR2B antagonist MK-0657 in patients with treatment-resistant major depressive disorder. J Clin Psychopharmacol 32(4):551–557

    Article  PubMed  CAS  Google Scholar 

  99. Heresco-Levy U, Javitt DC, Gelfin Y, Gorelik E, Bar M, Blanaru M, Kremer I (2006) Controlled trial of D-cycloserine adjuvant therapy for treatment-resistant major depressive disorder. J Affect Disord 93(1–3):239–243

    Article  PubMed  CAS  Google Scholar 

  100. Heresco-Levy U, Gelfin G, Bloch B, Levin R, Edelman S, Javitt DC, Kremer I (in press) A randomized add-on trial of high-dose d-cycloserine for treatment-resistant depression. Int J Neuropsychopharmacol 2012 Sep 17:1–6. [Epub ahead of print]

    Google Scholar 

  101. Moskal JR, Kuo AG, Weiss C, Wood PL, O’Connor Hanson A, Kelso S, Harris RB, Disterhoft JF (2005) GLYX-13: a monoclonal antibody-derived peptide that acts as an N-methyl-D-aspartate receptor modulator. Neuropharmacology 49(7):1077–1087

    Article  PubMed  CAS  Google Scholar 

  102. Moskal JR, Burgdorf J, Kroes RA, Brudzynski SM, Panksepp J (2011) A novel NMDA receptor glycine-site partial agonist, GLYX-13, has therapeutic potential for the treatment of autism. Neurosci Biobehav Rev 35(9):1982–1988

    Article  PubMed  CAS  Google Scholar 

  103. Burgdorf JS, Zhang XL, Nicholson KL, Balster RL, Leander JD, Stanton PK, Gross AL, Kroes RA, Moskal JR (in press) GLYX-13, an NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacology December 3, 2012. doi:10.1038/npp.2012.246

  104. Naurex Web Site [Homepage on the Internet]. Phase II data presented at ACNP 2012 shows novel antidepressant GLYX-13 significantly reduces depression scores within hours. [Hollywood, FL and Evanston, IL, December 6, 2012]. http://www.naurex.com/html/news.html

  105. Chaki S, Ago Y, Palucha-Paniewiera A, Matrisciano F, Pilc A (2013) mGlu2/3 and mGlu5 receptors: potential targets for novel antidepressants. Neuropharmacology 66:40–52

    Article  PubMed  CAS  Google Scholar 

  106. Chaki S, Yoshikawa R, Hirota S, Shimazaki T, Maeda M, Kawashima N, Yoshimizu T, Yasuhara A, Sakagami K, Okuyama S, Nakanishi S, Nakazato A (2004) MGS0039: a potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity. Neuropharmacology 46(4):457–467

    Article  PubMed  CAS  Google Scholar 

  107. Koike H, Iijima M, Chaki S (2011) Involvement of the mammalian target of rapamycin signaling in the antidepressant-like effect of group II metabotropic glutamate receptor antagonists. Neuropharmacology 61(8):1419–1423

    Article  PubMed  CAS  Google Scholar 

  108. Gradient RA, Wedel PC, Frisbie VM, Leuchter AF, Targum SD, Truong CT, Hutchinson JH (2012) Safety, pharmacokinetic and pharmacodynamics profile of BCI-632, a selective metabotropic glutamate 2/3 receptor antagonist, in healthy human subjects. Abstr Neurosci Meeting 42(841):20

    Google Scholar 

  109. Campo B, Kalinichev M, Lambeng N, El Yacoubi M, Royer-Urios I, Schneider M, Legrand C, Parron D, Girard F, Bessif A, Poli S, Vaugeois JM, Le Poul E, Celanire S (2011) Characterization of an mGluR2/3 negative allosteric modulator in rodent models of depression. J Neurogenet 25(4):152–166

    Article  PubMed  CAS  Google Scholar 

  110. Goeldner C, Ballard TM, Knoflach F, Wichmann J, Gatti S, Umbricht D (2013) Cognitive impairment in major depression and the mGlu2 receptor as a therapeutic target. Neuropharmacology 64(1):337–346

    Article  PubMed  CAS  Google Scholar 

  111. Porter RJ, Gallagher P, Thompson JM, Young AH (2003) Neurocognitive impairment in drug-free patients with major depressive disorder. British J Psychiatry 182:214–220

    Article  Google Scholar 

  112. Hindmarch I, Hashimoto K (2010) Cognition and depression: the effects of fluvoxamine, a sigma-1 receptor agonist, reconsidered. Human Psychopharmacol 25(3):193–200

    Article  CAS  Google Scholar 

  113. ClinicalTrails.gov: ARTDeCo Study: A study of RO4995819 in patients with major depressive disorder and inadequate response to ongoing antidepressant treatment. http://www.clinicaltrials.gov/ct2/show/NCT01457677

  114. Tokita K, Yamaji T, Hashimoto K (2012) Roles of glutamate signaling in preclinical and/or mechanistic models of depression. Pharmacol Biochem Behav 100(4):688–704

    Article  PubMed  CAS  Google Scholar 

  115. Li X, Need AB, Baez M, Witkin JM (2006) Metabotropic glutamate 5 receptor antagonism is associated with antidepressant-like effects in mice. J Pharmacol Exp Ther 319(1):254–259

    Article  PubMed  CAS  Google Scholar 

  116. Legutko B, Szewczyk B, Pomierny-Chamioło L, Nowak G, Pilc A (2006) Effect of MPEP treatment on brain-derived neurotrophic factor gene expression. Pharmacol Rep 58(3):427–430

    PubMed  CAS  Google Scholar 

  117. Hashimoto K, Shimizu E, Iyo M (2004) Critical role of brain-derived neurotrophic factor in mood disorders. Brain Res Brain Res Rev 45(2):104–114

    Article  PubMed  CAS  Google Scholar 

  118. Hashimoto K (2010) Brain-derived neurotrophic factor as a biomarker for mood disorders: an historical overview and future directions. Psychiatry Clin Neurosci 64(4):341–357

    Article  PubMed  CAS  Google Scholar 

  119. Hashimoto K (2013) Sigma-1 receptor chaperone and brain-derived neurotrophic factor: emerging links between cardiovascular disease and depression. Prog Neurobiol 100:15–29

    Article  PubMed  CAS  Google Scholar 

  120. ClinicalTrails.gov: 6-week study treatment to evaluate the safety and effectiveness of AZD2066 in patients with major depressive disorder. http://clinicaltrials.gov/ct2/show/NCT01145755

  121. ClinicalTrails.gov: a study of RO4917523 in patients with treatment resistant depression. http://clinicaltrials.gov/ct2/show/NCT00809562

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Acknowledgments

This study was supported by a Grant-in-Aid from the Minister of Education, Culture, Sports, Science, and Technology of Japan (to K. H.), a Grant-in-Aid for Scientific Research on Innovative Areas of the Ministry of Education, Culture, Sports, Science and Technology, Japan (to K. H.), and a Grant-in-Aid for Comprehensive Research on Disability, Health and Welfare, Health and Labour Sciences Research Grants, Japan (to K. H.).

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Authors and Affiliations

  1. Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba, 260-8670, Japan

    Kenji Hashimoto

  2. Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Nuβbaumstraße 7, 80336, Munich, Germany

    Berend Malchow, Peter Falkai & Andrea Schmitt

  3. Laboratory of Neuroscience (LIM27), Institute of Psychiatry, University of Sao Paulo, Rua Dr. Ovidio Pires de Campos 785, São Paulo, SP, 05453-010, Brazil

    Andrea Schmitt

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  1. Kenji Hashimoto
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  2. Berend Malchow
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Correspondence to Kenji Hashimoto.

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Hashimoto, K., Malchow, B., Falkai, P. et al. Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders. Eur Arch Psychiatry Clin Neurosci 263, 367–377 (2013). https://doi.org/10.1007/s00406-013-0399-y

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