Journal of Affective Disorders 173 (2015) 22–26

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Thiobarbituric acid reactive substances (TBARS) is a state biomarker of oxidative stress in bipolar patients in a manic phase Meng-Chang Tsai, Tiao-Lai Huang n Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC

art ic l e i nf o

a b s t r a c t

Article history: Received 19 July 2014 Received in revised form 23 October 2014 Accepted 25 October 2014 Available online 4 November 2014

Objectives: Oxidative stress may contribute to the pathophysiology of bipolar disorder. The aim of this study was to investigate the serum levels or activities of oxidative stress markers in bipolar patients in a manic phase, and evaluate the changes in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), thiobarbituric acid reactive substances (TBARS), protein carbonyl content (PCC) and 8-hydroxy 20 -deoxyguanosine after treatment (8-OHdG). Methods: We consecutively enrolled 23 bipolar inpatients in a manic phase and 40 healthy subjects. Serum oxidative stress markers were measured with assay kits. All patients were evaluated by examining the correlation between oxidative stress markers and Young Mania Rating Scale (YMRS) scores. Results: The serum TBARS levels in bipolar patients in a manic phase were significantly higher than those of healthy subjects (p¼0.006), and serum GPx activity was significant lower than that of healthy subjects (po 0.05). The YMRS scores had a significantly positive association with CAT activity and PCC levels (po 0.05) and a negative association with GPx activity (po0.05). Twenty bipolar patients were followed up, and their oxidative stress markers were measured at the end of treatment. We found significantly decreased changes in TBARS levels only in bipolar manic patients after treatment (p¼ 0.019). Limitation: Our sample size was limited. Conclusion: Our results suggest that serum TBARS levels might be a state biomarker of oxidative stress in bipolar patients in a manic phase and after treatment. In addition, GPx deficit might be a trait biomarker of severity of mania. & 2014 Elsevier B.V. All rights reserved.

Keywords: TBARS GPx Bipolar Mania SOD PCC

1. Introduction The pathophysiology of bipolar disorder is not completely understood, and accumulating evidence has shown bipolar disorder to be associated with oxidative stress (Andreazza et al., 2008a; Berk, 2009; Steckert et al., 2010). Excess free radicals cause an increase in oxidative stress which may play an important role in the etiology of bipolar disorder (Andreazza, 2012; Raffa et al., 2012). Oxidative stress causes excessive levels of reactive oxygen species (ROS) or reactive nitrogen species (RNS). Excessive ROS or RNS may cause DNA damage, lipid peroxidation, protein carbonylation and apoptosis (Berg et al., 2004; Andreazza, 2012). ROS also leads to lipid peroxidation which is damaging to the cell membrane and causes cell death (Horton and Fairhurst, 1987; Cochrane, 1991; Kwon et al., 2003). The primary antioxidant defense system, n Correspondence to: Tiao-Lai Huang, MD, Department of Psychiatry, Chang Gung Memorial Hospital–Kaohsiung Medical Center, 123, Ta-Pei Rd, Niao-Sung, Kaohsiung 833, Taiwan, ROC. Tel.: þ 886 7 7317123 8752; fax: þ 886 7 7326817. E-mail address: [email protected] (T.-L. Huang).

http://dx.doi.org/10.1016/j.jad.2014.10.045 0165-0327/& 2014 Elsevier B.V. All rights reserved.

which includes superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT), can protect brain cells from oxidative damage (Dringen et al., 2005; Andreazza et al., 2008a). In addition, oxidative pathway genes, including SOD2 and GPx3 haplotypes, might be risk factors for bipolar disorder (Fullerton et al., 2010). Several recent studies have reported inconsistent data involving SOD, CAT, GPx, DNA damage and protein carbonylation in bipolar patients (Andreazza et al., 2007b, 2008a, 2009; Kapczinski et al., 2011; Soeiro-de-Souza et al., 2013). SOD, GPx and CAT are primary antioxidant enzymes that act against oxidative stress and prevent the oxidation of DNA, protein and lipid (Sabens Liedhegner et al., 2012; Roszkowski, 2014). SOD is the first line of defense in scavenging the superoxide anion radical (O2 ), which has been reported as both decreased and increased in manic patients (Andreazza et al., 2007a; Gergerlioglu et al., 2007; Machado-Vieira et al., 2007; Kunz et al., 2008). CAT metabolizes excess hydrogen peroxide to water and oxygen. CAT activity was reported to be decreased and increased in patients with manic episode (Ozcan et al., 2004; Andreazza et al., 2007a;

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Table 1 Demographic characteristics and oxidative-stress markers of patients in an acute manic phase and healthy controls. Variable

Patients (n¼ 23)

Controls (n ¼40)

Age (years) BMI (kg/m2) SOD (U/ml) CAT (nmol/min/ml) GPx (nmol/min/ml) TBARS (μmol/l) PCC (nmol/mg) 8-OHdG (pg/ml)

41.3 7 12.0 22.8 7 3.5 2.0 7 0.7 198.9 7 342.3 194.8 7 39.8 9.8 7 5.0 0.6 7 0.2 4339.17 3941.0

30.4 7 5.0* 22.17 3.3 2.0 7 0.4 150.0 7 439.8 233.47 39.8* 7.4 7 1.6* 0.7 7 0.3 4422.9 7 3390.2

Plus–minus values are given as mean 7standard deviation. Abbreviation: BMI¼ body mass index; SOD¼ superoxide dismutase; CAT ¼catalase; GPx¼ glutathione peroxidase; TBARS¼thiobarbituric acid reactive substances; PCC ¼ protein carbonyl content; 8-OHdG ¼ 8-hydroxy 20 -deoxyguanosine. n

po 0.05.

Machado-Vieira et al., 2007). GPx can scavenge peroxides and hydroxyl radicals with glutathione (Chance et al., 1979). Levels of GPx were increased in some reports of euthymic and depressed patients with bipolar disorder (Andreazza et al., 2007a; de Sousa et al., 2014), and showed no significant changes in other reports (Andreazza et al., 2008a, 2009; Raffa et al., 2012). Oxidative stress leads to lipid peroxidation, protein oxidative damage and DNA oxidative damage in patients with bipolar disorder (Steckert et al., 2010). Malondialdehyde (MDA) and 4hydroxynonenal (4-HNE) are products of lipid peroxidation. 4HNE levels of postmortem anterior cingulate brain sections from bipolar patients were significantly increased, by approximately 60%, compared to controls, and the result suggested oxidative stress causes brain damage (Wang et al., 2009). MDA was measured using the thiobarbituric acid reactive substances (TBARS) method (Janero, 1990). Levels of MDA (or TBARS) were elevated in bipolar patients with manic and euthymic episodes, and decreased or increased in patients with depressed episodes (Ozcan et al., 2004; Andreazza et al., 2007a; Machado-Vieira et al., 2007; Kapczinski et al., 2011; de Sousa et al., 2014). In addition, free radicals react with guanosine DNA residues and produce 8-hydroxy 20 -deoxyguanosine (8-OHdG); free radicals also lead to cytosine damage (Lenaz, 2001; Kohen and Nyska, 2002). Oxidative stress-induced DNA damage in bipolar patients has been reported (Frey et al., 2007; Andreazza, 2012; Soeiro-de-Souza et al., 2013). Furthermore, ROS leads to protein damage measured by protein carbonyl content (PCC). Bipolar patients had higher serum levels of PCC than healthy controls (Kapczinski et al., 2011; Magalhaes et al., 2012). The objectives of this study were to investigate the serum levels or activities of oxidative stress-related markers, including SOD, CAT, GPx, TBARS, 8-OHdG and PCC, in bipolar patients in a manic phase compared to healthy controls. We also assessed the relationship between these markers and Young Mania Rating Scale (YMRS) scores (Young et al., 1978) in patients in a manic phase. In addition, we investigated the changes in these markers in bipolar patients after treatment.

2. Methods 2.1. Patients and study design All participants with bipolar I disorder in a manic phase were recruited from consecutive admissions to the inpatient ward of Kaohsiung Chang Gung Memorial Hospital, and were assessed by the same psychiatrist using the Structured Clinical Interview (SCID) for DSM-IV Axis I Disorders. All patients were hospitalized.

Fig. 1. There was a trend toward a significantly positive correlation between serum CAT activity and YMRS scores in patients in an acute phase (A), positive correlation between serum protein carbonyl content levels and YMRS scores (B), and negative correlation between serum GPx activity and YMRS scores (C).

The YMRS was used to evaluate severity of disease and was assessed at baseline and the endpoint after treatment by the same psychiatrist. The YMRS was used by two board-certified psychiatrists. Data including age, sex, body mass index (BMI: kg/m2), serum SOD, CAT, GPx, TBARS, 8-OHdG and PCC levels or activities was collected. All patients were assessed prior to starting treatment and were above age 18 and under age 65. They had no substance dependence, and were not heavy smokers. Chest X-ray, blood pressure, electrocardiogram (EKG) examinations and routine blood tests were performed to rule out participants with significant physical illnesses and systemic diseases. The healthy group included 40 healthy subjects who were recruited at Kaohsiung Chang Gung Memorial Hospital. They were

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Table 2 Pearson’s correlation between oxidative-stress markers and YMRS scores of patients in an acute manic phase.

YMRS n

SOD

CAT

GPx

TBARS

PCC

8-OHdG

 0.070

0.466n

 0.467n

0.212

0.425n

 0.188

po 0.05.

screened for personal or family history (first-degree relatives) of mental disorders and were excluded if they had any such history or medical disease. All subjects in the control group were free of medication. This study was performed at Kaohsiung Chang Gung Memorial Hospital from November 2012 to October 2013 and was approved by the Institutional Review Board of the hospital. The study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All participants gave written informed consent after receiving a full explanation of the study. 2.2. Laboratory data Blood samples from a forearm vein were drawn in a fasting state (i.e., fasting for at least 8 h). The serum samples were immediately separated by centrifugation at 3000g for 10 min and were stored at  80 1C for further analysis. Commercially available assay kits were used to perform the assays for SOD, CAT, GPx, TBARS, 8-OHdG and PCC (Cayman Chemical Company, Ann Arbor, USA). All analyses were performed at the same laboratory. 2.3. Statistical analysis The results were expressed as the means 7standard deviation (SD). Changes in the oxidative stress markers of the bipolar patients after treatment were analyzed by paired t-test. Relationships between oxidative stress markers and YMRS scores were assessed using Pearson’s correlation coefficient. A p value of less than 0.05 was used to indicate statistical significance. All tests were 2-tailed. These analyses were performed using SPSS for Windows, version 18.

3. Results We consecutively enrolled 23 bipolar inpatients (13 men and 10 women) in a manic phase and 40 healthy subjects (20 men and 20 women). Table 1 shows the demographic and oxidative stress biomarkers data. The bipolar patients in a manic phase had lower mean serum activity of GPx (p o0.05) and higher mean serum levels of TBARS (p ¼0.006) than the healthy subjects. Serum levels or activities of SOD, CAT, 8-OHdG and PCC showed no significant difference between the two groups (p 40.05). In terms of the correlation coefficients between oxidative stress markers and YMRS scores, serum CAT activity (p ¼0.025, Fig. 1A) and serum PCC levels (p ¼0.025, Fig. 1B) were significantly positively correlated with YMRS scores in the bipolar patients in a manic phase. Serum GPx activity was significantly negatively correlated with YMRS scores (p ¼0.043, Fig. 1C), and serum SOD, TBARS and 8-OHdG levels or activities had no significant association with YMRS scores (p 40.05) (Table 2). Twenty bipolar inpatients were followed up, and their serum SOD, CAT, GPx, TBARS, 8-OHdG and PCC levels or activities were measured after treatment. The 20 patients (12 men and 8 women) had mean hospitalization durations of 25.87 5.0 days. The medications received by the 20 patients were showed in Table 3. All patients were responders. The YMRS scores at baseline were

35.3 77.3, and 3.2 72.9 at the endpoint. The distribution of the baseline YMRS scores of manic patients were 5 patients for YMRS≧40, 11 patients for 30≦YMRS≦39 and 4 patients for 20≦YMRS≦29. The distribution of endpoint YMRS scores were 6 patients for YMRS ¼0, 10 patients for 1≦YMRS≦5 and 4 patients for 6≦YMRS≦9. The remission rate (YMRS scores≦5) was 80% (n ¼16). The response rate (decrease from baseline YMRS scores≧50%) was 20% (n ¼4). Using paired t-test analysis, we found significantly decreased changes in TBARS levels in bipolar patients who had received treatment (p ¼0.019); other markers (SOD, CAT, GPx, 8-OHdG and PCC) showed no significant changes after treatment (p 40.05, Table 4).

4. Discussion The most important finding in this study is that bipolar patients in a manic phase had significantly higher serum levels of TBARS than the healthy controls. In addition, serum TBARS levels were significantly decreased in bipolar patients who had received treatment. Andreazza et al. (2007a) reported that serum TBARS levels were increased in bipolar patients with a manic episode. Kunz et al. (2008), Kapczinski et al. (2011) also reported elevated serum levels of TBARS in bipolar patients in a manic phase compared to controls. In addition, plasma TBARS levels were elevated in unmedicated manic patients compared to healthy subjects (Machado-Vieira et al., 2007). TBARS levels were increased in bipolar patients in a manic phase regardless of the blood samples of serum or plasma. Furthermore, our study showed serum TBARS levels were significantly decreased in bipolar patients with a manic episode who had received treatment. Bipolar patients treated with lithium during a manic episode had significantly decreased plasma TBARS levels (Machado-Vieira et al., 2007). In a case report of bipolar twins in a manic phase, elevated serum levels of TBARS, compared to the healthy subjects, were found; however, the TBARS levels were normalized after a 6-week treatment (Frey et al., 2007). Our results showed that the other oxidative-stress biomarkers (SOD, CAT, PCC and 8-OHdG) were not significantly different between the patients with bipolar disorder and the healthy subjects. In previous studies, serum or RBC levels of SOD showed decreased, increased or no significant changes in bipolar patients with a manic episode compared to healthy controls (Andreazza et al., 2007a; Gergerlioglu et al., 2007; Machado-Vieira et al., 2007; Kunz et al., 2008). In addition to these conflicting data, serum CAT levels were decreased or increased in bipolar patients with a manic episode compared to healthy subjects (Andreazza et al., 2007a; Machado-Vieira et al., 2007). Serum CAT levels in bipolar patients in a manic phase also had controversial data. In a twin case study, greater DNA damage was noted in bipolar twins during a manic episode than in healthy controls, and the single-cell gel electrophoresis technique (Comet Assay) was used to assess DNA damage (Frey et al., 2007). However, no previous data on DNA oxidative damage (assessed by 8-OHdG) and protein oxidative damage (PCC) in bipolar patients in a manic phase was found. In addition, we found that serum GPx activity was significant lower in bipolar patients in a manic phase than in healthy subjects. Andreazza et al. (2007a) reported serum GPx activity was not significantly different in bipolar patients with a manic episode than in the controls. Therefore, serum GPx levels in bipolar patients in a manic phase also showed conflicting data. Taken together, these data suggest serum TBARS levels might be used as a state biomarker of oxidative stress in bipolar patients in a manic phase and in bipolar patients after treatment. The second finding of our study was that YMRS scores had a significantly positive association with serum CAT activity and PCC levels, and a negative association with serum GPx activity. However, SOD, TBARS and 8-OHdG were not significantly associated with YMRS scores. In our previous study, Positive and Negative Syndrome Scale (PANSS) total scores were significantly negatively

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Table 3 Medications used by the patients (n¼ 20). Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient

1 2 3 4 5 6 7 8 9 10

Drugs

Patient

Haloperidol 5 mg þ lithium 900 mg Olanzapine 20 mg þlithium 900 mg Risperidone 3 mg þ lithium 1200 mg Risperidone 4 mg þ valproate 1000 mg Haloperidol 5 mg þvalproate 1200 mg Risperidone 3 mg þ lithium 900 mg Valproate 1000 mg Risperidone 3 mg þ lithium 1200 mg Olanzapine 20 mg þvalproate 1000 mg Risperidone 3 mg þ lithium 1200 mg

Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient

Drugs 11 12 13 14 15 16 17 18 19 20

Aripiprazole 15 mg þ valproate 400 mg Clozapine 50 mg þvalproate 1000 mg Paliperidone 3 mgþ valproate 1200 mg Risperidone long-acting injection (Risperdal Consta) 37.5 mg þLithium 600 mg Aripiprazole 15 mg þ lithium 600 mg Risperidone 3 mg Valproate 1000 mg Risperidone 4 mg þ lithium 600 mg Risperidone long-acting injection (Risperdal Consta) 25 mg þ lithium 600 mg Risperidone 6 mg þ valproate 1200 mg

Table 4 Mean changes in serum oxidative-stress markers after treatment. Variable (n ¼20)

SOD (U/ml)

CAT (nmol/min/ml)

GPx (nmol/min/ml)

TBARS (μmol/l)

PCC (μmol/l)

8-OHdG (pg/ml)

YMRS scores

Baseline Endpoint p Value

1.9 7 0.6 2.3 7 1.2 0.114

214.2 7 364.7 101.5 7 206.2 0.262

195.9 7 41.4 191.4 7 36.7 0.436

10.17 5.3 7.5 7 1.8 0.019*

0.6 7 0.2 0.7 7 0.3 0.185

45077 4207 4107 72695 0.395

35.377.3 3.2 7 2.9 o 0.001

Plus–minus values are given as mean 7standard deviation. Abbreviation: SOD ¼ superoxide dismutase; CAT ¼ catalase; GPx¼ glutathione peroxidase; TBARS¼ thiobarbituric acid reactive substances; PCC ¼protein carbonyl content; 8-OHdG ¼ 8-hydroxy 20 -deoxyguanosine; YMRS ¼Young Mania Rating Scale. n

po 0.05.

associated with serum GPx activity, and positively associated with serum SOD activity in schizophrenic patients in an acute phase (Tsai et al., 2013). In our review of the literature, we found no previous study that compared the relationship between YMRS scores and oxidative stress markers. Moreover, our results might suggest that CAT, GPx and PCC are indicators of the severity of bipolar patients in a manic phase. However, our sample size was limited and larger sample sizes are needed to confirm our findings. The third finding of our study was the significant decrease in serum TBARS levels in manic patients who had received treatment, but no significant changes were seen in serum SOD, CAT, GPx, TBARS PCC and 8-OHdG levels or activities. Ozcan et al. (2004) reported that CAT levels, GPx activity and MDA levels (markers of lipid peroxidation) showed significant changes in bipolar patients who had received treatment. In a report of two monozygotic bipolar twins during a manic episode, TBARS and SOD levels were normalized after 6-week treatment, but there were no significant changes in CAT and DNA damage (Frey et al., 2007). Bipolar patients treated with lithium during a manic episode showed a significant decrease in the SOD/CAT ratio (Machado-Vieira et al., 2007). Several factors might account for the controversial data. Different drugs might affect oxidative stress. For example, a healthy subject with 2–4 weeks of lithium treatment had a significant reduction in the SOD/CAT ratio (Khairova et al., 2012). In an animal study of mania, rats with lithium or valproate treatment could modulate SOD and CAT activities (Jornada et al., 2011). In another animal study of mania, SOD, CAT, and TABRS levels in rats with lithium or valproate treatment had different changes and DNA damage was positively associated with lipid peroxidation (Andreazza et al., 2008b). In addition, our patients received different antipsychotic drugs combined with lithium or valproate. Different antipsychotics might have different influences on oxidative stress-related markers in schizophrenic patients receiving 4-week, 12-week or long-term treatment (Zhang et al., 2006, 2012; Huang et al., 2010). Decreased SOD activity and elevated lipid oxidation was seen in the brains of rats after haloperidol treatment, but not with risperidone, olanzapine or clozapine (Parikh et al., 2003). In another report, oxidative damage was found in rats with haloperidol or clozapine treatment, but not in rats with clozapine treatment (Reinke et al., 2004). Thus, different antipsychotic drugs, such as lithium and valproate, could affect free radical

metabolism. Therefore, future studies should investigate the relationship between oxidative stress-related markers and anti-manic drugs. There were several limitations in our study. First, heterogeneous mood stabilizers and antipsychotic drugs could have affected the results (Yao and Keshavan, 2011). Second, different blood samples (red blood cell, plasma or serum) of measuring oxidative stress markers may have caused some discrepancies. Third, age, food and smoking might also affect oxidative stress markers and could have influenced the results (Massudi et al., 2012; Faizal et al., 2013; Benzie and Choi, 2014). Fourth, our study lacked data on different gender groups. Gender might influence oxidative stress markers (Veglia et al., 2006; Vassalle et al., 2011; Wiener et al., 2014), since gender might be associated with testosterone and estrogens, which can affect oxidative stress (Bokov et al., 2009; Numakawa et al., 2011; Jia et al., 2012; Holmes et al., 2013). Future studies should include larger samples, age, male and female groups, and testosterone and estrogen levels to investigate the differences in oxidative stress markers and to confirm these findings. In conclusion, we found serum TBARS levels in bipolar patients in a manic phase were significantly higher than in healthy subjects. In addition, decreased TBARS levels were significant in bipolar patients in a manic phase after treatment. Therefore, serum TBARS levels might be a state biomarker of oxidative stress in bipolar patients in a manic phase and after treatment. Furthermore, GPx activity was significantly negatively associated with YMRS scores, and was significantly lower in bipolar patients in a manic phase than in healthy subjects. Therefore, GPx deficit might be a trait biomarker of severity of mania.

Role of the funding source We did not obtain financial support from any drug company.

Conflict of interest None.

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Contributors Huang TL and Tsai MC conceptualized and designed the study, and formulated the hypotheses and analytical strategies. Tsai MC wrote the manuscript. All authors contributed to and have approved the final manuscript. Acknowledgments This work was supported by grants from Chang Gung Memorial Hospital in Taiwan (research number: CMRPG8B0511) provided to Tsai MC.

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Thiobarbituric acid reactive substances (TBARS) is a state biomarker of oxidative stress in bipolar patients in a manic phase.

Oxidative stress may contribute to the pathophysiology of bipolar disorder. The aim of this study was to investigate the serum levels or activities of...
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