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Altered plasma glutathione levels in bipolar disorder indicates higher oxidative stress; a possible risk factor for illness onset despite normal brain-derived neurotrophic factor (BDNF) levels

Published online by Cambridge University Press:  27 January 2014

A. R. Rosa ,
N. Singh ,
E. Whitaker ,
M. de Brito ,
A. M. Lewis ,
E. Vieta ,
G. C. Churchill ,
J. R. Geddes  and
G. M. Goodwin
A. R. Rosa
Affiliation:
Bipolar Disorders Program, Institute of Neurosciences, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Spain Department of Pharmacology, University of Oxford, Oxford, UK Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK
N. Singh*
Affiliation:
Department of Pharmacology, University of Oxford, Oxford, UK
E. Whitaker
Affiliation:
Department of Pharmacology, University of Oxford, Oxford, UK
M. de Brito
Affiliation:
Department of Pharmacology, University of Oxford, Oxford, UK
A. M. Lewis
Affiliation:
Department of Pharmacology, University of Oxford, Oxford, UK
E. Vieta
Affiliation:
Bipolar Disorders Program, Institute of Neurosciences, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Spain
G. C. Churchill
Affiliation:
Department of Pharmacology, University of Oxford, Oxford, UK
J. R. Geddes
Affiliation:
Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK
G. M. Goodwin
Affiliation:
Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK
*
*Address for correspondence: Dr N. Singh, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK. (Email: nisha.singh@pharm.ox.ac.uk)
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Abstract

Background

Oxidative stress and neurotrophic factors have been implicated in the pathophysiology of bipolar disorder. Our objective was to determine whether plasma glutathione or brain-derived neurotrophic factor (BDNF) levels were abnormal in bipolar disorder and therefore useful as possible biomarkers.

Method

Blood samples were collected from subsyndromal, medicated bipolar I patients (n = 50), recruited from OXTEXT, University of Oxford, and from 50 matched healthy controls. Total and oxidized glutathione levels were measured using an enzymatic recycling method and used to calculate reduced, percentage oxidized, ratio of reduced:oxidized and redox state. BDNF was measured using an enzyme-linked immunoassay. Self-monitored mood scores for the bipolar group were available (Quick Inventory of Depressive Symptomatology and the Altman Self-Rating Mania Scale) over an 8-week period.

Results

Compared with controls, bipolar patients had significantly lower levels of total glutathione and it was more oxidized. BDNF levels were not different. Age of illness onset but not current mood state correlated with total glutathione levels and its oxidation status, so that lower levels of total and reduced glutathione were associated with later onset of disease, not length of illness.

Conclusions

Plasma glutathione levels and redox state detect oxidative stress even in subsyndromal patients with normal BDNF. It may relate to the onset and development of bipolar disorder. Plasma glutathione appears to be a suitable biomarker for detecting underlying oxidative stress and for evaluating the efficacy of antioxidant intervention studies.

Keywords

Bipolar disorderbrain-derived neurotrophic factordepressionglutathionemoodoxidative stress
Type
Original Articles
Information
Psychological Medicine , Volume 44 , Issue 11 , August 2014 , pp. 2409 - 2418
Copyright
Copyright © Cambridge University Press 2014 

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References

Altman, EG, Hedeker, D, Peterson, JL, Davis, JM (1997). The Altman Self-Rating Mania Scale. Biological Psychiatry 42, 948–955.CrossRefGoogle ScholarPubMed
Andreazza, AC, Cassini, C, Rosa, AR, Leite, MC, De Almeida, LM, Nardin, P, Cunha, AB, Cereser, KM, Santin, A, Gottfried, C, Salvador, M, Kapczinski, F, Goncalves, CA (2007). Serum s100b and antioxidant enzymes in bipolar patients. Journal of Psychiatric Research 41, 523–529.CrossRefGoogle ScholarPubMed
Andreazza, AC, Kapczinski, F, Kauer-Sant'anna, M, Walz, JC, Bond, DJ, Goncalves, CA, Young, LT, Yatham, LN (2009). 3-Nitrotyrosine and glutathione antioxidant system in patients in the early and late stages of bipolar disorder. Journal of Psychiatry and Neuroscience 34, 263–271.Google ScholarPubMed
APA (2000). Diagnostic and Statistical Manual of Mental Disorders, 4th edn, text revision. American Psychiatric Association: Washington, DC.Google Scholar
Berk, M, Copolov, DL, Dean, O, Lu, K, Jeavons, S, Schapkaitz, I, Anderson-Hunt, M, Bush, AI (2008). N-acetyl cysteine for depressive symptoms in bipolar disorder – a double-blind randomized placebo-controlled trial. Biological Psychiatry 64, 468–475.CrossRefGoogle ScholarPubMed
Berk, M, Dean, OM, Cotton, SM, Gama, CS, Kapczinski, F, Fernandes, B, Kohlmann, K, Jeavons, S, Hewitt, K, Moss, K, Allwang, C, Schapkaitz, I, Cobb, H, Bush, AI, Dodd, S, Malhi, GS (2012). Maintenance N-acetyl cysteine treatment for bipolar disorder: a double-blind randomized placebo controlled trial. BioMed Central Medicine 10, 91.Google ScholarPubMed
Bourne, C, Aydemir, O, Balanza-Martinez, V, Bora, E, Brissos, S, Cavanagh, JT, Clark, L, Cubukcuoglu, Z, Dias, VV, Dittmann, S, Ferrier, IN, Fleck, DE, Frangou, S, Gallagher, P, Jones, L, Kieseppa, T, Martinez-Aran, A, Melle, I, Moore, PB, Mur, M, Pfennig, A, Raust, A, Senturk, V, Simonsen, C, Smith, DJ, Bio, DS, Soeiro-De-Souza, MG, Stoddart, SD, Sundet, K, Szoke, A, Thompson, JM, Torrent, C, Zalla, T, Craddock, N, Andreassen, OA, Leboyer, M, Vieta, E, Bauer, M, Worhunsky, PD, Tzagarakis, C, Rogers, RD, Geddes, JR, Goodwin, GM (2013). Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: an individual patient data meta-analysis. Acta Psychiatrica Scandinavica 128, 149–162.CrossRefGoogle ScholarPubMed
Bowden, CL, Krishnan, AA (2004). Pharmacotherapy for bipolar depression: an economic assessment. Expert Opinion on Pharmacotherapy 5, 1101–1107.CrossRefGoogle ScholarPubMed
Curtin, F, Schulz, P (1998). Multiple correlations and Bonferroni's correction. Biological Psychiatry 44, 775–777.CrossRefGoogle ScholarPubMed
Das, P, Tanious, M, Fritz, K, Dodd, S, Dean, OM, Berk, M, Malhi, GS (2013). Metabolite profiles in the anterior cingulate cortex of depressed patients differentiate those taking N-acetyl-cysteine versus placebo. Australian and New Zealand Journal of Psychiatry 47, 347–354.CrossRefGoogle ScholarPubMed
Dean, OM, Bush, AI, Copolov, DL, Kohlmann, K, Jeavons, S, Schapkaitz, I, Anderson-Hunt, M, Berk, M (2012). Effects of N-acetyl cysteine on cognitive function in bipolar disorder. Psychiatry and Clinical Neurosciences 66, 514–517.CrossRefGoogle ScholarPubMed
Deneke, SM, Fanburg, BL (1989). Regulation of cellular glutathione. American Journal of Physiology 257, L163–L173.Google ScholarPubMed
Dias, VV, Brissos, S, Frey, BN, Andreazza, AC, Cardoso, C, Kapczinski, F (2009). Cognitive function and serum levels of brain-derived neurotrophic factor in patients with bipolar disorder. Bipolar Disorders 11, 663–677.CrossRefGoogle ScholarPubMed
Eriksson, SA, Mannervi, B (1970). The reduction of l-cysteine–glutathione mixed disulfide in rat liver. Involvement of an enzyme catalyzing thiol–disulfide interchange. FEBS Letters 7, 26.CrossRefGoogle ScholarPubMed
Essex, DW (2009). Redox control of platelet function. Antioxidants and Redox Signaling 11, 1191–1225.CrossRefGoogle ScholarPubMed
Frey, BN, Andreazza, AC, Houenou, J, Jamain, S, Goldstein, BI, Frye, MA, Leboyer, M, Berk, M, Malhi, GS, Lopez-Jaramillo, C, Taylor, VH, Dodd, S, Frangou, S, Hall, GB, Fernandes, BS, Kauer-Sant'anna, M, Yatham, LN, Kapczinski, F, Young, LT (2013). Biomarkers in bipolar disorder: a positional paper from the International Society for Bipolar Disorders Biomarkers Task Force. Australian and New Zealand Journal of Psychiatry 47, 321–332.CrossRefGoogle ScholarPubMed
Gawryluk, JW, Wang, JF, Andreazza, AC, Shao, L, Yatham, LN, Young, LT (2011 a). Prefrontal cortex glutathione S-transferase levels in patients with bipolar disorder, major depression and schizophrenia. International Journal of Neuropsychopharmacology 14, 1069–1074.CrossRefGoogle ScholarPubMed
Gawryluk, JW, Wang, JF, Andreazza, AC, Shao, L, Young, LT (2011 b). Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. International Journal of Neuropsychopharmacology 14, 123–130.CrossRefGoogle ScholarPubMed
Gilbert, HF (1990). Molecular and cellular aspects of thiol–disulfide exchange. Advances in Enzymology and Related Areas of Molecular Biology 63, 69–172.Google ScholarPubMed
Gitlin, MJ, Swendsen, J, Heller, TL, Hammen, C (1995). Relapse and impairment in bipolar disorder. American Journal of Psychiatry 152, 1635–1640.Google ScholarPubMed
Gong, L, Wyatt, RJ, Baker, I, Masserano, JM (1999). Brain-derived and glial cell line-derived neurotrophic factors protect a catecholaminergic cell line from dopamine induced cell death. Neuroscience Letters 263, 153–156.CrossRefGoogle ScholarPubMed
Grande, I, Kapczinski, F, Stertz, L, Colpo, GD, Kunz, M, Cereser, KM, Kauer-Sant'anna, M, Frey, B, Vieta, E, Magalhaes, PV (2012). Peripheral brain derived neurotrophic factor changes along treatment with extended release quetiapine during acute mood episodes: an open-label trial in drug-free patients with bipolar disorder. Journal of Psychiatric Research 46, 1511–1514.CrossRefGoogle ScholarPubMed
Jones, DP (2006 a). Extracellular redox state: refining the definition of oxidative stress in aging. Rejuvenation Research 9, 169–181.CrossRefGoogle ScholarPubMed
Jones, DP (2006 b). Redefining oxidative stress. Antioxidants and Redox Signaling 8, 1865–1879.CrossRefGoogle ScholarPubMed
Jones, DP, Carlson, JL, Mody, VC, Cai, J, Lynn, MJ, Sternberg, P (2000). Redox state of glutathione in human plasma. Free Radical Biology and Medicine 28, 625–635.CrossRefGoogle ScholarPubMed
Jones, DP, Carlson, JL, Samiec, PS, Sternberg, P Jr, Mody, VC Jr, Reed, RL, Brown, LA (1998). Glutathione measurement in human plasma. Evaluation of sample collection, storage and derivatization conditions for analysis of dansyl derivatives by HPLC. Clinica Chimica Acta 275, 175–184.CrossRefGoogle ScholarPubMed
Jones, DP, Liang, Y (2009). Measuring the poise of thiol/disulfide couples in vivo . Free Radical Biology and Medicine 47, 1329–1338.CrossRefGoogle ScholarPubMed
Jones, DP, Mody, VC Jr, Carlson, JL, Lynn, MJ, Sternberg, P Jr (2002). Redox analysis of human plasma allows separation of pro-oxidant events of aging from decline in antioxidant defenses. Free Radical Biology and Medicine 33, 1290–1300.CrossRefGoogle ScholarPubMed
Kapczinski, F, Dias, VV, Kauer-Sant'anna, M, Brietzke, E, Vazquez, GH, Vieta, E, Berk, M (2009). The potential use of biomarkers as an adjunctive tool for staging bipolar disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry 33, 1366–1371.CrossRefGoogle ScholarPubMed
Klein, AB, Williamson, R, Santini, MA, Clemmensen, C, Ettrup, A, Rios, M, Knudsen, GM, Aznar, S (2011). Blood BDNF concentrations reflect brain-tissue BDNF levels across species. International Journal of Neuropsychopharmacology 14, 347–353.CrossRefGoogle ScholarPubMed
Koga, M, Serritella, AV, Messmer, MM, Hayashi-Takagi, A, Hester, LD, Snyder, SH, Sawa, A, Sedlak, TW (2011). Glutathione is a physiologic reservoir of neuronal glutamate. Biochemical and Biophysical Research Communications 409, 596–602.CrossRefGoogle ScholarPubMed
Kuloglu, M, Ustundag, B, Atmaca, M, Canatan, H, Tezcan, AE, Cinkilinc, N (2002). Lipid peroxidation and antioxidant enzyme levels in patients with schizophrenia and bipolar disorder. Cell Biochemistry and Function 20, 171–175.CrossRefGoogle ScholarPubMed
Kunz, M, Gama, CS, Andreazza, AC, Salvador, M, Cereser, KM, Gomes, FA, Belmonte-De-Abreu, PS, Berk, M, Kapczinski, F (2008). Elevated serum superoxide dismutase and thiobarbituric acid reactive substances in different phases of bipolar disorder and in schizophrenia. Neuro-Psychopharmacology and Biological Psychiatry 32, 1677–1678.CrossRefGoogle ScholarPubMed
Lakhan, SE, Vieira, K, Hamlat, E (2010). Biomarkers in psychiatry: drawbacks and potential for misuse. International Archives of Medicine 3, 1.CrossRefGoogle ScholarPubMed
Lin, PY (2009). State-dependent decrease in levels of brain-derived neurotrophic factor in bipolar disorder: a meta-analytic study. Neuroscience Letters 466, 139–143.CrossRefGoogle ScholarPubMed
Machado-Vieira, R, Andreazza, AC, Viale, CI, Zanatto, V, Cereser, V Jr, Da Silva Vargas, R, Kapczinski, F, Portela, LV, Souza, DO, Salvador, M, Gentil, V (2007 a). Oxidative stress parameters in unmedicated and treated bipolar subjects during initial manic episode: a possible role for lithium antioxidant effects. Neuroscience Letters 421, 33–36.CrossRefGoogle ScholarPubMed
Machado-Vieira, R, Dietrich, MO, Leke, R, Cereser, VH, Zanatto, V, Kapczinski, F, Souza, DO, Portela, LV, Gentil, V (2007 b). Decreased plasma brain derived neurotrophic factor levels in unmedicated bipolar patients during manic episode. Biological Psychiatry 61, 142–144.CrossRefGoogle ScholarPubMed
Magalhaes, PV, Dean, OM, Bush, AI, Copolov, DL, Malhi, GS, Kohlmann, K, Jeavons, S, Schapkaitz, I, Anderson-Hunt, M, Berk, M (2011). N-acetyl cysteine add-on treatment for bipolar II disorder: a subgroup analysis of a randomized placebo-controlled trial. Journal of Affective Disorders 129, 317–320.CrossRefGoogle ScholarPubMed
Manji, H, Kato, T, Di Prospero, NA, Ness, S, Beal, MF, Krams, M, Chen, G (2012). Impaired mitochondrial function in psychiatric disorders. Nature Reviews Neuroscience 13, 293–307.CrossRefGoogle ScholarPubMed
Monteleone, P, Serritella, C, Martiadis, V, Maj, M (2008). Decreased levels of serum brain-derived neurotrophic factor in both depressed and euthymic patients with unipolar depression and in euthymic patients with bipolar I and II disorders. Bipolar Disorders 10, 95–100.CrossRefGoogle ScholarPubMed
Moran, MD (2003). Arguments for rejecting the sequential Bonferroni in ecological studies. Oikos 100, 403–405.CrossRefGoogle Scholar
Nakagawa, S (2004). A farewell to Bonferroni: the problems of low statistical power and publication bias. Behavioral Ecology 15, 1044–1045.CrossRefGoogle Scholar
Ng, F, Berk, M, Dean, O, Bush, AI (2008). Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. International Journal of Neuropsychopharmacology 11, 851–876.CrossRefGoogle ScholarPubMed
Palomino, A, Vallejo-Illarramendi, A, Gonzalez-Pinto, A, Aldama, A, Gonzalez-Gomez, C, Mosquera, F, Gonzalez-Garcia, G, Matute, C (2006). Decreased levels of plasma BDNF in first-episode schizophrenia and bipolar disorder patients. Schizophrenia Research 86, 321–322.CrossRefGoogle ScholarPubMed
Pan, W, Banks, WA, Fasold, MB, Bluth, J, Kastin, AJ (1998). Transport of brain derived neurotrophic factor across the blood–brain barrier. Neuropharmacology 37, 1553–1561.CrossRefGoogle ScholarPubMed
Phillips, PH, Glasier, CM, Brodsky, MC (2008). Neuro-ophthalmologic findings in patients with rhombencephalosynapsis. Journal of American Association for Paediatric Opthalmology and Strabismus 12, 97–99.Google ScholarPubMed
Post, RM (2007). Role of BDNF in bipolar and unipolar disorder: clinical and theoretical implications. Journal of Psychiatric Research 41, 979–990.CrossRefGoogle ScholarPubMed
Rahman, I, Kode, A, Biswas, SK (2006). Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method. Nature Protocols 1, 3159–3165.CrossRefGoogle ScholarPubMed
Rice, WR (1989). Analyzing tables of statistical tests. Evolution 43, 223–225.CrossRefGoogle ScholarPubMed
Rush, AJ, Trivedi, MH, Ibrahim, HM, Carmody, TJ, Arnow, B, Klein, DN, Markowitz, JC, Ninan, PT, Kornstein, S, Manber, R, Thase, ME, Kocsis, JH, Keller, MB (2003). The 16-item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biological Psychiatry 54, 573–583.CrossRefGoogle ScholarPubMed
Rybakowski, JK, Suwalska, A (2010). Excellent lithium responders have normal cognitive functions and plasma BDNF levels. International Journal of Neuropsychopharmacology 13, 617–622.CrossRefGoogle ScholarPubMed
Samiec, PS, Drews-Botsch, C, Flagg, EW, Kurtz, JC, Sternberg, P Jr, Reed, RL, Jones, DP (1998). Glutathione in human plasma: decline in association with aging, age-related macular degeneration, and diabetes. Free Radical Biology and Medicine 24, 699–704.CrossRefGoogle ScholarPubMed
Schafer, FQ, Buettner, GR (2001). Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radical Biology and Medicine 30, 1191–1212.CrossRefGoogle ScholarPubMed
Schulz, JB, Lindenau, J, Seyfried, J, Dichgans, J (2000). Glutathione, oxidative stress and neurodegeneration. European Journal of Biochemistry 267, 4904–4911.CrossRefGoogle ScholarPubMed
Sheehan, DV, Lecrubier, Y, Sheehan, KH, Amorim, P, Janavs, J, Weiller, E, Hergueta, T, Baker, R, Dunbar, GC (1998). The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. Journal of Clinical Psychiatry 59 (Suppl. 20), 22–57.Google ScholarPubMed
Singh, N, Halliday, AC, Thomas, JM, Kuznetsova, OV, Baldwin, R, Woon, EC, Aley, PK, Antoniadou, I, Sharp, T, Vasudevan, SR, Churchill, GC (2013). A safe lithium mimetic for bipolar disorder. Nature Communications 4, 1332.CrossRefGoogle ScholarPubMed
Suwalska, A, Sobieska, M, Rybakowski, JK (2010). Serum brain-derived neurotrophic factor in euthymic bipolar patients on prophylactic lithium therapy. Neuropsychobiology 62, 229–234.CrossRefGoogle ScholarPubMed
Tramontina, JF, Andreazza, AC, Kauer-Sant'anna, M, Stertz, L, Goi, J, Chiarani, F, Kapczinski, F (2009). Brain-derived neurotrophic factor serum levels before and after treatment for acute mania. Neuroscience Letters 452, 111–113.CrossRefGoogle ScholarPubMed
Tufte, ER (1985). The Visual Display of Quantitative Information. Graphics Press: Cheshire, CT.Google Scholar
Varga, V, Jenei, Z, Janaky, R, Saransaari, P, Oja, SS (1997). Glutathione is an endogenous ligand of rat brain N-methyl-d-aspartate (NMDA) and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors. Neurochemical Research 22, 1165–1171.CrossRefGoogle ScholarPubMed
Wang, JF, Shao, L, Sun, X, Young, LT (2009). Increased oxidative stress in the anterior cingulate cortex of subjects with bipolar disorder and schizophrenia. Bipolar Disorders 11, 523–529.CrossRefGoogle ScholarPubMed
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