Increased Oxidant Stress and Inflammation in Patients with Chronic Schizophrenia


Background: Several lines of evidence, including postmortem studies, suggest increased oxidative stress and inflammation in patients with schizophrenia. Alteration of oxidative stress markers has been reported in schizoprenia studies, but with inconsistent results. Oxidized low-density lipoproteins (oxLDL) have been reported to be capable of eliciting neurocytotoxicity. On the other hand, paraoxonase (PON1), an arylesterase(ARE), plays a role in protection against oxidative modifications of LDL and is considered to be one of the antioxidant enzymes. There are no studies showing the changes in oxidative stress and inflammation together, nor the activities of PON1 and ARE in schizophrenic patients. In this study, we examined PON1, ARE activities and oxidative/anti-oxidative markers in patients with chronic schizophrenia and healthy controls. Methods: We recruited 30 male chronic schizophrenic patients and 30 male healthy control subjects and examined C-reactive protein(CRP), fibrinogen, PON1, ARE and plasma total antioxidant status (TAS) and total oxidant status (TOS), oxidative stress index(OSI) in both groups. Schizophrenia symptoms were assessed using the positive and negative syndrome scale (PANSS). The related routine lipid profile parameters including HDL were also examined. Results: Patients had significantly higher CRP, fibrinogen, TOS and OSI levels; but the patients and control subjects did not differ on activities of the antioxidant enzymes PON1 and ARE. Interestingly, there were not any group differences in the lipid profile parameters except the triglyceride levels, that increased significantly in the patient group. Conclusions: In the present study, reporting the ARE activities besides the PON1 activities in schizophrenic patients for the first time, we showed that PON1 and ARE enzyme activities were not statistically different in patients with chronic schizophrenia. This study provides additional evidence of increased oxidative stress and inflammation in chronic schizophrenia, but no alterations in the antioxidant status were observed. Our results suggest that other mechanisms than the high density lipoprotein(HDL)-disfunctionality, namely decreases in PON1 or ARE enzyme activities, are more important in oxidative or antioxidative pathophysiological processes in schizophrenia.

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A. Yegin, N. Ay, O. Aydin, N. Yargici, E. Eren and N. Yilmaz, "Increased Oxidant Stress and Inflammation in Patients with Chronic Schizophrenia," International Journal of Clinical Medicine, Vol. 3 No. 5, 2012, pp. 368-376. doi: 10.4236/ijcm.2012.35070.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] J. van Os and S. Kapur, “Schizophrenia,” Lancet, Vol. 22, No. 374, 2009, pp. 635-645. doi:10.1016/S0140-6736(09)60995-8
[2] C. Fendri, A. Mechri, G. Khiari, A. Othman, A. Kerkeni and L. Gaha, “Oxidative Stress Involvement in Schi-zophrenia Pathophysiology: A Review,” L’Encéphale, Vol. 32, No. 2, 2006, pp. 244-252. doi:10.1016/S0013-7006(06)76151-6
[3] A. Ciobica, M. Padurariu, I. Dobrin, C. Stefanescu and R. Dobrin, “Oxidative Stress in Schizophrenia—Focusing on the Main Markers,” Psychiatria Danubina, Vol. 23, No. 3, 2011, pp. 237-245.
[4] C. H. Hennekens, A. R. Hennekens, D. Hollar and D. E. Casey, “Schizophrenia and Increased Risks of Cardio-vascular Disease,” American Heart Journal, Vol. 150, No. 6, 2005, pp. 1115-1121. doi:10.1016/j.ahj.2005.02.007
[5] M. J. T. Oud and B. M.-de Jong, “Somatic Diseases in Patients with Schizophrenia in General Practice: Their Prevalence and Health Care,” BMC Family Practice, Vol. 10, 2009, p. 32. doi:10.1186/1471-2296-10-32
[6] D. P. J. Osborn, I. Nazareth and M. B. King, “Risk for Coronary Heart Disease in People with Severe Mental ?llness. Cross-Sectional Comparative Study in Primary Care,” The British Journal of Psychiatry, Vol. 188, 2006, pp. 271-277. doi:10.1192/bjp.bp.104.008060
[7] S. Parthasarathy, J. Barnett and L. G. Fong, “High- Density Lipoprotein ?nhibits the Oxidative Modification of Low-Density Lipoprotein,” Biochimica et Biophysica Acta, Vol. 1044, No. 2, 1990, pp. 275-283. doi:10.1016/0005-2760(90)90314-N
[8] M. Navab, G. M. Ananthramaiah, S. T. Reddy, et al., “The Oxidation Hypothesis of Atherogenesis: The Role of Oxidized Phospholipids and HDL,” Journal of Lipid Research, Vol. 45, No. 6, 2004, pp. 993-1007. doi:10.1194/jlr.R400001-JLR200
[9] M. Navab, S. Y. Hama, G. M. Anantharamaiah, et al., “Normal High Density Lipoprotein Inhibits Three Steps in the Formation of Mildly Oxidized Low Density Lipoprotein: Steps 2 and 3,” Journal of Lipid Research, Vol. 41, No. 9, 2000, pp. 1495-1508.
[10] M. Navab, S. T. Reddy, B. J. Van Lenten, G. M. Anantharamaiah and A. M. Fogelman, “The Role of Dysfunctional HDL in Atherosclerosis,” Journal of Lipid Research, Vol. 50, 2009, pp. S145-S149. doi:10.1194/jlr.R800036-JLR200
[11] G. W. Cockerill, K. A. Rye, J. R. Gamble, M. A. Vadas and P. J. Barter, “High-Density Lipoproteins Inhibit Cytokine-Induced Expression of Endothelial Cell Adhesion Molecules,” Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 15, No. 11, 1995, pp. 1987-1994. doi:10.1161/01.ATV.15.11.1987
[12] L. Calabresi, M. Gomaraschi, B. Villa, L. Omoboni, C. Dmitrieff and G. Franceschini, “Elevated Soluble Cellular Adhesion Molecules in Subjects with Low HDL-Cholesterol,” Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 22, No. 4, 2002, pp. 656-661. doi:10.1161/hq0402.105901
[13] G. W. Cockerill, T. Y. Huehns, A. Weerasinghe, et al., “Elevation of Plasma High-Density Lipoprotein Concentration Reduces ?nterleukin-1-Induced Expression of E Selectin in an in Vivo Model of Acute ?nflammation,” Circulation, Vol. 103, No. 1, 2001, pp. 108-112. doi:10.1161/01.CIR.103.1.108
[14] C. Matsumoto, O. Ohmori, H. Hori, T. Shinkai and J. Nakamura, “Analysis of Association between the Gln192Arg Polymorphism of the Paraoxonase Gene and Schizophrenia in Humans,” Neuroscience Letters, Vol. 321, No. 3, 2002, pp. 165-168. doi:10.1016/S0304-3940(02)00049-6
[15] S. R. Kay, A. Fiszbein and L. A. Opler, “The Positive and Negative Syndrome Scale (PANSS) for Schizophrenia,” Schizophrenia Bulletin, Vol. 13, No. 2, 1987, pp. 261- 267.
[16] H. W. Eckerson, M. C. Wyte and B. N. La Du, “The Human Serum Paraoxonase/Arylesterase Polymorphism,” The American Journal of Human Genetics, Vol. 35, No. 6, 1983, pp. 1126-1138.
[17] L. Haagen and A. Brock, “A Newautomatedmethod for Phenotyping Arylesterase (E.C. Based upon ?nhibition of Enzymatic Hydrolisis of 4-Nitrophenyl Acetate,” European Journal of Clinical Chemistry and Clinical Biochemistry, Vol. 30, No. 7, 1992, pp. 391-395.
[18] O. Erel, “A Novel Automated Direct Measurement Method for Total Antioxidant Capacity Using a New Generationmore Stable ABTS Radical Cation,” Clinical Biochemistry, Vol. 37, No. 4, 2004, pp. 277-285. doi:10.1016/j.clinbiochem.2003.11.015
[19] O. Erel, “A New Automated Colorimetric Method for Measuring Total Oxidant Status,” Clinical Biochemistry, Vol. 38, No. 12, 2005, pp. 1103-1111. doi:10.1016/j.clinbiochem.2005.08.008
[20] M. Kosecik, O. Erel, E. Sevinc and S. Selek, “Increased Oxidative Stress in Children Exposed to Passive Smok- ing,” International Journal of Cardiology, Vol. 100, No. 1, 2005, pp. 61-64. doi:10.1016/j.ijcard.2004.05.069
[21] J. K. Yao and R. Reddy, “Oxidative Stress in Schizo- phrenia: Pathogenetic and Therapeutic ?mplications,” Anti- oxidants & Redox Signaling, Vol. 15, No. 7, 2011, pp. 1999-2002. doi:10.1089/ars.2010.3646
[22] A. Hoffer, H. Osmond and J. Smythies, “Schizophrenia: A New Approach,” Journal of Mental Science, Vol. 100, No. 418, 1954, pp. 29-45.
[23] M. Padurariu, A. Ciobica, L. Hritcu, B. Stoica, W. Bild and C. Stefanescu, “Changes of Some Oxidative Stress Markers in the Serum of Patients with Mild Cognitive ?mpairment and Alzheimer’s Disease,” Neuroscience Letters, Vol. 469, No. 1, 2010, pp. 6-10. doi:10.1016/j.neulet.2009.11.033
[24] M. Padurariu, A. Ciobica, I. Dobrin and C. Stefanescu, “Evaluation of Antioxidant Enzymes Activities and lipid Peroxidation in Schizophrenic Patients Treated with Typical and Atypical Antipsychotics,” Neuroscience Letters, Vol. 479, No. 3, 2010, pp. 317-320. doi:10.1016/j.neulet.2010.05.088
[25] C. Jennewein, N. Tran, P. Paulus, P. Ellinghaus, J. A. Eble and K. Zacharowski, “Novel Aspects of Fibrin(Ogen) Fragments during Inflammation,” Molecular Medicine, Vol. 17, No. 5-6, 2011, pp. 568-573. doi:10.2119/molmed.2010.00146
[26] B. E. Leonard, M. Schwarz and A. M. Myint, “The Metabolic Syndrome in Schizophrenia: Is Inflammation a Contributing Cause?” Journal of Psychopharmacology, Vol. 26, No. 5, 2012, pp. 33-41. doi:10.1177/0269881111431622
[27] S. R. Terlecky, L. J. Terlecky and C. R. Giordano, “Peroxisomes, Oxidative Stress, and Inflammation,” World Journal of Biological Chemistry, Vol. 3, No. 5, 2012, pp. 93-97. doi:10.4331/wjbc.v3.i5.93
[28] A. Dietrich-Muszalska, J. Malinowska, B. Olas, R. G?owacki, E. Bald, B. Wachowicz and J. Rabe-Jab?ońska, “The Oxidative Stress May Be Induced by the Elevated Homocysteine in Schizophrenic Patients,” Neurochemical Research, Vol. 37, No. 5, 2012, pp. 1057-1062. doi:10.1007/s11064-012-0707-3
[29] J. K. Yao and M. S. Keshavan, “Antioxidants, Redox Signaling, and Pathophysiology in Schizophrenia: An ?ntegrative View,” Antioxidants & Redox Signaling, Vol. 15, No. 7, 2011, pp. 2011-2035. doi:10.1089/ars.2010.3603
[30] G. Dadheech, S. Mishra, S. Gautam and P. Sharma, “Evaluation of Antioxidant Deficit in Schizophrenia,” Indian Journal of Psychiatry, Vol. 50, No. 1, 2008, pp. 16-20. doi:10.4103/0019-5545.39753
[31] M. Raffa, A. Mechri, L.B. Othman, C. Fendri, L. Gaha and A. Kerkeni, “Decreased Glutathione Levels and Antioxidant Enzyme Activities in Untreated and treated Schizophrenic Patients,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, Vol. 33, No. 7, 2009, pp. 1178-1183. doi:10.1016/j.pnpbp.2009.06.018
[32] O. P. Singh, I. Chakraborty, A. Dasgupta and S. Datta, “A Comparative Study of Oxidative Stress and Interrelationship of Important Antioxidants in Haloperidol and Olanzapine Treated Patients Suffering from Schizophrenia,” Indian Journal of Psychiatry, Vol. 50, No. 3, 2008, pp. 171-176. doi:10.4103/0019-5545.43627
[33] S. J. Wood, M. Yücel, C. Pantelis and M. Berk, “Neurobiology of Schizophrenia Spectrum Disorders: The Role of Oxidative Stress,” Annals Academy of Medicine Singapore, Vol. 38, No. 5, 2009, pp. 396-406.
[34] G. Dakhale, S. Khanzode, S. Khanzode, et al., “Oxidative Damage and Schizophrenia: The Potential Benefit by Atypical Antipsychotics,” Neuropsychobiology, Vol. 49, No. 4, 2004, pp. 205-209. doi:10.1159/000077368
[35] M. Kuloglu, B. Ustundag, M. Atmaca, et al., “Lipid Peroxidation and Antioxidant Enzyme Levels in Patients with Schizophrenia and Bipolar Disorder,” Cell Biochemistry and Function, Vol. 20, No. 2, 2002, pp. 171-175. doi:10.1002/cbf.940
[36] M. Kunz, C. S. Gama, A. C. Andreazza, et al., “Elevated Serum Superoxide Dismutase and Thiobarbituric Acid Reactive Substances in Different Phases of Bipolar Disorder and in Schizophrenia,” Progress in Neuro-Psycho- pharmacology and Biological Psychiatry, Vol. 32, No. 7, 2008, pp. 1677-1681. doi:10.1016/j.pnpbp.2008.07.001
[37] M. S. Rukmini, B. D’Souza and V. D’Souza, “Superoxide Dismutase and Catalase Activities and Their Correlation with Malondialdehyde in Schizophrenic Patients,” Indian Journal of Clinical Biochemistry, Vol. 19, No. 2, 2004, pp. 114-118. doi:10.1007/BF02894268
[38] R. Reddy, M. P. Sahebarao, S. Mukherjee and J. N. Murthy, “Enzymes of the Antioxidant System in Chronic Schizophrenic Patients,” Biological Psychiatry, Vol. 30, No. 4, 1991, pp. 409-412. doi:10.1016/0006-3223(91)90298-Z
[39] J. W. Newcomer, “Metabolic Syndrome and Mental Illness,” American Journal of Managed Care, Vol. 13, No. 7, 2007, pp. S170-S177.
[40] S. Selek, N. Cosar, A. Kocyigit, et al., “PON1 Activity and Total Oxidant Status in Patients with Active Pulmonary Tuberculosis,” Clinical Biochemistry, Vol. 41, No. 3, 2008, pp. 140-144. doi:10.1016/j.clinbiochem.2007.11.018
[41] N. Yilmaz, O. Aydin, A. Yegin, A. Tiltak and E. Eren, “Increased Levels of Total Oxidant Status and Decreased Activity of Arylesterase in Migraineurs,” Clinical Biochemistry, Vol. 44, No. 10-11, 2011, pp. 832-837. doi:10.1016/j.clinbiochem.2011.04.015
[42] T. Gaillard, S. Parthasarathy and K. Osei, “HDL Dysfunctionality (Paraoxonase) Is Worse in Nondiabetic, Postmenopausal African American than in White Wo men,” Diabetes Care, 2011, Vol. 34, No. 2, p. e19. doi:10.2337/dc10-1189
[43] K. N. Gan, A. Smolen, H. W. Eckerson and B. N. La Du, “Purification of Human Serum Paraoxonase/Arylesterase. Evidence for One Esterase Catalysing Both Activities,” Drug Metabolism and Disposition, Vol. 19, No. 1, 1991, pp. 100-106.
[44] B. Mackness, M. I Mackness, S. Arrol, W. Turkie and P. N. Durrington, “Effect of the Human Serum Paraoxonase 55 and 192 Genetic Polymorphisms on the Protection by High Density Lipoprotein against Low Density Lipoprotein Oxidative Modification,” FEBS Letters, Vol. 423, No. 1, 1998, pp. 57-60. doi:10.1016/S0014-5793(98)00064-7
[45] E. Boes, S. Coassin, B. Kollerits, I. M. Heid and F. Kronenberg, “Genetic-Epidemiological Evidence on Genes Associated with HDL Cholesterol Levels: A Systematic In-Depth Review,” Experimental Gerontology, Vol. 44, No. 3, 2009, pp. 136-160. doi:10.1016/j.exger.2008.11.003
[46] S. Imaizumi, M. Navab, C. Morgantini, et al., “Dysfunctional High-Density Lipoprotein and the Potential of Apolipoprotein A-1 Mimetic Peptides to Normalize the Composition and Function of Lipoproteins,” Circulation Journal, Vol. 75, No. 7, 2011, pp. 1533-1538. doi:10.1253/circj.CJ-11-0460
[47] N. Yilmaz, “Relationship between Paraoxonase and Homocysteine: Crossroads of Oxidative Diseases,” Archives of Medical Science, Vol. 8, No. 1, 2012, pp. 138-153.
[48] N. Yilmaz, A. Yegin and G. Aykal, “New Noninvasive Modalities in Coronary Angiography—Diagnostic Values of New Biomarkers for Cardiovascular Disease,” In: B. Baskot, Ed., Coronary Angiography—Advances in Non-invasive Imaging Approach for Evaluation of Coronary Artery Disease, InTech, Morn Hill, 2011, pp. 274-275.
[49] E. Eren, A. Ye?in, N. Yilmaz and H. Herken, “Serum Total Homocystein, Folate and Vitamin B12 Levels and Their Correlation with Antipsychotic Drug Doses in Adult Male Patients with Chronic Schizophrenia,” Clinical Laboratory, Vol. 56, No. 11-12, 2010, pp. 513-518.
[50] C. U. Pae, I. H. Paik, C. Lee, S. J. Lee, J. J. Kim and C. U. Lee, “Decreased Plasma Antioxidants in Schizophrenia,” Neuropsychobiology, Vol. 50, No. 1, 2004, pp. 54-56. doi:10.1159/000077942
[51] O. Virit, A. Altindag, M. Yumru, et al., “A Defect in the Antioxidant Defense System in Schizophrenia,” Neuro- psychobiology, Vol. 60, No. 2, 2009, pp. 87-93. doi:10.1159/000239684
[52] J. K. Yao, R. D. Reddy and D. P. van Kammen, “Abnormal Age-Related Changes of Plasma Antioxidant Proteins in Schizophrenia,” Psychiatry Research, Vol. 97, No. 2, 2000, pp. 137-151. doi:10.1016/S0165-1781(00)00230-4

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