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Oxidative stress in bipolar and schizophrenia patients Özgür Korhan Tunçel a,n, Gökhan Sarısoy b, Birşen Bilgici a, Ozan Pazvantoglu b, Eda Çetin b, Esra Ünverdi b, Bahattin Avcı a, Ömer Böke b a b

Medical Biochemistry Department, Faculty of Medicine, Ondokuz Mayıs University, 55139 Samsun, Turkey Psychiatry Department, Faculty of Medicine, Ondokuz Mayıs University, 55139 Samsun, Turkey

art ic l e i nf o

a b s t r a c t

Article history: Received 13 May 2014 Received in revised form 13 March 2015 Accepted 18 April 2015

Oxidative stress has an important place in studies investigating the pathophysiology of psychiatric diseases. In spite of this fact, longitudinal studies are required to clarify the subject. Therefore, in this study, we examined lipid peroxidation, protein oxidation, total oxidized guanine species, superoxide dismutase (SOD) and total glutathione (GSH) levels in blood collected from adult bipolar patients (n ¼ 18) during manic and euthymic episodes, schizophrenic patients (n ¼ 18) during acute psychotic attack and remission phases and the control group (n ¼ 18). There was a significant increase in the level of lipid peroxidation in the bipolar disorder manic episode group (BD-ME) compared to control group. The level of protein oxidation was significantly higher in the schizophrenia acute psychotic attack group (SZ-APA) compared to the control group. The level of total oxidized guanine species was statistically higher in all psychiatric groups compared to the control group. There was no significant difference among the groups with regard to SOD and GSH. Consequently, we believe that lipid peroxidation may be effective in the pathogenesis of bipolar patients; that protein oxidation may be of importance in the pathogenesis of schizophrenia and that total oxidized guanine species may be crucial in the pathogeneses of both psychiatric disorders. & 2015 Elsevier Ireland Ltd. All rights reserved.

Keywords: Protein oxidation Lipid peroxidation Oxidized guanine Glutathione Superoxide dismutase Psychiatric disorders

1. Introduction Bipolar disorder (BD) and schizophrenia (SZ) are highly common psychiatric disorders (Merikangas et al., 2007; Schultz et al., 2007). The molecular causes underlying these two disorders are still unclear. A part of the research on these disorders blame the decrease in the energy metabolism of the brain (Volz et al., 2000; Kato, 2005) and the abnormality in mitochondrial genes (Kato and Kato, 2000; Rollins et al., 2009) while another part of the research argue that the culprit is the oxidative stress (Andreazza et al., 2008a; Yao and Keshavan, 2011) which springs from the problems in mitochondrial activity (Andreazza et al., 2010; Gubert et al., 2013) and dopaminergic system (Grima et al., 2003; Kim et al., 2014). Oxidant agents may lead to oxidative damage in proteins, lipids and nucleic acids. This damage can be detected by measuring the protein oxidation, lipid peroxidation and 8-hydroxy deoxy guanosine. SOD and glutathione are the primary antioxidant defense systems combating the oxidative damage. Oxidative stress occurs when the balance between the oxidant and antioxidant systems is disrupted (Halliwell, 2007). The increased oxidative stress may

n

Corresponding author. Tel.: þ 90 362 312 19 19/2091; fax: þ 90 362 457 60 41. E-mail address: [email protected] (Ö.K. Tunçel).

play a role in the emergence of psychiatric disorders by affecting the neuronal plasticity, signal transduction and neurotransmitter intake which depends on the oxidation of the membrane proteins (Mahadik et al., 2001; Manji et al., 2012). Recently, the number of studies investigating the association between oxidative stress and psychiatric disorders has increased. However, there is no consensus on the association between the oxidative stress and these disorders (Andreazza et al., 2008a; Flatow et al., 2013). Studies on the oxidative stress generally evaluate its parameters within a single phase of the disease (Savas et al., 2006; Micó et al., 2011; Raffa et al., 2012). The studies comparing different phases of the disease (bipolar manic, euthymic and depressive episode, schizoprenia acute psychotic attack and remission phases) have used different phases of the disease in different patients (Arvindakshan et al., 2003; Andreazza et al., 2007a; Kunz et al., 2008). The number of studies measuring the oxidative stress parameters of the same patient at different phases is relatively limited (Gergerlioglu et al., 2007; Selek et al., 2008). Longitudinal studies are required in order to reveal the underlying causes of the bipolar disorder and schizophrenia (Kapczinski et al., 2011). Thus, the effect of individual differences (lifestyle, nutrition, socioeconomic status, etc.) which may lead to the oxidative stress can be alleviated, which, in turn, may enable more definite results (Raffa et al., 2012). Other counfounding factors used in studies conducted until today were obesity and smoking. Obesity and

http://dx.doi.org/10.1016/j.psychres.2015.04.046 0165-1781/& 2015 Elsevier Ireland Ltd. All rights reserved.

Please cite this article as: Tunçel, Ö.K., et al., Oxidative stress in bipolar and schizophrenia patients. Psychiatry Research (2015), http: //dx.doi.org/10.1016/j.psychres.2015.04.046i

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smoking are frequently observed in these patients and increase the oxidative stress significantly (Kalman et al., 2005; McIntyre et al., 2010). Therefore, studies on the subject should be careful about not including obese or smoker patients. In the light of these, we studied the levels of oxidative stress parameters in non-smoking bipolar and şchizophrenia patients with a body mass index of r25 kg/m2. We also studied how these parameters changed with treatment. To this end, we compared the lipid peroxidation, protein oxidation, total oxidized guanine species, SOD and total glutathione levels of bipolar patients in manic and euthymic episodes and of schizophrenia patients in acute psychotic attack and remission phases in this study. 2. Materials and methods 2.1. Subjects This study was approved by Ondokuz Mayıs University, Medical Research Ethical Committee (No: 2010/147 Issue: 315). All procedure was arranged in accordance with World Medical Association Declaration of Helsinki. All participants were informed orally and in writing. All subjects gave written informed consent. This study, which was conducted in Ondokuz Mayıs University, Psychiatry Clinic, involved adult bipolar (n ¼18) and schizophrenic patients (n¼ 18) and a control group (n¼ 18) consisting of subjects who did not differ from these patients with regard to age and sex. The age range for the subjects was 18–65 years. All subjects were evaluated by a psychiatrist prior to the study. Bipolar patients were evaluated in manic and euthymic episodes while schizophrenic patients were evaluated in acute psychotic attack and remission phases. Bipolar disorder and schizophrenia were diagnosed using The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). Bipolar patients diagnosed in manic episode Type 1 were considered euthymic if they had a Young Mania Rating Scale (YMRS) score less than 5 for 2 months following their treatment (Young et al., 1978). Of the patients diagnosed with schizophrenia in acute psychotic attack, those who had scored 3 or less in each of the 8 steps set in Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987) for 6 months after their treatment were considered in the remission phase and were included in the study. All subjects had a body mass index of r 25 kg/m2 and were non-smokers. They also had no substance abuse or chronic disease (infection, inflammatory disease, diabetes, hypertension, cancer, mental retardation, neurological disorder, etc.). The control group consisted of subjects who had never suffered from a psychiatric disease. None of the first-degree family members of the control group had a history of a major psychiatric disorder. The subjects of the study had no acute medical condition (e.g. infection) at the time of blood collection and received no medication. Moreover, female subjects were not pregnant. They did not have menstrual bleeding, either. 2.2. Collection of blood At 8 o'clock in the morning, blood was drawn from each subject on an empty stomach to a tube with no anticoagulant (8 ml) and to a tube with EDTA (2 ml). Blood samples from bipolar patients were drawn in the manic and euthymic episodes and from schizophrenic patients in acute psychotic attack and remission phases. The blood collected was centrifuged at 3000g for 5 min at þ4 1C. The serum and plasma were separated and stored at  80 1C until the beginning of the study. 2.3. Lipid peroxidation Lipid peroxidation level was measured in serum with a pre-defined method (Varshney and Kale., 1990). 0.2 ml standard solution which was prepared from malondialdehyde stock solution (10 μmol/L, 5 μmol/L, 2.5 μmol/L, 1.75 μmol/L, 0.875 μmol/L), serum and distilled water (for blank) were put into glass tubes. Then, 0.8 ml buffer solution (KH2PO4–K2HPO4, 100 mM, pH: 7,4) was added and mixed by vortex. 0.25 ml tricholorocarboxylic acid (TCA, %30 ) and 0.25 ml thiobarbituric acid (TBA, 52 mM, pH: 2,1; dissolved in 1 M glacial acetic acid ) were added into all tubes. After mixing by vortex, the tubes were incubated at 80 1C for 45 min. The pink color produced was measured at 532 nm. Sample concentrations were calculated using the equation obtained from the standard linear curve (R2 ¼ 0.99, SPSS for Windows 15.0). Results were expressed in mmol/L. 2.4. Protein oxidation Protein oxidation level was measured in plasma with a commercially available AOPP kit (Immundiagnostik, Bensheim, Germany, Lot: K7811w-111031). This

method is based on the spectroscopic analysis of AOPP (advanced oxidation protein product) levels, which emerge as a result of protein oxidative damage. Before assaying, samples were 1:6 diluted with Sample Dilution Buffer. Standards (100 mmol/L, 50 mmol/L, 25 mmol/L, 12.5 mmol/L, 6.25 mmol/L) and all samples were placed in the proper wells on a microtiter plate, the absorbance of the samples was read at 340 nm. Diluted sample concentrations were calculated using the equation obtained from the standard linear curve (R2 ¼ 0.98, SPSS for Windows 15.0). The obtained AOPP values were multiplied by 6. AOPP concentrates were expressed as CT (chloramine-T) equivalents. Results were expressed in mmol/L. 2.5. Total oxidized guanine species This measurement was conducted in serum with a DNA/RNA Oxidative Damage EIA kit (Cayman, Ann Arbor, USA, Lot no: 0451239). Several diseases are associated with nucleic acids oxidation. During the repair process of this damage, multiple oxidized guanine species including the ribose-free base (8-oxo-guanine or 8-hydroxyguanine), the nucleoside from RNA (8-oxoguanosine or 8 hydroxyguanosine) and the deoxynucleoside from DNA (8-oxo-deoxyguanosine or 8-hydroxy-20 -deoxyguanosine) are released into blood. In this method, oxidatively damaged guanine species (8-hydroxy-20 -deoxyguanosine, 8-hydroxyguanosine and 8-hydroxyguanine) and 8-OH-dG-acetylcholinesterase conjugate (DNA/RNA Oxidative Damage Tracer) compete in order to bind to a limited number of DNA/RNA Oxidative Damage Monoclonal antibodies. Afterwards, this antibody-oxidatively damaged guanine complex binds to polyclonal anti-mouse IgG, which is previously attached to the wells. After the wells are washed, Ellman's reagent is added and the yellow color formed is read at 412 nm. Absorbance values are inversely proportional to the amount of free 8-OH-dG. Before assaying, all samples were diluted (1:25) with EIA Buffer Solution. Standards (3000 pg/ml, 1333 pg/ml, 592.6 pg/ml, 263.4 pg/ml, 117.1 pg/ml, 52.0 pg/ml) were prepared from DNA/RNA Oxidative Damage EIA Standard solution. Diluted sample concentrations were calculated using the equation obtained from the standard logarithmic curve (Microsoft Office Excel 2007). The obtained total oxidized guanine species values were multiplied by 25. Results were expressed in pg/ml 2.6. SOD SOD was spectrophotometrically measured in serum with Superoxide Dismutase Assay Kit (Cayman, Ann Arbor, USA, Lot no: 0447900). This kit uses tetrazolium salt to detect superoxide radicals formed by xanhine oxidase. As the superoxide radical converts into O2, tetrazolium salt converts into formazan dye. The color formed is measured at 440–460 nm. The SOD found in the sample reduces the level of superoxide radical and the formation of formazan dye. SOD activity in the sample is measured as the percent inhibition of the rate of formazan dye formation. Before assaying, samples were diluted 1:5 with Sample Buffer Solution (50 mM Tris–HCl, pH 8.0, containing 0.1 mM diethylenetriaminepentaacetic acid and 0.1 mM hypoxanthine). Standards (0.25 U/ml, 0.2 U/ml, 0.15 U/ml, 0.1 U/ml, 0.05 U/ml, 0.025 U/ml) were prepared with Sample Buffer Solution. Diluted sample concentrations were calculated using the equation obtained from the standard linear curve (R2 ¼ 0.93, SPSS for Windows 15.0) The obtained SOD values were multiplied by 5. Results were expressed in U/ml. 2.7. GSH GSH level was spectrophotometrically measured in plasma with a Glutathione Assay Kit (Cayman, Ann Arbor, USA, Lot no: 0450302). In this method, the sulfhydryl group of GSH react with DTNB (5.50 -dithio-bis-2-(nitrobenzoic acid), Ellman's reagent) and 5-thio-2-nitrobenzoic acid (TNB) in yellow is formed. GSTNB, which is formed simultaneously, is converted into GSH and TNB by glutathione reductase. The TNB absorbance value measured at 405–414 nm is directly proportional to the amount of GSH. Before assaying, MPA reagent (%10, metaphosphoric acid, 500 ml), was added to the samples (500 ml) in equal volume for deproteination. After this, 50 ml of TEAM reagent (4 M, triethanolamine) was added to increase the pH of the sample. Standards (32 mmol/L, 16 mmol/L, 8 mmol/L, 4 mmol/L, 2 mmol/L, 1 mmol/L) were diluted with MES Buffer (0.4 M 2-(N-morpholino)ethanesulphonic acid, 0.1 M phosphate and 2 mM EDTA, pH 6.0). Diluted sample concentrations were calculated using the equation obtained from the standard linear curve (R2 ¼ 0.99, SPSS for Windows 15.0). The obtained GSH values are multiplied by 2.1. Results were expressed in mmol/L. 2.8. Statistical analysis SPSS for Windows 15.0. was used for statistical analysis. The normal distribution of the data was tested using Shapiro–Wilk Normality Test. The grouped data was compared with Chi square test while the measured values were compared with One-Way ANOVA (Post-Hoc Tukey HSD) and Independent Samples t test. Paired-Samples t test was used for dependent groups. Correlation analysis was conducted with Pearson Correlation and Spermann Correlation methods. A value of

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Table 1 Demographic and clinical features of the patients and the control group. Features

Control (n ¼18)

BD-ME Age, mean 7 S.D. in years Sex, No (%) Male Female BMI (kg/m2) mean 7 S.D. Education, mean 7 S.D. in years Current smoking, No (%) Yes No Socioeconomical status, No (%) Low Middle High YMRS, mean7 S.D. PANSS, mean 7 S.D. Number of attacks, mean 7S.D. First episode, No (%) Elevation Depression Age of onset, mean 7S.D. in years Duration of disease, mean 7S.D. in years Schizophrenia subtype, No (%) Undifferentiated Paranoid Residual Deorganised History of suicide, No (%) Yes No Psychiatry history in family, No (%) Yes No Medicines used, No (%) Li Liþ Va Liþ AT Liþ T þAT Va Vaþ AT Vaþ AT þT AT AT þT AT þSSRI

SZ (n ¼18)

BD (n¼ 18) BD-EE

SZ-APA

34.8 7 11.3

32.6 7 9.8

34.5 7 10.7

8 (44.4) 10 (55.6) 22.4 7 3.0 14.8 7 3.9n

8 (44.4) 10 (55.6) 22.2 7 1.7 9.6 7 4.1

8 (44.4) 10 (55.6) 23.2 7 2.1 7.2 7 2.7

0 18 (100.0)

0 18 (100.0)

0 18 (100.0)

0 (0) 17 (94.4) 1 (5.6)

5 (27.7) 12 (66.7) 1 (5.6) 32.9 7 6.6

2 (11.1) 16 (88.9) 0 (0)

23.7 7 2.1

Sig. SZ-R 0.80a 1.0b

24.27 2.1

0.37a 0.00a

0.12b

2.8 7 1.2

4.8 7 3.3

80.3 7 19.0 4.3 7 3.5

16 (88.9) 2 (11.1) 21.9 7 5.4 12.17 9.1

23.9 7 6.5 10.5 79.8

49.717 8.78

0.00c 0.00c 0.66d

0.31d 0.63d

10 (55.6) 6 (33.3) 1 (5.6) 1 (5.6) 0 18 (100.0)

2 (11.1) 16 (88.9)

6 (33.3) 12 (66.7)

0 18 (100.0)

4 (22.2) 14 (77.8)

7 (38.9) 11 (61.1)

1 1 5 1 0 7 3

(5.6) (5.6) (27.7) (5.6) (0) (38.9) (16.7) 11 (61.1) 4 (22.2) 3 (16.7)

Abbreviations: AT, atypical antipsychotics; BD, bipolar disorder; BD-ME, bipolar disorder manic episode group; BD-EE, bipolar disorder euthymic episode group; BMI, body mass index; Li, lithium; SSRI, selective serotonine reuptake inhibitor, SZ, schizophrenia; SZ-APA, schizophrenia acute psychothic attack group; SZ-R, schizophrenia remission group; T, typical antipsychotics Va, valproate; YMRS, Young Mania Rating Scale; PANSS, Positive and Negative Syndrome Scale. n

Tukey HSD, significant difference between control and bipolar, control and schizophrenia. One-Way ANOVA. Pearson Chi-Square. c Paired-Samples t test. d Independent Samples t test. a

b

p o 0.05 was considered as significant in statistical analysis. Results are expressed as means 7 standard deviation.

3. Results A total of 18 bipolar patients, 18 schizophrenia patients and 18 control-group subjects were included in this study. Groups did not differ with respect to age and sex. Of all the bipolar patients, 4 had a history of psychiatric disorder in their families. Of these, 2 had bipolar disorder, 1 had both bipolar disorder and schizophrenia and 1 had bipolar disorder and depression histories in their families. Of all the schizophrenia patients, 5 had schizophrenia, 1 had both schizophrenia and bipolar disorder and 1 had depression histories in their families. There was no history of a psychiatric disorder in the families of the control group. Of all the 18

bipolar patients, 13 (72.2%) had only manic attack, 2 (11.1%) had both manic and hypomanic attacks and 3 (16.7%) manic and depression attacks in the course of their diseases. Table 1 presents the demographic and clinical statuses of the subjects. There was a statistically significant increase in the level of lipid peroxidation (mmol/L) in bipolar disorder manic episode group (BD-ME) (7.7 72.4) compared to control group (5.7 71.4) (p o0.05). There was a significant decrease in the lipid peroxidation level in bipolar disorder euthymic episode group (BD-EE) (6.072.1) compared to BD-ME (p o0.01). There was no statistically significant difference between the control group and BD-EE (p 40.05). As for the schizophrenia group, there was no statistically significant difference in the lipid peroxidation level compared to the other groups (p 40.05). The level of protein oxidation (mmol/L) increased significantly in schizophrenia acute psychotic attack group (SZ-APA) (75.2727.0)

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Table 2 Oxidative stress parameters. Parameters

Control

BD

SZ

BD-ME

BD-EE

SZ-APA

SZ-R

Sig.a

Sigb

0.004 þ 0.59 þ þ 0.43 þ 0.009 þ þ 0.13 þ 0.8 þ þ 0.49 þ 0.88 þ þ 0.51 þ 0.36 þ þ

Lipid peroxidation (mmol/L)

5.7 7 1.4

7.7 7 2.4

6.0 7 2.1

6.7 7 2.3

6.2 7 2.0

0.04n

Protein oxidation (mmol/L)

47.8 7 23.3

67.6 7 21.8

58.6 730.5

75.2 7 27.0

41.8 7 21.1

0.004nn

Total oxidized guanine species (pg/ml)

5699.6 7 1812.1

9089.3 7 2700.7

10033.874045.9

9171.3 7 3073.8

9390.6 7 3628.1

0.003nnn

SOD (U/ml)

4.7 7 0,3

5.3 7 0.8

5.5 7 1.0

5.2 7 1.2

5.2 7 0.6

0.1

GSH (mmol/L)

34.3 7 18.0

41.6 7 16.0

39.4 718.3

46.2 7 15.7

40.9 7 15.8

0.4

Abbreviations: BD, bipolar disorder; BD-ME, bipolar disorder manic episode group; BD-EE, bipolar disorder euthymic episode group; GSH, total glutathione; SOD, superoxide dismutase; SZ, schizophrenia; SZ-APA, schizophrenia acute psychothic attack group; SZ-R, schizophrenia remission group. n

Tukey HSD, control vs BD-ME p ¼ 0.03. Tukey HSD, control vs SZ-APA p¼ 0.03. nnn Tukey HSD control vs BD-ME p¼ 0.03, control vs BD-EE p¼ 0.002, control vs SZ-APA p ¼ 0.03, control vs SZ-R p ¼ 0.02. þ p value for BD-ME vs BD-EE. þþ p value for SZ-APA vs SZ-R. a One-Way ANOVA. b Paired-Samples t test. nn

Total oxidized guanine species (pg/ml)

10000

4. Discussion

9000 8000 7000 6000 5000 4000 3000 2000 1000 0

0

10

20

30

40

50

60

70

Age (years) Fig. 1. Correlation between age and total oxidized guanine species in control group.

compared to control group (47.8723.3) (po0.05). It was also observed that the protein oxidation level significantly decreased in schizophrenia remission group (SZ-R) (41.8721.1) compared to SZAPA (po0.01) and that it decreased to the level of protein oxidation in the control group. There was no significant difference in the bipolar patients compared with the other groups. The level of total oxidized guanine species (pg/ml) was statistically higher in BD-ME (9089.372700.7), BD-EE (10033.874045.9), SZ-APA (9171.373073.8) and SZ-R (9390.673628.1) compared to the control group (5699.671812.1) (po0.05). There was no difference between the bipolar and schizophrenia patients in this respect. There was no statistically significant difference among the groups with regard to SOD and GSH (p 40.05). All data are presented in Table 2. When the schizophrenia patients were classified with regard to subtypes, suicide histories and medicines used, it was found out that there was no statistical difference among them in terms of the biochemical parameters. The correlation analysis conducted on the demographic and clinical findings and biochemical parameters of the subjects revealed that there was a correlation between level of total oxidized guanine species and age only in the control group (Pearson Correlation ¼ 0.552, p ¼0.033) (Fig. 1).

In this study, we found out that both the lipid peroxidation level in the bipolar manic episode group and the protein oxidation level in schizophrenia acute psychotic attack group increased and that these values decreased significantly to those of the control group in the bipolar euthymic episode group and in the schizophrenia remission group following the treatment. As for the level of total oxidized guanine species, we observed that in all psychiatric groups it was higher than that of the control group, independently of the current status of the disease. On the other hand, there was no significant difference with respect to SOD and GSH among the groups. In spite of the fact that there is a general consensus among the majority of present studies on the presence of higher levels of lipid peroxidation in bipolar patients (Kuloglu et al., 2002; MachadoVieira et al., 2007; Andreazza et al., 2008a), there are also studies showing that it does not change in these patients (Ranjekar et al., 2003; Gubert et al., 2013). Moreover, it was found out that lipid peroxidation level increased in postmortem anterior cingulate cortex (Wang et al., 2009). The studies based on the assumption that differences between the episodes in bipolar disorder might have an effect on lipid peroxidation reported that there was an increase in all episodes, including the euthymic episode (Andreazza et al., 2007a; Kunz et al., 2008). However, recent studies, as well as our study, have reported that there is an increase in lipid peroxidation level in the manic episode and that no such increase is observed in the euthymic episode (Kapczinski et al., 2011; Gubert et al., 2013). In this group of patients, certain factors such as smoking and obesity, both of which may affect the oxidative stress, are frequently observed (Kalman et al., 2005; McIntyre et al., 2010). The discrepancy in results obtained by different studies may result from the lack of attention given to excluding these factors. Another important point is that antimanic medicines used may decrease the level of lipid peroxidation (Shao et al., 2005). This effect was clearly showed in a study conducted with twin cases (Frey et al., 2007). However, the fact that our patients had been using medicines by the time our study began suggested that this difference might have been associated with pathophysiology. Contrary to the studies reporting an increase in lipid peroxidation levels in blood (Kuloglu et al., 2002; Kunz et al., 2008; Micó et al., 2011; Pedrini et al., 2012; Gubert et al., 2013) and

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central nervous system (Wang et al., 2009) of schizophrenia patients, we did not observe such an increase. However, a review of these studies revealed that these studies had not taken individual differences such as smoking, obesity, etc. into consideration. The studies which took these factors into consideration did not report an increase in lipid peroxidation, parallel to our study (Massuda et al., 2013; Ranjekar et al., 2003). The discrepancy in these results may result from the subtypes of the disease (Zhang et al., 2010), clinical features (Hernandez et al., 2007) and the medicines used (Gama et al., 2006). We did not find any difference among the biochemical parameters when the patients were classified into groups with regard to undifferentiated and paranoid subtypes of the disease and the medicines used. There are studies in literature which report high levels of protein oxidation in paranoid schizophrenia patients (DietrichMuszalska et al., 2009), in sublings (Massuda et al., 2013) and in early and late state chronicity schizophrenia patients (Pedrini et al., 2012). These studies are in conformity with our study. In addition, an increase in hippocampus protein oxidation was observed in a study conducted on postmortem schizophrenia patients (Nishioka and Arnold, 2004). The reason for this increase in schizophrenia patients may result from genetic abnormalities in glyoxalase 1 enzyme, which plays a role in detoxification of reactive carbonyl products (Arai et al., 2010, 2012).However, the increase of protein oxidation may be affected by different phases of schizophrenia. We did not detect this increase which was found in the schizophrenia acute psychotic attack group in the remission group. A recent study, which also confirms to our findings, has found no difference in stable schizophrenia patients (Gubert et al., 2013). In spite of the fact that there are studies reporting an increase in protein oxidation in bipolar patients (Kapczinski et al., 2011; Magalhães et al., 2012), it was reported that the difference was detected predominantly in the manic and depressive episodes and that no such difference was found in the euthymic episode (Kapczinski et al., 2011; Gubert et al., 2013). Moreover, an increase in protein oxidation in the brain tissues of bipolar patients was reported in postmortem studies (Andreazza et al., 2010, 2013). In our study, protein oxidation levels were not different from those of the control group neither in the manic episode nor the euthymic episode of the bipolar patients. The discrepancy among the results may result from the limited number of subjects, differences among the lifestyles and medication, all of which may affect the protein oxidation. However, postmortem studies might have been affected by factors such as postmortem interval, storage conditions of the tissues and course of the disease at the time of death (Andreazza et al., 2013). An interesting finding of this study was the total oxidized guanine species, which was not affected by the current status of the disease. Another finding was that there was a correlation between age and this parameter in the control group, which was not detected in the psychiatric groups. In a study, DNA damage was observed in comed assay and bipolar patients, which was associated with the severity of the disease (Andreazza et al., 2007b). Another study conducted by the same team of researchers on a bipolar manic episode twin revealed that the increase in DNA damage continued after treatment and that the other twin who refused to receive treatment had the same level of increase, too (Frey et al., 2007). Furthermore, this damage was correlated with the number of manic episodes undergone by the bipolar patients who were clean of medicines and that it was affected by the current mood state (Soeiro-de-Souza et al., 2013). Nucleic acid damage which did not change with treatment was also reported for schizophrenia patients (Jorgensen et al., 2013). There are postmortem studies in literature supporting these findings. These studies revealed that 8-OH guanine in hippocampus of schizophrenia patients increased (Nishioka and Arnold, 2004) and that

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this damage in hippocampus was mostly in cytoplasm, particularly in RNA, in bipolar and schizophrenia patients (Che et al., 2010). A group of researchers claimed that DNA damage detected in brain was mainly found in bipolar patients, not in schizophrenia patients (Benes et al., 2003, 2006; Buttner et al., 2007) and that schizophrenia patients were not different from healthy individuals with respect to basal DNA damage and DNA repair efficiency (Psimadas et al., 2004). However, this increase in bipolar patients may result from a decrease in DNA repair enzyme PARP-1 (poly(-adenosine diphosphate-ribosyl) polymerase) gene expression, which has an antioxidant effect (Benes et al., 2006). The limitations of the postmortem studies are agonal state, storage conditions of the tissues and analyses conducted in a single region or with few samples (Andreazza et al., 2010). Results may vary with different regions of the brain examined (Mustak et al., 2010). Moreover, possible effects of medicines used by these patients on DNA/RNA damage are another confusing factor. Researchers argued that medicines used did not affect this damage (Benes et al., 2006; Andreazza et al., 2007b; Jorgensen et al., 2013) and that DNA damage was observed in patients who did not use medicines or was clean of medicines (Frey et al., 2007; Mustak et al., 2010; Soeiro-de-Souza et al., 2013). However, it was reported that Li and Valproate inhibited DNA fragmentation in cerebral cortical cells of rats (Shao et al., 2005) and that Li decreased the transient DNA damage in hippocampus and peripheral blood (Andreazza et al., 2008b). Atypical antipsychotics such as olanzapine, risperidon and quetiapine did not induce genotoxicity in human whole blood cultures (Togar et al., 2012) and prevented DNA fragmentation (Qing et al., 2003). Contrary to these studies, there are studies in literature reporting that perphenazine (Gil-ad et al., 2001) valproic acid and ziprasidone (Karapidaki et al., 2011) and aripiprazole (Picada et al., 2011) leads to DNA damage. It is argued that typical antipsychotics are more toxic than atypical ones (Gil-ad et al., 2001; Parikh et al., 2002). In this study, we classified the schizophrenia patients into 3 groups according to the medicines they used (Table 1) and did not find any statistical difference among these groups. However, it is evident that further analyses are required on the effects of the medicines. There are studies in literature reporting an increase (Kuloglu et al., 2002; Savas et al., 2006; Frey et al., 2007; Machado-Vieira et al., 2007), a decrease (Gergerlioglu et al., 2007; Selek et al., 2008; Yamada et al., 1997) or no change (Andreazza et al., 2008a, 2013; Raffa et al., 2012) in SOD levels in bipolar patients. Similar findings have been found in studies conducted on schizophrenia patients. There are studies reporting low (Yamada et al., 1997; Ranjekar et al., 2003; Raffa et al., 2012; Flatow et al., 2013), increased (Yao et al., 1998; Michel et al., 2004; Gama et al., 2006; Kunz et al., 2008) and unchanged (Abdalla et al., 1986; Andreazza et al., 2013) levels. Numerous factors such as age, gender, BMI, smoking, dietary habits, sampling effects of different stages of disease progression have presented serious limitations to the studies conducted so far and may have contributed to the discrepancies in results (Andreazza et al., 2008a; Flatow et al., 2013). Another factor is the effect of medication. Li and valproate used in the treatment decreased the increasing SOD level or prevented the increase (Frey et al., 2007; Machado-Vieira et al., 2007; Andreazza et al., 2008b) and that lithium decreased the SOD level in healthy individuals (Khairova et al., 2012). However, increase in SOD can be inhibited by atypical antipsychotics (Qing et al., 2003). We did not find any difference among the groups with respect to SOD levels, which may result from the decreasing effect of medication on increased SOD levels. We could not detect this effect conclusively since the patients were not evaluated in the untreated phase. Secondly, the difference of our study from other studies regarding the samples and analyze methods used might have caused this result. Although there are many studies

Please cite this article as: Tunçel, Ö.K., et al., Oxidative stress in bipolar and schizophrenia patients. Psychiatry Research (2015), http: //dx.doi.org/10.1016/j.psychres.2015.04.046i

Ö.K. Tunçel et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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using the same sample (serum) (Gama et al., 2006; Kunz et al., 2008) and the same method as ours (tetrazolium salt) (Kuloglu et al., 2002; Savas et al., 2006; Selek et al., 2008), there also are other studies using different samples (plasma, RBC) and methods (Adrenochrome) (Andreazza et al., 2008a; Flatow et al., 2013). We did not observe any difference in the GSH level, either. Several studies have reported a decrease in the GSH levels of schizophrenia and bipolar patients (Dietrich-Muszalska et al., 2009; Micó et al., 2011; Raffa et al., 2012; Rosa et al., 2014). Postmortem studies found out a decrease in GSH levels in the prefrontal cortex of schizophrenia and bipolar patients (Gawryluk et al., 2011) and in caudate regions of schizophrenia patients (Yao et al., 2006). In spite of the studies reporting no difference between treated and non-treated groups with regard to GSH levels (Micó et al., 2011) and decreased GSH levels in patients who stopped using medicines (Do et al., 2000) or used atypical antipsychotics (Dietrich-Muszalska et al., 2009), normal levels of GSH found in our study may result from the GSH-increasing effects of Li and valproate (Cui et al., 2007) and antipsychotics (Grima et al., 2003). The differences in GSH measurement method might also have resulted in lack of differences in GSH levels. But, since majority of studies used similar samples and assay protocols, different results did not appear to be explained by technical differences (Andreazza et al., 2008a). However, studies reporting decreased levels of GSH should take the GSH-decreasing effects of obesity (Jankovic et al., 2014) and smoking (Reddy et al., 2002) into consideration. The primary limitation of this study was the limited number of patients. This problem arose due to the difficulty in finding patients with normal BMI, no smoking habits and chronic diseases. Another limitation of our study was that we could not evaluate the effects of the drugs on the patients due to the fact that we could not evaluate the untreated periods of the patients and that the number of patients was limited. Consequently, we believe that lipid peroxidation may be effective in the pathogenesis of bipolar patients; that protein oxidation may be of importance in the pathogenesis of schizophrenia and that total oxidized guanine species may be crucial in the pathogeneses of both disorders. However, further studies involving more subjects and evaluating the untreated first episodes of the patients are required in order to effectively understand the association between oxidative stress and psychiatric diseases.

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Please cite this article as: Tunçel, Ö.K., et al., Oxidative stress in bipolar and schizophrenia patients. Psychiatry Research (2015), http: //dx.doi.org/10.1016/j.psychres.2015.04.046i