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


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4


  1. 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.

  2. 2.

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

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  21. 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.

  22. 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.

  23. 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.

  24. 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.

  25. 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.

  26. 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.

  27. 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.

  28. 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.

  29. 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.

  30. 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.

  31. 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.

  32. 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.

  33. 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.

  34. 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.

  35. 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.

  36. 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.

  37. 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.

  38. 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.

  39. 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.

  40. 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.

  41. 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.

  42. 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.

  43. 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. 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. 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.

  46. 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. 47.

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

  48. 48.

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

  49. 49.

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

  50. 50.

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

  51. 51.

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

  52. 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.

  53. 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.

  54. 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.

  55. 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.

  56. 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.

  57. 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.

  58. 58.

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

  59. 59.

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

  60. 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.

  61. 61.

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

  62. 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.

  63. 63.

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

  64. 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. 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.

  66. 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.

  67. 67.

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

  68. 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.

  69. 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.

  70. 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.

  71. 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.

  72. 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.

  73. 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.

  74. 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.

  75. 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. 76.

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

  77. 77.

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

  78. 78.

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

  79. 79.

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

  80. 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.

  81. 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.

  82. 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.

  83. 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.

  84. 84.

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

  85. 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.

  86. 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.

  87. 87.

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

  88. 88.

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

  89. 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.

  90. 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.

  91. 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.

  92. 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.

  93. 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.

  94. 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.

  95. 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.

  96. 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.

Download references


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.

Author information

Correspondence to Tyler A. Lesh.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

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

Supplementary information

Supplementary Information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark