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A five-year follow-up study of antioxidants, oxidative stress and polyunsaturated fatty acids in schizophrenia

  • Dag K. Solberg (a1), Helge Refsum (a1), Ole A. Andreassen (a2) (a3) and Håvard Bentsen (a1) (a4)

Abstract

Objective:

Oxidative stress and dysregulated antioxidant defence may be involved in the pathophysiology of schizophrenia. In the present study, we investigated changes in antioxidants and oxidative stress from an acute to a later stable phase. We hypothesised that the levels of oxidative markers are increased in schizophrenia compared with healthy controls; change from the acute to the stable phase; and are associated with the levels of membrane polyunsaturated fatty acids (PUFAs) and symptom severity.

Methods:

Fifty-five patients with schizophrenia spectrum disorders, assessed during an acute phase and 5 years later during a stable phase, and 51 healthy controls were included. We measured antioxidants (α-tocopherol, uric acid, albumin and bilirubin), markers of oxidative stress (F2-isoprostane and reactive oxygen metabolites) and membrane fatty acids. Antioxidants and oxidative stress markers were compared in schizophrenia versus healthy controls, adjusting for differences in sex, age and smoking, and changes over time. Associations between symptoms and PUFA were also investigated.

Results:

In the acute phase, α-tocopherol was significantly higher (p < 0.001), while albumin was lower (p < 0.001) compared with the stable phase. Changes in α-tocopherol were associated with PUFA levels in the acute phase. In the stable phase, schizophrenia patients had higher uric acid (p = 0.009) and lower bilirubin (p = 0.046) than healthy controls. CRP was higher in patients in the stable phase (p < 0.001), and there was no significant change from the acute phase.

Conclusion:

The present findings of change in antioxidant levels in the acute versus stable phase of schizophrenia the present findings suggest that redox regulation is dynamic and changes during different phases of the disorder.

Copyright

Corresponding author

Author for correspondence: Dag Kristen Solberg, Email: dag.solberg@diakonsyk.no

References

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Anderson, G and Maes, M (2013) Schizophrenia: linking prenatal infection to cytokines, the tryptophan catabolite (TRYCAT) pathway, NMDA receptor hypofunction, neurodevelopment and neuroprogression. Progress in Neuro-Psychopharmacology and Biological Psychiatry 42, 519.
Ballesteros, A, Jiang, P, Summerfelt, A, Du, X, Chiappelli, J, O’Donnell, P, Kochunov, P and Hong, LE. (2013) No evidence of exogenous origin for the abnormal glutathione redox state in schizophrenia. Schizophrenia Research 146, 184189.
Barron, H, Hafizi, S, Andreazza, AC and Mizrahi, R (2017) Neuroinflammation and oxidative stress in psychosis and psychosis risk. International Journal of Molecular Sciences 18, pii: E651.
Bastani, NE, Gundersen, TE and Blomhoff, R (2009) Determination of 8-epi PGF(2alpha) concentrations as a biomarker of oxidative stress using triple-stage liquid chromatography/tandem mass spectrometry. Rapid Communications in Mass Spectrometry 23, 28852890.
Ben, OL, Mechri, A, Fendri, C, Bost, M, Chazot, G, Gaha, L and Kerkeni, A. (2008) Altered antioxidant defense system in clinically stable patients with schizophrenia and their unaffected siblings. Progress in Neuro-Psychopharmacology & Biological Psychiatry 32, 155159.
Bentsen, H, Osnes, K, Refsum, H, Solberg, DK and Bohmer, T (2013) A randomized placebo-controlled trial of an omega-3 fatty acid and vitamins E+C in schizophrenia. Translational Psychiatry 3, e335.
Bentsen, H, Solberg, DK, Refsum, H and Bohmer, T (2012) Clinical and biochemical validation of two endophenotypes of schizophrenia defined by levels of polyunsaturated fatty acids in red blood cells. Prostaglandins, Leukotrienes & Essential Fatty Acids 87, 3541.
Bentsen, H, Solberg, DK, Refsum, H, Gran, JM, Bohmer, T, Torjesen, PA, Halvorsen, O and Lingjaerde, O. (2011) Bimodal distribution of polyunsaturated fatty acids in schizophrenia suggests two endophenotypes of the disorder. Biological Psychiatry 70, 97105.
Bergink, V, Gibney, SM and Drexhage, HA (2014) Autoimmunity, inflammation, and psychosis: a search for peripheral markers. Biological Psychiatry 75, 324–321.
Bitanihirwe, BK and Woo, TU (2011) Oxidative stress in schizophrenia: an integrated approach. Neuroscience & Biobehavioral Reviews 35, 878893.
Block, ML, Zecca, L and Hong, JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nature Reviews Neuroscience 8, 5769.
Boskovic, M, Vovk, T, Kores, PB and Grabnar, I (2011) Oxidative stress in schizophrenia. Current Neuropharmacology 9, 301312.
Boulanger, LM (2009) Immune proteins in brain development and synaptic plasticity. Neuron 64, 93109.
Bulbul, F, Virit, O, Alpak, G, Unal, A, Bulut, M, Kaya, MC, Altindag, A, Celik, H and Savas, HA. (2014) Are oxidative stress markers useful to distinguish schizoaffective disorder from schizophrenia and bipolar disorder? Acta Neuropsychiatrica 26, 120124.
Cesarone, MR, Belcaro, G, Carratelli, M, Cornelli, U, De Sanctis, MT, Incandela, L, Barsotti, A, Terranova, R and Nicolaides, A. (1999) A simple test to monitor oxidative stress. International Angiology 18, 127130.
Chen, ML, Wu, S, Tsai, TC, Wang, LK and Tsai, FM (2013) Regulation of macrophage immune responses by antipsychotic drugs. Immunopharmacol Immunotoxicol 35, 573580.
Christensen, H and Hermann, M (2012) Immunological response as a source to variability in drug metabolism and transport. Frontiers in Pharmacology 3, 8.
Ciobica, A, Padurariu, M, Dobrin, I, Stefanescu, C and Dobrin, R (2011) Oxidative stress in schizophrenia - focusing on the main markers. Psychiatria Danubina 23, 237245.
Dadheech, G, Mishra, S, Gautam, S and Sharma, P (2006) Oxidative stress, alpha-tocopherol, ascorbic acid and reduced glutathione status in schizophrenics. Indian Journal of Clinical Biochemistry 21, 3438.
de Witte, L, Tomasik, J, Schwarz, E, Guest, PC, Rahmoune, H, Kahn, RS and Bahn, S. (2014) Cytokine alterations in first-episode schizophrenia patients before and after antipsychotic treatment. Schizophrenia Research 154, 2329.
Debnath, M (2015) Adaptive immunity in schizophrenia: functional implications of T cells in the etiology, course and treatment. Journal of Neuroimmune Pharmacology 10, 610619.
Dipasquale, S, Pariante, CM, Dazzan, P, Aguglia, E, McGuire, P and Mondelli, V (2013) The dietary pattern of patients with schizophrenia: a systematic review. Journal of Psychiatric Research 47, 197207.
Do, KQ, Cabungcal, JH, Frank, A, Steullet, P and Cuenod, M (2009) Redox dysregulation, neurodevelopment, and schizophrenia. Current Opinion in Neurobiology 19, 220230.
Don, BR and Kaysen, G (2004) Serum albumin: relationship to inflammation and nutrition. Seminars in Dialysis 17, 432437.
Emiliani, FE, Sedlak, TW and Sawa, A (2014) Oxidative stress and schizophrenia: recent breakthroughs from an old story. Current Opinion in Psychiatry 27, 185190.
Fernandes, BS, Steiner, J, Bernstein, HG, Dodd, S, Pasco, JA, Dean, OM, Nardin, P, Goncalves, CA and Berk, M. (2016) C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: meta-analysis and implications. Molecular Psychiatry 21, 554564.
Flatow, J, Buckley, P and Miller, BJ (2013) Meta-analysis of oxidative stress in schizophrenia. Biological Psychiatry 74, 400409.
Ford, L, Farr, J, Morris, P and Berg, J (2006) The value of measuring serum cholesterol-adjusted vitamin E in routine practice. Annals of Clinical Biochemistry 43, 130134.
Fraguas, D, Diaz-Caneja, CM, Rodriguez-Quiroga, A and Arango, C (2017) Oxidative stress and inflammation in early onset first episode psychosis: a systematic review and meta-analysis. The International Journal of Neuropsychopharmacology 20, 435444.
Herken, H, Uz, E, Ozyurt, H, Sogut, S, Virit, O and Akyol, O (2001) Evidence that the activities of erythrocyte free radical scavenging enzymes and the products of lipid peroxidation are increased in different forms of schizophrenia. Molecular Psychiatry 6, 6673.
Hope, S, Ueland, T, Steen, NE, Dieset, I, Lorentzen, S, Berg, AO, Agartz, I, Aukrust, P and Andreassen, OA. (2013) Interleukin 1 receptor antagonist and soluble tumor necrosis factor receptor 1 are associated with general severity and psychotic symptoms in schizophrenia and bipolar disorder. Schizophrenia Research 145, 3642.
Howes, OD and Murray, RM (2014) Schizophrenia: an integrated sociodevelopmental-cognitive model. Lancet 383, 16771687.
Jansen, T and Daiber, A (2012) Direct antioxidant properties of bilirubin and biliverdin. Is there a role for Biliverdin Reductase? Frontiers in Pharmacology 3, 30.
Johnsen, E, Fathian, F, Kroken, RA, Steen, VM, Jorgensen, HA, Gjestad, R and Loberg, EM. (2016) The serum level of C-reactive protein (CRP) is associated with cognitive performance in acute phase psychosis. BMC Psychiatry 16, 60.
Jordan, W, Dobrowolny, H, Bahn, S, Bernstein, HG, Brigadski, T, Frodl, T, Isermann, B, Lessmann, V, Pilz, J, Rodenbeck, A, Schiltz, K, Schwedhelm, E, Tumani, H, Wiltfang, J, Guest, PC and Steiner, J. (2018) Oxidative stress in drug-naive first episode patients with schizophrenia and major depression: effects of disease acuity and potential confounders. European Archives of Psychiatry and Clinical Neuroscience 268, 129143.
Katsuta, N, Ohnuma, T, Maeshima, H, Takebayashi, Y, Higa, M, Takeda, M, Nakamura, T, Nishimon, S, Sannohe, T, Hotta, Y, Hanzawa, R, Higashiyama, R, Shibata, N and Arai, H. (2014) Significance of measurements of peripheral carbonyl stress markers in a cross-sectional and longitudinal study in patients with acute-stage schizophrenia. Schizophrenia Bulletin 40, 13661373.
Khandaker, GM, Cousins, L, Deakin, J, Lennox, BR, Yolken, R and Jones, PB (2015) Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. Lancet Psychiatry 2, 258270.
Kharb, S and Singh, GP (2000) Effect of smoking on lipid profile, lipid peroxidation and antioxidant status in normal subjects and in patients during and after acute myocardial infarction. Clinica Chimica Acta 302, 213219.
Koga, M, Serritella, AV, Sawa, A and Sedlak, TW (2016) Implications for reactive oxygen species in schizophrenia pathogenesis. Schizophrenia Research 176, 5271.
Krystal, JH and Anticevic, A (2015) Toward illness phase-specific pharmacotherapy for schizophrenia. Biological Psychiatry 78, 738740.
Krystal, JH, Anticevic, A, Yang, GJ, Dragoi, G, Driesen, NR, Wang, XJ and Murray, JD. (2017) Impaired tuning of neural ensembles and the pathophysiology of schizophrenia: a translational and computational neuroscience perspective. Biological Psychiatry 81, 874885.
Labad, J, Stojanovic-Perez, A, Montalvo, I, Sole, M, Cabezas, A, Ortega, L, Moreno, I, Vilella, E, Martorell, L, Reynolds, RM and Gutierrez-Zotes, A. (2015) Stress biomarkers as predictors of transition to psychosis in at-risk mental states: roles for cortisol, prolactin and albumin. Journal of Psychiatric Research 60, 163169.
Lai, CY, Scarr, E, Udawela, M, Everall, I, Chen, WJ and Dean, B (2016) Biomarkers in schizophrenia: a focus on blood based diagnostics and theranostics. World Journal of Psychiatry 6, 102117.
Lee, EE, Eyler, LT, Wolkowitz, OM, Martin, AS, Reuter, C, Kraemer, H, et al. (2016) Elevated plasma F2-isoprostane levels in schizophrenia. Schizophrenia Research 176, 320326.
Li, XF, Zheng, YL, Xiu, MH, Chen, DC, Kosten, TR and Zhang, XY (2011) Reduced plasma total antioxidant status in first-episode drug-naive patients with schizophrenia. Progress in Neuro-Psychopharmacology & Biological Psychiatry 35, 10641067.
Liu, GH, Qu, J and Shen, X (2008) NF-kappaB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK. Biochimica et Biophysica Acta 1783, 713727.
Liu, ML, Zheng, P, Liu, Z, Xu, Y, Mu, J, Guo, J, et al. (2014) GC-MS based metabolomics identification of possible novel biomarkers for schizophrenia in peripheral blood mononuclear cells. Molecular BioSystems 10, 23982406.
Mazzio, EA, Kolta, MG, Reams, RR and Soliman, KF (2005) Inhibitory effects of cigarette smoke on glial inducible nitric oxide synthase and lack of protective properties against oxidative neurotoxins in vitro. Neurotoxicology 26, 4962.
McCreadie, RG, Macdonald, E, Wiles, D, Campbell, G and Paterson, JR (1995) The Nithsdale Schizophrenia Surveys. XIV: Plasma lipid peroxide and serum vitamin E levels in patients with and without tardive dyskinesia, and in normal subjects. British Journal of Psychiatry 167, 610617.
Medema, S, Mocking, RJ, Koeter, MW, Vaz, FM, Meijer, C, de, HL, et al. (2015) Levels of red blood cell fatty acids in patients with psychosis, their unaffected siblings, and healthy controls. Schizophrenia Bulletin 42, 358368.
Mico, JA, Rojas-Corrales, MO, Gibert-Rahola, J, Parellada, M, Moreno, D, Fraguas, D, et al. (2011) Reduced antioxidant defense in early onset first-episode psychosis: a case-control study. BMC Psychiatry 11, 26.
Miller, BJ, Buckley, P, Seabolt, W, Mellor, A and Kirkpatrick, B (2011) Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biological Psychiatry 70, 663671.
Miller, BJ and Goldsmith, DR (2017) Towards an immunophenotype of schizophrenia: progress, potential mechanisms, and future directions. Neuropsychopharmacology 42, 299317.
Miller, JD, Chu, Y, Brooks, RM, Richenbacher, WE, Pena-Silva, R and Heistad, DD (2008) Dysregulation of antioxidant mechanisms contributes to increased oxidative stress in calcific aortic valvular stenosis in humans. Journal of the American College of Cardiology 52, 843850.
Mitra, S, Natarajan, R, Ziedonis, D and Fan, X (2017) Antioxidant and anti-inflammatory nutrient status, supplementation, and mechanisms in patients with schizophrenia. Progress in Neuro-Psychopharmacology & Biological Psychiatry 78, 111.
Miyaoka, T, Seno, H, Itoga, M, Iijima, M, Inagaki, T and Horiguchi, J (2000) Schizophrenia-associated idiopathic unconjugated hyperbilirubinemia (Gilbert’s syndrome). The Journal of Clinical Psychiatry 61, 868871.
Morch, RH, Dieset, I, Faerden, A, Hope, S, Aas, M, Nerhus, M, et al. (2017) Persistent increase in TNF and IL-1 markers in severe mental disorders suggests trait-related inflammation: a one year follow-up study. Acta Psychiatrica Scandinavica 136, 400408.
Muller, N (2018) Inflammation in Schizophrenia: pathogenetic Aspects and Therapeutic Considerations. Schizophrenia Bulletin 44, 973982.
Muller, N, Weidinger, E, Leitner, B and Schwarz, MJ (2015) The role of inflammation in schizophrenia. Frontiers in Neuroscience 9, 372.
Pae, CU, Paik, IH, Lee, C, Lee, SJ, Kim, JJ and Lee, CU (2004) Decreased plasma antioxidants in schizophrenia. Neuropsychobiology 50, 5456.
Pandya, CD, Howell, KR and Pillai, A (2013) Antioxidants as potential therapeutics for neuropsychiatric disorders. Progress in Neuro-Psychopharmacology & Biological Psychiatry 46, 214223.
Pisoschi, AM and Pop, A (2015) The role of antioxidants in the chemistry of oxidative stress: a review. European Journal of Medicinal Chemistry 97, 5574.
Raederstorff, D, Wyss, A, Calder, PC, Weber, P and Eggersdorfer, M (2015) Vitamin E function and requirements in relation to PUFA. British Journal of Nutrition 114, 11131122.
Reddy, R, Keshavan, M and Yao, JK (2003) Reduced plasma antioxidants in first-episode patients with schizophrenia. Schizophrenia Research 62, 205212.
Reddy, RD and Yao, JK (1996) Free radical pathology in schizophrenia: a review. Prostaglandins Leukotrienes & Essential Fatty Acids 55, 3343.
Roge, R, Moller, BK, Andersen, CR, Correll, CU and Nielsen, J (2012) Immunomodulatory effects of clozapine and their clinical implications: what have we learned so far? Schizophrenia Research 140, 204213.
Sekar, A, Bialas, AR, de Rivera, H, Davis, A, Hammond, TR, Kamitaki, N, Tooley, K, Presumey, J, Baum, M, Van Doren, V, Genovese, G, Rose, SA, Handsaker, RE, Schizophrenia Working Group of the Psychiatric Genomics C, Daly, MJ, Carroll, MC, Stevens, B and McCarroll, SA. (2016) Schizophrenia risk from complex variation of complement component 4. Nature 530, 177183.
Semnani, Y, Nazemi, F, Azariyam, A and Ardakani, MJ (2010) Alteration of serum bilirubin level in schizophrenia. International Journal of Psychiatry in Clinical Practice 14, 262267.
Sertan, CU, Virit, O, Hanifi, KM, Orkmez, M, Bulbul, F, Binnur, EA, Semiz, M, Alpak, G, Unal, A, Ari, M and Savas, HA. (2015) Increased oxidative stress and oxidative DNA damage in non-remission schizophrenia patients. Psychiatry Research 229, 200205.
Shi, J, Levinson, DF, Duan, J, Sanders, AR, Zheng, Y, Pe’er, I, Dudbridge, F, Holmans, PA, Whittemore, AS, Mowry, BJ, Olincy, A, Amin, F, Cloninger, CR, Silverman, JM, Buccola, NG, Byerley, WF, Black, DW, Crowe, RR, Oksenberg, JR, Mirel, DB Kendler, KS Freedman, R and Gejman, PV. (2009) Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460, 753757.
Solberg, DK, Bentsen, H, Refsum, H and Andreassen, OA (2015) Association between serum lipids and membrane fatty acids and clinical characteristics in patients with schizophrenia. Acta Psychiatrica Scandinavica 132, 293300.
Solberg, DK, Bentsen, H, Refsum, H and Andreassen, OA (2016) Lipid profiles in schizophrenia associated with clinical traits: a five year follow-up study. BMC Psychiatry 16, 299.
Steullet, P, Cabungcal, JH, Monin, A, Dwir, D, O’Donnell, P, Cuenod, M and Do, KQ. (2016) Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: a “central hub” in schizophrenia pathophysiology? Schizophrenia Research 176, 4151.
Strassnig, M, Singh Brar, J and Ganguli, R (2005) Dietary fatty acid and antioxidant intake in community-dwelling patients suffering from schizophrenia. Schizophrenia Research 76, 343351.
Suboticanec, K, Folnegovic-Smalc, V, Korbar, M, Mestrovic, B and Buzina, R (1990) Vitamin C status in chronic schizophrenia. Biological Psychiatry 28, 959966.
Traber, MG (2007) Vitamin E regulatory mechanisms. Annual Review of Nutrition 27, 347362.
Tuncel, OK, Sarisoy, G, Bilgici, B, Pazvantoglu, O, Cetin, E, Unverdi, E, Avci, B and Boke, O. (2015) Oxidative stress in bipolar and schizophrenia patients. Psychiatry Research 228, 688694.
van Os, J, Rutten, BP and Poulton, R (2008) Gene-environment interactions in schizophrenia: review of epidemiological findings and future directions. Schizophr Bulletin 34, 10661082.
Van’t Erve, TJ, Lih, FB, Jelsema, C, Deterding, LJ, Eling, TE, Mason, RP and Kadiiska, MB. (2016) Reinterpreting the best biomarker of oxidative stress: the 8-iso-prostaglandin F2alpha/prostaglandin F2alpha ratio shows complex origins of lipid peroxidation biomarkers in animal models. Free Radical Biology and Medicine 95, 6573.
Vasilaki, AT, Leivaditi, D, Talwar, D, Kinsella, J, Duncan, A, O’Reilly, DS and McMillan, DC. (2009) Assessment of vitamin E status in patients with systemic inflammatory response syndrome: plasma, plasma corrected for lipids or red blood cell measurements? Clinica Chimica Acta 409, 4145.
Widschwendter, CG, Rettenbacher, MA, Kemmler, G, Edlinger, M, Baumgartner, S, Fleischhacker, WW and Hofer, A. (2016) Bilirubin concentration correlates with positive symptoms in patients with schizophrenia. The Journal of Clinical Psychiatry 77, 512516.
Wollmann, BM, Syversen, SW, Lie, E, Gjestad, C, Mehus, LL, Olsen, IC and Molden, E. (2017) 4beta-Hydroxycholesterol Level in Patients With Rheumatoid Arthritis Before vs. After Initiation of bDMARDs and Correlation With Inflammatory State. Clinical and Translational Science 10, 4249.
Wu, JQ, Kosten, TR and Zhang, XY (2013) Free radicals, antioxidant defense systems, and schizophrenia. Progress in Neuro-Psychopharmacology & Biological Psychiatry 46, 200206.
Yao, JK and Keshavan, MS (2011) Antioxidants, redox signaling, and pathophysiology in schizophrenia: an integrative view. Antioxidants & Redox Signaling 15, 20112035.
Yao, JK, Reddy, R, McElhinny, LG and van Kammen, DP (1998) Reduced status of plasma total antioxidant capacity in schizophrenia. Schizophrenia Research 32, 18.
Yao, JK, Reddy, R and van Kammen, DP (2000) Abnormal age-related changes of plasma antioxidant proteins in schizophrenia. Psychiatry Research 97, 137151.
Zhang, XY and Yao, JK (2013) Oxidative stress and therapeutic implications in psychiatric disorders. Progress in Neuro-Psychopharmacology & Biological Psychiatry 46, 197199.
Zhang, XY, Chen, DC, Xiu, MH, Wang, F, Qi, LY, Sun, HQ, Chen, S, He, SC, Wu, GY, Haile, CN, Kosten, TA, Lu, L and Kosten, TR. (2009) The novel oxidative stress marker thioredoxin is increased in first-episode schizophrenic patients. Schizophrenia Research 113, 151157.
Zhang, XY, Tan, YL, Cao, LY, Wu, GY, Xu, Q, Shen, Y and Zhou, DF. (2006) Antioxidant enzymes and lipid peroxidation in different forms of schizophrenia treated with typical and atypical antipsychotics. Schizophrenia Research 81, 291300.
Zhang, XY, Tan, YL, Zhou, DF, Haile, CN, Wu, GY, Cao, LY, Kosten, TA and Kosten, TR. (2007) Nicotine dependence, symptoms and oxidative stress in male patients with schizophrenia. Neuropsychopharmacology 32, 20202024.

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