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Imaging glutamate in schizophrenia: review of findings and implications for drug discovery

Molecular Psychiatry volume 19, pages 20–29 (2014)Cite this article

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Abstract

Currently, all treatments for schizophrenia (SCZ) function primarily by blocking D2-type dopamine receptors. Given the limitations of these medications, substantial efforts have been made to identify alternative neurochemical targets for treatment development in SCZ. One such target is brain glutamate. The objective of this article is to review and synthesize the proton magnetic resonance spectroscopy (1H MRS) and positron emission tomography (PET)/single-photon emission computed tomography (SPECT) investigations that have examined glutamatergic indices in SCZ, including those of modulatory compounds such as glutathione (GSH) and glycine, as well as data from ketamine challenge studies. The reviewed 1H MRS and PET/SPECT studies support the theory of hypofunction of the N-methyl-D-aspartate receptor (NMDAR) in SCZ, as well as the convergence between the dopamine and glutamate models of SCZ. We also review several advances in MRS and PET technologies that have opened the door for new opportunities to investigate the glutamate system in SCZ and discuss some ways in which these imaging tools can be used to facilitate a greater understanding of the glutamate system in SCZ and the successful and efficient development of new glutamate-based treatments for SCZ.

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References

  1. Miyamoto S, Miyake N, Jarskog LF, Fleischhacker WW, Lieberman JA . Pharmacological treatment of schizophrenia: an update and critical review of the pharmacology and clinical profiles of current and future therapeutic agents. Mol Psychiatry 2012; 17: 1206–1227.

    Article  CAS  PubMed  Google Scholar 

  2. Miyamoto S, Duncan GE, Marx CE, Lieberman JA . Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry 2005; 10: 79–104.

    CAS  PubMed  Google Scholar 

  3. Baker DA, Madayag A, Kristiansen LV, Meador-Woodruff JH, Haroutunian V, Raju I . Contribution of cystine-glutamate antiporters to the psychotomimetic effects of phencyclidine. Neuropsychopharmacology 2008; 33: 1760–1772.

    Article  CAS  PubMed  Google Scholar 

  4. Kantrowitz JT, Javitt DC . N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia? Brain Res Bull 2010; 83: 108–121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Singh SP, Singh V . Meta-analysis of the efficacy of adjunctive NMDA receptor modulators in chronic schizophrenia. CNS Drugs 2011; 25: 859–868.

    Article  CAS  PubMed  Google Scholar 

  6. Pinard E, Alanine A, Alberati D, Bender M, Borroni E, Bourdeaux P et al. 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 2010; 53: 4603–4614.

    Article  CAS  PubMed  Google Scholar 

  7. Javitt DC, Schoepp D, Kalivas PW, Volkow ND, Zarate C, Merchant K et al. Translating glutamate: from pathophysiology to treatment. Sci Transl Med 2011; 3: 102mr102.

    Article  Google Scholar 

  8. Luby ED, Gottlieb JS, Cohen BD, Rosenbaum G, Domino EF . Model psychoses and schizophrenia. Am J Psychiatry 1962; 119: 61–67.

    Article  CAS  PubMed  Google Scholar 

  9. Javitt DC, Zukin SR . Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 1991; 148: 1301–1308.

    Article  CAS  PubMed  Google Scholar 

  10. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994; 51: 199–214.

    Article  CAS  PubMed  Google Scholar 

  11. Adler CM, Malhotra AK, Elman I, Goldberg T, Egan M, Pickar D et al. Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia. Am J Psychiatry 1999; 156: 1646–1649.

    Article  CAS  PubMed  Google Scholar 

  12. Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA . Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology 2001; 25: 455–467.

    Article  CAS  PubMed  Google Scholar 

  13. Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D et al. Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology 1997; 17: 141–150.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Hietala J, Syvalahti E, Vuorio K, Rakkolainen V, Bergman J, Haaparanta M et al. Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients. Lancet 1995; 346: 1130–1131.

    Article  CAS  PubMed  Google Scholar 

  16. McGowan S, Lawrence AD, Sales T, Quested D, Grasby P . Presynaptic dopaminergic dysfunction in schizophrenia: a positron emission tomographic [F-18]fluorodopa study. Arch Gen Psychiat 2004; 61: 134–142.

    Article  PubMed  Google Scholar 

  17. Reith J, Benkelfat C, Sherwin A, Yasuhara Y, Kuwabara H, Andermann F et al. Elevated Dopa decarboxylase activity in living brain of patients with psychosis. Proc Natl Acad Sci USA 1994; 91: 11651–11654.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D'Souza CD, Erdos J et al. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci USA 1996; 93: 9235–9240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M et al. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 1998; 155: 761–767.

    Article  CAS  PubMed  Google Scholar 

  20. Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartolomeis A et al. Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci USA 1997; 94: 2569–2574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS et al. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci USA 2000; 97: 8104–8109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Weinberger DR . Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987; 44: 660–669.

    Article  CAS  PubMed  Google Scholar 

  23. Davis KL, Kahn RS, Ko G, Davidson M . Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 1991; 148: 1474–1486.

    Article  CAS  PubMed  Google Scholar 

  24. Abi-Dargham A, Mawlawi O, Lombardo I, Gil R, Martinez D, Huang Y et al. Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci 2002; 22: 3708–3719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Abi-Dargham A, Xu X, Thompson JL, Gil R, Kegeles LS, Urban NB et al. Increased prefrontal cortical D1 receptors in drug naive patients with schizophrenia: a PET study with [11C]NNC112. J Psychopharmacol 2011; 26: 794–805.

    Article  PubMed  CAS  Google Scholar 

  26. Okubo Y, Suhara T, Suzuki K, Kobayashi K, Inoue O, Terasaki O et al. Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET. Nature 1997; 385: 634–636.

    Article  CAS  PubMed  Google Scholar 

  27. Karlsson P, Farde L, Halldin C, Sedvall G . PET study of D(1) dopamine receptor binding in neuroleptic-naive patients with schizophrenia. Am J Psychiatry 2002; 159: 761–767.

    Article  PubMed  Google Scholar 

  28. Javitt DC, Hashim A, Sershen H . Modulation of striatal dopamine release by glycine transport inhibitors. Neuropsychopharmacology 2005; 30: 649–656.

    Article  CAS  PubMed  Google Scholar 

  29. Smith GS, Schloesser R, Brodie JD, Dewey SL, Logan J, Vitkun SA et al. Glutamate modulation of dopamine measured in vivo with positron emission tomography (PET) and 11C-raclopride in normal human subjects. Neuropsychopharmacology 1998; 18: 18–25.

    Article  CAS  PubMed  Google Scholar 

  30. Breier A, Adler CM, Weisenfeld N, Su TP, Elman I, Picken L et al. Effects of NMDA antagonism on striatal dopamine release in healthy subjects: application of a novel PET approach. Synapse 1998; 29: 142–147.

    Article  CAS  PubMed  Google Scholar 

  31. Vollenweider FX, Vontobel P, Oye I, Hell D, Leenders KL . Effects of (S)-ketamine on striatal dopamine: a [11C]raclopride PET study of a model psychosis in humans. J Psychiatr Res 2000; 34: 35–43.

    Article  CAS  PubMed  Google Scholar 

  32. Aalto S, Hirvonen J, Kajander J, Scheinin H, Nagren K, Vilkman H et al. Ketamine does not decrease striatal dopamine D2 receptor binding in man. Psychopharmacology (Berl) 2002; 164: 401–406.

    Article  CAS  Google Scholar 

  33. Kegeles LS, Martinez D, Kochan LD, Hwang DR, Huang Y, Mawlawi O et al. NMDA antagonist effects on striatal dopamine release: positron emission tomography studies in humans. Synapse 2002; 43: 19–29.

    Article  CAS  PubMed  Google Scholar 

  34. Aalto S, Ihalainen J, Hirvonen J, Kajander J, Scheinin H, Tanila H et al. Cortical glutamate-dopamine interaction and ketamine-induced psychotic symptoms in man. Psychopharmacology 2005; 182: 375–383.

    Article  CAS  PubMed  Google Scholar 

  35. Kegeles LS, Abi-Dargham A, Zea-Ponce Y, Rodenhiser-Hill J, Mann JJ, Van Heertum RL et al. Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia. Biol Psychiatry 2000; 48: 627–640.

    Article  CAS  PubMed  Google Scholar 

  36. Narendran R, Frankle WG, Keefe R, Gil R, Martinez D, Slifstein M et al. Altered prefrontal dopaminergic function in chronic recreational ketamine users. Am J Psychiatry 2005; 162: 2352–2359.

    Article  PubMed  Google Scholar 

  37. Miller DW, Abercrombie ED . Effects of MK-801 on spontaneous and amphetamine-stimulated dopamine release in striatum measured with in vivo microdialysis in awake rats. Brain Res Bull 1996; 40: 57–62.

    Article  CAS  PubMed  Google Scholar 

  38. Galinska B, Szulc A, Tarasow E, Kubas B, Dzienis W, Czernikiewicz A et al. Duration of untreated psychosis and proton magnetic resonance spectroscopy (1H-MRS) findings in first-episode schizophrenia. Med Sci Monit 2009; 15: CR82–CR88.

    PubMed  Google Scholar 

  39. Goto N, Yoshimura R, Kakeda S, Nishimura J, Moriya J, Hayashi K et al. Six-month treatment with atypical antipsychotic drugs decreased frontal-lobe levels of glutamate plus glutamine in early-stage first-episode schizophrenia. Neuropsychiatr Dis Treat 2012; 8: 119–122.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Ohrmann P, Kugel H, Bauer J, Siegmund A, Kolkebeck K, Suslow T et al. Learning potential on the WCST in schizophrenia is related to the neuronal integrity of the anterior cingulate cortex as measured by proton magnetic resonance spectroscopy. Schizophr Res 2008; 106: 156–163.

    Article  PubMed  Google Scholar 

  41. da Silva Alves F, Boot E, Schmitz N, Nederveen A, Vorstman J, Lavini C et al. Proton magnetic resonance spectroscopy in 22q11 deletion syndrome. PLoS One 2011; 6: e21685.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Szulc A, Galinska B, Tarasow E, Waszkiewicz N, Konarzewska B, Poplawska R et al. Proton magnetic resonance spectroscopy study of brain metabolite changes after antipsychotic treatment. Pharmacopsychiatry 2011; 44: 148–157.

    Article  CAS  PubMed  Google Scholar 

  43. Rowland LM, Spieker EA, Francis A, Barker PB, Carpenter WT, Buchanan RW . White matter alterations in deficit schizophrenia. Neuropsychopharmacology 2009; 34: 1514–1522.

    Article  CAS  PubMed  Google Scholar 

  44. Block W, Bayer TA, Tepest R, Traber F, Rietschel M, Muller DJ et al. Decreased frontal lobe ratio of N-acetyl aspartate to choline in familial schizophrenia: a proton magnetic resonance spectroscopy study. Neurosci Lett 2000; 289: 147–151.

    Article  CAS  PubMed  Google Scholar 

  45. Seese RR, O'Neill J, Hudkins M, Siddarth P, Levitt J, Tseng B et al. Proton magnetic resonance spectroscopy and thought disorder in childhood schizophrenia. Schizophr Res 2011; 133: 82–90.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Yoo SY, Yeon S, Choi CH, Kang DH, Lee JM, Shin NY et al. Proton magnetic resonance spectroscopy in subjects with high genetic risk of schizophrenia: investigation of anterior cingulate, dorsolateral prefrontal cortex and thalamus. Schizophr Res 2009; 111: 86–93.

    Article  PubMed  Google Scholar 

  47. Kegeles LS, Mao X, Stanford AD, Girgis R, Ojeil N, Xu X et al. Elevated prefrontal cortex gamma-aminobutyric acid and glutamate-glutamine levels in schizophrenia measured in vivo with proton magnetic resonance spectroscopy. Arch Gen Psychiatry 2012; 69: 449–459.

    Article  CAS  PubMed  Google Scholar 

  48. Olbrich HM, Valerius G, Rusch N, Buchert M, Thiel T, Hennig J et al. Frontolimbic glutamate alterations in first episode schizophrenia: evidence from a magnetic resonance spectroscopy study. World J Biol Psychiatry 2008; 9: 59–63.

    Article  PubMed  Google Scholar 

  49. van Elst LT, Valerius G, Buchert M, Thiel T, Rusch N, Bubl E et al. Increased prefrontal and hippocampal glutamate concentration in schizophrenia: evidence from a magnetic resonance spectroscopy study. Biol Psychiatry 2005; 58: 724–730.

    Article  PubMed  CAS  Google Scholar 

  50. Rusch N, Tebartz van Elst L, Valerius G, Buchert M, Thiel T, Ebert D et al. Neurochemical and structural correlates of executive dysfunction in schizophrenia. Schizophr Res 2008; 99: 155–163.

    Article  PubMed  Google Scholar 

  51. Stanley JA, Williamson PC, Drost DJ, Rylett RJ, Carr TJ, Malla A et al. An in vivo proton magnetic resonance spectroscopy study of schizophrenia patients. Schizophr Bull 1996; 22: 597–609.

    Article  CAS  PubMed  Google Scholar 

  52. Ohrmann P, Siegmund A, Suslow T, Spitzberg K, Kersting A, Arolt V et al. Evidence for glutamatergic neuronal dysfunction in the prefrontal cortex in chronic but not in first-episode patients with schizophrenia: a proton magnetic resonance spectroscopy study. Schizophr Res 2005; 73: 153–157.

    Article  PubMed  Google Scholar 

  53. Ohrmann P, Siegmund A, Suslow T, Pedersen A, Spitzberg K, Kersting A et al. Cognitive impairment and in vivo metabolites in first-episode neuroleptic-naive and chronic medicated schizophrenic patients: a proton magnetic resonance spectroscopy study. J Psychiatr Res 2007; 41: 625–634.

    Article  PubMed  Google Scholar 

  54. Theberge J, Bartha R, Drost DJ, Menon RS, Malla A, Takhar J et al. Glutamate and glutamine measured with 4.0T proton MRS in never-treated patients with schizophrenia and healthy volunteers. Am J Psychiatry 2002; 159: 1944–1946.

    Article  PubMed  Google Scholar 

  55. Bartha R, Williamson PC, Drost DJ, Malla A, Carr TJ, Cortese L et al. Measurement of glutamate and glutamine in the medial prefrontal cortex of never-treated schizophrenic patients and healthy controls by proton magnetic resonance spectroscopy. Arch Gen Psychiatry 1997; 54: 959–965.

    Article  CAS  PubMed  Google Scholar 

  56. Theberge J, Williamson KE, Aoyama N, Drost DJ, Manchanda R, Malla AK et al. Longitudinal grey-matter and glutamatergic losses in first-episode schizophrenia. Br J Psychiatry 2007; 191: 325–334.

    Article  PubMed  Google Scholar 

  57. Aoyama N, Theberge J, Drost DJ, Manchanda R, Northcott S, Neufeld RW et al. Grey matter and social functioning correlates of glutamatergic metabolite loss in schizophrenia. Br J Psychiatry 2011; 198: 448–456.

    Article  PubMed  Google Scholar 

  58. Bustillo JR, Chen H, Gasparovic C, Mullins P, Caprihan A, Qualls C et al. Glutamate as a marker of cognitive function in schizophrenia: a proton spectroscopic imaging study at 4 Tesla. Biol Psychiatry 2011; 69: 19–27.

    Article  CAS  PubMed  Google Scholar 

  59. Ongur D, Jensen JE, Prescot AP, Stork C, Lundy M, Cohen BM et al. Abnormal glutamatergic neurotransmission and neuronal-glial interactions in acute mania. Biol Psychiatry 2008; 64: 718–726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wood SJ, Yucel M, Wellard RM, Harrison BJ, Clarke K, Fornito A et al. Evidence for neuronal dysfunction in the anterior cingulate of patients with schizophrenia: a proton magnetic resonance spectroscopy study at 3T. Schizophr Res 2007; 94: 328–331.

    Article  PubMed  Google Scholar 

  61. Kraguljac NV, Reid MA, White DM, den Hollander J, Lahti AC . Regional decoupling of N-acetyl-aspartate and glutamate in schizophrenia. Neuropsychopharmacology 2012; 37: 2635–2642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bustillo JR, Rowland LM, Mullins P, Jung R, Chen H, Qualls C et al. 1H-MRS at 4 tesla in minimally treated early schizophrenia. Mol Psychiatry 2010; 15: 629–636.

    Article  CAS  PubMed  Google Scholar 

  63. Reid MA, Stoeckel LE, White DM, Avsar KB, Bolding MS, Akella NS et al. Assessments of function and biochemistry of the anterior cingulate cortex in schizophrenia. Biol Psychiatry 2010; 68: 625–633.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Choe BY, Suh TS, Shinn KS, Lee CW, Lee C, Paik IH . Observation of metabolic changes in chronic schizophrenia after neuroleptic treatment by in vivo hydrogen magnetic resonance spectroscopy. Invest Radiol 1996; 31: 345–352.

    Article  CAS  PubMed  Google Scholar 

  65. Szulc A, Galinska B, Tarasow E, Dzienis W, Kubas B, Konarzewska B et al. The effect of risperidone on metabolite measures in the frontal lobe, temporal lobe, and thalamus in schizophrenic patients. A proton magnetic resonance spectroscopy (1H MRS). Pharmacopsychiatry 2005; 38: 214–219.

    Article  CAS  PubMed  Google Scholar 

  66. Egerton A, Brugger S, Raffin M, Barker GJ, Lythgoe DJ, McGuire PK et al. Anterior cingulate glutamate levels related to clinical status following treatment in first-episode schizophrenia. Neuropsychopharmacology 2012; 37: 2515–2521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Thomas MA, Ke Y, Levitt J, Caplan R, Curran J, Asarnow R et al. Preliminary study of frontal lobe 1H MR spectroscopy in childhood-onset schizophrenia. J Magn Reson Imaging 1998; 8: 841–846.

    Article  CAS  PubMed  Google Scholar 

  68. Chang L, Friedman J, Ernst T, Zhong K, Tsopelas ND, Davis K . Brain metabolite abnormalities in the white matter of elderly schizophrenic subjects: implication for glial dysfunction. Biol Psychiatry 2007; 62: 1396–1404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ota M, Ishikawa M, Sato N, Hori H, Sasayama D, Hattori K et al. Glutamatergic changes in the cerebral white matter associated with schizophrenic exacerbation. Acta Psychiatr Scand 2012; 126: 72–78.

    Article  CAS  PubMed  Google Scholar 

  70. Hutcheson NL, Reid MA, White DM, Kraguljac NV, Avsar KB, Bolding MS et al. Multimodal analysis of the hippocampus in schizophrenia using proton magnetic resonance spectroscopy and functional magnetic resonance imaging. Schizophr Res 2012; 140: 136–142.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Bartha R, al-Semaan YM, Williamson PC, Drost DJ, Malla AK, Carr TJ et al. A short echo proton magnetic resonance spectroscopy study of the left mesial-temporal lobe in first-onset schizophrenic patients. Biol Psychiatry 1999; 45: 1403–1411.

    Article  CAS  PubMed  Google Scholar 

  72. Fusar-Poli P, Stone JM, Broome MR, Valli I, Mechelli A, McLean MA et al. Thalamic glutamate levels as a predictor of cortical response during executive functioning in subjects at high risk for psychosis. Arch Gen Psychiatry 2011; 68: 881–890.

    Article  CAS  PubMed  Google Scholar 

  73. Valli I, Stone J, Mechelli A, Bhattacharyya S, Raffin M, Allen P et al. Altered medial temporal activation related to local glutamate levels in subjects with prodromal signs of psychosis. Biol Psychiatry 2011; 69: 97–99.

    Article  CAS  PubMed  Google Scholar 

  74. Theberge J, Al-Semaan Y, Jensen JE, Williamson PC, Neufeld RW, Menon RS et al. Comparative study of proton and phosphorus magnetic resonance spectroscopy in schizophrenia at 4 Tesla. Psychiatry Res 2004; 132: 33–39.

    Article  PubMed  Google Scholar 

  75. Keshavan MS, Dick RM, Diwadkar VA, Montrose DM, Prasad KM, Stanley JA . Striatal metabolic alterations in non-psychotic adolescent offspring at risk for schizophrenia: a (1)H spectroscopy study. Schizophr Res 2009; 115: 88–93.

    Article  PubMed  Google Scholar 

  76. Stone JM, Day F, Tsagaraki H, Valli I, McLean MA, Lythgoe DJ et al. Glutamate dysfunction in people with prodromal symptoms of psychosis: relationship to gray matter volume. Biol Psychiatry 2009; 66: 533–539.

    Article  CAS  PubMed  Google Scholar 

  77. de la Fuente-Sandoval C, Leon-Ortiz P, Favila R, Stephano S, Mamo D, Ramirez-Bermudez J et al. Higher levels of glutamate in the associative-striatum of subjects with prodromal symptoms of schizophrenia and patients with first-episode psychosis. Neuropsychopharmacology 2011; 36: 1781–1791.

    Article  CAS  PubMed  Google Scholar 

  78. Tayoshi S, Sumitani S, Taniguchi K, Shibuya-Tayoshi S, Numata S, Iga J et al. Metabolite changes and gender differences in schizophrenia using 3-Tesla proton magnetic resonance spectroscopy (1H-MRS). Schizophr Res 2009; 108: 69–77.

    Article  PubMed  Google Scholar 

  79. de la Fuente-Sandoval C, Leon-Ortiz P, Azcarraga M, Stephano S, Favila R, Diaz-Galvis L et al. Glutamate in the associative striatum before and after 4 weeks of antipsychotic treatment in first-episodepsychosis: a longitudinal proton magnetic resonance spectroscopy study. JAMA Psychiatry 2013; 70: 1057–1066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. de la Fuente-Sandoval C, Leon-Ortiz P, Azcarraga M, Favila R, Stephano S, Graff-Guerrero A . Striatal glutamate and the conversion to psychosis: a prospective 1H-MRS imaging study. Int J Neuropsychopharmacol 2013; 16: 471–475.

    Article  CAS  PubMed  Google Scholar 

  81. Stone JM, Dietrich C, Edden R, Mehta MA, De Simoni S, Reed LJ et al. Ketamine effects on brain GABA and glutamate levels with 1H-MRS: relationship to ketamine-induced psychopathology. Mol Psychiatry 2012; 17: 664–665.

    Article  CAS  PubMed  Google Scholar 

  82. Rowland LM, Bustillo JR, Mullins PG, Jung RE, Lenroot R, Landgraf E et al. Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: a 4-T proton MRS study. Am J Psychiatry 2005; 162: 394–396.

    Article  PubMed  Google Scholar 

  83. Taylor MJ, Tiangga ER, Mhuircheartaigh RN, Cowen PJ . Lack of effect of ketamine on cortical glutamate and glutamine in healthy volunteers: a proton magnetic resonance spectroscopy study. J Psychopharmacol 2012; 26: 733–737.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Bressan RA, Erlandsson K, Mulligan RS, Gunn RN, Cunningham VJ, Owens J et al. Evaluation of NMDA receptors in vivo in schizophrenic patients with [123I]CNS 1261 and SPET: preliminary findings. Ann NY Acad Sci 2003; 1003: 364–367.

    Article  CAS  PubMed  Google Scholar 

  85. Bressan RA, Erlandsson K, Stone JM, Mulligan RS, Krystal JH, Ell PJ et al. Impact of schizophrenia and chronic antipsychotic treatment on [123I]CNS-1261 binding to N-methyl-D-aspartate receptors in vivo. Biol Psychiatry 2005; 58: 41–46.

    Article  CAS  PubMed  Google Scholar 

  86. Pilowsky LS, Bressan RA, Stone JM, Erlandsson K, Mulligan RS, Krystal JH et al. First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients. Mol Psychiatry 2006; 11: 118–119.

    Article  CAS  PubMed  Google Scholar 

  87. Stone JM, Erlandsson K, Arstad E, Squassante L, Teneggi V, Bressan RA et al. Relationship between ketamine-induced psychotic symptoms and NMDA receptor occupancy: a [(123)I]CNS-1261 SPET study. Psychopharmacology 2008; 197: 401–408.

    Article  CAS  PubMed  Google Scholar 

  88. Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 2007; 27: 1533–1539.

    Article  CAS  PubMed  Google Scholar 

  89. Dean O, Giorlando F, Berk M . N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci 2011; 36: 78–86.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Kohr G, Eckardt S, Luddens H, Monyer H, Seeburg PH . NMDA receptor channels: subunit-specific potentiation by reducing agents. Neuron 1994; 12: 1031–1040.

    Article  CAS  PubMed  Google Scholar 

  91. Atkuri KR, Mantovani JJ, Herzenberg LA . N-Acetylcysteine—a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol 2007; 7: 355–359.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Duarte JM, Kulak A, Gholam-Razaee MM, Cuenod M, Gruetter R, Do KQ . N-acetylcysteine normalizes neurochemical changes in the glutathione-deficient schizophrenia mouse model during development. Biol Psychiatry 2012; 71: 1006–1014.

    Article  CAS  Google Scholar 

  93. Steullet P, Neijt HC, Cuenod M, Do KQ . Synaptic plasticity impairment and hypofunction of NMDA receptors induced by glutathione deficit: relevance to schizophrenia. Neuroscience 2006; 137: 807–819.

    Article  CAS  PubMed  Google Scholar 

  94. Dean O, Bush AI, Berk M, Copolov DL, van den Buuse M . Glutathione depletion in the brain disrupts short-term spatial memory in the Y-maze in rats and mice. Behav Brain Res 2009; 198: 258–262.

    Article  CAS  PubMed  Google Scholar 

  95. Cruz-Aguado R, Almaguer-Melian W, Diaz CM, Lorigados L, Bergado J . Behavioral and biochemical effects of glutathione depletion in the rat brain. Brain Res Bull 2001; 55: 327–333.

    Article  CAS  PubMed  Google Scholar 

  96. Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I et al. N-acetyl cysteine as a glutathione precursor for schizophrenia—a double-blind, randomized, placebo-controlled trial. Biol Psychiatry 2008; 64: 361–368.

    Article  CAS  PubMed  Google Scholar 

  97. Wood SJ, Berger GE, Wellard RM, Proffitt TM, McConchie M, Berk M et al. Medial temporal lobe glutathione concentration in first episode psychosis: a 1H-MRS investigation. Neurobiol Dis 2009; 33: 354–357.

    Article  CAS  PubMed  Google Scholar 

  98. Do KQ, Trabesinger AH, Kirsten-Kruger M, Lauer CJ, Dydak U, Hell D et al. Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. Eur J Neurosci 2000; 12: 3721–3728.

    Article  CAS  PubMed  Google Scholar 

  99. Matsuzawa D, Obata T, Shirayama Y, Nonaka H, Kanazawa Y, Yoshitome E et al. Negative correlation between brain glutathione level and negative symptoms in schizophrenia: a 3T 1H-MRS study. PLoS One 2008; 3: e1944.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Terpstra M, Vaughan TJ, Ugurbil K, Lim KO, Schulz SC, Gruetter R . Validation of glutathione quantitation from STEAM spectra against edited 1H NMR spectroscopy at 4T: application to schizophrenia. MAGMA 2005; 18: 276–282.

    Article  CAS  PubMed  Google Scholar 

  101. Trabesinger AH, Boesiger P . Improved selectivity of double quantum coherence filtering for the detection of glutathione in the human brain in vivo. Magn Reson Med 2001; 45: 708–710.

    Article  CAS  PubMed  Google Scholar 

  102. Zhao T, Heberlein K, Jonas C, Jones DP, Hu X . New double quantum coherence filter for localized detection of glutathione in vivo. Magn Reson Med 2006; 55: 676–680.

    Article  CAS  PubMed  Google Scholar 

  103. Huang HL, Yeh CN, Chang KW, Chen JT, Lin KJ, Chiang LW et al. Synthesis and evaluation of [18F]Fluorobutyl ethacrynic amide: a potential PET tracer for studying glutathione transferase. Bioorg Med Chem Lett 2012; 22: 3998–4003.

    Article  CAS  PubMed  Google Scholar 

  104. Caglar M, Ciftci I, Hosal S, Kilinc K, Ercan MT . Detection of head and neck cancer with 99Tc(m) glutathione: a correlative study with tissue glutathione and glutathione S-transferase levels. Nucl Med Commun 2001; 22: 33–38.

    Article  CAS  PubMed  Google Scholar 

  105. Gunn RN, Murthy V, Catafau AM, Searle G, Bullich S, Slifstein M et al. Translational characterization of [11C]GSK931145, a PET ligand for the glycine transporter type 1. Synapse 2011; 65: 1319–1332.

    Article  CAS  PubMed  Google Scholar 

  106. Bullich S, Slifstein M, Passchier J, Murthy NV, Kegeles LS, Kim JH et al. Biodistribution and radiation dosimetry of the glycine transporter-1 ligand 11C-GSK931145 determined from primate and human whole-body PET. Mol Imaging Biol 2011; 13: 776–784.

    Article  PubMed  Google Scholar 

  107. Wong DF, Ostrowitzki S, Zhou Y, Raymont V, Hofmann C, Borroni E et al. Characterization of [(11)C]RO5013853, a novel PET tracer for the glycine transporter type 1 (GlyT1) in humans. Neuroimage 2011; 15: 282–290.

    Google Scholar 

  108. Martin-Facklam M, Pizzagalli F, Zhou Y, Ostrowitzki S, Raymont V, Brasic JR et al. Glycine transporter type 1 occupancy by bitopertin: a positron emission tomography study in healthy volunteers. Neuropsychopharmacology 2013; 38: 504–512.

    Article  CAS  PubMed  Google Scholar 

  109. Zheng M, Holden D, Hamill T, Lin S, Ropchan J, Najafzadeh S et al. Comparative study of two glycine transporter 1 radiotracers [11C]GSK931145 and [18F]MK6577 in baboons. J Nucl Med Meeting Abstracts 2013; 54: 414.

    Google Scholar 

  110. Hamill TG, Eng W, Jennings A, Lewis R, Thomas S, Wood S et al. The synthesis and preclinical evaluation in rhesus monkey of [(1)(8)F]MK-6577 and [(1)(1)C]CMPyPB glycine transporter 1 positron emission tomography radiotracers. Synapse 2011; 65: 261–270.

    Article  CAS  PubMed  Google Scholar 

  111. Chavez-Noriega LE, Schaffhauser H, Campbell UC . Metabotropic glutamate receptors: potential drug targets for the treatment of schizophrenia. Curr Drug Targets CNS Neurol Disord 2002; 1: 261–281.

    Article  CAS  PubMed  Google Scholar 

  112. Javitt DC . Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry 2004; 9: 984–997, 979.

    Article  CAS  PubMed  Google Scholar 

  113. Pisani A, Bernardi G, Bonsi P, Centonze D, Giacomini P, Calabresi P . Cell-type specificity of mGluR activation in striatal neuronal subtypes. Amino Acids 2000; 19: 119–129.

    Article  CAS  PubMed  Google Scholar 

  114. Pisani A, Gubellini P, Bonsi P, Conquet F, Picconi B, Centonze D et al. Metabotropic glutamate receptor 5 mediates the potentiation of N-methyl-D-aspartate responses in medium spiny striatal neurons. Neuroscience 2001; 106: 579–587.

    Article  CAS  PubMed  Google Scholar 

  115. Krystal JH, Mathew SJ, D'Souza DC, Garakani A, Gunduz-Bruce H, Charney DS . Potential psychiatric applications of metabotropic glutamate receptor agonists and antagonists. CNS Drugs 2010; 24: 669–693.

    Article  CAS  PubMed  Google Scholar 

  116. Ehlers MD . Synapse structure: glutamate receptors connected by the shanks. Curr Biol 1999; 9: R848–R850.

    Article  CAS  PubMed  Google Scholar 

  117. Naisbitt S, Kim E, Tu JC, Xiao B, Sala C, Valtschanoff J et al. Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin. Neuron 1999; 23: 569–582.

    Article  CAS  PubMed  Google Scholar 

  118. Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brakeman P et al. Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron 1999; 23: 583–592.

    Article  CAS  PubMed  Google Scholar 

  119. Liu F, Grauer S, Kelley C, Navarra R, Graf R, Zhang G et al. ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piper idin-1-yl}-methanone]: a novel metabotropic glutamate receptor 5-selective positive allosteric modulator with preclinical antipsychotic-like and procognitive activities. J Pharmacol Exp Ther 2008; 327: 827–839.

    Article  CAS  PubMed  Google Scholar 

  120. Uslaner JM, Parmentier-Batteur S, Flick RB, Surles NO, Lam JS, McNaughton CH et al. Dose-dependent effect of CDPPB, the mGluR5 positive allosteric modulator, on recognition memory is associated with GluR1 and CREB phosphorylation in the prefrontal cortex and hippocampus. Neuropharmacology 2009; 57: 531–538.

    Article  CAS  PubMed  Google Scholar 

  121. Ayala JE, Chen Y, Banko JL, Sheffler DJ, Williams R, Telk AN et al. mGluR5 positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning. Neuropsychopharmacology 2009; 34: 2057–2071.

    Article  CAS  PubMed  Google Scholar 

  122. Koros E, Rosenbrock H, Birk G, Weiss C, Sams-Dodd F . The selective mGlu5 receptor antagonist MTEP, similar to NMDA receptor antagonists, induces social isolation in rats. Neuropsychopharmacology 2007; 32: 562–576.

    Article  CAS  PubMed  Google Scholar 

  123. Lu YM, Jia Z, Janus C, Henderson JT, Gerlai R, Wojtowicz JM et al. Mice lacking metabotropic glutamate receptor 5 show impaired learning and reduced CA1 long-term potentiation (LTP) but normal CA3 LTP. J Neurosci 1997; 17: 5196–5205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Kinney GG, Burno M, Campbell UC, Hernandez LM, Rodriguez D, Bristow LJ et al. Metabotropic glutamate subtype 5 receptors modulate locomotor activity and sensorimotor gating in rodents. J Pharmacol Exp Ther 2003; 306: 116–123.

    Article  CAS  PubMed  Google Scholar 

  125. Brody SA, Conquet F, Geyer MA . Effect of antipsychotic treatment on the prepulse inhibition deficit of mGluR5 knockout mice. Psychopharmacology (Berl) 2004; 172: 187–195.

    Article  CAS  Google Scholar 

  126. Henry SA, Lehmann-Masten V, Gasparini F, Geyer MA, Markou A . The mGluR5 antagonist MPEP, but not the mGluR2/3 agonist LY314582, augments PCP effects on prepulse inhibition and locomotor activity. Neuropharmacology 2002; 43: 1199–1209.

    Article  CAS  PubMed  Google Scholar 

  127. Ametamey SM, Kessler LJ, Honer M, Wyss MT, Buck A, Hintermann S et al. Radiosynthesis and preclinical evaluation of 11C-ABP688 as a probe for imaging the metabotropic glutamate receptor subtype 5. J Nucl Med 2006; 47: 698–705.

    CAS  PubMed  Google Scholar 

  128. Delorenzo C, Kumar JS, Mann JJ, Parsey RV . In vivo variation in metabotropic glutamate receptor subtype 5 binding using positron emission tomography and [(11)C]ABP688. J Cereb Blood Flow Metab 2011; 31: 2169–2180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Miyake N, Skinbjerg M, Easwaramoorthy B, Kumar D, Girgis RR, Xu X et al. Imaging changes in glutamate transmission in vivo with the metabotropic glutamate receptor 5 tracer [11C] ABP688 and N-acetylcysteine challenge. Biol Psychiatry 2011; 69: 822–824.

    Article  CAS  PubMed  Google Scholar 

  130. Elmenhorst D, Aliaga A, Bauer A, Rosa-Neto P . Test-retest stability of cerebral mGluR(5) quantification using [(1)(1)C]ABP688 and positron emission tomography in rats. Synapse 2012; 66: 552–560.

    Article  CAS  PubMed  Google Scholar 

  131. DeLorenzo C, Milak MS, Brennan KG, Kumar JS, Mann JJ, Parsey RV . In vivo positron emission tomography imaging with [(1)(1)C]ABP688: binding variability and specificity for the metabotropic glutamate receptor subtype 5 in baboons. Eur J Nucl Med Mol Imaging 2011; 38: 1083–1094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Hefti K, Holst SC, Sovago J, Bachmann V, Buck A, Ametamey SM et al. Increased metabotropic glutamate receptor subtype 5 availability in human brain after one night without sleep. Biol Psychiatry 2012; 73: 161–168.

    Article  PubMed  CAS  Google Scholar 

  133. Deschwanden A, Karolewicz B, Feyissa AM, Treyer V, Ametamey SM, Johayem A et al. Reduced metabotropic glutamate receptor 5 density in major depression determined by [(11)C]ABP688 PET and postmortem study. Am J Psychiatry 2011; 168: 727–734.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Sullivan JM, Lim K, Labaree D, Lin SF, McCarthy TJ, Seibyl JP et al. Kinetic analysis of the metabotropic glutamate subtype 5 tracer [(18)F]FPEB in bolus and bolus-plus-constant-infusion studies in humans. J Cereb Blood Flow Metab 2013; 33: 532–541.

    Article  CAS  PubMed  Google Scholar 

  135. Wong DF, Waterhouse R, Kuwabara H, Kim J, Brasic JR, Chamroonrat W et al. 18F-FPEB, a PET radiopharmaceutical for quantifying metabotropic glutamate 5 receptors: a first-in-human study of radiochemical safety, biokinetics, and radiation dosimetry. J Nucl Med 2013; 54: 388–396.

    Article  CAS  PubMed  Google Scholar 

  136. Kapur S, Zipursky R, Jones C, Remington G, Houle S . Relationship between dopamine D-2 occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry 2000; 157: 514–520.

    Article  CAS  PubMed  Google Scholar 

  137. Nordstrom AL, Farde L, Wiesel FA, Forslund K, Pauli S, Halldin C et al. Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects–a double-blind pet study of schizophrenic-patients. Biol Psychiatry 1993; 33: 227–235.

    Article  CAS  PubMed  Google Scholar 

  138. Kinon BJ, Zhang L, Millen BA, Osuntokun OO, Williams JE, Kollack-Walker S et al. A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia. J Clin Psychopharmacol 2011; 31: 349–355.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Institute of Mental Health (P50 MH066171-01A1) and NCRR grant 2KL2RR024157-06.

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Authors and Affiliations

  1. Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA

    E M P Poels, L S Kegeles, J T Kantrowitz, M Slifstein, D C Javitt, J A Lieberman, A Abi-Dargham & R R Girgis

  2. New York State Psychiatric Institute, New York, NY, USA

    E M P Poels, L S Kegeles, J T Kantrowitz, M Slifstein, D C Javitt, J A Lieberman, A Abi-Dargham & R R Girgis

  3. Department of Radiology, Columbia University College of Physicians and Surgeons, New York, NY, USA

    A Abi-Dargham

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  1. E M P Poels
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  2. L S Kegeles
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Correspondence to R R Girgis.

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Competing interests

EMP Poels declares no conflict of interest. Dr Kegeles has received research support from Pfizer and Amgen. Dr Kantrowitz reports having received consulting payments within the last 2 years from Quadrant Health, RTI Health solutions, the Sacoor Medical Group, the Healthcare Advisory Board and AgencyRx. He has conducted clinical research supported by the NIMH, Roche-Genetech, EnVivo, Psychogenics, Sunovion, Novartis, Pfizer, Lilly and GlaxoSmithKline. He owns a small number of shares of common stock in GlaxoSmithKline. Dr Slifstein has consulted for Amgen and has received research support from Pierre Fabre. Dr Javitt holds intellectual property for use of glycine, D-serine and glycine transport inhibitors in the treatment of schizophrenia, and holds equity in Glytech. Dr Lieberman serves on the Advisory Board of Bioline, Intracellular Therapies and PsychoGenics. He does not receive direct financial compensation or salary support for participation in research, consulting or advisory board activities. He receives grant support from Allon, F Hoffman-La Roche, GlaxoSmithKline, Eli Lilly, Merck, Novartis, Pfizer, Psychogenics, Sepracor (Sunovion) and Targacept; and he holds a patent from Repligen. Dr Abi-Dargham has received research support from Pierre Fabre and Forest, and has been a consultant for or on the scientific advisory board of Roche, Pfizer, Takeda, Otsuka, Amgen and Shire. Dr Girgis has received research support from Eli Lilly through APIRE.

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Poels, E., Kegeles, L., Kantrowitz, J. et al. Imaging glutamate in schizophrenia: review of findings and implications for drug discovery. Mol Psychiatry 19, 20–29 (2014). https://doi.org/10.1038/mp.2013.136

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