Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Glutamatergic and GABAergic metabolite levels in schizophrenia-spectrum disorders: a meta-analysis of 1H-magnetic resonance spectroscopy studies

Molecular Psychiatry volume 27, pages 744–757 (2022)Cite this article

Subjects

Abstract

Background

The glutamate (Glu) and gamma aminobutyric acid (GABA) hypotheses of schizophrenia were proposed in the 1980s. However, current findings on those metabolite levels in schizophrenia have been inconsistent, and the relationship between their abnormalities and the pathophysiology of schizophrenia remains unclear. To summarize the nature of the alterations of glutamatergic and GABAergic systems in schizophrenia, we conducted meta-analyses of proton magnetic resonance spectroscopy (1H-MRS) studies examining these metabolite levels.

Methods

A systematic literature search was conducted using Embase, Medline, PsycINFO, and PubMed. Original studies that compared four metabolite levels (Glu, glutamine [Gln], Glx [Glu+Gln], and GABA), as measured by 1H-MRS, between individuals at high risk for psychosis, patients with first-episode psychosis, or patients with schizophrenia and healthy controls (HC) were included. A random-effects model was used to calculate the effect sizes for group differences in these metabolite levels of 18 regions of interest between the whole group or schizophrenia group and HC. Subgroup analysis and meta-regression were performed based on the status of antipsychotic treatment, illness stage, treatment resistance, and magnetic field strength.

Results

One-hundred-thirty-four studies met the eligibility criteria, totaling 7993 participants with SZ-spectrum disorders and 8744 HC. 14 out of 18 ROIs had enough numbers of studies to examine the group difference in the metabolite levels. In the whole group, Glx levels in the basal ganglia (g = 0.32; 95% CIs: 0.18–0.45) were elevated. Subgroup analyses showed elevated Glx levels in the hippocampus (g = 0.47; 95% CIs: 0.21–0.73) and dorsolateral prefrontal cortex (g = 0.25; 95% CIs: 0.05–0.44) in unmedicated patients than HC. GABA levels in the MCC were decreased in the first-episode psychosis group compared with HC (g = −0.40; 95% CIs: −0.62 to −0.17). Treatment-resistant schizophrenia (TRS) group had elevated Glx and Glu levels in the MCC (Glx: g = 0.7; 95% CIs: 0.38–1.01; Glu: g = 0.63; 95% CIs: 0.31–0.94) while MCC Glu levels were decreased in the patient group except TRS (g = −0.17; 95% CIs: −0.33 to −0.01).

Conclusions

Increased glutamatergic metabolite levels and reduced GABA levels indicate that the disruption of excitatory/inhibitory balance may be related to the pathophysiology of schizophrenia-spectrum disorders.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Summary effect sizes for metabolite group differences in each brain region.

Similar content being viewed by others

References

  1. Kim JS, Kornhuber HH, Schmid-Burgk W, Holzmüller B. Low cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis on schizophrenia. Neurosci Lett. 1980;20:379–82.

    Article  CAS  PubMed  Google Scholar 

  2. Grace AA. Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nat Rev Neurosci 2016;17:524–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cohen SM, Tsien RW, Goff DC, Halassa MM. The impact of NMDA receptor hypofunction on GABAergic neurons in the pathophysiology of schizophrenia. Schizophr Res 2015;167:98–107.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Coyle JT. NMDA receptor and schizophrenia: a brief history. Schizophr Bull 2012;38:920–6.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Consortium SWG of TPG, Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014;511:421–7.

    Article  Google Scholar 

  6. Ferguson BR, Gao W-J. PV Interneurons: Critical Regulators of E/I Balance for Prefrontal Cortex-Dependent Behavior and Psychiatric Disorders. Front Neural Circuits. 2018;12:37.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Marsman A, van den Heuvel MP, Klomp DWJ, Kahn RS, Luijten PR, Hulshoff, et al. Glutamate in schizophrenia: a focused review and meta-analysis of 1H-MRS studies. Schizophr Bull. 2013;39:120–9.

    Article  PubMed  Google Scholar 

  8. Merritt K, Egerton A, Kempton MJ, Taylor MJ, McGuire PK. Nature of Glutamate Alterations in Schizophrenia: A Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies. JAMA Psychiatry. 2016;73:665–74.

    Article  PubMed  Google Scholar 

  9. Egerton A, Modinos G, Ferrera D, McGuire P. Neuroimaging studies of GABA in schizophrenia: a systematic review with meta-analysis. Transl Psychiatry. 2017;7:e1147.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wenneberg C, Glenthøj BY, Hjorthøj C, Zingenberg FJB, Glenthøj LB, Rostrup E, et al. Cerebral glutamate and GABA levels in high-risk of psychosis states: A focused review and meta-analysis of 1H-MRS studies. Schizophrenia Res. 2020;215:38–48.

    Article  Google Scholar 

  11. Iwata Y, Nakajima S, Plitman E, Mihashi Y, Caravaggio F, Chung JK, et al. Neurometabolite levels in antipsychotic-naïve/free patients with schizophrenia: A systematic review and meta-analysis of 1H-MRS studies. Prog Neuro-Psychopharmacol Biol Psychiatry. 2018;86:340–52.

    Article  CAS  Google Scholar 

  12. Kumar J, Liddle EB, Fernandes CC, Palaniyappan L, Hall EL, Robson SE, et al. Glutathione and glutamate in schizophrenia: a 7T MRS study. Mol Psychiatry 2020;25:873–82.

    Article  CAS  PubMed  Google Scholar 

  13. Sydnor VJ, Roalf DR. A meta-analysis of ultra-high field glutamate, glutamine, GABA and glutathione 1HMRS in psychosis: Implications for studies of psychosis risk. Schizophr Res 2020;226:61–9.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kaminski J, Mascarell-Maricic L, Fukuda Y, Katthagen T, Heinz A, Schlagenhauf F. Glutamate in the Dorsolateral Prefrontal Cortex in Patients With Schizophrenia: A Meta-analysis of H-Magnetic Resonance Spectroscopy Studies. Biol Psychiatry 2021;89:270–7.

    Article  CAS  PubMed  Google Scholar 

  15. Kumar V, Vajawat B, Rao NP. Frontal GABA in schizophrenia: A meta-analysis of H-MRS studies. World J Biol Psychiatry 2021;22:1–13.

    Article  PubMed  Google Scholar 

  16. Bush G, Shin LM, Holmes J, Rosen BR, Vogt BA. The Multi-Source Interference Task: validation study with fMRI in individual subjects. Mol Psychiatry 2003;8:60–70.

    Article  CAS  PubMed  Google Scholar 

  17. Egerton A, Broberg BV, Van Haren N, Merritt K, Barker GJ, Lythgoe DJ, et al. Response to initial antipsychotic treatment in first episode psychosis is related to anterior cingulate glutamate levels: a multicentre H-MRS study (OPTiMiSE). Mol Psychiatry 2018;23:2145–55.

    Article  CAS  PubMed  Google Scholar 

  18. 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;8:119–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Aoyama N, Théberge J, Drost DJ, Manchanda R, Northcott S, Neufeld RWJ, et al. Grey matter and social functioning correlates of glutamatergic metabolite loss in schizophrenia. Br J Psychiatry 2011;198:448–56.

    Article  PubMed  Google Scholar 

  20. Kubota M, Moriguchi S, Takahata K, Nakajima S, Horita N. Treatment effects on neurometabolite levels in schizophrenia: A systematic review and meta-analysis of proton magnetic resonance spectroscopy studies. Schizophr Res 2020;222:122–32.

    Article  PubMed  Google Scholar 

  21. Moher D, Liberati A, Tetzlaff J, Altman DG, for the PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009;339:b2535–b2535.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Snyder J, Wilman A. Field strength dependence of PRESS timings for simultaneous detection of glutamate and glutamine from 1.5 to 7T. J Magn Reson 2010;203:66–72.

    Article  CAS  PubMed  Google Scholar 

  23. Kim SY, Park JE, Lee YJ, Seo H-J, Sheen S-S, Hahn S, et al. Testing a tool for assessing the risk of bias for nonrandomized studies showed moderate reliability and promising validity. J Clin Epidemiol 2013;66:408–14.

    Article  PubMed  Google Scholar 

  24. Galińska B, Szulc A, Tarasów 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:CR82–8.

    PubMed  Google Scholar 

  25. 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;68:625–33.

    Article  PubMed  PubMed Central  Google Scholar 

  26. 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;66:533–9.

    Article  CAS  PubMed  Google Scholar 

  27. Purdon SE, Valiakalayil A, Hanstock CC, Seres P, Tibbo P. Elevated 3T proton MRS glutamate levels associated with poor Continuous Performance Test (CPT-0X) scores and genetic risk for schizophrenia. Schizophr Res 2008;99:218–24.

    Article  PubMed  Google Scholar 

  28. 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;62:1396–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wood SJ, Yücel 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 3 T. Schizophr Res 2007;94:328–31.

    Article  PubMed  Google Scholar 

  30. Girgis RR, Baker S, Mao X, Gil R, Javitt DC, Kantrowitz JT, et al. Effects of acute N-acetylcysteine challenge on cortical glutathione and glutamate in schizophrenia: A pilot in vivo proton magnetic resonance spectroscopy study. Psychiatry Res 2019;275:78–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Iwata Y, Nakajima S, Plitman E, Caravaggio F, Kim J, Shah P, et al. Glutamatergic Neurometabolite Levels in Patients With Ultra-Treatment-Resistant Schizophrenia: A Cross-Sectional 3T Proton Magnetic Resonance Spectroscopy Study. Biol Psychiatry 2019;85:596–605.

    Article  CAS  PubMed  Google Scholar 

  32. de la Fuente-Sandoval C, Reyes-Madrigal F, Mao X, León-Ortiz P, Rodríguez-Mayoral O, Jung-Cook H, et al. Prefrontal and Striatal Gamma-Aminobutyric Acid Levels and the Effect of Antipsychotic Treatment in First-Episode Psychosis Patients. Biol Psychiatry 2018;83:475–83.

    Article  PubMed  Google Scholar 

  33. Shakory S, Watts JJ, Hafizi S, Da Silva T, Khan S, Kiang M, et al. Hippocampal glutamate metabolites and glial activation in clinical high risk and first episode psychosis. Neuropsychopharmacology 2018;43:2249–55.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Modinos G, Simsek F, Horder J, Bossong M, Bonoldi I, Azis M, et al. Cortical GABA in Subjects at Ultra-High Risk of Psychosis: Relationship to Negative Prodromal Symptoms. Int J Neuropsychopharmacol 2018;21:114–9.

    Article  CAS  PubMed  Google Scholar 

  35. Plitman E, Chavez S, Nakajima S, Iwata Y, Chung JK, Caravaggio F, et al. Striatal neurometabolite levels in patients with schizophrenia undergoing long-term antipsychotic treatment: A proton magnetic resonance spectroscopy and reliability study. Psychiatry Res Neuroimaging 2018;273:16–24.

    Article  PubMed  Google Scholar 

  36. Pillinger T, Rogdaki M, McCutcheon RA, Hathway P, Egerton A, Howes OD. Altered glutamatergic response and functional connectivity in treatment resistant schizophrenia: the effect of riluzole and therapeutic implications. Psychopharmacology 2019;236:1985–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chiappelli J, Rowland LM, Notarangelo FM, Wijtenburg SA, Thomas MAR, Pocivavsek A, et al. Salivary kynurenic acid response to psychological stress: inverse relationship to cortical glutamate in schizophrenia. Neuropsychopharmacology 2018;43:1706–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Modinos G, Egerton A, McLaughlin A, McMullen K, Kumari V, Lythgoe DJ, et al. Neuroanatomical changes in people with high schizotypy: relationship to glutamate levels. Psychol Med 2018;48:1880–9.

    Article  PubMed  Google Scholar 

  39. Legind CS, Broberg BV, Mandl RCW, Brouwer R, Anhøj SJ, Hilker R, et al. Heritability of cerebral glutamate levels and their association with schizophrenia spectrum disorders: a [H]-spectroscopy twin study. Neuropsychopharmacology 2019;44:581–9.

    Article  CAS  PubMed  Google Scholar 

  40. Huang M, Guo W, Lu S, Pan F, Chen J, Hu J, et al. The relationship between the alterations in metabolite levels in the dorsolateral prefrontal cortex and clinical symptoms of patients with first-episode schizophrenia: a one year follow-up study. Oncotarget 2019;10:606–15.

    Article  CAS  PubMed  Google Scholar 

  41. Grent-’t-Jong T, Gross J, Goense J, Wibral M, Gajwani R, Gumley AI, et al. Resting-state gamma-band power alterations in schizophrenia reveal E/I-balance abnormalities across illness-stages. Elife. 2018;7.

  42. Chiu PW, Lui SSY, Hung KSY, Chan RCK, Chan Q, Sham PC, et al. In vivo gamma-aminobutyric acid and glutamate levels in people with first-episode schizophrenia: A proton magnetic resonance spectroscopy study. Schizophr Res 2018;193:295–303.

    Article  CAS  PubMed  Google Scholar 

  43. White DM, Kraguljac NV, Reid MA, Lahti AC. Contribution of substantia nigra glutamate to prediction error signals in schizophrenia: a combined magnetic resonance spectroscopy/functional imaging study. NPJ Schizophr 2015;1:14001.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Sivaraman S, Kraguljac NV, White DM, Morgan CJ, Gonzales SS, Lahti AC. Neurometabolic abnormalities in the associative striatum in antipsychotic-naïve first episode psychosis patients. Psychiatry Res Neuroimaging 2018;281:101–6.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Maddock RJ, Caton MD, Daniel Ragland J. Estimating glutamate and Glx from GABA-optimized MEGA-PRESS: Off-resonance but not difference spectra values correspond to PRESS values. Psychiatry Res: Neuroimaging 2018;279:22–30.

    Article  PubMed  Google Scholar 

  46. Singh S, Khushu S, Kumar P, Goyal S, Bhatia T, Deshpande SN. Evidence for regional hippocampal damage in patients with schizophrenia. Neuroradiology 2018;60:199–205.

    Article  PubMed  Google Scholar 

  47. Ćurčić-Blake B, Bais L, Sibeijn-Kuiper A, Pijnenborg HM, Knegtering H, Liemburg E, et al. Glutamate in dorsolateral prefrontal cortex and auditory verbal hallucinations in patients with schizophrenia: A H MRS study. Prog Neuropsychopharmacol Biol Psychiatry 2017;78:132–9.

    Article  PubMed  Google Scholar 

  48. Wijtenburg SA, Andrea Wijtenburg S, Wright SN, Korenic SA, Gaston FE, Ndubuizu N, et al. Altered Glutamate and Regional Cerebral Blood Flow Levels in Schizophrenia: A 1H-MRS and pCASL study. Neuropsychopharmacology 2017;42:562–71.

    Article  CAS  PubMed  Google Scholar 

  49. Thakkar KN, Rösler L, Wijnen JP, Boer VO, Klomp DWJ, Cahn W, et al. 7T Proton Magnetic Resonance Spectroscopy of Gamma-Aminobutyric Acid, Glutamate, and Glutamine Reveals Altered Concentrations in Patients With Schizophrenia and Healthy Siblings. Biol Psychiatry 2017;81:525–35.

    Article  CAS  PubMed  Google Scholar 

  50. Huang M-L, Khoh T-T, Lu S-J, Pan F, Chen J-K, Hu J-B, et al. Relationships between dorsolateral prefrontal cortex metabolic change and cognitive impairment in first-episode neuroleptic-naive schizophrenia patients. Medicine 2017;96:e7228.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Hugdahl K, Craven AR, Nygård M, Løberg E-M, Berle JØ, Johnsen E, et al. Glutamate as a mediating transmitter for auditory hallucinations in schizophrenia: a (1)H MRS study. Schizophr Res 2015;161:252–60.

    Article  PubMed  Google Scholar 

  52. de la Fuente-Sandoval C, Reyes-Madrigal F, Mao X, León-Ortiz P, Rodríguez-Mayoral O, Solís-Vivanco R, et al. Cortico-Striatal GABAergic and Glutamatergic Dysregulations in Subjects at Ultra-High Risk for Psychosis Investigated with Proton Magnetic Resonance Spectroscopy. Int J Neuropsychopharmacol. 2015;19:yv105.

    Article  Google Scholar 

  53. Coughlin JM, Tanaka T, Marsman A, Wang H, Bonekamp S, Kim PK, et al. Decoupling of N-acetyl-aspartate and glutamate within the dorsolateral prefrontal cortex in schizophrenia. Curr Mol Med 2015;15:176–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chiappelli J, Rowland LM, Wijtenburg SA, Muellerklein F, Tagamets M, McMahon RP, et al. Evaluation of Myo-Inositol as a Potential Biomarker for Depression in Schizophrenia. Neuropsychopharmacology 2015;40:2157–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Goldstein ME, Anderson VM, Pillai A, Kydd RR, Russell BR. Glutamatergic neurometabolites in clozapine-responsive and -resistant schizophrenia. Int J Neuropsychopharmacol. 2015;18.

  56. de la Fuente-Sandoval C, León-Ortiz P, Azcárraga M, Stephano S, Favila R, Díaz-Galvis L, et al. Glutamate levels in the associative striatum before and after 4 weeks of antipsychotic treatment in first-episode psychosis: a longitudinal proton magnetic resonance spectroscopy study. JAMA Psychiatry 2013;70:1057–66.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Rowland LM, Kontson K, West J, Edden RA, Zhu H, Wijtenburg SA, et al. In vivo measurements of glutamate, GABA, and NAAG in schizophrenia. Schizophr Bull 2013;39:1096–104.

    Article  PubMed  Google Scholar 

  58. Kraguljac NV, White DM, Reid MA, Lahti AC. Increased hippocampal glutamate and volumetric deficits in unmedicated patients with schizophrenia. JAMA Psychiatry 2013;70:1294–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Reid MA, Kraguljac NV, Avsar KB, White DM, den Hollander JA, Lahti AC. Proton magnetic resonance spectroscopy of the substantia nigra in schizophrenia. Schizophr Res 2013;147:348–54.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Natsubori T, Inoue H, Abe O, Takano Y, Iwashiro N, Aoki Y, et al. Reduced Frontal Glutamate Glutamine and N-Acetylaspartate Levels in Patients With Chronic Schizophrenia but not in Those at Clinical High Risk for Psychosis or With First-Episode Schizophrenia. Schizophrenia Bull. 2014;40:1128–39.

    Article  Google Scholar 

  61. Jessen F, Fingerhut N, Sprinkart AM, Kühn K-U, Petrovsky N, Maier W, et al. N-acetylaspartylglutamate (NAAG) and N-acetylaspartate (NAA) in patients with schizophrenia. Schizophr Bull 2013;39:197–205.

    Article  PubMed  Google Scholar 

  62. Kraguljac NV, Reid MA, White DM, den Hollander J, Lahti AC. Regional decoupling of N-acetyl-aspartate and glutamate in schizophrenia. Neuropsychopharmacology 2012;37:2635–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 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;140:136–42.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Kegeles LS, Mao X, Stanford AD, Girgis R, Ojeil N, Xu X, et al. Elevated prefrontal cortex γ-aminobutyric acid and glutamate-glutamine levels in schizophrenia measured in vivo with proton magnetic resonance spectroscopy. Arch Gen Psychiatry 2012;69:449–59.

    Article  CAS  PubMed  Google Scholar 

  65. de la Fuente-Sandoval C, León-Ortiz P, Favila R, Stephano S, Mamo D, Ramírez-Bermúdez 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;36:1781–91.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Kraguljac NV, Morgan CJ, Reid MA, White DM, Jindal RD, Sivaraman S, et al. A longitudinal magnetic resonance spectroscopy study investigating effects of risperidone in the anterior cingulate cortex and hippocampus in schizophrenia. Schizophr Res 2019;210:239–44.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Egerton A, Stone JM, Chaddock CA, Barker GJ, Bonoldi I, Howard RM, et al. Relationship between brain glutamate levels and clinical outcome in individuals at ultra high risk of psychosis. Neuropsychopharmacology 2014;39:2891–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cadena EJ, White DM, Kraguljac NV, Reid MA, Maximo JO, Nelson EA, et al. A Longitudinal Multimodal Neuroimaging Study to Examine Relationships Between Resting State Glutamate and Task Related BOLD Response in Schizophrenia. Front Psychiatry 2018;9:632.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Wang J, Tang Y, Zhang T, Cui H, Xu L, Zeng B, et al. Reducedγ-Aminobutyric Acid and Glutamate Glutamine Levels in Drug-Naïve Patients with First-Episode Schizophrenia but Not in Those at Ultrahigh Risk. Neural Plasticity 2016;2016:1–9.

    Google Scholar 

  70. Larabi DI, Liemburg EJ, Pijnenborg GHM, Sibeijn-Kuiper A, de Vos AE, Bais L, et al. Association between prefrontal N-acetylaspartate and insight in psychotic disorders. Schizophr Res 2017;179:112–8.

    Article  PubMed  Google Scholar 

  71. Bernier D, Bartha R, McAllindon D, Hanstock CC, Marchand Y, Dillen KNH, et al. Illness versus substance use effects on the frontal white matter in early phase schizophrenia: A 4Tesla (1)H-MRS study. Schizophr Res 2016;175:4–11.

    Article  PubMed  Google Scholar 

  72. Wood SJ, Berger GE, Wellard RM, Proffitt T, McConchie M, Velakoulis D, et al. A 1H-MRS investigation of the medial temporal lobe in antipsychotic-naïve and early-treated first episode psychosis. Schizophr Res 2008;102:163–70.

    Article  PubMed  Google Scholar 

  73. Wood SJ, Kennedy D, Phillips LJ, Seal ML, Yücel M, Nelson B, et al. Hippocampal pathology in individuals at ultra-high risk for psychosis: a multi-modal magnetic resonance study. Neuroimage 2010;52:62–8.

    Article  CAS  PubMed  Google Scholar 

  74. Demjaha A, Egerton A, Murray RM, Kapur S, Howes OD, Stone JM, et al. Antipsychotic treatment resistance in schizophrenia associated with elevated glutamate levels but normal dopamine function. Biol Psychiatry 2014;75:e11–13.

    Article  CAS  PubMed  Google Scholar 

  75. Coughlin JM, Yang K, Marsman A, Pradhan S, Wang M, Ward RE, et al. A multimodal approach to studying the relationship between peripheral glutathione, brain glutamate, and cognition in health and in schizophrenia. Mol Psychiatry. 2020. 19 October 2020. https://doi.org/10.1038/s41380-020-00901-5.

  76. Borgan F, Veronese M, Reis Marques T, Lythgoe DJ, Howes O. Association between cannabinoid 1 receptor availability and glutamate levels in healthy controls and drug-free patients with first episode psychosis: a multi-modal PET and 1H-MRS study. Eur Arch Psychiatry Clin Neurosci. 2020. 28 September 2020. https://doi.org/10.1007/s00406-020-01191-2.

  77. Wenneberg C, Nordentoft M, Rostrup E, Glenthøj LB, Bojesen KB, Fagerlund B, et al. Cerebral Glutamate and Gamma-Aminobutyric Acid Levels in Individuals at Ultra-high Risk for Psychosis and the Association With Clinical Symptoms and Cognition. Biol Psychiatry Cogn Neurosci Neuroimaging 2020;5:569–79.

    PubMed  Google Scholar 

  78. Nelson EA, Kraguljac NV, Maximo JO, Briend F, Armstrong W, Ver Hoef LW, et al. Hippocampal Dysconnectivity and Altered Glutamatergic Modulation of the Default Mode Network: A Combined Resting-State Connectivity and Magnetic Resonance Spectroscopy Study in Schizophrenia. Biol Psychiatry Cogn Neurosci Neuroimaging. 2020. 6 May 2020. https://doi.org/10.1016/j.bpsc.2020.04.014.

  79. Cen H, Xu J, Yang Z, Mei L, Chen T, Zhuo K, et al. Neurochemical and brain functional changes in the ventromedial prefrontal cortex of first-episode psychosis patients: A combined functional magnetic resonance imaging-proton magnetic resonance spectroscopy study. Aust N. Z J Psychiatry 2020;54:519–27.

    Article  PubMed  Google Scholar 

  80. Hjelmervik H, Craven AR, Sinceviciute I, Johnsen E, Kompus K, Bless JJ, et al. Intra-Regional Glu-GABA vs Inter-Regional Glu-Glu Imbalance: A 1H-MRS Study of the Neurochemistry of Auditory Verbal Hallucinations in Schizophrenia. Schizophr Bull 2020;46:633–42.

    Article  PubMed  Google Scholar 

  81. Birur B, Kraguljac NV, VerHoef L, Morgan CJ, Jindal RD, Reid MA, et al. Neurometabolic correlates of 6 and 16 weeks of treatment with risperidone in medication-naive first-episode psychosis patients. Transl Psychiatry 2020;10:15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Tarumi R, Tsugawa S, Noda Y, Plitman E, Honda S, Matsushita K, et al. Levels of glutamatergic neurometabolites in patients with severe treatment-resistant schizophrenia: a proton magnetic resonance spectroscopy study. Neuropsychopharmacology 2020;45:632–40.

    Article  CAS  PubMed  Google Scholar 

  83. Ragland JD, Maddock RJ, Hurtado MY, Tanase C, Lesh TA, Niendam TA, et al. Disrupted GABAergic facilitation of working memory performance in people with schizophrenia. Neuroimage Clin 2020;25:102127.

    Article  CAS  PubMed  Google Scholar 

  84. Provenzano FA, Guo J, Wall MM, Feng X, Sigmon HC, Brucato G, et al. Hippocampal Pathology in Clinical High-Risk Patients and the Onset of Schizophrenia. Biol Psychiatry 2020;87:234–42.

    Article  CAS  PubMed  Google Scholar 

  85. Merritt K, Perez-Iglesias R, Sendt K-V, Goozee R, Jauhar S, Pepper F, et al. Remission from antipsychotic treatment in first episode psychosis related to longitudinal changes in brain glutamate. NPJ Schizophr 2019;5:12.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Rowland LM, Pradhan S, Korenic S, Wijtenburg SA, Hong LE, Edden RA, et al. Elevated brain lactate in schizophrenia: a 7 T magnetic resonance spectroscopy study. Transl Psychiatry 2016;6:e967.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Capizzano AA, Toscano JLN, Ho B-C. Magnetic resonance spectroscopy of limbic structures displays metabolite differences in young unaffected relatives of schizophrenia probands. Schizophr Res 2011;131:4–10.

    Article  PubMed  PubMed Central  Google Scholar 

  88. 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  Google Scholar 

  89. Rowland LM, Spieker EA, Francis A, Barker PB, Carpenter WT, Buchanan RW. White matter alterations in deficit schizophrenia. Neuropsychopharmacology 2009;34:1514–22.

    Article  CAS  PubMed  Google Scholar 

  90. Bojesen KB, Broberg BV, Fagerlund B, Jessen K, Thomas MB, Sigvard A, et al. Associations Between Cognitive Function and Levels of Glutamatergic Metabolites and Gamma-Aminobutyric Acid in Antipsychotic-Naïve Patients With Schizophrenia or Psychosis. Biol Psychiatry 2021;89:278–87.

    Article  CAS  PubMed  Google Scholar 

  91. Yoon JH, Maddock RJ, DongBo Cui E, Minzenberg MJ, Niendam TA, Lesh T, et al. Reduced in vivo visual cortex GABA in schizophrenia, a replication in a recent onset sample. Schizophr Res 2020;215:217–22.

    Article  PubMed  Google Scholar 

  92. Plitman E, de la Fuente-Sandoval C, Reyes-Madrigal F, Chavez S, Gómez-Cruz G, León-Ortiz P, et al. Elevated Myo-Inositol, Choline, and Glutamate Levels in the Associative Striatum of Antipsychotic-Naive Patients With First-Episode Psychosis: A Proton Magnetic Resonance Spectroscopy Study With Implications for Glial Dysfunction. Schizophr Bull 2016;42:415–24.

    Article  PubMed  Google Scholar 

  93. Wang AM, Pradhan S, Coughlin JM, Trivedi A, DuBois SL, Crawford JL, et al. Assessing Brain Metabolism With 7-T Proton Magnetic Resonance Spectroscopy in Patients With First-Episode Psychosis. JAMA Psychiatry 2019;76:314–23.

    Article  PubMed  PubMed Central  Google Scholar 

  94. 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;15:629–36.

    Article  CAS  PubMed  Google Scholar 

  95. Lutkenhoff ES, van Erp TG, Thomas MA, Therman S, Manninen M, Huttunen MO, et al. Proton MRS in twin pairs discordant for schizophrenia. Mol Psychiatry 2010;15:308–18.

    Article  CAS  PubMed  Google Scholar 

  96. Ongür D, Prescot AP, McCarthy J, Cohen BM, Renshaw PF. Elevated gamma-aminobutyric acid levels in chronic schizophrenia. Biol Psychiatry 2010;68:667–70.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Shirayama Y, Obata T, Matsuzawa D, Nonaka H, Kanazawa Y, Yoshitome E, et al. Specific metabolites in the medial prefrontal cortex are associated with the neurocognitive deficits in schizophrenia: a preliminary study. Neuroimage 2010;49:2783–90.

    Article  CAS  PubMed  Google Scholar 

  98. Tayoshi S’ya, Sumitani S, Taniguchi K, Shibuya-Tayoshi S, Numata S, Iga J-I, 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 

  99. Théberge J, Bartha R, Drost DJ, Menon RS, Malla A, Takhar J, et al. Glutamate and Glutamine Measured With 4.0 T Proton MRS in Never-Treated Patients With Schizophrenia and Healthy Volunteers. Am J Psychiatry. 2002;159:1944–6.

    Article  PubMed  Google Scholar 

  100. Taylor R, Osuch EA, Schaefer B, Rajakumar N, Neufeld RWJ, Théberge J, et al. Neurometabolic abnormalities in schizophrenia and depression observed with magnetic resonance spectroscopy at 7 T. BJPsych Open 2017;3:6–11.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Kim S-Y, Kaufman MJ, Cohen BM, Jensen JE, Coyle JT, Du F, et al. In Vivo Brain Glycine and Glutamate Concentrations in Patients With First-Episode Psychosis Measured by Echo Time-Averaged Proton Magnetic Resonance Spectroscopy at 4T. Biol Psychiatry 2018;83:484–91.

    Article  CAS  PubMed  Google Scholar 

  102. Posporelis S, Coughlin JM, Marsman A, Pradhan S, Tanaka T, Wang H, et al. Decoupling of Brain Temperature and Glutamate in Recent Onset of Schizophrenia: A 7T Proton Magnetic Resonance Spectroscopy Study. Biol Psychiatry Cogn Neurosci Neuroimaging 2018;3:248–54.

    PubMed  Google Scholar 

  103. Rigucci S, Xin L, Klauser P, Baumann PS, Alameda L, Cleusix M, et al. Cannabis use in early psychosis is associated with reduced glutamate levels in the prefrontal cortex. Psychopharmacology 2018;235:13–22.

    Article  CAS  PubMed  Google Scholar 

  104. Reid MA, Salibi N, White DM, Gawne TJ, Denney TS, Lahti AC. 7T Proton Magnetic Resonance Spectroscopy of the Anterior Cingulate Cortex in First-Episode Schizophrenia. Schizophr Bull 2019;45:180–9.

    Article  PubMed  Google Scholar 

  105. Xin L, Mekle R, Fournier M, Baumann PS, Ferrari C, Alameda L, et al. Genetic Polymorphism Associated Prefrontal Glutathione and Its Coupling With Brain Glutamate and Peripheral Redox Status in Early Psychosis. Schizophr Bull 2016;42:1185–96.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Gallinat J, McMahon K, Kühn S, Schubert F, Schaefer M. Cross-sectional Study of Glutamate in the Anterior Cingulate and Hippocampus in Schizophrenia. Schizophr Bull 2016;42:425–33.

    Article  PubMed  Google Scholar 

  107. Brandt AS, Unschuld PG, Pradhan S, Lim IAL, Churchill G, Harris AD, et al. Age-related changes in anterior cingulate cortex glutamate in schizophrenia: A (1)H MRS Study at 7 Tesla. Schizophr Res 2016;172:101–5.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Nenadic I, Maitra R, Basu S, Dietzek M, Schönfeld N, Lorenz C, et al. Associations of hippocampal metabolism and regional brain grey matter in neuroleptic-naïve ultra-high-risk subjects and first-episode schizophrenia. Eur Neuropsychopharmacol 2015;25:1661–8.

    Article  CAS  PubMed  Google Scholar 

  109. Atagün MI, Şıkoğlu EM, Can SS, Karakaş-Uğurlu G, Ulusoy-Kaymak S, Çayköylü A, et al. Investigation of Heschl’s gyrus and planum temporale in patients with schizophrenia and bipolar disorder: a proton magnetic resonance spectroscopy study. Schizophr Res 2015;161:202–9.

    Article  PubMed  Google Scholar 

  110. Bustillo JR, Chen H, Jones T, Lemke N, Abbott C, Qualls C, et al. Increased glutamine in patients undergoing long-term treatment for schizophrenia: a proton magnetic resonance spectroscopy study at 3 T. JAMA Psychiatry 2014;71:265–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Crocker CE, Bernier DC, Hanstock CC, Lakusta B, Purdon SE, Seres P, et al. Prefrontal glutamate levels differentiate early phase schizophrenia and methamphetamine addiction: a (1)H MRS study at 3Tesla. Schizophr Res 2014;157:231–7.

    Article  PubMed  Google Scholar 

  112. Falkenberg LE, Westerhausen R, Craven AR, Johnsen E, Kroken RA, L Berg E-M, et al. Impact of glutamate levels on neuronal response and cognitive abilities in schizophrenia. Neuroimage Clin 2014;4:576–84.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Tibbo PG, Bernier D, Hanstock CC, Seres P, Lakusta B, Purdon SE. 3-T proton magnetic spectroscopy in unmedicated first episode psychosis: a focus on creatine. Magn Reson Med 2013;69:613–20.

    Article  CAS  PubMed  Google Scholar 

  114. Balz J, Roa Romero Y, Keil J, Schubert F, Ittermann B, Mekle R, et al. Glutamate Concentration in the Superior Temporal Sulcus Relates to Neuroticism in Schizophrenia. Front Psychol 2018;9:578.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Wijtenburg SA, Kapogiannis D, Korenic SA, Mullins RJ, Tran J, Gaston FE, et al. Brain insulin resistance and altered brain glucose are related to memory impairments in schizophrenia. Schizophr Res 2019;208:324–30.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Yoon JH, Maddock RJ, Rokem A, Silver MA, Minzenberg MJ, Ragland JD, et al. GABA concentration is reduced in visual cortex in schizophrenia and correlates with orientation-specific surround suppression. J Neurosci 2010;30:3777–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 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;18:276–82.

    Article  CAS  PubMed  Google Scholar 

  118. Yang Z, Zhu Y, Song Z, Mei L, Zhang J, Chen T, et al. Comparison of the density of gamma-aminobutyric acid in the ventromedial prefrontal cortex of patients with first-episode psychosis and healthy controls. Shanghai Arch Psychiatry. 2015;27:341–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Limongi R, Jeon P, Mackinley M, Das T, Dempster K, Théberge J, et al. Glutamate and Dysconnection in the Salience Network: Neurochemical, Effective Connectivity, and Computational Evidence in Schizophrenia. Biol Psychiatry 2020;88:273–81.

    Article  CAS  PubMed  Google Scholar 

  120. León-Ortiz P, Reyes-Madrigal F, Kochunov P, Gómez-Cruz G, Moncada-Habib T, Malacara M, et al. White matter alterations and the conversion to psychosis: A combined diffusion tensor imaging and glutamate H MRS study. Schizophr Res. 2020. 25 June 2020. https://doi.org/10.1016/j.schres.2020.06.006.

  121. Howes OD, Bonoldi I, McCutcheon RA, Azis M, Antoniades M, Bossong M, et al. Glutamatergic and dopaminergic function and the relationship to outcome in people at clinical high risk of psychosis: a multi-modal PET-magnetic resonance brain imaging study. Neuropsychopharmacology 2020;45:641–8.

    Article  CAS  PubMed  Google Scholar 

  122. Kaminski J, Gleich T, Fukuda Y, Katthagen T, Gallinat J, Heinz A, et al. Association of Cortical Glutamate and Working Memory Activation in Patients With Schizophrenia: A Multimodal Proton Magnetic Resonance Spectroscopy and Functional Magnetic Resonance Imaging Study. Biol Psychiatry 2020;87:225–33.

    Article  CAS  PubMed  Google Scholar 

  123. Korenic SA, Klingaman EA, Wickwire EM, Gaston FE, Chen H, Wijtenburg SA, et al. Sleep quality is related to brain glutamate and symptom severity in schizophrenia. J Psychiatr Res 2020;120:14–20.

    Article  PubMed  Google Scholar 

  124. Bloemen OJN, Gleich T, de Koning MB, da Silva Alvis F, de Haan L, Linszen DH, et al. Hippocampal Glutamate Levels and Striatal Dopamine D2/3 Receptor Occupancy in Subjects at Ultra High Risk of Psychosis. Biol Psychiatry 2011;70:e1–2.

    Article  PubMed  Google Scholar 

  125. Ongür 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;64:718–26.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Stan AD, Ghose S, Zhao C, Hulsey K, Mihalakos P, Yanagi M, et al. Magnetic resonance spectroscopy and tissue protein concentrations together suggest lower glutamate signaling in dentate gyrus in schizophrenia. Mol Psychiatry 2015;20:433–9.

    Article  CAS  PubMed  Google Scholar 

  127. Tunc-Skarka N, Weber-Fahr W, Hoerst M, Meyer-Lindenberg A, Zink M, Ende GMR. spectroscopic evaluation of N-acetylaspartate’s T2 relaxation time and concentration corroborates white matter abnormalities in schizophrenia. Neuroimage 2009;48:525–31.

    Article  PubMed  Google Scholar 

  128. de la Fuente-Sandoval C, León-Ortiz P, Azcárraga 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;16:471–5.

    Article  PubMed  Google Scholar 

  129. Chen T, Wang Y, Zhang J, Wang Z, Xu J, Li Y, et al. Abnormal Concentration of GABA and Glutamate in The Prefrontal Cortex in Schizophrenia.-An in Vivo 1H-MRS Study. Shanghai Arch Psychiatry 2017;29:277–86.

    PubMed  Google Scholar 

  130. Marsman A, Mandl RCW, Klomp DWJ, Bohlken MM, Boer VO, Andreychenko A, et al. GABA and glutamate in schizophrenia: a 7 T 1H-MRS study. Neuroimage Clin 2014;6:398–407.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Dempster K, Jeon P, MacKinley M, Williamson P, Théberge J, Palaniyappan L. Early treatment response in first episode psychosis: a 7-T magnetic resonance spectroscopic study of glutathione and glutamate. Mol Psychiatry 2020;25:1640–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Marenco S, Meyer C, Kuo S, van der Veen JW, Shen J, DeJong K, et al. Prefrontal GABA Levels Measured With Magnetic Resonance Spectroscopy in Patients With Psychosis and Unaffected Siblings. Am J Psychiatry 2016;173:527–34.

    Article  PubMed  Google Scholar 

  133. Goto N, Yoshimura R, Moriya J, Kakeda S, Ueda N, Ikenouchi-Sugita A, et al. Reduction of brain gamma-aminobutyric acid (GABA) concentrations in early-stage schizophrenia patients: 3T Proton MRS study. Schizophr Res 2009;112:192–3.

    Article  PubMed  Google Scholar 

  134. Shaw AD, Knight L, Freeman TCA, Williams GM, Moran RJ, Friston KJ, et al. Oscillatory, Computational, and Behavioral Evidence for Impaired GABAergic Inhibition in Schizophrenia. Schizophr Bull 2020;46:345–53.

    PubMed  Google Scholar 

  135. Da Silva T, Hafizi S, Rusjan PM, Houle S, Wilson AA, Prce I, et al. GABA levels and TSPO expression in people at clinical high risk for psychosis and healthy volunteers: a PET-MRS study. J Psychiatry Neurosci 2019;44:111–9.

    Article  PubMed  Google Scholar 

  136. Tayoshi S’ya, Nakataki M, Sumitani S, Taniguchi K, Shibuya-Tayoshi S, Numata S, et al. GABA concentration in schizophrenia patients and the effects of antipsychotic medication: a proton magnetic resonance spectroscopy study. Schizophr Res 2010;117:83–91.

    Article  PubMed  Google Scholar 

  137. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010;25:603–5.

    Article  PubMed  Google Scholar 

  138. Moghaddam B, Adams B, Verma A, Daly D. 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. 1997;17:2921–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Lodge DJ, Grace AA. Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia. Trends Pharm Sci 2011;32:507–13.

    Article  CAS  PubMed  Google Scholar 

  140. Gleich T, Deserno L, Lorenz RC, Boehme R, Pankow A, Buchert R, et al. Prefrontal and Striatal Glutamate Differently Relate to Striatal Dopamine: Potential Regulatory Mechanisms of Striatal Presynaptic Dopamine Function? J Neurosci 2015;35:9615–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, et al. The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry 2012;69:776–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Fuente-Sandoval C, de la, de la Fuente-Sandoval C, León-Ortiz P, Azcárraga M, Stephano S, Favila R, et al. Glutamate Levels in the Associative Striatum Before and After 4 Weeks of Antipsychotic Treatment in First-Episode Psychosis. JAMA Psychiatry 2013;70:1057.

    Article  PubMed  PubMed Central  Google Scholar 

  143. Kehr J, Yoshitake T, Ichinose F, Yoshitake S, Kiss B, Gyertyán I, et al. Effects of cariprazine on extracellular levels of glutamate, GABA, dopamine, noradrenaline and serotonin in the medial prefrontal cortex in the rat phencyclidine model of schizophrenia studied by microdialysis and simultaneous recordings of locomotor activity. Psychopharmacology 2018;235:1593–607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Amitai N, Kuczenski R, Behrens MM, Markou A. Repeated phencyclidine administration alters glutamate release and decreases GABA markers in the prefrontal cortex of rats. Neuropharmacology 2012;62:1422–31.

    Article  CAS  PubMed  Google Scholar 

  145. López-Gil X, Babot Z, Amargós-Bosch M, Suñol C, Artigas F, Adell A. Clozapine and haloperidol differently suppress the MK-801-increased glutamatergic and serotonergic transmission in the medial prefrontal cortex of the rat. Neuropsychopharmacology 2007;32:2087–97.

    Article  PubMed  Google Scholar 

  146. Kubota M, Moriguchi S, Takahata K, Nakajima S, Horita N. Treatment effects on neurometabolite levels in schizophrenia: a meta-analysis dataset of proton magnetic resonance spectroscopy. Data Brief. 2020;31:105862.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Kraguljac NV, Frölich MA, Tran S, White DM, Nichols N, Barton-McArdle A, et al. Ketamine modulates hippocampal neurochemistry and functional connectivity: a combined magnetic resonance spectroscopy and resting-state fMRI study in healthy volunteers. Mol Psychiatry 2017;22:562–9.

    Article  CAS  PubMed  Google Scholar 

  148. Palomero-Gallagher N, Vogt BA, Schleicher A, Mayberg HS, Zilles K. Receptor architecture of human cingulate cortex: evaluation of the four-region neurobiological model. Hum Brain Mapp 2009;30:2336–55.

    Article  PubMed  Google Scholar 

  149. Vogt BA. Midcingulate cortex: structure, connections, homologies, functions and diseases. J Chem Neuroanat 2016;74:28–46.

    Article  CAS  PubMed  Google Scholar 

  150. Volk DW, Austin MC, Pierri JN, Sampson AR, Lewis DA. Decreased glutamic acid decarboxylase67 messenger rna expression in a subset of prefrontal cortical γ-aminobutyric acid neurons in subjects with schizophrenia. Arch Gen Psychiatry. 2000;57:237.

    Article  CAS  PubMed  Google Scholar 

  151. Hashimoto T, Volk DW, Eggan SM, Mirnics K, Pierri JN, Sun Z, et al. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci. 2003;23:6315–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoli A, Bunney WE Jr, et al. Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch Gen Psychiatry 1995;52:258–66.

    Article  CAS  PubMed  Google Scholar 

  153. Lewis DA, Curley AA, Glausier JR, Volk DW. Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci. 2012;35:57–67.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by JSPS KAKENHI Grant Numbers 18H02755, PE19015, 19H03587, 20K20603, and National Institutes of Health Grant Numbers R01 MH110270.

Author information

Author notes

  1. These authors contributed equally: Tomomi Nakahara, Sakiko Tsugawa.

Authors and Affiliations

  1. Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan

    Tomomi Nakahara, Sakiko Tsugawa, Yoshihiro Noda, Fumihiko Ueno, Shiori Honda, Megumi Kinjo, Hikari Segawa, Nobuaki Hondo, Yukino Mori, Honoka Watanabe, Kazuho Nakahara, Kazunari Yoshida, Masataka Wada, Ryosuke Tarumi, Yusuke Iwata, Sho Moriguchi, Hiroyuki Uchida, Masaru Mimura & Shinichiro Nakajima

  2. Multimodal Imaging Group, Research Imaging Centre, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada

    Fumihiko Ueno & Ariel Graff-Guerrero

  3. Tanenbaum Centre for Pharmacogenetics, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada

    Kazunari Yoshida

  4. Azrieli Adult Neurodevelopmental Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada

    Kazunari Yoshida

  5. Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Eric Plitman

  6. Laboratory of Experimental Psychiatry & Neuropsychiatry Department, Instituto Nacional de Neurología y Neurocirugía, Mexico City, Mexico

    Camilo de la Fuente-Sandoval

Authors
  1. Tomomi Nakahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sakiko Tsugawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoshihiro Noda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fumihiko Ueno
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shiori Honda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Megumi Kinjo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hikari Segawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nobuaki Hondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yukino Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Honoka Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kazuho Nakahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kazunari Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Masataka Wada
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Ryosuke Tarumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Yusuke Iwata
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Eric Plitman
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Sho Moriguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Camilo de la Fuente-Sandoval
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Hiroyuki Uchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Masaru Mimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Ariel Graff-Guerrero
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Shinichiro Nakajima
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TN and ST equally contributed to the hand search, initial screening, assessment of eligibility, data extraction, and writing the manuscript. ST, YN, and SN design the study and were in charge of overall direction and planning. KY performed study search. FU, EP, SH, and RT verified the screening or eligibility assessment. MK, HS, NH, YM, and HW extracted the data from articles. ST performed statistical analysis and NH double-checked it. KN supported to make figures. MW, YI, SM, CdlF-S, MM, AG-G, and HU contributed to the interpretation of the results. All authors provided critical feedback and contributed to the final manuscript.

Corresponding authors

Correspondence to Sakiko Tsugawa, Yoshihiro Noda or Shinichiro Nakajima.

Ethics declarations

Competing interests

TN, ST, SH, MK, HS, NH, YM, HW, KN, MW, CdlF-S, RT, AG-G, and HU report no biomedical interests. YN has received a Grant-in-Aid for Young Scientists (18K15375) and a Grant-in-Aid for Scientific Research (B) (21H02813) from the Japan Society for the Promotion of Science (JSPS), research grants from Japan Agency for Medical Research and development (AMED), an investigator-initiated clinical study grant from TEIJIN PHARMA LIMITED. He also receives research grants from Japan Health Foundation, Meiji Yasuda Mental Health Foundation, Mitsui Life Social Welfare Foundation, Takeda Science Foundation, SENSHIN Medical Research Foundation, Health Science Center Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, and Daiichi Sankyo Scholarship Donation Program. He receives equipment-in-kind support for an investigator-initiated study from Magventure Inc and research supports from Otsuka Pharmaceutical, Shionogi, and Meiji Seika Pharma. FU has received fellowship grants from Discovery Fund, Nakatani Foundation, and the Canadian Institutes of Health Research (CIHR); and consultant fee from VeraSci, and Uchiyama Underwriting within the past three years. KY has received manuscript fees from Sumitomo Dainippon Pharma, fellowship grants from the Japan Research Foundation for Clinical Pharmacology and Azrieli Adult Neurodevelopmental Centre Postdoctoral Fellowship at CAMH, and consultant fees from Signant Health, VeraSci, and MedAvante-ProPhase within the past three years.YI has received fellowship grants from Canadian Institute of Health Research (CIHR), Keio University Medical Science Foundation, Mitsukoshi Foundation. YI has also received manuscript fees from Dainippon Sumitomo Pharma. EP reports receiving funding from the Healthy Brains for Healthy Lives Postdoctoral Fellowship, Vanier Canada Graduate Scholarship, the Ontario Graduate Scholarship, and the Canada Graduate Scholarship – Master’s. YI has also received manuscript fees from Dainippon Sumitomo Pharma. A.G-G. has received support from the United States National Institute of Health, CIHR, Ontario Mental Health Foundation, the Ontario Ministry of Health and Long-Term Care, the Ontario Ministry of Research and Innovation Early Research Award during the last 5 years. HU has received grants from Eisai, Otsuka Pharmaceutical, Dainippon-Sumitomo Pharma, Daiichi Sankyo Company, Mochida Pharmaceutical, and Meiji-Seika Pharma; speaker’s honoraria from Otsuka Pharmaceutical, Dainippon-Sumitomo Pharma, Eisai, and Meiji-Seika Pharma; and advisory panel payments from Dainippon-Sumitomo Pharma within the past three years. MM has received research support from Japan Society for the Promotion of Science and grants or speaker’s honoraria from Daiichi Sankyo, Dainippon-Sumitomo Pharma, Eisai, Eli Lilly, Fuji Film RI Pharma, Janssen Pharmaceutical, Mochida Pharmaceutical, MSD, Nippon Chemipher, Novartis Pharma, Ono Yakuhin, Otsuka Pharmaceutical, Pfizer, Takeda Yakuhin, Tsumura, and Yoshitomi Yakuhin within the past three years. SN has received grants from Japan Society for the Promotion of Science, Japan Agency for Medical Research and development (AMED), Japan Research Foundation for Clinical Pharmacology, Naito Foundation, Takeda Science Foundation, Uehara Memorial Foundation, and Daiichi Sankyo Scholarship Donation Program within the past three years. SN has also received research support, manuscript fees or speaker’s honoraria from Dainippon Sumitomo Pharma, Meiji-Seika Pharma, Otsuka Pharmaceutical, Shionogi, and Yoshitomi Yakuhin within the past three years.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nakahara, T., Tsugawa, S., Noda, Y. et al. Glutamatergic and GABAergic metabolite levels in schizophrenia-spectrum disorders: a meta-analysis of 1H-magnetic resonance spectroscopy studies. Mol Psychiatry 27, 744–757 (2022). https://doi.org/10.1038/s41380-021-01297-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-021-01297-6

This article is cited by

Search

Advanced search

Quick links