Skip to main content Accessibility help
×
×
Home

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

  • A. R. Rosa (a1) (a2) (a3), N. Singh (a2), E. Whitaker (a2), M. de Brito (a2), A. M. Lewis (a2), E. Vieta (a1), G. C. Churchill (a2), J. R. Geddes (a3) and G. M. Goodwin (a3)...
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.

Copyright
Corresponding author
* 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)
References
Hide All
Altman, EG, Hedeker, D, Peterson, JL, Davis, JM (1997). The Altman Self-Rating Mania Scale. Biological Psychiatry 42, 948955.
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, 523529.
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, 263271.
APA (2000). Diagnostic and Statistical Manual of Mental Disorders, 4th edn, text revision. American Psychiatric Association: Washington, DC.
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, 468475.
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.
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, 149162.
Bowden, CL, Krishnan, AA (2004). Pharmacotherapy for bipolar depression: an economic assessment. Expert Opinion on Pharmacotherapy 5, 11011107.
Curtin, F, Schulz, P (1998). Multiple correlations and Bonferroni's correction. Biological Psychiatry 44, 775777.
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, 347354.
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, 514517.
Deneke, SM, Fanburg, BL (1989). Regulation of cellular glutathione. American Journal of Physiology 257, L163L173.
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, 663677.
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.
Essex, DW (2009). Redox control of platelet function. Antioxidants and Redox Signaling 11, 11911225.
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, 321332.
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, 10691074.
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, 123130.
Gilbert, HF (1990). Molecular and cellular aspects of thiol–disulfide exchange. Advances in Enzymology and Related Areas of Molecular Biology 63, 69172.
Gitlin, MJ, Swendsen, J, Heller, TL, Hammen, C (1995). Relapse and impairment in bipolar disorder. American Journal of Psychiatry 152, 16351640.
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, 153156.
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, 15111514.
Jones, DP (2006 a). Extracellular redox state: refining the definition of oxidative stress in aging. Rejuvenation Research 9, 169181.
Jones, DP (2006 b). Redefining oxidative stress. Antioxidants and Redox Signaling 8, 18651879.
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, 625635.
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, 175184.
Jones, DP, Liang, Y (2009). Measuring the poise of thiol/disulfide couples in vivo . Free Radical Biology and Medicine 47, 13291338.
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, 12901300.
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, 13661371.
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, 347353.
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, 596602.
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, 171175.
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, 16771678.
Lakhan, SE, Vieira, K, Hamlat, E (2010). Biomarkers in psychiatry: drawbacks and potential for misuse. International Archives of Medicine 3, 1.
Lin, PY (2009). State-dependent decrease in levels of brain-derived neurotrophic factor in bipolar disorder: a meta-analytic study. Neuroscience Letters 466, 139143.
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, 3336.
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, 142144.
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, 317320.
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, 293307.
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, 95100.
Moran, MD (2003). Arguments for rejecting the sequential Bonferroni in ecological studies. Oikos 100, 403405.
Nakagawa, S (2004). A farewell to Bonferroni: the problems of low statistical power and publication bias. Behavioral Ecology 15, 10441045.
Ng, F, Berk, M, Dean, O, Bush, AI (2008). Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. International Journal of Neuropsychopharmacology 11, 851876.
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, 321322.
Pan, W, Banks, WA, Fasold, MB, Bluth, J, Kastin, AJ (1998). Transport of brain derived neurotrophic factor across the blood–brain barrier. Neuropharmacology 37, 15531561.
Phillips, PH, Glasier, CM, Brodsky, MC (2008). Neuro-ophthalmologic findings in patients with rhombencephalosynapsis. Journal of American Association for Paediatric Opthalmology and Strabismus 12, 9799.
Post, RM (2007). Role of BDNF in bipolar and unipolar disorder: clinical and theoretical implications. Journal of Psychiatric Research 41, 979990.
Rahman, I, Kode, A, Biswas, SK (2006). Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method. Nature Protocols 1, 31593165.
Rice, WR (1989). Analyzing tables of statistical tests. Evolution 43, 223225.
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, 573583.
Rybakowski, JK, Suwalska, A (2010). Excellent lithium responders have normal cognitive functions and plasma BDNF levels. International Journal of Neuropsychopharmacology 13, 617622.
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, 699704.
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, 11911212.
Schulz, JB, Lindenau, J, Seyfried, J, Dichgans, J (2000). Glutathione, oxidative stress and neurodegeneration. European Journal of Biochemistry 267, 49044911.
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), 2257.
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.
Suwalska, A, Sobieska, M, Rybakowski, JK (2010). Serum brain-derived neurotrophic factor in euthymic bipolar patients on prophylactic lithium therapy. Neuropsychobiology 62, 229234.
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, 111113.
Tufte, ER (1985). The Visual Display of Quantitative Information. Graphics Press: Cheshire, CT.
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, 11651171.
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, 523529.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords

Type Description Title
WORD
Supplementary materials

Rosa Supplementary Material
Figures

 Word (447 KB)
447 KB

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed