Potentiation of the NMDA receptor in the treatment of schizophrenia: focused on the glycine site

  • Seong S. Shim
  • Michael D. Hammonds
  • Baik S. Kee


N-methyl-d-aspartate receptor (NMDAR) hypo-function theory of schizophrenia proposes that impairment in NMDAR function be associated with the pathophysiology of schizophrenia and suggests that enhancement of the receptor function may produce efficacy for schizophrenia. Consistent with this theory, for the last decade, clinical trials have demonstrated that the enhancement of NMDAR function by potentiating the glycine site of the receptor is efficacious in the treatment of schizophrenia. Full agonists of the glycine site, glycine and d-serine and a glycine transporter-1 inhibitor, sarcosine, added to antipsychotic drugs, have been shown to be effective in the treatment of negative symptoms and possibly cognitive symptoms without significantly affecting the positive symptoms of schizophrenia. A partial agonist of the glycine site, d-cycloserine, added to antipsychotic drugs, can be effective for the negative symptoms at the therapeutic doses. However, these drugs have not shown clinical efficacy when added to clozapine, suggesting that the interactions of clozapine and the glycine site potentiators may be different from those of other antipsychotic drugs and the potentiators. This article suggests that the glycine site potentiators may produce efficacy for negative and cognitive symptoms by blocking apoptosis-like neuropathological processes in patients with chronic schizophrenia and thereby can deter progressive deterioration of the disorder. This article proposes a polypharmacy of glycine site potentiators augmented with antipsychotic drugs to control positive and negative symptoms in a synergistic manner and block deterioration in schizophrenia. Since the NMDAR complex consists of multiple sites modulating receptor functions, the efficacy of glycine site potentiators for schizophrenia suggests the possibility that manipulation of other modulating sites of the NMDAR can also be efficacious in the treatment of schizophrenia.


glycine site agonists NMDA receptor negative symptoms cognitive symptoms neurodegeneration schizophrenia 


  1. 1.
    Arvanov VL, Liang X, Schwartz J, Grossman S, Wang RY (1997) Clozapine and haloperidol modulate N-methyl-d-aspartate- and non-N-methyl-d-aspartate receptor-mediated neurotransmission in rat prefrontal cortical neurons in vitro. J Pharmacol Exp Ther 283:226–234PubMedGoogle Scholar
  2. 2.
    Arvanov VL, Wang RY (1999) Clozapine, but not haloperidol, prevents the functional hyperactivity of N-methyl-d-aspartate receptors in rat cortical neurons induced by subchronic administration of phencyclidine. J Pharmacol Exp Ther 289:1000–1006PubMedGoogle Scholar
  3. 3.
    Baxter MG, Lanthorn TH, Frick KM, Golski S, Wan RQ, Olton DS (1994) d-cycloserine, a novel cognitive enhancer, improves spatial memory in aged rats. Neurobiol Aging 15:207–213PubMedGoogle Scholar
  4. 4.
    van Berckel BN, Evenblij CN, van Loon BJ, Maas MF, van der Geld MA, Wynne HJ, van Ree JM, Kahn RS (1999) d-cycloserine increases positive symptoms in chronic schizophrenic patients when administered in addition to antipsychotics: a double-blind, parallel, placebo-controlled study. Neuropsychopharmacology 21:203–210PubMedGoogle Scholar
  5. 5.
    van Berckel BN, Hijman R, van der Linden JA, Westenberg HG, van Ree JM, Kahn RS (1996) Efficacy and tolerance of d-cycloserine in drug-free schizophrenic patients. Biol Psychiatry 40:1298–1300PubMedGoogle Scholar
  6. 6.
    Bergeron R, Meyer TM, Coyle JT, Greene RW (1998) Modulation of N-methyl-d-aspartate receptor function by glycine transport. Proc Natl Acad Sci USA 95:15730–15734PubMedGoogle Scholar
  7. 7.
    Breier A, Adler CM, Weisenfeld N, Su TP, Elman I, Picken L, Malhotra AK, Pickar D (1998) Effects of NMDA antagonism on striatal dopamine release in healthy subjects: application of a novel PET approach. Synapse 29:142–147PubMedGoogle Scholar
  8. 8.
    Carlsson M, Carlsson A (1989) The NMDA antagonist MK-801 causes marked locomotor stimulation in monoamine-depleted mice. J Neural Transm 75:221–226PubMedGoogle Scholar
  9. 9.
    Cascella NG, Macciardi F, Cavallini C, Smeraldi E (1994) d-cycloserine adjuvant therapy to conventional neuroleptic treatment in schizophrenia: an open-label study. J Neural Transm Gen Sect 95:105–111PubMedGoogle Scholar
  10. 10.
    Chiamulera C, Costa S, Reggiani A (1990) Effect of NMDA- and strychnine-insensitive glycine site antagonists on NMDA-mediated convulsions and learning. Psychopharmacology (Berl) 102:551–552Google Scholar
  11. 11.
    Corbett R, Camacho F, Woods AT, Kerman LL, Fishkin RJ, Brooks K, Dunn RW (1995) Antipsychotic agents antagonize non-competitive N-methyl-d-aspartate antagonist-induced behaviors. Psychopharmacology (Berl) 120:67–74Google Scholar
  12. 12.
    Costa J, Khaled E, Sramek J, Bunney W Jr, Potkin SG (1990) An open trial of glycine as an adjunct to neuroleptics in chronic treatment-refractory schizophrenics. J Clin Psychopharmacol 10:71–72PubMedGoogle Scholar
  13. 13.
    Coyle JT, Puttfarcken P (1993) Oxidative stress, glutamate, and neurodegenerative disorders. Science 262:689–695PubMedGoogle Scholar
  14. 14.
    Crow TJ, Ferrier IN, Johnstone EC (1986) The two-syndrome concept and neuroendocrinology of schizophrenia. Psychiatr Clin North Am 9:99–113PubMedGoogle Scholar
  15. 15.
    Davis KL, Buchsbaum MS, Shihabuddin L, Spiegel-Cohen J, Metzger M, Frecska E, Keefe RS, Powchik P (1998) Ventricular enlargement in poor-outcome schizophrenia. Biol Psychiatry 43:783–793PubMedGoogle Scholar
  16. 16.
    Davis KL, Kahn RS, Ko G, Davidson M (1991) Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 148:1474–1486PubMedGoogle Scholar
  17. 17.
    DeLisi LE, Tew W, Xie S, Hoff AL, Sakuma M, Kushner M, Lee G, Shedlack K, Smith AM, Grimson R (1995) A prospective follow-up study of brain morphology and cognition in first-episode schizophrenic patients: preliminary findings. Biol Psychiatry 38:349–360PubMedGoogle Scholar
  18. 18.
    Dingledine R, Kleckner NW, McBain CJ (1990) The glycine co-agonist site of the NMDA receptor. In: Ben-Ari Y (ed) The glycine co-agonist site of the NMDA receptor. Plenum Press, New York, pp 17–26Google Scholar
  19. 19.
    Domino EF, Luby E (1981) Abnormal mental states induced by phencyclidine as a model of schizophrenia. In: Domino EF (ed) Abnormal mental states induced by phencyclidine as a model of schizophrenia. NPP Books, Ann Arbor, p 537Google Scholar
  20. 20.
    Duncan GE, Leipzig JN, Mailman RB, Lieberman JA (1998) Differential effects of clozapine and haloperidol on ketamine-induced brain metabolic activation. Brain Res 812:65–75PubMedGoogle Scholar
  21. 21.
    Duncan EJ, Szilagyi S, Schwartz MP, Bugarski-Kirola D, Kunzova A, Negi S, Stephanides M, Efferen TR, Angrist B, Peselow E, Corwin J, Gonzenbach S, Rotrosen JP (2004) Effects of d-cycloserine on negative symptoms in schizophrenia. Schizophr Res 71:239–248PubMedGoogle Scholar
  22. 22.
    Ellison G (1994) Competitive and non-competitive NMDA antagonists induce similar limbic degeneration. Neuroreport 5:2688–2692PubMedGoogle Scholar
  23. 23.
    Ellison G (1995) The N-methyl-d-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias. Brain Res Brain Res Rev 20:250–267PubMedGoogle Scholar
  24. 24.
    Ellison G, Switzer RC 3rd (1993) Dissimilar patterns of degeneration in brain following four different addictive stimulants. Neuroreport 5:17–20PubMedGoogle Scholar
  25. 25.
    Erhart SM, Marder SR, Carpenter WT (2006) Treatment of schizophrenia negative symptoms: future prospects. Schizophr Bull 32:234–237PubMedGoogle Scholar
  26. 26.
    Evins AE, Fitzgerald SM, Wine L, Rosselli R, Goff DC (2000) Placebo-controlled trial of glycine added to clozapine in schizophrenia. Am J Psychiatry 157:826–828PubMedGoogle Scholar
  27. 27.
    Farber NB, Wozniak DF, Price MT, Labruyere J, Huss J, St Peter H, Olney JW (1995) Age-specific neurotoxicity in the rat associated with NMDA receptor blockade: potential relevance to schizophrenia? Biol Psychiatry 38:788–796PubMedGoogle Scholar
  28. 28.
    File SE, Fluck E, Fernandes C (1999) Beneficial effects of glycine (bioglycin) on memory and attention in young and middle-aged adults. J Clin Psychopharmacol 19:506–512PubMedGoogle Scholar
  29. 29.
    Fix AS, Horn JW, Wightman KA, Johnson CA, Long GG, Storts RW, Farber N, Wozniak DF, Olney JW (1993) Neuronal vacuolization and necrosis induced by the noncompetitive N-methyl-d-aspartate (NMDA) antagonist MK(+)801 (dizocilpine maleate): a light and electron microscopic evaluation of the rat retrosplenial cortex. Exp Neurol 123:204–215PubMedGoogle Scholar
  30. 30.
    Fleischhacker W (2000) Negative symptoms in patients with schizophrenia with special reference to the primary versus secondary distinction. Encephale 26 Spec No 1:12–14Google Scholar
  31. 31.
    Gelder MG, López Ibor JJ, Andreasen NC (2000) New Oxford textbook of psychiatry. Oxford University Press, Oxford, p 2131Google Scholar
  32. 32.
    Goff DC, Coyle JT (2001) The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry 158:1367–1377PubMedGoogle Scholar
  33. 33.
    Goff DC, Henderson DC, Evins AE, Amico E (1999) A placebo-controlled crossover trial of d-cycloserine added to clozapine in patients with schizophrenia. Biol Psychiatry 45:512–514PubMedGoogle Scholar
  34. 34.
    Goff DC, Herz L, Posever T, Shih V, Tsai G, Henderson DC, Freudenreich O, Evins AE, Yovel I, Zhang H, Schoenfeld D (2005) A six-month, placebo-controlled trial of d-cycloserine co-administered with conventional antipsychotics in schizophrenia patients. Psychopharmacology (Berl) 179:144–150Google Scholar
  35. 35.
    Goff DC, Tsai G, Levitt J, Amico E, Manoach D, Schoenfeld DA, Hayden DL, McCarley R, Coyle JT (1999) A placebo-controlled trial of d-cycloserine added to conventional neuroleptics in patients with schizophrenia. Arch Gen Psychiatry 56:21–27PubMedGoogle Scholar
  36. 36.
    Goff DC, Tsai G, Manoach DS, Coyle JT (1995) Dose-finding trial of d-cycloserine added to neuroleptics for negative symptoms in schizophrenia. Am J Psychiatry 152:1213–1215PubMedGoogle Scholar
  37. 37.
    Goff DC, Tsai G, Manoach DS, Flood J, Darby DG, Coyle JT (1996) d-cycloserine added to clozapine for patients with schizophrenia. Am J Psychiatry 153:1628–1630PubMedGoogle Scholar
  38. 38.
    Goldman-Rakic PS, Selemon LD (1997) Functional and anatomical aspects of prefrontal pathology in schizophrenia. Schizophr Bull 23:437–458PubMedGoogle Scholar
  39. 39.
    Gur RE, Cowell P, Turetsky BI, Gallacher F, Cannon T, Bilker W, Gur RC (1998) A follow-up magnetic resonance imaging study of schizophrenia. Relationship of neuroanatomical changes to clinical and neurobehavioral measures. Arch Gen Psychiatry 55:145–152PubMedGoogle Scholar
  40. 40.
    Gutstein HB, Johnson KL, Heard MB, Gregory GA (1992) Oral ketamine preanesthetic medication in children. Anesthesiology 76:28–33PubMedGoogle Scholar
  41. 41.
    Heckers S (1997) Neuropathology of schizophrenia: cortex, thalamus, basal ganglia, and neurotransmitter-specific projection systems. Schizophr Bull 23:403–421PubMedGoogle Scholar
  42. 42.
    Hegarty JD, Baldessarini RJ, Tohen M, Waternaux C, Oepen G (1994) One hundred years of schizophrenia: a meta-analysis of the outcome literature. Am J Psychiatry 151:1409–1416PubMedGoogle Scholar
  43. 43.
    Heresco-Levy U, Ermilov M, Shimoni J, Shapira B, Silipo G, Javitt DC (2002) Placebo-controlled trial of d-cycloserine added to conventional neuroleptics, olanzapine, or risperidone in schizophrenia. Am J Psychiatry 159:480–482PubMedGoogle Scholar
  44. 44.
    Heresco-Levy U, Javitt DC (2004) Comparative effects of glycine and d-cycloserine on persistent negative symptoms in schizophrenia: a retrospective analysis. Schizophr Res 66:89–96PubMedGoogle Scholar
  45. 45.
    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 57:577–585PubMedGoogle Scholar
  46. 46.
    Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Horowitz A, Kelly D (1996) Double-blind, placebo-controlled, crossover trial of glycine adjuvant therapy for treatment-resistant schizophrenia. Br J Psychiatry 169:610–617PubMedGoogle Scholar
  47. 47.
    Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Silipo G, Lichtenstein M (1999) Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Arch Gen Psychiatry 56:29–36PubMedGoogle Scholar
  48. 48.
    Heresco-Levy U, Javitt DC, Ermilov M, Silipo G, Shimoni J (1998) Double-blind, placebo-controlled, crossover trial of d-cycloserine adjuvant therapy for treatment-resistant schizophrenia. Int J Neuropsychopharmcol 1:131–135Google Scholar
  49. 49.
    Heresco-Levy U, Silipo G, Javitt DC (1996) Glycinergic augmentation of NMDA receptor-mediated neurotransmission in the treatment of schizophrenia. Psychopharmacol Bull 32:731–740PubMedGoogle Scholar
  50. 50.
    Hoffman DC (1992) Typical and atypical neuroleptics antagonize MK-801-induced locomotion and stereotypy in rats. J Neural Transm Gen Sect 89:1–10PubMedGoogle Scholar
  51. 51.
    Hood WF, Compton RP, Monahan JB (1989) d-cycloserine: a ligand for the N-methyl-d-aspartate coupled glycine receptor has partial agonist characteristics. Neurosci Lett 98:91–95PubMedGoogle Scholar
  52. 52.
    Jarskog LF, Glantz LA, Gilmore JH, Lieberman JA (2005) Apoptotic mechanisms in the pathophysiology of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 29:846–858PubMedGoogle Scholar
  53. 53.
    Javitt DC (1999) Treatment of negative and cognitive symptoms. Curr Psychiatry Rep 1:25–30PubMedGoogle Scholar
  54. 54.
    Javitt DC (2006) Is the glycine site half saturated or half unsaturated? Effects of glutamatergic drugs in schizophrenia patients. Curr Opin Psychiatry 19:151–157PubMedGoogle Scholar
  55. 55.
    Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301–1308PubMedGoogle Scholar
  56. 56.
    Javitt DC, Zylberman I, Zukin SR, Heresco-Levy U, Lindenmayer JP (1994) Amelioration of negative symptoms in schizophrenia by glycine. Am J Psychiatry 151:1234–1236PubMedGoogle Scholar
  57. 57.
    Jentsch JD, Dazzi L, Chhatwal JP, Verrico CD, Roth RH (1998) Reduced prefrontal cortical dopamine, but not acetylcholine, release in vivo after repeated, intermittent phencyclidine administration to rats. Neurosci Lett 258:175–178PubMedGoogle Scholar
  58. 58.
    Jentsch JD, Elsworth JD, Taylor JR, Redmond DE Jr, Roth RH (1998) Dysregulation of mesoprefrontal dopamine neurons induced by acute and repeated phencyclidine administration in the nonhuman primate: implications for schizophrenia. Adv Pharmacol 42:810–814PubMedGoogle Scholar
  59. 59.
    Jentsch JD, Tran A, Taylor JR, Roth RH (1998) Prefrontal cortical involvement in phencyclidine-induced activation of the mesolimbic dopamine system: behavioral and neurochemical evidence. Psychopharmacology (Berl) 138:89–95Google Scholar
  60. 60.
    Johnson JW, Ascher P (1987) Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325:529–531PubMedGoogle Scholar
  61. 61.
    Kane J, Honigfeld G, Singer J, Meltzer H (1988) Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45:789–796PubMedGoogle Scholar
  62. 62.
    Kasai K, Iwanami A, Yamasue H, Kuroki N, Nakagome K, Fukuda M (2002) Neuroanatomy and neurophysiology in schizophrenia. Neurosci Res 43:93–110PubMedGoogle Scholar
  63. 63.
    Kegeles LS, Abi-Dargham A, Zea-Ponce Y, Rodenhiser-Hill J, Mann JJ, Van Heertum RL, Cooper TB, Carlsson A, Laruelle M (2000) Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia. Biol Psychiatry 48:627–640PubMedGoogle Scholar
  64. 64.
    Kemp JA, Leeson PD (1993) The glycine site of the NMDA receptor–five years on. Trends Pharmacol Sci 14:20–25PubMedGoogle Scholar
  65. 65.
    Kim JS, Kornhuber HH, Schmid-Burgk W, Holzmuller B (1980) Low cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis on schizophrenia. Neurosci Lett 20:379–382PubMedGoogle Scholar
  66. 66.
    Kinon BJ, Noordsy DL, Liu-Seifert H, Gulliver AH, Ascher-Svanum H, Kollack-Walker S (2006) Randomized, double-blind 6-month comparison of olanzapine and quetiapine in patients with schizophrenia or schizoaffective disorder with prominent negative symptoms and poor functioning. J Clin Psychopharmacol 26:453–461PubMedGoogle Scholar
  67. 67.
    Kirkpatrick B, Buchanan RW, McKenney PD, Alphs LD, Carpenter WT Jr (1989) The schedule for the deficit syndrome: an instrument for research in schizophrenia. Psychiatry Res 30:119–123PubMedGoogle Scholar
  68. 68.
    Kirkpatrick B, Buchanan RW, Ross DE, Carpenter WT Jr (2001) A separate disease within the syndrome of schizophrenia. Arch Gen Psychiatry 58:165–171PubMedGoogle Scholar
  69. 69.
    Kirkpatrick B, Fenton WS, Carpenter WT Jr, Marder SR (2006) The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull 32:214–219PubMedGoogle Scholar
  70. 70.
    Kleckner NW, Dingledine R (1988) Requirement for glycine in activation of NMDA-receptors expressed in Xenopus oocytes. Science 241:835–837PubMedGoogle Scholar
  71. 71.
    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 7:125–143PubMedGoogle Scholar
  72. 72.
    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 51:199–214PubMedGoogle Scholar
  73. 73.
    Lancelot E, Beal MF (1998) Glutamate toxicity in chronic neurodegenerative disease. Prog Brain Res 116:331–347PubMedCrossRefGoogle Scholar
  74. 74.
    Lane HY, Huang CL, Wu PL, Liu YC, Chang YC, Lin PY, Chen PW, Tsai G (2006) Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia. Biol Psychiatry 60:645–649PubMedGoogle Scholar
  75. 75.
    Laruelle M, Kegeles LS, Abi-Dargham A (2003) Glutamate, dopamine, and schizophrenia: from pathophysiology to treatment. Ann N Y Acad Sci 1003:138–158PubMedGoogle Scholar
  76. 76.
    Leeson PD, Iversen LL (1994) The glycine site on the NMDA receptor: structure-activity relationships and therapeutic potential. J Med Chem 37:4053–4067PubMedGoogle Scholar
  77. 77.
    Leiderman E, Zylberman I, Zukin SR, Cooper TB, Javitt DC (1996) Preliminary investigation of high-dose oral glycine on serum levels and negative symptoms in schizophrenia: an open-label trial. Biol Psychiatry 39:213–215PubMedGoogle Scholar
  78. 78.
    Lieberman JA (1999) Is schizophrenia a neurodegenerative disorder? A clinical and neurobiological perspective. Biol Psychiatry 46:729–739PubMedGoogle Scholar
  79. 79.
    Lieberman JA, Alvir JM, Koreen A, Geisler S, Chakos M, Sheitman B, Woerner M (1996) Psychobiologic correlates of treatment response in schizophrenia. Neuropsychopharmacology 14:13S–21SPubMedGoogle Scholar
  80. 80.
    Lindsley CW, Shipe WD, Wolkenberg SE, Theberge CR, Williams DL Jr, Sur C, Kinney GG (2006) Progress towards validating the NMDA receptor hypofunction hypothesis of schizophrenia. Curr Top Med Chem 6:771–785PubMedGoogle Scholar
  81. 81.
    Mayer ML, Westbrook GL, Guthrie PB (1984) Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature 309:261–263PubMedGoogle Scholar
  82. 82.
    McGlashan TH, Fenton WS (1993) Subtype progression and pathophysiologic deterioration in early schizophrenia. Schizophr Bull 19:71–84PubMedGoogle Scholar
  83. 83.
    Moghaddam B, Adams BW (1998) Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281:1349–1352PubMedGoogle Scholar
  84. 84.
    Mohn AR, Gainetdinov RR, Caron MG, Koller BH (1999) Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 98:427–436PubMedGoogle Scholar
  85. 85.
    Murphy BP, Chung YC, Park TW, McGorry PD (2006) Pharmacological treatment of primary negative symptoms in schizophrenia: a systematic review. Schizophr Res 88:5–25PubMedGoogle Scholar
  86. 86.
    Nakanishi S (1992) Molecular diversity of glutamate receptors and implications for brain function. Science 258:597–603PubMedGoogle Scholar
  87. 87.
    O’Brien EM, Tipton KF, Strolin Benedetti M, Bonsignori A, Marrari P, Dostert P (1991) Is the oxidation of milacemide by monoamine oxidase a major factor in its anticonvulsant actions? Biochem Pharmacol 41:1731–1737PubMedGoogle Scholar
  88. 88.
    Olney JW, Farber NB (1995) Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 52:998–1007PubMedGoogle Scholar
  89. 89.
    Olney JW, Labruyere J, Price MT (1989) Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 244:1360–1362PubMedGoogle Scholar
  90. 90.
    Olney JW, Labruyere J, Wang G, Wozniak DF, Price MT, Sesma MA (1991) NMDA antagonist neurotoxicity: mechanism and prevention. Science 254:1515–1518PubMedGoogle Scholar
  91. 91.
    Olney JW, Newcomer JW, Farber NB (1999) NMDA receptor hypofunction model of schizophrenia. J Psychiatr Res 33:523–533PubMedGoogle Scholar
  92. 92.
    Patel J, Zinkand WC, Thompson C, Keith R, Salama A (1990) Role of glycine in the N-methyl-d-aspartate-mediated neuronal cytotoxicity. J Neurochem 54:849–854PubMedGoogle Scholar
  93. 93.
    Potkin SG, Costa J, Roy S, Jin Y, Gulasekaram B (1992) Glycine in the treatment of schizophrenia. In: Meltzer HY (ed) Glycine in the treatment of schizophrenia. Raven Press, New York, pp 179–188Google Scholar
  94. 94.
    Potkin SG, Jin Y, Bunney BG, Costa J, Gulasekaram B (1999) Effect of clozapine and adjunctive high-dose glycine in treatment-resistant schizophrenia. Am J Psychiatry 156:145–147PubMedGoogle Scholar
  95. 95.
    Reich DL, Silvay G (1989) Ketamine: an update on the first 25 years of clinical experience. Can J Anaesth 36:186–197PubMedCrossRefGoogle Scholar
  96. 96.
    Riedel G, Platt B, Micheau J (2003) Glutamate receptor function in learning and memory. Behav Brain Res 140:1–47PubMedGoogle Scholar
  97. 97.
    Robins LN, Regier DA (eds) (1991) Psychiatric disorders in America : the epidemiologic catchment area study. Free Press, New York, p 449Google Scholar
  98. 98.
    Robinson MB, Coyle JT (1987) Glutamate and related acidic excitatory neurotransmitters: from basic science to clinical application. Faseb J 1:446–455PubMedGoogle Scholar
  99. 99.
    Rosse RB, Fay-McCarthy M, Kendrick K, Davis RE, Deutsch SI (1996) d-cycloserine adjuvant therapy to molindone in the treatment of schizophrenia. Clin Neuropharmacol 19:444–450PubMedGoogle Scholar
  100. 100.
    Rosse RB, Schwartz BL, Davis RE, Deutsch SI (1991) An NMDA intervention strategy in schizophrenia with “low-dose” milacemide. Clin Neuropharmacol 14:268–272PubMedGoogle Scholar
  101. 101.
    Rosse RB, Schwartz BL, Leighton MP, Davis RE, Deutsch SI (1990) An open-label trial of milacemide in schizophrenia: an NMDA intervention strategy. Clin Neuropharmacol 13:348–354PubMedGoogle Scholar
  102. 102.
    Sams-Dodd F (1997) Effect of novel antipsychotic drugs on phencyclidine-induced stereotyped behaviour and social isolation in the rat social interaction test. Behav Pharmacol 8:196–215PubMedGoogle Scholar
  103. 103.
    Schell MJ, Molliver ME, Snyder SH (1995) d-serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release. Proc Natl Acad Sci USA 92:3948–3952PubMedGoogle Scholar
  104. 104.
    Schiffer WK, Logan J, Dewey SL (2003) Positron emission tomography studies of potential mechanisms underlying phencyclidine-induced alterations in striatal dopamine. Neuropsychopharmacology 28:2192–2198PubMedGoogle Scholar
  105. 105.
    Schuster GM, Schmidt WJ (1992) d-cycloserine reverses the working memory impairment of hippocampal-lesioned rats in a spatial learning task. Eur J Pharmacol 224:97–98PubMedGoogle Scholar
  106. 106.
    Serretti A, De Ronchi D, Lorenzi C, Berardi D (2004) New antipsychotics and schizophrenia: a review on efficacy and side effects. Curr Med Chem 11:343–358PubMedGoogle Scholar
  107. 107.
    Shenton ME, Dickey CC, Frumin M, McCarley RW (2001) A review of MRI findings in schizophrenia. Schizophr Res 49:1–52PubMedGoogle Scholar
  108. 108.
    Simeon J, Fink M, Itil TM, Ponce D (1970) d-Cycloserine therapy of psychosis by symptom provocation. Compr Psychiatry 11:80–88PubMedGoogle Scholar
  109. 109.
    Steinpresis RE (1996) The behavioral and neurochemical effects of phencyclidine in humans and animals: some implications for modeling psychosis. Behav Brain Res 74:45–55Google Scholar
  110. 110.
    Svensson TH (2000) Dysfunctional brain dopamine systems induced by psychotomimetic NMDA-receptor antagonists and the effects of antipsychotic drugs. Brain Res Brain Res Rev 31:320–329PubMedGoogle Scholar
  111. 111.
    Tamminga CA, Cascella NG, Fakouhi TD, Herting RL (1992) Enhancement of NMDA-mediated transmission in schizophrenia. In: Meltzer HY (ed) Enhancement of NMDA-mediated transmission in schizophrenia. Raven Press, New York, pp 171–177Google Scholar
  112. 112.
    Temple MD, Hamm RJ (1996) Chronic, post-injury administration of d-cycloserine, an NMDA partial agonist, enhances cognitive performance following experimental brain injury. Brain Res 741:246–251PubMedGoogle Scholar
  113. 113.
    Thomson CG, Duncan K, Fletcher SR, Huscroft IT, Pillai G, Raubo P, Smith AJ, Stead D (2006) Sarcosine based indandione hGlyT1 inhibitors. Bioorg Med Chem Lett 16:1388–1391PubMedGoogle Scholar
  114. 114.
    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 55:452–456PubMedGoogle Scholar
  115. 115.
    Tsai GE, Yang P, Chang YC, Chong MY (2006) d-alanine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 59:230–234PubMedGoogle Scholar
  116. 116.
    Tsai G, Yang P, Chung LC, Lange N, Coyle JT (1998) d-serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 44:1081–1089PubMedGoogle Scholar
  117. 117.
    Tsai GE, Yang P, Chung LC, Tsai IC, Tsai CW, Coyle JT (1999) d-serine added to clozapine for the treatment of schizophrenia. Am J Psychiatry 156:1822–1825PubMedGoogle Scholar
  118. 118.
    Tsukada H, Nishiyama S, Fukumoto D, Sato K, Kakiuchi T, Domino EF (2005) Chronic NMDA antagonism impairs working memory, decreases extracellular dopamine, and increases D1 receptor binding in prefrontal cortex of conscious monkeys. Neuropsychopharmacology 30:1861–1869PubMedGoogle Scholar
  119. 119.
    Vollenweider FX, Vontobel P, Oye I, Hell D, Leenders KL (2000) Effects of (S)-ketamine on striatal dopamine: a [11C]raclopride PET study of a model psychosis in humans. J Psychiatr Res 34:35–43PubMedGoogle Scholar
  120. 120.
    Wang RY, Liang X (1998) M100907 and clozapine, but not haloperidol or raclopride, prevent phencyclidine-induced blockade of NMDA responses in pyramidal neurons of the rat medial prefrontal cortical slice. Neuropsychopharmacology 19:74–85PubMedGoogle Scholar
  121. 121.
    Watkins JC, Olverman HJ (1987) Agonists and antagonists for excitatory amino acid receptors. Trends Neurosci 10:265–272Google Scholar
  122. 122.
    Waziri R (1988) Glycine therapy of schizophrenia. Biol Psychiatry 23:210–211PubMedGoogle Scholar
  123. 123.
    Wyatt RJ (1991) Early intervention with neuroleptics may decrease the long-term morbidity of schizophrenia. Schizophr Res 5:201–202PubMedGoogle Scholar
  124. 124.
    Yamamoto BK, Cooperman MA (1994) Differential effects of chronic antipsychotic drug treatment on extracellular glutamate and dopamine concentrations. J Neurosci 14:4159–4166PubMedGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Seong S. Shim
    • 1
    • 2
  • Michael D. Hammonds
    • 3
  • Baik S. Kee
    • 4
  1. 1.Department of PsychiatryCase Western Reserve University School of Medicine, Cleveland VA Medical Center Psychiatric Services 116 A(W)ClevelandUSA
  2. 2.Psychiatric Services 116 W(A), Cleveland VA Medical CenterClevelandUSA
  3. 3.Research and Education FoundationCleveland VA Medical CenterClevelandUSA
  4. 4.Department of Neuropsychiatry, College of MedicineChung-Ang University HospitalSeoulKorea

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