Involvement of oxidative stress in the pathophysiology of schizophrenia (SZ) is suggested by studies of peripheral tissue. Nonetheless, it is unclear how such biological changes are linked to relevant, pathological neurochemistry, and brain function. We designed a multi-faceted study by combining biochemistry, neuroimaging, and neuropsychology to test how peripheral changes in a key marker for oxidative stress, glutathione (GSH), may associate with central neurochemicals or neuropsychological performance in health and in SZ. GSH in dorsal anterior cingulate cortex (dACC) was acquired as a secondary 3T 1H-MRS outcome using a MEGA-PRESS sequence. Fifty healthy controls and 46 patients with SZ were studied cross-sectionally, and analyses were adjusted for effects of confounding variables. We observed lower peripheral total GSH in SZ compared to controls in extracellular (plasma) and intracellular (lymphoblast) pools. Total GSH levels in plasma positively correlated with composite neuropsychological performance across the total population and within patients. Total plasma GSH levels were also positively correlated with the levels of Glx in the dACC across the total population, as well as within each individual group (controls, patients). Furthermore, the levels of dACC Glx and dACC GSH positively correlated with composite neuropsychological performance in the patient group. Exploring the relationship between systemic oxidative stress (in particular GSH), central glutamate, and cognition in SZ will benefit further from assessment of patients with more varied neuropsychological performance.
Subscribe to Journal
Get full journal access for 1 year
only $41.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Landek-Salgado MA, Faust TE, Sawa A. Molecular substrates of schizophrenia: homeostatic signaling to connectivity. Mol Psychiatry. 2016;21:10–28.
Emiliani FE, Sedlak TW, Sawa A. Oxidative stress and schizophrenia: recent breakthroughs from an old story. Curr Opin Psychiatry. 2014;27:185–90.
Kulak A, Steullet P, Cabungcal JH, Werge T, Ingason A, Cuenod M, et al. Redox dysregulation in the pathophysiology of schizophrenia and bipolar disorder: insights from animal models. Antioxid Redox Signal. 2013;18:1428–43.
Owen MJ, Sawa A, Mortensen PB. Schizophrenia. Lancet. 2016;388:86–97.
Koga M, Serritella AV, Sawa A, Sedlak TW. Implications for reactive oxygen species in schizophrenia pathogenesis. Schizophr Res. 2016;176:52–71.
Zhang Y, Catts VS, Shannon Weickert C. Lower antioxidant capacity in the prefrontal cortex of individuals with schizophrenia. Aust N. Z J Psychiatry. 2018;52:690–8.
Flatow J, Buckley P, Miller BJ. Meta-analysis of oxidative stress in schizophrenia. Biol Psychiatry. 2013;74:400–9.
Fraguas D, Díaz-Caneja CM, Ayora M, Hernández-Álvarez F, Rodríguez-Quiroga A, Recio S, et al. Oxidative stress and inflammation in first-episode psychosis: a systematic review and meta-analysis. Schizophr Bull. 2019;45:742–51.
Nguyen TT, Eyler LT, Jeste DV. Systemic biomarkers of accelerated aging in schizophrenia: a critical review and future directions. Schizophr Bull. 2018;44:398–408.
Dietrich-Muszalska A, Olas B, Głowacki R, Bald E. Oxidative/nitrative modifications of plasma proteins and thiols from patients with schizophrenia. Neuropsychobiology. 2009;59:1–7.
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.
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.
Ruiz-Litago F, Seco J, Echevarría E, Martínez-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.
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.
Vidović B, Milovanović S, Dorđević B, Kotur-Stevuljević J, Stefanović A, Ivanišević J, et al. Effect of alpha-lipoic acid supplementation on oxidative stress markers and antioxidative defense in patients with schizophrenia. Psychiatr Danub. 2014;26:205–13.
Vidović B, Stefanović A, Milovanović S, Ðorđević B, Kotur-Stevuljević J, Ivanišević 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.
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.
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.
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.
Altuntas I, Aksoy H, Coskun I, Cayköylü A, Akçay 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.
Do KQ, Trabesinger AH, Kirsten-Krüger 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.
Matsuzawa D, Hashimoto K. Magnetic resonance spectroscopy study of the antioxidant defense system in schizophrenia. Antioxid Redox Signal. 2011;15:2057–65.
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.
Monin A, Baumann PS, Griffa A, Xin L, Mekle R, Fournier M, et al. Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients. Mol Psychiatry. 2015;20:827–38.
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.
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.
Dwyer GE, Hugdahl K, Specht K, Grüner R. Current Practice and New Developments in the Use of In Vivo Magnetic Resonance Spectroscopy for the Assessment of Key Metabolites Implicated in the Pathophysiology of Schizophrenia. Curr Top Med Chem. 2018;18:1908–24.
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.
Lesh TA, Maddock RJ, Howell A, Wang H, Tanase C, Daniel Ragland J, et al. Extracellular free water and glutathione in first-episode psychosis-a multimodal investigation of an inflammatory model for psychosis. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0428-y. Online ahead of print.
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.
Hafizi S, Da Silva T, Meyer JH, Kiang M, Houle S, Remington G, et al. Interaction between TSPO-a neuroimmune marker-and redox status in clinical high risk for psychosis: a PET-MRS study. Neuropsychopharmacology. 2018;43:1700–5.
Das TK, Javadzadeh A, Dey A, Sabesan P, Théberge J, Radua J, et al. Antioxidant defense in schizophrenia and bipolar disorder: A meta-analysis of MRS studies of anterior cingulate glutathione. Prog Neuropsychopharmacol Biol Psychiatry. 2019;91:94–102.
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.
Sedlak TW, Nucifora LG, Koga M, Shaffer LS, Higgs C, Tanaka T, et al. Sulforaphane augments glutathione and influences brain metabolites in human subjects: a clinical pilot study. Mol Neuropsychiatry. 2018;3:214–22.
Cabungcal JH, Counotte DS, Lewis E, Tejeda HA, Piantadosi P, Pollock C, et al. Juvenile antioxidant treatment prevents adult deficits in a developmental model of schizophrenia. Neuron. 2014;83:1073–84.
Johnson AW, Jaaro-Peled H, Shahani N, Sedlak TW, Zoubovsky S, Burruss D, et al. Cognitive and motivational deficits together with prefrontal oxidative stress in a mouse model for neuropsychiatric illness. Proc Natl Acad Sci USA. 2013;110:12462–7.
Baumann PS, Griffa A, Fournier M, Golay P, Ferrari C, Alameda L, et al. Impaired fornix-hippocampus integrity is linked to peripheral glutathione peroxidase in early psychosis. Transl Psychiatry. 2016;6:e859.
Geiser E, Retsa C, Knebel JF, Ferrari C, Jenni R, Fournier M, et al. The coupling of low-level auditory dysfunction and oxidative stress in psychosis patients. Schizophr Res. 2017;190:52–59.
Lavoie S, Berger M, Schlögelhofer M, Schäfer MR, Rice S, Kim SW, et al. Erythrocyte glutathione levels as long-term predictor of transition to psychosis. Transl Psychiatry. 2017;7:e1064.
Shirai Y, Fujita Y, Hashimoto R, Ohi K, Yamamori H, Yasuda Y, et al. Dietary intake of sulforaphane-rich broccoli sprout extracts during juvenile and adolescence can prevent phencyclidine-induced cognitive deficits at adulthood. PLoS One. 2015;10:e0127244.
Koga M, Serritella AV, Messmer MM, Hayashi-Takagi A, Hester LD, Snyder SH, et al. Glutathione is a physiologic reservoir of neuronal glutamate. Biochem Biophys Res Commun. 2011;409:596–602.
Steullet P, Cabungcal JH, Monin A, Dwir D, O’Donnell P, Cuenod M, et al. Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology? Schizophr Res. 2016;176:41–51.
Sedlak TW, Paul BD, Parker GM, Hester LD, Snowman AM, Taniguchi Y, et al. The glutathione cycle shapes synaptic glutamate activity. Proc Natl Acad Sci USA. 2019;116:2701–6.
Gasquoine PG. Localization of function in anterior cingulate cortex: from psychosurgery to functional neuroimaging. Neurosci Biobehav Rev. 2013;37:340–8.
Marsman A, van den Heuvel MP, Klomp DW, Kahn RS, Luijten PR, Hulshoff Pol HE. Glutamate in schizophrenia: a focused review and meta-analysis of ¹H-MRS studies. Schizophr Bull. 2013;39:120–9.
Poels EM, Kegeles LS, Kantrowitz JT, Slifstein M, Javitt DC, Lieberman JA, et al. Imaging glutamate in schizophrenia: review of findings and implications for drug discovery. Mol Psychiatry. 2014;19:20–29.
Wijtenburg SA, Wright SN, Korenic SA, Gaston FE, Ndubuizu N, Chiappelli J, et al. Altered glutamate and regional cerebral blood flow levels in schizophrenia: A (1)H-MRS and pCASL study. Neuropsychopharmacology. 2017;42:562–71.
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 (1)H-MRS study (OPTiMiSE). Mol Psychiatry. 2018;23:2145–55.
Ojeda N, Peña J, Schretlen DJ, Sánchez P, Aretouli E, Elizagárate E, et al. Hierarchical structure of the cognitive processes in schizophrenia: the fundamental role of processing speed. Schizophr Res. 2012;135:72–78.
Schretlen DJ, Vannorsdall T. Calibrated ideational fluency assessment professional manual. Lutz, FL: Psychological Assessment Resources; 2010.
Tietze F. Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Anal Biochem. 1969;27:502–22.
Provencher SW. Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med. 1993;30:672–9.
Ongür D, Prescot AP, Jensen JE, Cohen BM, Renshaw PF. Creatine abnormalities in schizophrenia and bipolar disorder. Psychiatry Res. 2009;172:44–48.
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.
Barch DM, Bustillo J, Gaebel W, Gur R, Heckers S, Malaspina D, et al. Logic and justification for dimensional assessment of symptoms and related clinical phenomena in psychosis: relevance to DSM-5. Schizophr Res. 2013;150:15–20.
McClure MM, Bowie CR, Patterson TL, Heaton RK, Weaver C, Anderson H, et al. Correlations of functional capacity and neuropsychological performance in older patients with schizophrenia: evidence for specificity of relationships? Schizophr Res. 2007;89:330–8.
Sánchez P, Ojeda N, Peña J, Elizagárate E, Yoller AB, Gutiérrez M, et al. Predictors of longitudinal changes in schizophrenia: the role of processing speed. J Clin Psychiatry. 2009;70:888–96.
Schaefer J, Giangrande E, Weinberger DR, Dickinson D. The global cognitive impairment in schizophrenia: consistent over decades and around the world. Schizophr Res. 2013;150:42–50.
Houghton CA. Sulforaphane: its “coming of age” as a clinically relevant nutraceutical in the prevention and treatment of chronic disease. Oxid Med Cell Longev. 2019;2019:2716870.
Shiina A, Kanahara N, Sasaki T, Oda Y, Hashimoto T, Hasegawa T, et al. An open study of sulforaphane-rich broccoli sprout extract in patients with schizophrenia. Clin Psychopharmacol Neurosci. 2015;13:62–67.
Singh K, Connors SL, Macklin EA, Smith KD, Fahey JW, Talalay P, et al. Sulforaphane treatment of autism spectrum disorder (ASD). Proc Natl Acad Sci USA. 2014;111:15550–5.
Reid MA, White DM, Kraguljac NV, Lahti AC. A combined diffusion tensor imaging and magnetic resonance spectroscopy study of patients with schizophrenia. Schizophr Res. 2016;170:341–50.
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.
This work was supported by the National Institute of Mental Health (MH-094268 Silvio O. Conte center, MH-092443, MH-105660, MH-107730) (AS), as well as grants from Stanley (AS), S-R (AS), RUSK (AS), NARSAD (JC and AS), and support of the Alexander Wilson Schweizer Fellowship (JC). This project also applies tools developed under P41 EB015909 (RE and PB) and R01 EB016089 (RE). The design, writing, and the decision of publication are only of the authors, who have no conflict of interest to declare. A fund from Mitsubishi Tanabe Pharma Corporation was partly used for recruitment of 11 healthy controls. The authors thank Drs. Kim Do and Michel Cuenod for kindly contributing to scientific discussions and feedback related to this work. They thank Dr. Laurent Younes and Dr. Brian Caffo for discussions regarding medical statistics and data analysis, and also sincerely thank Yukiko Lema for assistance in graphical design of the figures.
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Coughlin, J.M., Yang, K., Marsman, A. et al. A multimodal approach to studying the relationship between peripheral glutathione, brain glutamate, and cognition in health and in schizophrenia. Mol Psychiatry (2020). https://doi.org/10.1038/s41380-020-00901-5
Journal of Affective Disorders (2021)