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Extracellular free water and glutathione in first-episode psychosis—a multimodal investigation of an inflammatory model for psychosis

Molecular Psychiatry volume 26, pages 761–771 (2021)Cite this article

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Abstract

Evidence has been accumulating for an immune-based component to the etiology of psychotic disorders. Advancements in diffusion magnetic resonance imaging (MRI) have enabled estimation of extracellular free water (FW), a putative biomarker of neuroinflammation. Furthermore, inflammatory processes may be associated with altered brain levels of metabolites, such as glutathione (GSH). Consequently, we sought to test the hypotheses that FW is increased and associated with decreased GSH in patients with first-episode schizophrenia (SZ) compared with healthy controls (HC). SZ (n = 36) and HC (n = 40) subjects underwent a multi-shell diffusion MRI scan on a Siemens 3T scanner. 1H-MR spectroscopy data were acquired using a GSH-optimized MEGA-PRESS editing sequence and GSH/creatine ratios were calculated for DLPFC (SZ: n = 33, HC: n = 37) and visual cortex (SZ: n = 29, HC: n = 35) voxels. Symptoms and functioning were measured using the SANS, SAPS, BPRS, and GSF/GRF. SZ demonstrated significantly elevated FW in whole-brain gray (p = .001) but not white matter (p = .060). There was no significant difference between groups in GSH in either voxel. However, there was a significant negative correlation between DLPFC GSH and both whole-brain and DLPFC-specific gray matter FW in SZ (r = –.48 and –.47, respectively; both p < .05), while this relationship was nonsignificant in HC and in both groups in the visual cortex. These data illustrate an important relationship between a metabolite known to be important for immune function—GSH—and the diffusion extracellular FW measure, which provides additional support for these measures as neuroinflammatory biomarkers that could potentially provide tractable treatment targets to guide pharmacological intervention.

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References

  1. Mednick SA, Machon RA, Huttunen MO, Bonett D. Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch Gen Psychiatry. 1988;45:189–92.

    Article  CAS  PubMed  Google Scholar 

  2. Brown AS, Derkits EJ. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry. 2010;167:261–80.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530:177–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011;70:663–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Doorduin J, de Vries EF, Willemsen AT, de Groot JC, Dierckx RA, Klein HC. Neuroinflammation in schizophrenia-related psychosis: a PET study. J Nucl Med. 2009;50:1801–7.

    Article  PubMed  Google Scholar 

  6. van Berckel BN, Bossong MG, Boellaard R, Kloet R, Schuitemaker A, Caspers E, et al. Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study. Biol Psychiatry. 2008;64:820–2.

    Article  PubMed  Google Scholar 

  7. Takano A, Arakawa R, Ito H, Tateno A, Takahashi H, Matsumoto R, et al. Peripheral benzodiazepine receptors in patients with chronic schizophrenia: a PET study with [11C]DAA1106. Int J Neuropsychopharmacol. 2010;13:943–50.

    Article  CAS  PubMed  Google Scholar 

  8. Hafizi S, Tseng HH, Rao N, Selvanathan T, Kenk M, Bazinet RP, et al. Imaging microglial activation in untreated first-episode psychosis: a PET study with [(18)F]FEPPA. Am J Psychiatry. 2017;174:118–24.

    Article  PubMed  Google Scholar 

  9. Collste K, Plaven-Sigray P, Fatouros-Bergman H, Victorsson P, Schain M, Forsberg A, et al. Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and [(11)C]PBR28. Mol Psychiatry. 2017;22:850–6.

    Article  CAS  PubMed  Google Scholar 

  10. van der Doef TF, de Witte LD, Sutterland AL, Jobse E, Yaqub M, Boellaard R, et al. In vivo (R)-[(11)C]PK11195 PET imaging of 18kDa translocator protein in recent onset psychosis. NPJ Schizophr. 2016;2:16031.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Pasternak O, Sochen N, Gur Y, Intrator N, Assaf Y. Free water elimination and mapping from diffusion MRI. Magn Reson Med. 2009;62:717–30.

    Article  PubMed  Google Scholar 

  12. Pasternak O, Westin CF, Bouix S, Seidman LJ, Goldstein JM, Woo TU, et al. Excessive extracellular volume reveals a neurodegenerative pattern in schizophrenia onset. J Neurosci. 2012;32:17365–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pasternak O, Westin CF, Dahlben B, Bouix S, Kubicki M. The extent of diffusion MRI markers of neuroinflammation and white matter deterioration in chronic schizophrenia. Schizophr Res. 2015;161:113–8.

    Article  PubMed  Google Scholar 

  14. Oestreich LK, Pasternak O, Shenton ME, Kubicki M, Gong X, Australian Schizophrenia Research B, et al. Abnormal white matter microstructure and increased extracellular free-water in the cingulum bundle associated with delusions in chronic schizophrenia. Neuroimage Clin. 2016;12:405–14.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Buhl R, Jaffe HA, Holroyd KJ, Wells FB, Mastrangeli A, Saltini C, et al. Systemic glutathione deficiency in symptom-free HIV-seropositive individuals. Lancet. 1989;2:1294–8.

    Article  CAS  PubMed  Google Scholar 

  16. Carvalho AN, Lim JL, Nijland PG, Witte ME, Van Horssen J. Glutathione in multiple sclerosis: more than just an antioxidant? Mult Scler. 2014;20:1425–31.

    Article  CAS  PubMed  Google Scholar 

  17. Markoutsa E, Xu P. Redox potential-sensitive N-acetyl cysteine-prodrug nanoparticles inhibit the activation of microglia and improve neuronal survival. Mol Pharm. 2017;14:1591–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhang L, Xu S, Huang Q, Xu H. N-acetylcysteine attenuates the cuprizone-induced behavioral changes and oligodendrocyte loss in male C57BL/7 mice via its anti-inflammation actions. J Neurosci Res. 2018;96:803–16.

    Article  CAS  PubMed  Google Scholar 

  19. 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 

  20. Ballesteros A, Jiang P, Summerfelt A, Du X, Chiappelli J, O’Donnell P, et al. No evidence of exogenous origin for the abnormal glutathione redox state in schizophrenia. Schizophr Res. 2013;146:184–9.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Gonzalez-Liencres C, Tas C, Brown EC, Erdin S, Onur E, Cubukcoglu Z, et al. Oxidative stress in schizophrenia: a case-control study on the effects on social cognition and neurocognition. BMC Psychiatry. 2014;14:268.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Mico JA, Rojas-Corrales MO, Gibert-Rahola J, Parellada M, Moreno D, Fraguas D, et al. Reduced antioxidant defense in early onset first-episode psychosis: a case-control study. BMC Psychiatry. 2011;11:26.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Langbein K, Hesse J, Gussew A, Milleit B, Lavoie S, Amminger GP, et al. Disturbed glutathione antioxidative defense is associated with structural brain changes in neuroleptic-naive first-episode psychosis patients. Prostaglandins Leukot Essent Fatty Acids. 2018;136:103–10.

    Article  CAS  PubMed  Google Scholar 

  24. Altuntas I, Aksoy H, Coskun I, Caykoylu A, Akcay F. Erythrocyte superoxide dismutase and glutathione peroxidase activities, and malondialdehyde and reduced glutathione levels in schizophrenic patients. Clin Chem Lab Med. 2000;38:1277–81.

    Article  CAS  PubMed  Google Scholar 

  25. Raffa M, Atig F, Mhalla A, Kerkeni A, Mechri A. Decreased glutathione levels and impaired antioxidant enzyme activities in drug-naive first-episode schizophrenic patients. BMC Psychiatry. 2011;11:124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dietrich-Muszalska A, Olas B, Glowacki R, Bald E. Oxidative/nitrative modifications of plasma proteins and thiols from patients with schizophrenia. Neuropsychobiology. 2009;59:1–7.

    Article  CAS  PubMed  Google Scholar 

  27. Nucifora LG, Tanaka T, Hayes LN, Kim M, Lee BJ, Matsuda T, et al. Reduction of plasma glutathione in psychosis associated with schizophrenia and bipolar disorder in translational psychiatry. Transl Psychiatry. 2017;7:e1215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Raffa M, Mechri A, Othman LB, Fendri C, Gaha L, Kerkeni A. Decreased glutathione levels and antioxidant enzyme activities in untreated and treated schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:1178–83.

    Article  CAS  PubMed  Google Scholar 

  29. Samuelsson M, Skogh E, Lundberg K, Vrethem M, Ollinger K. Taurine and glutathione in plasma and cerebrospinal fluid in olanzapine treated patients with schizophrenia. Psychiatry Res. 2013;210:819–24.

    Article  CAS  PubMed  Google Scholar 

  30. Ruiz-Litago F, Seco J, Echevarria E, Martinez-Cengotitabengoa M, Gil J, Irazusta J, et al. Adaptive response in the antioxidant defence system in the course and outcome in first-episode schizophrenia patients: a 12-months follow-up study. Psychiatry Res. 2012;200:218–22.

    Article  CAS  PubMed  Google Scholar 

  31. Raffa M, Barhoumi S, Atig F, Fendri C, Kerkeni A, Mechri A. Reduced antioxidant defense systems in schizophrenia and bipolar I disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2012;39:371–5.

    Article  CAS  PubMed  Google Scholar 

  32. Vidovic B, Stefanovic A, Milovanovic S, Ethordevic B, Kotur-Stevuljevic J, Ivanisevic J, et al. Associations of oxidative stress status parameters with traditional cardiovascular disease risk factors in patients with schizophrenia. Scand J Clin Lab Invest. 2014;74:184–91.

    Article  CAS  PubMed  Google Scholar 

  33. Al-Asmari AK, Khan MW. Inflammation and schizophrenia: alterations in cytokine levels and perturbation in antioxidative defense systems. Hum Exp Toxicol. 2014;33:115–22.

    Article  CAS  PubMed  Google Scholar 

  34. Fukushima T, Iizuka H, Yokota A, Suzuki T, Ohno C, Kono Y, et al. Quantitative analyses of schizophrenia-associated metabolites in serum: serum D-lactate levels are negatively correlated with gamma-glutamylcysteine in medicated schizophrenia patients. PLoS ONE. 2014;9:e101652.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Tsai MC, Liou CW, Lin TK, Lin IM, Huang TL. Changes in oxidative stress markers in patients with schizophrenia: the effect of antipsychotic drugs. Psychiatry Res. 2013;209:284–90.

    Article  CAS  PubMed  Google Scholar 

  36. 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;12:3721–8.

    Article  CAS  PubMed  Google Scholar 

  37. Terpstra M, Henry PG, Gruetter R. Measurement of reduced glutathione (GSH) in human brain using LCModel analysis of difference-edited spectra. Magn Reson Med. 2003;50:19–23.

    Article  CAS  PubMed  Google Scholar 

  38. Holmay MJ, Terpstra M, Coles LD, Mishra U, Ahlskog M, Oz G, et al. N-Acetylcysteine boosts brain and blood glutathione in Gaucher and Parkinson diseases. Clin Neuropharmacol. 2013;36:103–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Nezhad FS, Anton A, Parkes LM, Deakin B, Williams SR. Quantification of glutathione in the human brain by MR spectroscopy at 3 Tesla: Comparison of PRESS and MEGA-PRESS. Magn Reson Med. 2016;78:1257–66.

    Article  CAS  Google Scholar 

  40. 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 

  41. 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 

  42. 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;33:354–7.

    Article  CAS  PubMed  Google Scholar 

  43. 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. 2018. https://www.nature.com/articles/s41380-018-0104-7. [Epub ahead of print]

  44. 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

  45. Brandt AS, Unschuld PG, Pradhan S, Lim IA, 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 

  46. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition. (SCID-I/P). Biometrics Research, New York State Psychiatric Institute: New York, 2002.

  47. Andreasen N. The Scale for the Assessment of Negative Symptoms (SANS). The University of Iowa: Iowa City; 1983.

  48. Andreasen N. The Scale for the Assessment of Positive Symptoms (SAPS). The University of Iowa: Iowa City; 1984.

  49. Lukoff D, Nuechterlein KH, Ventura J. Manual for the Expanded Brief Psychiatric Rating Scale (BPRS). Schizophr Bull. 1986;12:594–602.

    Google Scholar 

  50. Auther AM, Smith CW, Cornblatt BA. Global Functioning: Social Scale (GF: Social). Zucker-Hillside Hospital: Glen Oaks; 2006.

  51. Niendam TA, Bearden CE, Johnson JK, Cannon TD. Global Functioning: Role Scale (GF: Role). University of California, Los Angeles: Los Angeles; 2006.

  52. An L, Zhang Y, Thomasson DM, Latour LL, Baker EH, Shen J, et al. Measurement of glutathione in normal volunteers and stroke patients at 3T using J-difference spectroscopy with minimized subtraction errors. J Magn Reson Imaging. 2009;30:263–70.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Mescher M, Merkle H, Kirsch J, Garwood M, Gruetter R. Simultaneous in vivo spectral editing and water suppression. NMR Biomed. 1998;11:266–72.

    Article  CAS  PubMed  Google Scholar 

  54. Sanaei Nezhad F, Anton A, Parkes LM, Deakin B, Williams SR. Quantification of glutathione in the human brain by MR spectroscopy at 3 Tesla: comparison of PRESS and MEGA-PRESS. Magn Reson Med. 2017;78:1257–66.

    Article  CAS  PubMed  Google Scholar 

  55. Andersson JLR, Sotiropoulos SN. An integrated approach to correction for off-resonance effects and subject movement in diffusion MR imaging. Neuroimage. 2016;125:1063–78.

    Article  PubMed  Google Scholar 

  56. Garyfallidis E, Brett M, Amirbekian B, Rokem A, van der Walt S, Descoteaux M, et al. Dipy, a library for the analysis of diffusion MRI data. Front Neuroinform. 2014;8:8.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Hoy AR, Koay CG, Kecskemeti SR, Alexander AL. Optimization of a free water elimination two-compartment model for diffusion tensor imaging. Neuroimage. 2014;103:323–33.

    Article  PubMed  Google Scholar 

  58. Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage. 1999;9:179–94.

    Article  CAS  PubMed  Google Scholar 

  59. Greve DN, Fischl B. Accurate and robust brain image alignment using boundary-based registration. Neuroimage. 2009;48:63–72.

    Article  PubMed  Google Scholar 

  60. Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE, et al. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage. 2006;31:1487–505.

    Article  PubMed  Google Scholar 

  61. Nichols TE, Holmes AP. Nonparametric permutation tests for functional neuroimaging: a primer with examples. Hum Brain Mapp. 2002;15:1–25.

    Article  PubMed  Google Scholar 

  62. Smith SM, Nichols TE. Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference. Neuroimage. 2009;44:83–98.

    Article  PubMed  Google Scholar 

  63. Provencher SW. Automatic quantitation of localized in vivo 1H spectra with LCModel. NMR Biomed. 2001;14:260–4.

    Article  CAS  PubMed  Google Scholar 

  64. Stefan D, Di Cesare F, Andrasescu A, Popa E, Lazariev A, Vescovo E, et al. Quantitation of magnetic resonance spectroscopy signals: the jMRUI software package. Meas Sci Technol. 2009;20:104035 (9pp).

  65. Schneider P, Weber-Fahr W, Schweinfurth N, Ho YJ, Sartorius A, Spanagel R, et al. Central metabolite changes and activation of microglia after peripheral interleukin-2 challenge. Brain Behav Immun. 2012;26:277–83.

    Article  CAS  PubMed  Google Scholar 

  66. Chang L, Munsaka SM, Kraft-Terry S, Ernst T. Magnetic resonance spectroscopy to assess neuroinflammation and neuropathic pain. J Neuroimmune Pharmacol. 2013;8:576–93.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Maddock RJ, Buonocore MH. MR spectroscopic studies of the brain in psychiatric disorders. Curr Top Behav Neurosci. 2012;11:199–251.

    Article  PubMed  Google Scholar 

  68. Lyall AE, Pasternak O, Robinson DG, Newell D, Trampush JW, Gallego JA, et al. Greater extracellular free-water in first-episode psychosis predicts better neurocognitive functioning. Mol Psychiatry. 2017;23:701–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Oestreich LKL, Lyall AE, Pasternak O, Kikinis Z, Newell DT, Savadjiev P, et al. Characterizing white matter changes in chronic schizophrenia: a free-water imaging multi-site study. Schizophr Res. 2017;189:153–61.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Bora E, Pantelis C. Structural trait markers of bipolar disorder: disruption of white matter integrity and localized gray matter abnormalities in anterior fronto-limbic regions. Biol Psychiatry. 2011;69:299–300.

    Article  PubMed  Google Scholar 

  71. Glahn DC, Laird AR, Ellison-Wright I, Thelen SM, Robinson JL, Lancaster JL, et al. Meta-analysis of gray matter anomalies in schizophrenia: application of anatomic likelihood estimation and network analysis. Biol Psychiatry. 2008;64:774–81.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Narr KL, Bilder RM, Toga AW, Woods RP, Rex DE, Szeszko PR, et al. Mapping cortical thickness and gray matter concentration in first episode schizophrenia. Cereb Cortex. 2005;15:708–19.

    Article  PubMed  Google Scholar 

  73. Rimol LM, Hartberg CB, Nesvag R, Fennema-Notestine C, Hagler DJ Jr., et al. Cortical thickness and subcortical volumes in schizophrenia and bipolar disorder. Biol Psychiatry. 2010;68:41–50.

    Article  PubMed  Google Scholar 

  74. Minzenberg MJ, Laird AR, Thelen S, Carter CS, Glahn DC. Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia. Arch Gen Psychiatry. 2009;66:811–22.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Kelly S, Jahanshad N, Zalesky A, Kochunov P, Agartz I, Alloza C, et al. Widespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group. Mol Psychiatry. 2018;23:1261–9.

  76. Karlsgodt KH. Diffusion imaging of white matter in schizophrenia: progress and future directions. Biol Psychiatry Cogn Neurosci Neuroimaging. 2016;1:209–17.

    PubMed  PubMed Central  Google Scholar 

  77. Ellison-Wright I, Bullmore E. Meta-analysis of diffusion tensor imaging studies in schizophrenia. Schizophr Res. 2009;108:3–10.

    Article  PubMed  Google Scholar 

  78. Aoyama K, Watabe M, Nakaki T. Regulation of neuronal glutathione synthesis. J Pharmacol Sci. 2008;108:227–38.

    Article  CAS  PubMed  Google Scholar 

  79. McBean GJ. Cysteine, glutathione, and thiol redox balance in astrocytes. Antioxidants (Basel). 2017;6:E62.

    Article  CAS  Google Scholar 

  80. Choi IY, Lee SP, Denney DR, Lynch SG. Lower levels of glutathione in the brains of secondary progressive multiple sclerosis patients measured by 1H magnetic resonance chemical shift imaging at 3 T. Mult Scler. 2011;17:289–96.

    Article  CAS  PubMed  Google Scholar 

  81. Choi IY, Lee P, Hughes AJ, Denney DR, Lynch SG. Longitudinal changes of cerebral glutathione (GSH) levels associated with the clinical course of disease progression in patients with secondary progressive multiple sclerosis. Mult Scler. 2017;23:956–62.

    Article  PubMed  Google Scholar 

  82. Cheong I, Marjanska M, Deelchand DK, Eberly LE, Walk D, Oz G. Ultra-high field proton MR spectroscopy in early-stage amyotrophic lateral sclerosis. Neurochem Res. 2017;42:1833–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Atassi N, Xu M, Triantafyllou C, Keil B, Lawson R, Cernasov P, et al. Ultra high-field (7tesla) magnetic resonance spectroscopy in Amyotrophic Lateral Sclerosis. PLoS ONE. 2017;12:e0177680.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Ongur D, Prescot AP, Jensen JE, Cohen BM, Renshaw PF. Creatine abnormalities in schizophrenia and bipolar disorder. Psychiatry Res. 2009;172:44–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kraguljac NV, Reid M, White D, Jones R, den Hollander J, Lowman D, et al. Neurometabolites in schizophrenia and bipolar disorder—a systematic review and meta-analysis. Psychiatry Res. 2012;203:111–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Tourjman V, Kouassi E, Koue ME, Rocchetti M, Fortin-Fournier S, Fusar-Poli P, et al. Antipsychotics’ effects on blood levels of cytokines in schizophrenia: a meta-analysis. Schizophr Res. 2013;151:43–7.

    Article  PubMed  Google Scholar 

  87. Monji A, Kato T, Kanba S. Cytokines and schizophrenia: microglia hypothesis of schizophrenia. Psychiatry Clin Neurosci. 2009;63:257–65.

    Article  CAS  PubMed  Google Scholar 

  88. Horvath S, Mirnics K. Immune system disturbances in schizophrenia. Biol Psychiatry. 2014;75:316–23.

    Article  CAS  PubMed  Google Scholar 

  89. Fillman SG, Cloonan N, Catts VS, Miller LC, Wong J, McCrossin T, et al. Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia. Mol Psychiatry. 2013;18:206–14.

    Article  CAS  PubMed  Google Scholar 

  90. Muller N, Riedel M, Scheppach C, Brandstatter B, Sokullu S, Krampe K, et al. Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. Am J Psychiatry. 2002;159:1029–34.

    Article  PubMed  Google Scholar 

  91. Muller N, Krause D, Dehning S, Musil R, Schennach-Wolff R, Obermeier M, et al. Celecoxib treatment in an early stage of schizophrenia: results of a randomized, double-blind, placebo-controlled trial of celecoxib augmentation of amisulpride treatment. Schizophr Res. 2010;121:118–24.

    Article  PubMed  Google Scholar 

  92. Akhondzadeh S, Tabatabaee M, Amini H, Ahmadi Abhari SA, Abbasi SH, Behnam B. Celecoxib as adjunctive therapy in schizophrenia: a double-blind, randomized and placebo-controlled trial. Schizophr Res. 2007;90:179–85.

    Article  PubMed  Google Scholar 

  93. Chaudhry IB, Hallak J, Husain N, Minhas F, Stirling J, Richardson P, et al. Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment. J Psychopharmacol. 2012;26:1185–93.

    Article  PubMed  CAS  Google Scholar 

  94. Levkovitz Y, Mendlovich S, Riwkes S, Braw Y, Levkovitch-Verbin H, Gal G, et al. A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry. 2010;71:138–49.

    Article  CAS  PubMed  Google Scholar 

  95. Nitta M, Kishimoto T, Muller N, Weiser M, Davidson M, Kane JM, et al. Adjunctive use of nonsteroidal anti-inflammatory drugs for schizophrenia: a meta-analytic investigation of randomized controlled trials. Schizophr Bull. 2013;39:1230–41.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Rapaport MH, Delrahim KK, Bresee CJ, Maddux RE, Ahmadpour O, Dolnak D. Celecoxib augmentation of continuously ill patients with schizophrenia. Biol Psychiatry. 2005;57:1594–6.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was funded by National Institutes of Health P50MH106438 and R01MH059883 grants awarded to C.S.C. The authors would like to thank Dr. Thorsten Feiweier from Siemens AG, Healthcare for providing the prototype software package for advanced diffusion imaging, which was used to acquire data in this study and Michael Maddock for assistance in development of custom software for MRS data processing.

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  1. Department of Psychiatry, University of California, Davis, USA

    Tyler A. Lesh, Richard J. Maddock, Amber Howell, Huan Wang, Costin Tanase, J. Daniel Ragland, Tara A. Niendam & Cameron S. Carter

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Lesh, T.A., Maddock, R.J., Howell, A. et al. Extracellular free water and glutathione in first-episode psychosis—a multimodal investigation of an inflammatory model for psychosis. Mol Psychiatry 26, 761–771 (2021). https://doi.org/10.1038/s41380-019-0428-y

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  • DOI: https://doi.org/10.1038/s41380-019-0428-y

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