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disulphide homeostasis in bipolar disorder
Psychiatry Research 261 (2018) 237–242
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Thiol/disulphide homeostasis in bipolar disorder a,⁎,1
a,2
b
T c
d
Gamze Erzin , Vahap Ozan Kotan , Canan Topçuoğlu , Güven Özkaya , Özcan Erel , Rabia Nazik Yüksela, Emre Ürere, Makbule Çiğdem Aydemira,3, Erol Gökaa a
Ankara Numune Training and Research Hospital, Psychiatry Department, Ankara, Turkey Ankara Numune Training and Research Hospital, Biochemistry Department, Ankara, Turkey Uludağ University, Faculty of Medicine, Biostatistics Department, Bursa, Turkey d Yıldırım Beyazıt University, Biochemistry Department, Ankara, Turkey e Ankara University, School of Medicine, Child and Adolescent Psychiatry, Ankara, Turkey b c
A R T I C L E I N F O
A B S T R A C T
Keywords: Oxidative stress Mania Remission Mood disorder Oxidative markers
Bipolar disorder (BD) patients have increased oxidative stress, which can disturb thiol/disulphide homeostasis, causing disulphide formation. The aim of the study is to investigate dynamic thiol/disulphide (SH/SS) homeostasis in BD patients, which is a novel evaluation method of oxidative status. Ninety-four BD patients (50 in the manic episode and 44 in remission) and 44 healthy controls were included in the study. Blood serum native thiol (SH) and total thiol (ToSH) concentrations were measured in a paired test. The half value of the difference between native thiol and total thiol concentrations was calculated as the disulphide (SS) bond amount. Serum native thiol levels of the mania group were found to be lower than the remission and the control groups. There was a significant difference between the remission group and the control group in terms of native thiol. Serum total thiol level was lower in mania group than the control group. Detection of oxidative molecules for BD could be helpful, especially in treatment, follow-up periods and reducing morbidity. The results of our study besides the data available in the literature support that thiol and disulphide levels are useful markers for BD and promising therapeutic targets in terms of future pharmacological modulation.
1. Introduction Bipolar disorder (BD) is associated with increased mortality (Laursen et al., 2007) and one of the most debilitating psychiatric disorders characterized by disruptive episodes of mania/hypomania and depression (Anderson et al., 2012). Understanding the etiology of BD has always been an important research topic. The roles of inflammatory processes and oxidative stress are being investigated with possible etiologic factors due to BD's indeterminate pathophysiology (Bauer et al., 2014; Gubert et al., 2013). Oxidative stress, which means the excess of reactive oxygen species (ROS), could have a role in the etiology of BD (Raffa et al., 2012). Excessive ROS may cause cellular injuries, lipid peroxidation, damage, apoptosis and protein carbonylation (Berg et al., 2004; Filomeni and Ciriolo, 2006; Maes et al., 2013). As the brain tissue is more susceptible to oxidative damage, the body also has an antioxidative mechanism against this oxidative damage (Ciobica et al., 2011). The antioxidant
mechanism of the body includes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-px) (Pavlović et al., 2002). Studies investigating the oxidative stress in patients with BD are conducted in the literature. Thiobarbituric acid reactive substances (TBARS) as lipid peroxidation marker, have been also investigated in these studies. TBARS have been by far the most widely used markers of oxidative stress in clinical studies (Grignon and Chianetta, 2007; Andreazza et al., 2008). Related to that point, Machado-Vieira et al. (2007) reported higher levels of TBARS and antioxidant enzyme activities (SOD and CAT) in unmedicated patients with BD in manic episode. According to results of this study, initial manic episodes are considered to be associated with both increased oxidative stress parameters and activated antioxidant defenses, which could be related to dysfunctions on energy metabolism and neuroplasticity pathways. Kunz et al. (2008) also found that serum SOD activity was significantly increased in patients with BD who are either in mania or in depression but not euthymic. TBARS levels were also found to be significantly higher
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Correspondence to: Dışkapı Yıldırım Beyazıt Training and Research Hospital, Psychiatry Department, Altındağ, Ankara, Turkey. E-mail addresses: [email protected] (G. Erzin), [email protected] (V.O. Kotan), [email protected] (C. Topçuoğlu), [email protected] (G. Özkaya), [email protected] (Ö. Erel), [email protected] (R.N. Yüksel), [email protected] (E. Ürer), [email protected] (M.Ç. Aydemir), [email protected] (E. Göka). 1 Present and permanent work address: Dışkapı Yıldırım Beyazıt Training and Research Hospital, Psychiatry Department, Ankara, Turkey. 2 Present and permanent work address: Başkent University Faculty of Medicine, Psychiatry Department, Ankara, Turkey. 3 Present and permanent work address: Ankara University, School of Medicine, Psychiatry Department, Ankara, Turkey. https://doi.org/10.1016/j.psychres.2017.12.062 Received 12 April 2017; Received in revised form 31 October 2017; Accepted 30 December 2017 Available online 02 January 2018 0165-1781/ © 2018 Elsevier B.V. All rights reserved.
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interrater reliability. The Turkish version of the scale was found to be valid and reliable (Akdemir et al., 2001). In our study, patients were evaluated with the 17-item version.
in patients with schizophrenia, bipolar euthymic group, bipolar manic group and bipolar depressed group compared to controls (Kunz et al., 2008). Thiols also have a significant role in antioxidant defence (Sen and Packer, 2000). Thiols can experience oxidation reaction through oxidants and form disulphide bonds (Cremers and Jakob, 2013). Oxidation of cysteine residues can prompt to reversible development of mixed disulfides between low-molecular mass thiols and protein thiol groups when oxidative stress enhances. Thiol disulphide homeostasis is maintained by reducement of formed disulphide bonds to thiol groups (Jones and Liang, 2009; Biswas et al., 2006). Thiol/disulphide ratio (TDR) has critical roles in detoxification, antioxidant protection, signal transduction, regulation of enzymatic activity, apoptosis, and cellular signaling mechanisms (Biswas et al., 2006; Circu and Aw, 2010). Determination of dynamic thiol disulphide homeostasis can provide significant information on different normal or abnormal biochemical processes, because the abnormal thiol disulphide homeostasis state is involved in the pathogenesis of a variety of diseases, including schizophrenia and neurodegenerative disorders (Smeyne and Smeyne, 2013; Steele et al., 2013; Topcuoglu et al., 2017). Methods that measure only thiol values can only provide information about the status of the antioxidant buffer system. However, thiol disulphide homeostasis, which is the dynamic redox system of the organism, can be evaluated objectively with the method of Erel et al. (Erel and Neselioglu, 2014). To evaluate the thiol/disulphide balance globally, both thiol and disulphide need to be measured by this method (Vural et al., 2017). In this study, we aimed to evaluate BD patients who were on manic episode and in remission in terms of thiol disulphide balance, and to compare them with healthy controls.
2.2. Young Mania Rating Scale (YMRS) YMRS is an 11-item diagnostic questionnaire used to measure the severity of ME. Each item measures five degrees of severity; seven items are answered by using a five-point Likert-type scale, while four items are answered by using a 9-point Likert-type scale. The Turkish version of the scale was found to be both valid and reliable (Karadağ et al., 2002). 2.3. Biochemical tests Fasting blood samples were obtained from the patients and the controls in plain tubes. Serum samples were separated after centrifugation at 1300g for 10 min and stored at − 80 °C until the analysis was conducted. Thiol disulphide homeostasis tests were performed. Reducible disulphide bonds were first reduced to form free functional thiol groups. Unused reductant sodium borohydride was consumed and removed with formaldehyde, and all thiol groups including reduced and native thiol groups were determined after the reaction with 5,5′-dithiobis-(2-nitrobenzoic) acid (DTNB). Half of the difference between the total thiols and the native thiols gave the dynamic disulphide amount. After the native and total thiols were determined, disulphide amounts, disulphide/total thiol percent ratios (SS/SH+SS), native thiol/total thiol percent ratios (SH/SH+SS), and disulphide/native thiol percent ratios (SS/SH) were calculated (Erel and Neselioglu, 2014).
2. Methods 2.4. Statistical analysis Before recruiting the participants, an experienced clinician interviewed patients according to the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, fifth version (DSM–5), to confirm manic episode diagnosis of manic episode group members, to acknowledge that patients in the remission group did not meet DSM-5 criteria for any BD episode (i.e., depressive, mixed, manic, or hypomanic) in last 6 months, and that healthy control group members showed no evidence of any present or previous psychiatric disease. The Hamilton Depression Rating Scale (HAM-D) and Young Mania Rating Scale (YMRS) were also used to support the diagnoses of remission (i.e., HAM-D score < 7 or YMRS score < 4) and mania (i.e., YMRS score > 20). Our study was approved by the ethics committee of the Ankara Numune Training and Research Hospital. Written consents were obtained from each patient and one of their first-degree relatives and also from controls. Clinician filled out a socio-demographic data form. A 5 cc of venous blood was collected from each subject. Blood cells were separated from serum and serum samples were stored at − 80 °C. Biochemical analyses were performed on these samples. All patients underwent laboratory tests, including complete blood count, blood lipids, fasting blood glucose, C-Reactive Protein (CRP) and insulin measurements. Height, weight, waist and hip circumferences of the subjects were measured. Gender and age of each subject were recorded. When collecting data in our study, the amount of cigarette consumption was obtained for each patient and patients with obesity were excluded from the study. Mental retardation, pregnancy, previous electroconvulsive therapy (ECT) history and having any systemic or metabolic disease were also included in the exclusion criteria.
The data was examined by the Shapiro Wilk test whether or not it presents normal distribution. One-way ANOVA was applied for comparison of 3 groups. For pairwise comparison, Tukey test was used. Mann-Whitney U test was used for the comparison of 2 groups and Kruskal Wallis test was used to compare more than two groups were used when the data was not normally distributed. Categorical variables were compared using Pearson's chi-squared test and Fisher-FreemanHalton test. Correlations between variables were tested using Pearson and Spearman correlation coefficients. p < 0.05 was considered as significance levels. Statistical analysis was performed using IBM Statistics SPSS 23.0 (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.). 3. Results Mania and remission groups were presented similar results when data concerning gender (df = 2, χ2 = 0.535, p = .765), age (df = 2, F = 0.033, p = .968), marital status (Fisher-Freeman-Halton = 2.320 p = .696), BMI (Body Mass Index) (df = 2, F = 1.598, p = .206) and smoking (df = 2, F = 1.805, p = .171) were compared (Table 1). When the demographic and clinical characteristics of mania and remission groups were examined; a statistically significant difference between the groups was found in terms of monthly income, which was lower in mania group (Fisher-Freeman-Halton = 2.870 p = .378). The number of antipsychotic users was found to be higher in mania group (FisherFreeman-Halton = 10.399, p = .004). There was no statistically significant difference obtained between mania and remission groups in terms of blood count, lipids, insulin, CRP, fasting glucose (p > .05). While 96% of mania group had antipsychotic medication, this ratio was found to be 73% in the remission group. Of the mania group, 64% were using valproic acid/sodium valproate, 12% were using lithium, 8% were using carbamazepine, 2% were using lithium and valproic acid/sodium valproate, and 14% were
2.1. Hamilton Depression Rating Scale (HAM-D) Designed by Hamilton (1960), the original version of the HAM-D contains 17 items, each scored from 0 to 4 for a maximum total score of 53. Decades later, Williams (1988) developed the Structured Interview for HAM-D-21 as another version of the HAM-D that improved its 238
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Table 1 Evaluation of socio-demographic characteristics.
Gender (%) Female Male Age (years) Marital status Single Married Divorced Body mass index (kg/m2) Smoking (packet-year) Age at disease onset (years) Duration of disease (years) Number of hospitalizations Number of previous manic episode Number of depressive episode Young mania rating scale score Hamilton depression scale score a b c d e
Mania (n = 50)
Remission (n = 44)
Control (n = 44)
26 (52%) 24 (48%) 38.5 ± 11.5
23 (52.3%) 21 (47.7%) 37.9 ± 10.3
20 (45.5%) 24 (54.5%) 38 ± 10.4
18 (36%) 28 (56%) 4 (8%) 25.4 ± 3.1 9.8 ± 7.7 26.9 ± 10.2 11.6 ± 9.2 3 (1–10) 3 (1–10) 0 (0–1) 37.1 ± 5.3 0.9 ± 0.8
15 (34.1%) 28 (63.6%) 1 (2.3%) 26.6 ± 3.5 13.5 ± 7.3 27.0 ± 9.3 10.9 ± 7.8 2 (0–10) 2 (0–10) 0 (0–1) 1.6 ± 0.8 0.9 ± 0.9
16 (36.4%) 24 (54.5%) 4 (9.1%) 25.9 ± 3.3 11.0 ± 7.5 – – – – – – –
p 0.765a
0.968b 0.696c
0.206b 0.171b 0.952d 0.714d 0.011e 0.033e 0.533e 0.00d 0.83d
p value determined by Pearson Chi-Square test. p value determined by ANOVA. p value determined by Fisher-Freeman-Halton test. p value determined by independent sample t-test. p value determined by Mann Whitney U test.
= .051 and p = .051). Disulphide/native thiol ratio was statistically significantly higher in mania group than control group (p = .039) (Table 4). There was no statistically significant difference obtained in mania and remission groups, when the correlations between age at disease onset, duration of the disease, number of hospitalizations, number of previous manic episodes, number of depressive episodes, young mania total score and hamilton depression score were compared individually with native thiol, disulphide, disulphide/native thiol, disulphide/total thiol, native thiol/total thiol (p > .05). In our study, no statistically significant difference was found between measurements of waist and hip circumferences, weight and height in mania and remission groups (p > .05).
Table 2 Evaluation of Mood Stabilizer Use in patients with BD. Mood stabilizer Valproic acid/Sodium valproate Drug doses (mg/day) 1150 (500–2000)
Lithium
Carbamazepine
950 (600–1200) 650 (400–800)
not on any mood stabilizer treatment. Of the remission group, 68% were using valproic acid/sodium valproate, 14% were using lithium, 7% were using carbamazepine, 2% were using lithium and valproic acid/sodium valproate and 9% were not on any mood stabilizer treatment. While 92% of the mania group were having second generation and 4% were having first generation antipsychotic treatment, 4% of them did not have any antipsychotic treatment. While 68% of remission group were having second generation and 5% were having first generation antipsychotic treatment, 27% of them did not have any antipsychotic treatment. Table 2 and 3 present details about the drug doses of patients with BD. Serum native thiol level in mania group was lower than remission and control groups (respectively p = .034 and p < .001). There was a difference between remission group and control group in terms of native thiol level (p = .010). Serum total thiol level was different in patients with BD than control group (p < .001 for mania and p = .019 for remission). There was not any difference between mania and remission groups in terms of serum total thiol level (p = .086). In terms of serum disulphide levels, disulphide/total thiol and native thiol/ total thiol ratios, there were not any statistically significant difference between mania, remission and control groups (respectively p = .858, p
4. Discussion Oxidative imbalance is involved in the pathophysiology of psychiatric diseases such as schizophrenia, BD and depressive disorder (Bitanihirwe and Woo, 2011; Andreazza et al., 2008; Maes et al., 2011). Although the level of thiol as an antioxidant parameter has been previously investigated in a variety of diseases, to our knowledge, this is the first study investigating dynamic thiol/disulphide homeostasis in patients with BD. In our study, both total thiol and native thiol levels of the patients in remission and control group were found to be significantly higher than patients in mania group. In our study, there was no statistically significant difference found in disulphide level indicating oxidative stress in mania group compared to control group. The total thiol level was significantly lower in mania and remission groups than in control group. This suggests that the decrease in total thiol level without change in disulphide level in mania and remission group may be due to a decrease in the native thiol level.
Table 3 Evaluation of Antipsychotic Drug Use in patients with BD. Antipsychotic Drug
Drug doses (mg/day)
Haloperidol
Quetiapine
Olanzapine
Paliperidone
Risperidone
10 (5–15)
700 (300–1200)
15 (5–20)
8 (3–12)
6 (4–8)
239
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Table 4 Levels of native thiol, total thiol, disulphide, disulphide/native thiol, disulphide/total thiol and native/total thiol according to groups. Mania (Mean ± SD)
Remission (Mean ± SD)
Control (Mean ± SD)
p
Pairwise comparison
Native Thiol
332.1 ± 48.7
360.5 ± 66.3
394.9 ± 47.0
< 0.001
Total Thiol
370.1 ± 54.5
396.9 ± 73.3
432.3 ± 52.7
< 0.001
Disulphide Disulphide/Native Thiol
19. 1 ± 7.3 5.7 ± 2.2
18.2 ± 7.1 5.1 ± 2.0
18.7 ± 6.5 4.7 ± 1.7
0.858 0.046
Disulphide/Total Thiol Native Thiol/Total Thiol
5.1 ± 1.7 89.8 ± 3.5
4.6 ± 1.6 90.9 ± 3.2
4.3 ± 1.4 91.4 ± 2.8
0.051 0.051
M-R .034 M-C < .001 R-C .01 M-R .086 M-C < .001 R-C .019 – M-R .266 M-C .039 R-C .656 – –
p value determined by ANOVA and Tukey test was used for pairwise comparison.
et al., 2008; Flatow et al., 2013). When demographic and clinical characteristics of mania and remission groups were examined; statistically significant differences were found between the groups in terms of monthly income, number of antipsychotics used, number of hospitalization, number of previous manic episodes. Number of hospitalizations and number of previous manic episodes in mania period were significantly higher than in remission period, which may have affected the functioning of mania group and may lead to a lower monthly income. The high number of antipsychotic users in the manic episode is also an expected result. The effect of gender on oxidative markers was also examined in the literature. In a study investigating level of TBARS, in BD and schizophrenia, TBARS levels were found to be higher in male patients than female patients (Tunçel et al., 2015). It was found that oxidative and anti-oxidative parameters in BD could be affected by estrogen and progesterone, DNA repair, and activation of antioxidant defence. (Requintina and Oxenkrug, 2005; Dietrich et al., 2013; Frey and Dias, 2014; Spence et al., 2013). In our study, no statistically significant difference was obtained in terms of native thiol, total thiol, disulphide, disulphide/native thiol, disulphide/total thiol and native thiol/total thiol regarding gender groups. In our study, BD patients who were either in mania or in remission were using antipsychotics and mood stabilizers. The antipsychotic and mood stabilizer drugs used can also affect the oxidation process. Use of mood stabilizer drugs may reduce the level of lipid peroxidation (Shao et al., 2005). However, it has been found that participants taking lithium had the lowest TBARS levels, while patients taking atypical antipsychotics had higher oxidative stress markers (Bengesser et al., 2016). Since the patients were not evaluated at the untreated stage in our study, we could not pinpoint this effect. In one study, use of antipsychotics in first episode of psychotic attacks resulted in decrease in oxidative markers (Kriisa et al., 2016). In addition to this, allostatic load may reduce oxidative stress during antipsychotic use, avoidance of stressors, or recovery in psychotic symptoms (Kapczinski et al., 2011; Gama et al., 2006). Thiol level was found significantly lower in mania group than remission group and control group, although the patients in our study were using mood stabilizers in both mania and remission period. However there are studies in the literature indicating that atypical antipsychotics have also been shown to inhibit the increase in SOD, leading to a decrease in anti-oxidative markers (Qing et al., 2003). In our study, number of atypical antipsychotic users was found to be higher in patients with manic episode. However, no significant difference was found between levels of disulphide. Although, there are no studies which evaluates thiol levels in untreated patients with BD in the literature, in a study conducted on untreated patients with schizophrenia, thiol level was lower in patients with schizophrenia and disulphide level was lower in control group (Topcuoglu et al., 2017). In our study, patients in the mania group had more manic episodes and more hospitalizations compared to the patients in the remission group. This may be one of the reasons behind that the thiol level is
When oxidative and antioxidative processes in different stages of BD are examined; different results were found for the levels of oxidative markers. The level of TBARS, a state biomarker of oxidative stress, was found to be higher in patients with BD in the manic phase (Tsai and Huang, 2015). In another study, Tsai et al. was found that the serum SOD and CAT activities were significantly higher in patients with major depressive disorder in an acute phase than in healthy subjects (Tsai and Huang, 2016). When myeloperoxidase (MPO) activity, known as an oxidative stress and inflammation marker, and catalase activity, known as an antioxidant enzyme, were investigated in BD patients with different episodes; manic and depressive bipolar patients had significantly lower CAT activities than euthymic bipolar patients and it was found that patients with BD had lower MPO levels compared to healthy controls (Selek et al., 2015). In our study, there was no statistically significant difference obtained between the three groups in terms of disulphide level and disulphide/total thiol ratio. While there was no statistically significant difference between mania, remission and control groups in terms of disulphide level; thiol and accordingly total thiol levels were statistically significantly lower in mania group than the other two groups. The lower thiol level may also be due to thiol loss. Oxidizing thiols to disulfides and their use in other syntheses (for example, synthesis of pheomelanin, neuromelanin) as well as insufficient intake are the ways of losing thiols (Erel and Neselioglu, 2014; Zecca et al., 2003). Excessive decrease of thiol level without an increase in disulphide levels could be the result of insufficient intake or increased consumption due to its use in other syntheses rather than transformation of thiol to disulphide (Durrieu et al., 1992). In our study, although no statistically significant difference was found between levels of BMI, cholesterol, low density lipoprotein, high density lipoprotein and triglyceride in mania and remission groups, insufficient nutrition might be the cause of low native thiol and total thiol levels in mania group. In our study, as a limitation, we did not have the knowledge of the lipid values for control group that could affect oxidation such as blood cholesterol, low density lipoprotein, high density lipoprotein and triglyceride levels. The low level of native thiol in the BD (mania and remission) group may be associated with dietary habits. Patients with bipolar disorder were found to have higher total energy intake, total daily sucrose intake, percentage of energy from carbohydrates, total fluid intake and intake of sweetened drinks than control group (Elmslie et al., 2001). In a study that examined the dietary habits of bipolar disorder patients, the vast majority of patients reported having less than three servings of juice, fruit or vegetables per day. Patients with BD have poor eating habits, notably, eating only one meal per day, eating alone, and having difficulty obtaining or cooking food for themselves (Kilbourne et al., 2007). There are numerous factors, which may have caused the differences in results, that were seen as serious limitations for the studies conducted so far such as age, gender, BMI, smoking, dietary habits and sampling effects of different stages of disease progression (Andreazza 240
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lower in the mania group than the remission group. But in our study, there was no statistically significant difference between the three groups in terms of disulphide level. There was no statistically significant correlation between the number of previous manic episodes and levels of native thiol, disulphide, total thiol, disulphide/native thiol, native thiol/total thiol, disulphide/total thiol. Native thiol and total thiol reduction in the mania and remission without increased disulphide level suggests that this may be more related to nutrition rather than oxidative stress.
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Scand. 127, 344–354. http://dx.doi.org/10. 1111/j.1600-0447.2012.01908.x. Maes, M., Kubera, M., Obuchowiczwa, E., Goehler, L., Brzeszcz, J., 2011. Depression's multiple comorbidities explained by (neuro)inflammatory and oxidative & nitrosative stress pathways. Neuro Endocrinol. Lett. 32, 7–24. Pavlović, D., Tamburić, V., Stojanović, I., Kocić, G., Jevtović-Stoimenov, T., Đorđević Vidosava, B.,, 2002. Oxidative stress as marker of positive symptoms in schizophrenia. Facta Univ. - Ser.: Med. Biol. 9, 157–161. Qing, H., Xu, H., Wei, Z., Gibson, K., Li, X.-M., 2003. The ability of atypical antipsychotic drugs vs. haloperidol to protect PC12 cells against MPP +-induced apoptosis. Eur. J. Neurosci. 17, 1563–1570. Raffa, M., Barhoumi, S., Atig, F., Fendri, C., Kerkeni, A., Mechri, A., 2012. Reduced antioxidant defense systems in schizophrenia and bipolar I disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry 39, 371–375. http://dx.doi.org/10.1016/j. pnpbp.2012.07.013. 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4.1. Limitations Having a small number of subjects was a limitation for the study. No longitudinal follow-up of the same patients assessed during disease and remission due to cross-sectional design, no comparison with patients in bipolar depression period can be listed as the limitations of our study. In our sample, the patients did not have a homogeneous distribution in terms of the first and second generation antipsychotic use. Since we could not include the untreated patients in our study, we could not evaluate the effects of the drugs on the patients. This can be stated as another limitation of our study. 4.2. Conclusion According to our knowledge, this is the first study concerning thiol/ disulphide homeostasis in BD. Detection of oxidative molecules for BD will be helpful in reducing morbidity especially in treatment and follow-up periods. Although there is not enough evidence yet, results of our study may imply that thiol and disulphide levels could be oxidative markers for BD and also therapeutic targets in terms of future pharmacological trials. However, to better understand the relationship between oxidative stress and BD, there is a need for further studies. Conflict of interest The authors declare no conflict of interest. References Akdemir, A., Türkçapar, M.H., Orsel, S.D., Demirergi, N., Dag, I., Ozbay, M.H., 2001. Reliability and validity of the Turkish version of the Hamilton Depression Rating Scale. Compr. Psychiatry 42, 161–165. http://dx.doi.org/10.1053/comp.2001. 19756. Anderson, I.M., Haddad, P.M., Scott, J., 2012. Bipolar disorder. BMJ 345, e8508. Andreazza, A.C., Kauer-Sant’anna, M., Frey, B.N., Bond, D.J., Kapczinski, F., Young, L.T., Yatham, L.N., 2008. Oxidative stress markers in bipolar disorder: a meta-analysis. J. Affect. Disord. 111, 135–144. http://dx.doi.org/10.1016/j.jad.2008.04.013. Bauer, I.E., Pascoe, M.C., Wollenhaupt-Aguiar, B., Kapczinski, F., Soares, J.C., 2014. Inflammatory mediators of cognitive impairment in bipolar disorder. J. Psychiatr. Res 56, 18–27. http://dx.doi.org/10.1016/j.jpsychires.2014.04.017. Bengesser, S.A., Lackner, N., Birner, A., Platzer, M., Fellendorf, F.T., Queissner, R., Filic, K., Reininghaus, B., Wallner-Liebmann, S.J., Mangge, H., Zelzer, S., Fuchs, D., Kapfhammer, H.-P., McIntyre, R.S., Reininghaus, E.Z., 2016. Mood stabilizers, oxidative stress and antioxidative defense in euthymia of bipolar disorder. CNS Neurol. Disord. Drug Targets 15, 381–389. Berg, D., Youdim, M.B.H., Riederer, P., 2004. Redox imbalance. Cell Tissue Res. 318, 201–213. http://dx.doi.org/10.1007/s00441-004-0976-5. Biswas, S., Chida, A.S., Rahman, I., 2006. Redox modifications of protein-thiols: emerging roles in cell signaling. Biochem. Pharmacol. 71, 551–564. http://dx.doi.org/10. 1016/j.bcp.2005.10.044. Bitanihirwe, B.K.Y., Woo, T.-U.W., 2011. Oxidative stress in schizophrenia: an integrated approach. Neurosci. Biobehav. Rev. 35, 878–893. http://dx.doi.org/10.1016/j. neubiorev.2010.10.008. Ciobica, A., Padurariu, M., Dobrin, I., Stefanescu, C., Dobrin, R., 2011. Oxidative stress in schizophrenia - focusing on the main markers. Psychiatr. Danub 23, 237–245. Circu, M.L., Aw, T.Y., 2010. Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic. Biol. Med. 48, 749–762. http://dx.doi.org/10.1016/j. freeradbiomed.2009.12.022. Cremers, C.M., Jakob, U., 2013. Oxidant sensing by reversible disulfide bond formation. J. Biol. Chem. 288, 26489–26496. http://dx.doi.org/10.1074/jbc.R113.462929. Dietrich, A.K., Humphreys, G.I., Nardulli, A.M., 2013. 17β-estradiol increases expression of the oxidative stress response and DNA repair protein apurinic endonuclease (Ape1) in the cerebral cortex of female mice following hypoxia. J. Steroid Biochem. Mol. Biol. 138, 410–420. http://dx.doi.org/10.1016/j.jsbmb.2013.07.007.
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Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Thiol/disulphide homeostasis in bipolar disorder a,⁎,1
a,2
b
T c
d
Gamze Erzin , Vahap Ozan Kotan , Canan Topçuoğlu , Güven Özkaya , Özcan Erel , Rabia Nazik Yüksela, Emre Ürere, Makbule Çiğdem Aydemira,3, Erol Gökaa a
Ankara Numune Training and Research Hospital, Psychiatry Department, Ankara, Turkey Ankara Numune Training and Research Hospital, Biochemistry Department, Ankara, Turkey Uludağ University, Faculty of Medicine, Biostatistics Department, Bursa, Turkey d Yıldırım Beyazıt University, Biochemistry Department, Ankara, Turkey e Ankara University, School of Medicine, Child and Adolescent Psychiatry, Ankara, Turkey b c
A R T I C L E I N F O
A B S T R A C T
Keywords: Oxidative stress Mania Remission Mood disorder Oxidative markers
Bipolar disorder (BD) patients have increased oxidative stress, which can disturb thiol/disulphide homeostasis, causing disulphide formation. The aim of the study is to investigate dynamic thiol/disulphide (SH/SS) homeostasis in BD patients, which is a novel evaluation method of oxidative status. Ninety-four BD patients (50 in the manic episode and 44 in remission) and 44 healthy controls were included in the study. Blood serum native thiol (SH) and total thiol (ToSH) concentrations were measured in a paired test. The half value of the difference between native thiol and total thiol concentrations was calculated as the disulphide (SS) bond amount. Serum native thiol levels of the mania group were found to be lower than the remission and the control groups. There was a significant difference between the remission group and the control group in terms of native thiol. Serum total thiol level was lower in mania group than the control group. Detection of oxidative molecules for BD could be helpful, especially in treatment, follow-up periods and reducing morbidity. The results of our study besides the data available in the literature support that thiol and disulphide levels are useful markers for BD and promising therapeutic targets in terms of future pharmacological modulation.
1. Introduction Bipolar disorder (BD) is associated with increased mortality (Laursen et al., 2007) and one of the most debilitating psychiatric disorders characterized by disruptive episodes of mania/hypomania and depression (Anderson et al., 2012). Understanding the etiology of BD has always been an important research topic. The roles of inflammatory processes and oxidative stress are being investigated with possible etiologic factors due to BD's indeterminate pathophysiology (Bauer et al., 2014; Gubert et al., 2013). Oxidative stress, which means the excess of reactive oxygen species (ROS), could have a role in the etiology of BD (Raffa et al., 2012). Excessive ROS may cause cellular injuries, lipid peroxidation, damage, apoptosis and protein carbonylation (Berg et al., 2004; Filomeni and Ciriolo, 2006; Maes et al., 2013). As the brain tissue is more susceptible to oxidative damage, the body also has an antioxidative mechanism against this oxidative damage (Ciobica et al., 2011). The antioxidant
mechanism of the body includes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-px) (Pavlović et al., 2002). Studies investigating the oxidative stress in patients with BD are conducted in the literature. Thiobarbituric acid reactive substances (TBARS) as lipid peroxidation marker, have been also investigated in these studies. TBARS have been by far the most widely used markers of oxidative stress in clinical studies (Grignon and Chianetta, 2007; Andreazza et al., 2008). Related to that point, Machado-Vieira et al. (2007) reported higher levels of TBARS and antioxidant enzyme activities (SOD and CAT) in unmedicated patients with BD in manic episode. According to results of this study, initial manic episodes are considered to be associated with both increased oxidative stress parameters and activated antioxidant defenses, which could be related to dysfunctions on energy metabolism and neuroplasticity pathways. Kunz et al. (2008) also found that serum SOD activity was significantly increased in patients with BD who are either in mania or in depression but not euthymic. TBARS levels were also found to be significantly higher
⁎
Correspondence to: Dışkapı Yıldırım Beyazıt Training and Research Hospital, Psychiatry Department, Altındağ, Ankara, Turkey. E-mail addresses: [email protected] (G. Erzin), [email protected] (V.O. Kotan), [email protected] (C. Topçuoğlu), [email protected] (G. Özkaya), [email protected] (Ö. Erel), [email protected] (R.N. Yüksel), [email protected] (E. Ürer), [email protected] (M.Ç. Aydemir), [email protected] (E. Göka). 1 Present and permanent work address: Dışkapı Yıldırım Beyazıt Training and Research Hospital, Psychiatry Department, Ankara, Turkey. 2 Present and permanent work address: Başkent University Faculty of Medicine, Psychiatry Department, Ankara, Turkey. 3 Present and permanent work address: Ankara University, School of Medicine, Psychiatry Department, Ankara, Turkey. https://doi.org/10.1016/j.psychres.2017.12.062 Received 12 April 2017; Received in revised form 31 October 2017; Accepted 30 December 2017 Available online 02 January 2018 0165-1781/ © 2018 Elsevier B.V. All rights reserved.
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interrater reliability. The Turkish version of the scale was found to be valid and reliable (Akdemir et al., 2001). In our study, patients were evaluated with the 17-item version.
in patients with schizophrenia, bipolar euthymic group, bipolar manic group and bipolar depressed group compared to controls (Kunz et al., 2008). Thiols also have a significant role in antioxidant defence (Sen and Packer, 2000). Thiols can experience oxidation reaction through oxidants and form disulphide bonds (Cremers and Jakob, 2013). Oxidation of cysteine residues can prompt to reversible development of mixed disulfides between low-molecular mass thiols and protein thiol groups when oxidative stress enhances. Thiol disulphide homeostasis is maintained by reducement of formed disulphide bonds to thiol groups (Jones and Liang, 2009; Biswas et al., 2006). Thiol/disulphide ratio (TDR) has critical roles in detoxification, antioxidant protection, signal transduction, regulation of enzymatic activity, apoptosis, and cellular signaling mechanisms (Biswas et al., 2006; Circu and Aw, 2010). Determination of dynamic thiol disulphide homeostasis can provide significant information on different normal or abnormal biochemical processes, because the abnormal thiol disulphide homeostasis state is involved in the pathogenesis of a variety of diseases, including schizophrenia and neurodegenerative disorders (Smeyne and Smeyne, 2013; Steele et al., 2013; Topcuoglu et al., 2017). Methods that measure only thiol values can only provide information about the status of the antioxidant buffer system. However, thiol disulphide homeostasis, which is the dynamic redox system of the organism, can be evaluated objectively with the method of Erel et al. (Erel and Neselioglu, 2014). To evaluate the thiol/disulphide balance globally, both thiol and disulphide need to be measured by this method (Vural et al., 2017). In this study, we aimed to evaluate BD patients who were on manic episode and in remission in terms of thiol disulphide balance, and to compare them with healthy controls.
2.2. Young Mania Rating Scale (YMRS) YMRS is an 11-item diagnostic questionnaire used to measure the severity of ME. Each item measures five degrees of severity; seven items are answered by using a five-point Likert-type scale, while four items are answered by using a 9-point Likert-type scale. The Turkish version of the scale was found to be both valid and reliable (Karadağ et al., 2002). 2.3. Biochemical tests Fasting blood samples were obtained from the patients and the controls in plain tubes. Serum samples were separated after centrifugation at 1300g for 10 min and stored at − 80 °C until the analysis was conducted. Thiol disulphide homeostasis tests were performed. Reducible disulphide bonds were first reduced to form free functional thiol groups. Unused reductant sodium borohydride was consumed and removed with formaldehyde, and all thiol groups including reduced and native thiol groups were determined after the reaction with 5,5′-dithiobis-(2-nitrobenzoic) acid (DTNB). Half of the difference between the total thiols and the native thiols gave the dynamic disulphide amount. After the native and total thiols were determined, disulphide amounts, disulphide/total thiol percent ratios (SS/SH+SS), native thiol/total thiol percent ratios (SH/SH+SS), and disulphide/native thiol percent ratios (SS/SH) were calculated (Erel and Neselioglu, 2014).
2. Methods 2.4. Statistical analysis Before recruiting the participants, an experienced clinician interviewed patients according to the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, fifth version (DSM–5), to confirm manic episode diagnosis of manic episode group members, to acknowledge that patients in the remission group did not meet DSM-5 criteria for any BD episode (i.e., depressive, mixed, manic, or hypomanic) in last 6 months, and that healthy control group members showed no evidence of any present or previous psychiatric disease. The Hamilton Depression Rating Scale (HAM-D) and Young Mania Rating Scale (YMRS) were also used to support the diagnoses of remission (i.e., HAM-D score < 7 or YMRS score < 4) and mania (i.e., YMRS score > 20). Our study was approved by the ethics committee of the Ankara Numune Training and Research Hospital. Written consents were obtained from each patient and one of their first-degree relatives and also from controls. Clinician filled out a socio-demographic data form. A 5 cc of venous blood was collected from each subject. Blood cells were separated from serum and serum samples were stored at − 80 °C. Biochemical analyses were performed on these samples. All patients underwent laboratory tests, including complete blood count, blood lipids, fasting blood glucose, C-Reactive Protein (CRP) and insulin measurements. Height, weight, waist and hip circumferences of the subjects were measured. Gender and age of each subject were recorded. When collecting data in our study, the amount of cigarette consumption was obtained for each patient and patients with obesity were excluded from the study. Mental retardation, pregnancy, previous electroconvulsive therapy (ECT) history and having any systemic or metabolic disease were also included in the exclusion criteria.
The data was examined by the Shapiro Wilk test whether or not it presents normal distribution. One-way ANOVA was applied for comparison of 3 groups. For pairwise comparison, Tukey test was used. Mann-Whitney U test was used for the comparison of 2 groups and Kruskal Wallis test was used to compare more than two groups were used when the data was not normally distributed. Categorical variables were compared using Pearson's chi-squared test and Fisher-FreemanHalton test. Correlations between variables were tested using Pearson and Spearman correlation coefficients. p < 0.05 was considered as significance levels. Statistical analysis was performed using IBM Statistics SPSS 23.0 (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.). 3. Results Mania and remission groups were presented similar results when data concerning gender (df = 2, χ2 = 0.535, p = .765), age (df = 2, F = 0.033, p = .968), marital status (Fisher-Freeman-Halton = 2.320 p = .696), BMI (Body Mass Index) (df = 2, F = 1.598, p = .206) and smoking (df = 2, F = 1.805, p = .171) were compared (Table 1). When the demographic and clinical characteristics of mania and remission groups were examined; a statistically significant difference between the groups was found in terms of monthly income, which was lower in mania group (Fisher-Freeman-Halton = 2.870 p = .378). The number of antipsychotic users was found to be higher in mania group (FisherFreeman-Halton = 10.399, p = .004). There was no statistically significant difference obtained between mania and remission groups in terms of blood count, lipids, insulin, CRP, fasting glucose (p > .05). While 96% of mania group had antipsychotic medication, this ratio was found to be 73% in the remission group. Of the mania group, 64% were using valproic acid/sodium valproate, 12% were using lithium, 8% were using carbamazepine, 2% were using lithium and valproic acid/sodium valproate, and 14% were
2.1. Hamilton Depression Rating Scale (HAM-D) Designed by Hamilton (1960), the original version of the HAM-D contains 17 items, each scored from 0 to 4 for a maximum total score of 53. Decades later, Williams (1988) developed the Structured Interview for HAM-D-21 as another version of the HAM-D that improved its 238
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Table 1 Evaluation of socio-demographic characteristics.
Gender (%) Female Male Age (years) Marital status Single Married Divorced Body mass index (kg/m2) Smoking (packet-year) Age at disease onset (years) Duration of disease (years) Number of hospitalizations Number of previous manic episode Number of depressive episode Young mania rating scale score Hamilton depression scale score a b c d e
Mania (n = 50)
Remission (n = 44)
Control (n = 44)
26 (52%) 24 (48%) 38.5 ± 11.5
23 (52.3%) 21 (47.7%) 37.9 ± 10.3
20 (45.5%) 24 (54.5%) 38 ± 10.4
18 (36%) 28 (56%) 4 (8%) 25.4 ± 3.1 9.8 ± 7.7 26.9 ± 10.2 11.6 ± 9.2 3 (1–10) 3 (1–10) 0 (0–1) 37.1 ± 5.3 0.9 ± 0.8
15 (34.1%) 28 (63.6%) 1 (2.3%) 26.6 ± 3.5 13.5 ± 7.3 27.0 ± 9.3 10.9 ± 7.8 2 (0–10) 2 (0–10) 0 (0–1) 1.6 ± 0.8 0.9 ± 0.9
16 (36.4%) 24 (54.5%) 4 (9.1%) 25.9 ± 3.3 11.0 ± 7.5 – – – – – – –
p 0.765a
0.968b 0.696c
0.206b 0.171b 0.952d 0.714d 0.011e 0.033e 0.533e 0.00d 0.83d
p value determined by Pearson Chi-Square test. p value determined by ANOVA. p value determined by Fisher-Freeman-Halton test. p value determined by independent sample t-test. p value determined by Mann Whitney U test.
= .051 and p = .051). Disulphide/native thiol ratio was statistically significantly higher in mania group than control group (p = .039) (Table 4). There was no statistically significant difference obtained in mania and remission groups, when the correlations between age at disease onset, duration of the disease, number of hospitalizations, number of previous manic episodes, number of depressive episodes, young mania total score and hamilton depression score were compared individually with native thiol, disulphide, disulphide/native thiol, disulphide/total thiol, native thiol/total thiol (p > .05). In our study, no statistically significant difference was found between measurements of waist and hip circumferences, weight and height in mania and remission groups (p > .05).
Table 2 Evaluation of Mood Stabilizer Use in patients with BD. Mood stabilizer Valproic acid/Sodium valproate Drug doses (mg/day) 1150 (500–2000)
Lithium
Carbamazepine
950 (600–1200) 650 (400–800)
not on any mood stabilizer treatment. Of the remission group, 68% were using valproic acid/sodium valproate, 14% were using lithium, 7% were using carbamazepine, 2% were using lithium and valproic acid/sodium valproate and 9% were not on any mood stabilizer treatment. While 92% of the mania group were having second generation and 4% were having first generation antipsychotic treatment, 4% of them did not have any antipsychotic treatment. While 68% of remission group were having second generation and 5% were having first generation antipsychotic treatment, 27% of them did not have any antipsychotic treatment. Table 2 and 3 present details about the drug doses of patients with BD. Serum native thiol level in mania group was lower than remission and control groups (respectively p = .034 and p < .001). There was a difference between remission group and control group in terms of native thiol level (p = .010). Serum total thiol level was different in patients with BD than control group (p < .001 for mania and p = .019 for remission). There was not any difference between mania and remission groups in terms of serum total thiol level (p = .086). In terms of serum disulphide levels, disulphide/total thiol and native thiol/ total thiol ratios, there were not any statistically significant difference between mania, remission and control groups (respectively p = .858, p
4. Discussion Oxidative imbalance is involved in the pathophysiology of psychiatric diseases such as schizophrenia, BD and depressive disorder (Bitanihirwe and Woo, 2011; Andreazza et al., 2008; Maes et al., 2011). Although the level of thiol as an antioxidant parameter has been previously investigated in a variety of diseases, to our knowledge, this is the first study investigating dynamic thiol/disulphide homeostasis in patients with BD. In our study, both total thiol and native thiol levels of the patients in remission and control group were found to be significantly higher than patients in mania group. In our study, there was no statistically significant difference found in disulphide level indicating oxidative stress in mania group compared to control group. The total thiol level was significantly lower in mania and remission groups than in control group. This suggests that the decrease in total thiol level without change in disulphide level in mania and remission group may be due to a decrease in the native thiol level.
Table 3 Evaluation of Antipsychotic Drug Use in patients with BD. Antipsychotic Drug
Drug doses (mg/day)
Haloperidol
Quetiapine
Olanzapine
Paliperidone
Risperidone
10 (5–15)
700 (300–1200)
15 (5–20)
8 (3–12)
6 (4–8)
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Table 4 Levels of native thiol, total thiol, disulphide, disulphide/native thiol, disulphide/total thiol and native/total thiol according to groups. Mania (Mean ± SD)
Remission (Mean ± SD)
Control (Mean ± SD)
p
Pairwise comparison
Native Thiol
332.1 ± 48.7
360.5 ± 66.3
394.9 ± 47.0
< 0.001
Total Thiol
370.1 ± 54.5
396.9 ± 73.3
432.3 ± 52.7
< 0.001
Disulphide Disulphide/Native Thiol
19. 1 ± 7.3 5.7 ± 2.2
18.2 ± 7.1 5.1 ± 2.0
18.7 ± 6.5 4.7 ± 1.7
0.858 0.046
Disulphide/Total Thiol Native Thiol/Total Thiol
5.1 ± 1.7 89.8 ± 3.5
4.6 ± 1.6 90.9 ± 3.2
4.3 ± 1.4 91.4 ± 2.8
0.051 0.051
M-R .034 M-C < .001 R-C .01 M-R .086 M-C < .001 R-C .019 – M-R .266 M-C .039 R-C .656 – –
p value determined by ANOVA and Tukey test was used for pairwise comparison.
et al., 2008; Flatow et al., 2013). When demographic and clinical characteristics of mania and remission groups were examined; statistically significant differences were found between the groups in terms of monthly income, number of antipsychotics used, number of hospitalization, number of previous manic episodes. Number of hospitalizations and number of previous manic episodes in mania period were significantly higher than in remission period, which may have affected the functioning of mania group and may lead to a lower monthly income. The high number of antipsychotic users in the manic episode is also an expected result. The effect of gender on oxidative markers was also examined in the literature. In a study investigating level of TBARS, in BD and schizophrenia, TBARS levels were found to be higher in male patients than female patients (Tunçel et al., 2015). It was found that oxidative and anti-oxidative parameters in BD could be affected by estrogen and progesterone, DNA repair, and activation of antioxidant defence. (Requintina and Oxenkrug, 2005; Dietrich et al., 2013; Frey and Dias, 2014; Spence et al., 2013). In our study, no statistically significant difference was obtained in terms of native thiol, total thiol, disulphide, disulphide/native thiol, disulphide/total thiol and native thiol/total thiol regarding gender groups. In our study, BD patients who were either in mania or in remission were using antipsychotics and mood stabilizers. The antipsychotic and mood stabilizer drugs used can also affect the oxidation process. Use of mood stabilizer drugs may reduce the level of lipid peroxidation (Shao et al., 2005). However, it has been found that participants taking lithium had the lowest TBARS levels, while patients taking atypical antipsychotics had higher oxidative stress markers (Bengesser et al., 2016). Since the patients were not evaluated at the untreated stage in our study, we could not pinpoint this effect. In one study, use of antipsychotics in first episode of psychotic attacks resulted in decrease in oxidative markers (Kriisa et al., 2016). In addition to this, allostatic load may reduce oxidative stress during antipsychotic use, avoidance of stressors, or recovery in psychotic symptoms (Kapczinski et al., 2011; Gama et al., 2006). Thiol level was found significantly lower in mania group than remission group and control group, although the patients in our study were using mood stabilizers in both mania and remission period. However there are studies in the literature indicating that atypical antipsychotics have also been shown to inhibit the increase in SOD, leading to a decrease in anti-oxidative markers (Qing et al., 2003). In our study, number of atypical antipsychotic users was found to be higher in patients with manic episode. However, no significant difference was found between levels of disulphide. Although, there are no studies which evaluates thiol levels in untreated patients with BD in the literature, in a study conducted on untreated patients with schizophrenia, thiol level was lower in patients with schizophrenia and disulphide level was lower in control group (Topcuoglu et al., 2017). In our study, patients in the mania group had more manic episodes and more hospitalizations compared to the patients in the remission group. This may be one of the reasons behind that the thiol level is
When oxidative and antioxidative processes in different stages of BD are examined; different results were found for the levels of oxidative markers. The level of TBARS, a state biomarker of oxidative stress, was found to be higher in patients with BD in the manic phase (Tsai and Huang, 2015). In another study, Tsai et al. was found that the serum SOD and CAT activities were significantly higher in patients with major depressive disorder in an acute phase than in healthy subjects (Tsai and Huang, 2016). When myeloperoxidase (MPO) activity, known as an oxidative stress and inflammation marker, and catalase activity, known as an antioxidant enzyme, were investigated in BD patients with different episodes; manic and depressive bipolar patients had significantly lower CAT activities than euthymic bipolar patients and it was found that patients with BD had lower MPO levels compared to healthy controls (Selek et al., 2015). In our study, there was no statistically significant difference obtained between the three groups in terms of disulphide level and disulphide/total thiol ratio. While there was no statistically significant difference between mania, remission and control groups in terms of disulphide level; thiol and accordingly total thiol levels were statistically significantly lower in mania group than the other two groups. The lower thiol level may also be due to thiol loss. Oxidizing thiols to disulfides and their use in other syntheses (for example, synthesis of pheomelanin, neuromelanin) as well as insufficient intake are the ways of losing thiols (Erel and Neselioglu, 2014; Zecca et al., 2003). Excessive decrease of thiol level without an increase in disulphide levels could be the result of insufficient intake or increased consumption due to its use in other syntheses rather than transformation of thiol to disulphide (Durrieu et al., 1992). In our study, although no statistically significant difference was found between levels of BMI, cholesterol, low density lipoprotein, high density lipoprotein and triglyceride in mania and remission groups, insufficient nutrition might be the cause of low native thiol and total thiol levels in mania group. In our study, as a limitation, we did not have the knowledge of the lipid values for control group that could affect oxidation such as blood cholesterol, low density lipoprotein, high density lipoprotein and triglyceride levels. The low level of native thiol in the BD (mania and remission) group may be associated with dietary habits. Patients with bipolar disorder were found to have higher total energy intake, total daily sucrose intake, percentage of energy from carbohydrates, total fluid intake and intake of sweetened drinks than control group (Elmslie et al., 2001). In a study that examined the dietary habits of bipolar disorder patients, the vast majority of patients reported having less than three servings of juice, fruit or vegetables per day. Patients with BD have poor eating habits, notably, eating only one meal per day, eating alone, and having difficulty obtaining or cooking food for themselves (Kilbourne et al., 2007). There are numerous factors, which may have caused the differences in results, that were seen as serious limitations for the studies conducted so far such as age, gender, BMI, smoking, dietary habits and sampling effects of different stages of disease progression (Andreazza 240
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lower in the mania group than the remission group. But in our study, there was no statistically significant difference between the three groups in terms of disulphide level. There was no statistically significant correlation between the number of previous manic episodes and levels of native thiol, disulphide, total thiol, disulphide/native thiol, native thiol/total thiol, disulphide/total thiol. Native thiol and total thiol reduction in the mania and remission without increased disulphide level suggests that this may be more related to nutrition rather than oxidative stress.
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4.1. Limitations Having a small number of subjects was a limitation for the study. No longitudinal follow-up of the same patients assessed during disease and remission due to cross-sectional design, no comparison with patients in bipolar depression period can be listed as the limitations of our study. In our sample, the patients did not have a homogeneous distribution in terms of the first and second generation antipsychotic use. Since we could not include the untreated patients in our study, we could not evaluate the effects of the drugs on the patients. This can be stated as another limitation of our study. 4.2. Conclusion According to our knowledge, this is the first study concerning thiol/ disulphide homeostasis in BD. Detection of oxidative molecules for BD will be helpful in reducing morbidity especially in treatment and follow-up periods. Although there is not enough evidence yet, results of our study may imply that thiol and disulphide levels could be oxidative markers for BD and also therapeutic targets in terms of future pharmacological trials. However, to better understand the relationship between oxidative stress and BD, there is a need for further studies. Conflict of interest The authors declare no conflict of interest. References Akdemir, A., Türkçapar, M.H., Orsel, S.D., Demirergi, N., Dag, I., Ozbay, M.H., 2001. Reliability and validity of the Turkish version of the Hamilton Depression Rating Scale. Compr. Psychiatry 42, 161–165. http://dx.doi.org/10.1053/comp.2001. 19756. Anderson, I.M., Haddad, P.M., Scott, J., 2012. Bipolar disorder. BMJ 345, e8508. Andreazza, A.C., Kauer-Sant’anna, M., Frey, B.N., Bond, D.J., Kapczinski, F., Young, L.T., Yatham, L.N., 2008. Oxidative stress markers in bipolar disorder: a meta-analysis. J. Affect. Disord. 111, 135–144. http://dx.doi.org/10.1016/j.jad.2008.04.013. Bauer, I.E., Pascoe, M.C., Wollenhaupt-Aguiar, B., Kapczinski, F., Soares, J.C., 2014. Inflammatory mediators of cognitive impairment in bipolar disorder. J. Psychiatr. Res 56, 18–27. http://dx.doi.org/10.1016/j.jpsychires.2014.04.017. Bengesser, S.A., Lackner, N., Birner, A., Platzer, M., Fellendorf, F.T., Queissner, R., Filic, K., Reininghaus, B., Wallner-Liebmann, S.J., Mangge, H., Zelzer, S., Fuchs, D., Kapfhammer, H.-P., McIntyre, R.S., Reininghaus, E.Z., 2016. Mood stabilizers, oxidative stress and antioxidative defense in euthymia of bipolar disorder. CNS Neurol. Disord. Drug Targets 15, 381–389. Berg, D., Youdim, M.B.H., Riederer, P., 2004. Redox imbalance. Cell Tissue Res. 318, 201–213. http://dx.doi.org/10.1007/s00441-004-0976-5. Biswas, S., Chida, A.S., Rahman, I., 2006. Redox modifications of protein-thiols: emerging roles in cell signaling. Biochem. Pharmacol. 71, 551–564. http://dx.doi.org/10. 1016/j.bcp.2005.10.044. Bitanihirwe, B.K.Y., Woo, T.-U.W., 2011. Oxidative stress in schizophrenia: an integrated approach. Neurosci. Biobehav. Rev. 35, 878–893. http://dx.doi.org/10.1016/j. neubiorev.2010.10.008. Ciobica, A., Padurariu, M., Dobrin, I., Stefanescu, C., Dobrin, R., 2011. Oxidative stress in schizophrenia - focusing on the main markers. Psychiatr. Danub 23, 237–245. Circu, M.L., Aw, T.Y., 2010. Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic. Biol. Med. 48, 749–762. http://dx.doi.org/10.1016/j. freeradbiomed.2009.12.022. Cremers, C.M., Jakob, U., 2013. Oxidant sensing by reversible disulfide bond formation. J. Biol. Chem. 288, 26489–26496. http://dx.doi.org/10.1074/jbc.R113.462929. Dietrich, A.K., Humphreys, G.I., Nardulli, A.M., 2013. 17β-estradiol increases expression of the oxidative stress response and DNA repair protein apurinic endonuclease (Ape1) in the cerebral cortex of female mice following hypoxia. J. Steroid Biochem. Mol. Biol. 138, 410–420. http://dx.doi.org/10.1016/j.jsbmb.2013.07.007.
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