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Oxidative imbalance in bipolar disorder subtypes: A comparative study
Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 1070–1074
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Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p n p
Oxidative imbalance in bipolar disorder subtypes: A comparative study Mehmet Yumru a, Haluk A. Savas a,⁎, Aysun Kalenderoglu a, Mahmut Bulut a, Hakim Celik b, Ozcan Erel b a b
Psychiatry Department, Gaziantep University, Medical Faculty, Gaziantep, Turkey Biochemistry Department, Harran University, Medical Faculty, Sanliurfa, Turkey
a r t i c l e
i n f o
Article history: Received 18 November 2008 Received in revised form 6 June 2009 Accepted 6 June 2009 Available online 12 June 2009 Keywords: Bipolar disorder Oxidative stress Total antioxidant status Total oxidant status
a b s t r a c t Objective: The oxidants are related with the membrane-associated pathologies in the central nervous system and may have an important role in neuropsychiatric disorders. Several studies were performed on the effects of free radicals in bipolar disorder. However, there are no studies investigating the effects of free radicals both in the subtypes of BD (Bipolar disorders I and II) and in antidepressant induced mania (AIM). In this study, we aimed to investigate the status of oxidative metabolism in BD and its subtypes. Methods: 94 bipolar patients (BD I–II and AIM) diagnosed according to DSM IV and as control group 41 healthy subjects were included to the study. The total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI) were examined in the properly obtained plasma samples of subjects and healthy controls included in the study. Results: The patients' TAS, TOS and OSI were significantly higher than the controls. TAS is negatively correlated with the number of previous total episodes in BD I. The BD I group appeared to have higher TOS compared to BD II group. Conclusions: Oxidative balance is impaired in bipolar disorder. Antioxidant levels may be increased compensatorily in response to increased oxidant levels. Another important result of our study was that in the comparison of the three disease subtypes BD I group was found to have higher TOS compared to the BD II group. This finding is compatible with the literature on BD I and may be associated with the more severe course of BD I. © 2009 Elsevier Inc. All rights reserved.
1. Introduction Oxidative stress is an excessive exposure to oxidants and/or reduction in antioxidant capacity. In biological systems atoms or molecules that contain one or more unshared electrons are called “oxidants” or “free radicals”. The oxidants impair the cell structure, extracellular matrix, cilia functions and the genetic structure by causing DNA damage (Guemouri et al., 1991). The body has developed several defense mechanisms to prevent the formation of free radicals and the damage they cause. Free radicals have a role in the pathogenesis of several diseases including atherosclerosis, neurodegenerative diseases, cancer, allergy, diabetes and cataract and therefore are one of the most studied topics (Guemouri et al., 1991). Our studies on the role of oxidative stress in the course and treatment of psychiatric disorders demonstrated that oxidative balance is impaired in schizophrenia, autistic disorder, bipolar disorder, depression, panic disorder and adult attention deficit-hyperactivity disorder; in certain diseases this imbalance persisted even during remission. This imbalance
Abbreviation: BD, Bipolar Disorder; AIM, Antidepressant induced mania; TOS, Total oxidant status; TAS, Total antioxidant status; OSI, Oxidative stress index; CGI, Clinical global impression; NO, Nitric oxide, SOD, Superoxide dismutase. ⁎ Corresponding author. Tel.: +90 342 3606060. E-mail address: [email protected] (H.A. Savas). 0278-5846/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2009.06.005
is associated with some specific signs and in certain diseases it improves with treatment (Gergerlioglu et al., 2007; Herken et al., 2006; Kuloglu et al., 2002a; Savas et al., 2006; Selek et al., 2008a; Sogut et al., 2003; Yanik et al., 2003). There are various assumptions as to how this impairment emerges. For instance, the oxidants may react with the membrane-associated proteins and impair enzymes or uptake of neurotransmitters involved in the normal process leading to a tendency to develop the disease. The oxidants are related with the membrane-associated pathologies in the central nervous system and may have an important role in neuropsychiatric disorders (Berk et al., 2008a; Kuloglu et al., 2002a; Ng et al., 2008). Some of the specific oxidants may lead to “adverse” increases in other components of the metabolism which may lead to specific symptoms of psychiatric disorders. For instance, the increased nitric oxide levels may lead to such an effect via the glutamate pathway in manic patients presenting with the psychotic symptom as delusion (Gergerlioglu et al., 2007). Also, N-acetyl cysteine (orally bioavailable precursor of glutathione) was found to be an effective augmentation strategy for depressive symptoms in bipolar disorder (Berk et al., 2008b). According to the results of these studies, there exists an impaired oxidative balance in psychiatric disorders. In certain diseases, this impairment may improve even with clinical response to treatment, whereas the oxidative imbalance persists in moderate or severe
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psychiatric disorders. The information regarding oxidative imbalance still does not explain the entire psychiatric pictures; however, they do enlighten some certain topics including the presence of alternative treatment, more specific monitorisation of treatment response with biological markers and screening of specific markers in plasma samples. Several studies were performed on the effects of free radicals in bipolar disorder (BD) (Gergerlioglu et al., 2007; Hoekstra et al., 2006; Sadeghipour et al., 2007; Savas et al., 2006; Selek et al., 2008a). Recently published meta analysis has shown oxidative stress markers may play a role in the pathophysiology of bipolar disorder (Andreazza et al., 2008). However, there are no studies investigating the effects of free radicals both in the subtypes of BD (Bipolar disorders I and II) and in antidepressant induced mania (AIM). AIM is classified as “BD III” by some authors (Akiskal and Pinto, 1999). Comparison of oxidative metabolism in the subtypes of BD, may prove its result in the clinical appearance between subtypes showing the biological sign of differentiation. In this study, we aimed to investigate the status of oxidative metabolism in BD and its subtypes. 2. Method 2.1. Subjects The study population consisted of 94 patients who referred to the Mood Disorders Unit of Gaziantep University Department of Psychiatry between the dates of 15.11.2006–15.05.2007 and met the inclusion and exclusion criteria of the study. The control group is formed of 41 healthy subjects who were chosen among the doctors and hospital staff. The inclusion criteria of the study included euthymic patients diagnosed with bipolar disease according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition, (DSM IV) (American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 2004) and a control group without any present or previous psychiatric disorder. BD I was accepted with at least one or more manic/mixed episodes. Major depressive episodes with spontaneous hypomania were assigned to BD II. AIMs were accepted when all the following criteria were met: 1. Antidepressant use for at least 3 days in the last 2 weeks, 2. Onset of symptoms within 16 weeks after beginning antidepressants (Tamada et al., 2004). The exclusion criteria were: Patients having concomitant psychiatric or other medical diseases in the non-euthymic episode of the bipolar disease, hypertension, diabetes or other serious medical conditions including endocrinopathies, patients with or have history of alcohol and/or substance abuse, and patients that receive any antioxidant agents (e.g. vitamin E and C). Seventeen patients were excluded for not conforming to the exclusion criteria. Among the 314 patients registered to the Mood Disorders Unit, 94 euthymic patients who had received a diagnosis of bipolar disease and attended a visit at the clinic between the above stated dates were included. Patients were evaluated by a psychiatrist (MY) according to the DSM IV criteria. All patient records in the Mood Disorders observation form were examined; sociodemographic parameters including age and sex and concomitant diseases and present medications as well as smoking status were noted. Clinical global impression (CGI) Scale (Guy, 1976), Young mania rating scale (YMRS) (Young et al., 1978) and Hamilton depression rating scale (Ham-D) (Hamilton, 1960) were applied to patients to determine disease severity. All of the patients were euthymic for at least 2 months, as confirmed by a HAM-D b8, YMRS b6 and CGI equal or less than 2. The control group included healthy and volunteer 41 persons from hospital staff. The sociodemographic parameters including age and sex as well as smoking status of them were also noted. The control group consisted of individuals who had no history of medication or non-medication drug use in the last 6 weeks and no history or family history of psychiatric disorders.
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Ethics committee approval was obtained for the study. Written informed consent was obtained from all participants. 2.2. Instrument 2.2.1. Gaziantep mood disorders observation form Mood Disorders Unit of the Gaziantep University Department of Psychiatry is a clinic that follows up and treats patients with mood disorders on one day of the week since 2000. Each patient receives routine follow-up at this unit and side effect scales as well as Gaziantep Mood Disorders Observation Form are used to record the height, weight and laboratory results. Data regarding the patients were obtained via this form. 2.3. Biochemical analysis Blood samples of the patient and control groups were drawn from the antecubital vein following a 12-h period of fasting. The blood samples were transferred to tubes and in the presence of ice their plasma were separated by centrifuging at 3000 rpm for 5 min to be in process within 6 h. The plasma were stored at − 80 °C for determination of the total antioxidants status (TAS) and total oxidants status (TOS). TAS and TOS were measured and oxidative stress index (OSI) was calculated in the Biochemistry Laboratory of Harran University. 2.3.1. Measurement of total antioxidant status (TAS) This is a full-automatic method designed by Erel et al. (2004a) and measures the total antioxidant capacity of the body against powerful free radicals. Fe2+-o-dianisidine complex gives a Fenton type reaction with the hydrogen peroxide to form the OH radical. This powerful reactive oxygen species reacts with the colorless o-dianisidine molecule at the reducting low pH and leads to the formation of yellow–brown dianisidyl radicals. Dianisidyl radicals participate in further oxidation reactions resulting in more color formation. However, antioxidants in the samples suppress these oxidation reactions and inhibit color formation. This reaction is measured spectrophotometrically in automatic analysers ( Erel, 2004b). 2.3.2. Measurement of total oxidant status (TOS) This is a full-automatic colorimetric method developed by Erel et al. (2005). The oxidants in the sample oxidize the ferrous ion-odianisidine complex to ferric ion. The glycerol in the media accelerates this reaction about three fold. Ferric ions form a colored compound with xylenol orange in the acidic media. This color is associated with the amount of oxidant in the sample and is measured spectrophotometrically (Erel, 2005). 2.3.3. Calculation of the oxidative stress index (OSI) Oxidative stress index (OSI) was calculated by dividing the total oxidants status (TOS) with the total antioxidants status (TAS) (Kosecik et al., 2005). 2.4. Apparatus A Cecil 3000 spectrophotometer with a temperature controlled cuvette holder (Cecil) and an Aeroset automated analyzer (Abbott) were used (Erel, 2004a). 2.5. Statistical analysis SPSS (Statistical Package for Social Sciences) for Windows 13.0 was used to perform the statistical analysis and p b 0.05 was considered statistically significant. The Chi-Square test was used for the comparison of parameters with two variables such as sex and in ratios. The
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Table 1 The sociodemographic and clinical features of the patient and control groups. Patient
Control
BD I
BD II
AIM
N (%)
N (%)
N (%)
Sex Male Female Total
22 (48.9) 23 (51.1) 45 (100)
5 (22.7) 17 (77.3) 22 (100)
14 (51.9) 13 (48.1) 27 (100)
41 (43.6) 53 (56.4) 94 (100)
p N 0.05
Occupation Employed Unemployed
17 (37.8) 28 (62.2)
5 (22.7) 17 (77.3)
12 (44.4) 15 (55.6)
34 (36.2) 60 (63.8)
p N 0.05
Family history Yes No
11 (24.4) 34 (75.6)
4 (18.2) 18 (81.8)
7 (25.9) 20 (74.1)
22 (23.4) 72 (76.6)
p N 0.05
Smoking status Yes No
Statistic
Total N (%) 22 (53.7) 19 (46.3) 41 (100)
χ2 = 1.1, p = 0.34
20 (21.3) 74 (78.7)
9 (22.0) 32 (78.0)
χ2 = 0.0, p = 1.00
31.4 ± 7.1
31.0 ± 11.1
p N 0.05
Mean ± SD Age 31.0 ± 6.3
31.5 ± 6.8
31.8 ± 8.6
4.9 ± 3.5
4.6 ± 2.4
1.2 ± 0.5
p b 0.01
24.2 ± 6.6
25.8 ± 6.4
30.8 ± 8.6
p b 0.01
Number of episodes Age of onset BD: Bipolar disorder. AIM: Antidepressant induced mania. SD: Standard deviation.
parameters were assumed to have a normal distribution and the student's t-test was used to evaluate the difference between the groups, and ANOVA and post-hoc analysis were used as LSD. Pearson's relation analysis was performed to evaluate the relationship between the variables. Multiple linear regression analysis was performed to evaluate the relationship between biochemical and multiple clinical variables (such as age, sex, and age of onset). 3. Results 3.1. Sociodemographic and clinical data Summaries of the sociodemographic and clinical features of the patient and control groups are presented in Table 1. No significant differences were determined between the two groups in terms of sociodemographic data. The total number of episodes was 3.8 ± 3.1 and the mean age of disease onset was 26.5 ± 7.6 years in the patient group. In the AIM
Fig. 1. Total antioxidants status in patient and control groups (µmol Trolox Eqv./L). TAS: Total antioxidant status. BD: Bipolar disorder. AIM: Antidepressant induced mania. ⁎p b 0.05. ⁎⁎p N 0.05.
group, the number of episodes was lower than the other patient groups (BD I-II) (p b 0.05). However, the age of disease onset was found to be statistically significantly higher than the other patient groups (p b 0.05). 3.2. Oxidative data The oxidative parameters of the patient and control groups are given in Figs. 1 and 2. The TAS of the patient group was found to be statistically significantly higher than that of the control group (t = 35.7, p b 0.01) (Fig. 1). In the patient group, the total level of oxidants were also higher than those of the control group (t = 4.3, p b 0.01) (Fig. 2). OSI values were significantly higher in the patient group compared to the control group (t = 3.2, p b 0.01). Plasma oxidative parameters and OSI values between the disease subtypes showed that there were no significant differences among the three groups of diagnosis in terms of TAS, TOS and OSI (F = 0.48, p N 0.05, F = 2.62, p N 0.05, F = 2.13, p N 0.05). The post-hoc analysis revealed that BD I and BD II differed significantly in terms of TOS. The
Fig. 2. Total oxidant status in patient and control groups (µmol H2O2 Eqv./L). TOS: Total oxidant status. BD: Bipolar disorder. AIM: Antidepressant induced mania. ⁎p b 0.05. ⁎⁎p N 0.05.
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BD I group appeared to have higher TOS compared to BD II group (p = 0.03). No relations were determined in the patient group between TAS, TOS and OSI values, the number of episodes, and age of onset. The comparison of disease subtypes and control groups separately is as follows: BD I-control: The two groups did not differ in terms of age, sex and smoking status. The BD I group had significantly higher TAS, TOS and OSI (t = 32.6, p b 0.01; t = 4.7, p b 0.01; t = 3.8, p b 0.01). In addition, a negative relationship was determined between the number of episodes and TAS in BD I (r = 0.37, p = 0.01). In other words, in BD I, TAS reduces as the number of episodes increases. BD II-control: There were more females in the BD II group compared to the control group (a2 = 5.5, df = 1, p = 0.03). There were no significant differences between the groups in terms of age (t = 0.2, p N 0.05). TAS was found to be significantly higher in the BD II group compared to the control group (t = 25.9, p b 0.01). The two groups did not differ significantly in terms of TOS and OSI. The oxidative parameters and clinical features also were not associated in the BD II group. Antidepressant induced mania-control: The two groups did not differ in terms of age, sex and smoking status. The AIM group had significantly higher TAS, TOS and OSI (t = 26.0, p b 0.01; t = 5.3, p b 0.01; t = 4.2, p b 0.01). The oxidative parameters and clinical features were not associated in the AIM group. 4. Discussion Although the distribution of sex by subtypes in the patients' group revealed more females in BD II group, no significant differences were observed between the three groups in terms of sex. Although statistically not significant, the fact that there were more female patients in BD II seems to comply with the literature (Akiskal and Pinto, 1999). The number of episodes was lower and age of disease onset was higher in the group of AIM. This may be associated with the delayed establishment of diagnosis in AIM. One of the most important findings of the study is that TOS is higher in the BD patients compared to the control group. There are several studies that have shown increased levels of oxidants in psychiatric diseases (Sogut et al., 2003; Zoroglu et al., 2003). In recent studies performed in our clinic, NO and malondialdehyde (MDA) were found to be increased in adult attention deficit and hyperactivity disorders (Bulut et al., 2008; Selek et al., 2008b. In another study performed recently in our clinic however, patients with panic disorder were found to have higher NO levels, though statistically not significant. The higher NO levels in the study decreased significantly with antidepressant therapy (Herken et al., 2006). Similar findings were also obtained in our study performed on patients with major depression (Herken et al., 2007). In another study of ours on patients with schizophrenia, NO and adrenomedullin levels were found to be higher compared to the control group (Zoroglu et al., 2002). One study demonstrated that the NO metabolite nitrite was higher in schizophrenia patients (Yanik et al., 2003). Several studies in our clinic have also been performed on BD. In the first study of our clinic on this topic, BD patients in manic episode were found to have higher NO levels compared to the control group (Savas et al., 2002). Again in BD I, another study performed on patients in manic episode revealed higher NO levels. This study indicates that the arginine-NO pathway might have a role in the pathogenesis of BD (Yanik et al., 2004a). In a recent study of ours on the three different episodes of BD, increased NO levels were determined in the euthymic, manic and depressive episodes (Gergerlioglu et al., 2007; Savas et al., 2006; Selek et al., 2008a). In our study regarding the bipolar depressive episode, it was observed that the increased NO levels decrease to normal after the treatment (Selek et al., 2008a). In another
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study, NO levels were also found to be increased, though not significantly, and they reduced with treatment in major depressive disorder (Herken et al., 2007). Other studies in literature on BD and antioxidants focus more on BD I. In this study, TOS were found to be higher in the patient group consisting of BDs I and II and AIM patients compared to the control group. In the comparison of BD subtypes individually with the control group, however, patients with BD I and AIM were found to have higher TOS whereas no differences were determined for patients with BD II. To our knowledge, there are no studies in the literature investigating the oxidant levels in BD II and AIM. Another important result of our study was that in the comparison of the three disease subtypes BD I group was found to have higher TOS compared to the BD II group. This finding may be associated with the more severe course of BD I. In our study, no relationship was found between the BD subtypes and the number of previous episodes and TOS. However, in our previous study on BD I euthymic patients, we had found a positive correlation between NO levels and number of previous episodes (Savas et al., 2006). The causal relationship between psychiatric disorders and increased oxidants is yet unclear. It is not known whether the increased oxidants cause psychiatric disorders or psychiatric disorders lead to increases in oxidants. However, the presence of signs of oxidative stress even in the euthymic episodes of BD and the reduction in the level of oxidants with treatment in some psychiatric disorder suggest that oxidants may lead to psychiatric disorders (Herken et al., 2006; Savas et al., 2006; Yanik et al., 2003). The second result of the study is the increased antioxidant levels. Similarly to studies on oxidants, studies on psychiatric disorders also included various investigations regarding specific antioxidants. In schizophrenia, the antioxidant superoxide dismutase (SOD) was found to be increased in drug-free period and decreased with treatment (Yao et al., 1998; Yu et al., 2003). In one study performed on patients with attention deficit-hyperactivity disorder, SOD was found to be decreased (Selek et al., 2008b). In the study by Kuloglu et al. (2002c), patients with BD and schizophrenia were observed to have increased SOD levels. Studies performed on BD I patients reported decreased SOD levels during the depressive episode, normalized even if it increased with treatment, whereas it was demonstrated to increase in the euthymic and manic episodes. Authors have interpreted the increased SOD in euthymic and manic episodes as a reactive increase (Savas et al., 2006; Selek et al., 2008a). In another study the authors had found increased SOD levels during depressive and manic episodes (Kunz et al., 2008). In our study, the increased TAS in BD compared to the control is possibly a response of the body to increased oxidants. In the comparison of the BD subtypes with the controls, however, all subtypes were found to have higher TAS. To our knowledge there are no studies in the literature investigating the antioxidant levels in BD II and AIM. Our findings regarding BD I seemed compatible with the literature (Savas et al., 2006; Gergerlioglu et al., 2007). There was no significant difference in TAS levels among the subtypes in patients group. This finding suggests no different patterns of antioxidative system among the subtypes. In addition, a negative correlation was determined between the total number of episodes in BD I and TAS. This means that in BD I, TAS decreases with the increasing number of episodes. Similarly, another recently published study has shown that previous number of manic episodes and levels of the antioxidant SOD were inversely correlated in patients with BD I (Gergerlioglu et al., 2007). These results may indicate that the oxidative balance may shift towards oxidants in the long term. The third result of our study was the increased OSI in patients with BD. OSI is an index obtained by dividing TOS with TAS and is used as a parameter for evaluation of the oxidative stress (Kuloglu et al., 2002a,b). Both antioxidant–oxidant sides of the oxidative metabolism may be assessed with OSI and antioxidants and oxidants may be compared. Despite the compensatory increase to balance the antioxidants, the increased OSI levels compared to the controls indicate the impairment of
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the system in favor of oxidants. The compensatory increase in TAS cannot balance the metabolism. There is an overt oxidative stress in BD and internal regulatory mechanisms are inadequate to balance the oxidative stress. However, Yanik et al. (2004b) performed a similar study with biochemical design in major depression and found that oxidant levels were reduced whereas OSI was increased. Two recently published studies have also shown that oxidative stress is increased in BD (Frey et al., 2007; Machado-Vieira et al., 2007). In this study, our findings regarding OSI comply with those of the previous oxidative stress studies in BD. The limitation of our study occurs by the result of ignoring the effects of the mood stabilizators and other drugs about oxidative balance. However, the most important feature of our study is that it is the first study comparing BD subtypes with the control group separately and as a whole. 5. Conclusion As a conclusion, there is a gradual increase in oxidants in BD; however, the compensatory increase in antioxidants is not enough to maintain the balance. The resulting oxidative stress leads to impairments in various cellular structural elements and functional compounds which are thought to play an important role in the development of the disease. References Akiskal HS, Pinto O. The evolving bipolar spectrum. Prototypes I, II, III, and IV. Psychiatr Clin North Am 1999;22:517–34. Andreazza AC, Kauer-Sant'anna M, Frey BN, Bond DJ, Kapczinski F, Young LT, et al. Oxidative stress markers in bipolar disorder: a meta-analysis. J Affect Disord 2008;111:135–44. American Psychiatric Association: Diagnostic and statistical manual of mental disorders 4th edition, 2004. American Psychiatric Association, Washington D.C. Berk M, Ng F, Dean O, Dodd S, Bush AI. Glutathione: a novel treatment target in psychiatry. Trends Pharmacol Sci 2008a;29:346–51. Berk M, Copolov DL, Dean O, Lu K, Jeavons S, Schapkaitz I, et al. N-acetyl cysteine for depressive symptoms in bipolar disorder—a double-blind randomized placebocontrolled trial. Biol Psychiatry 2008b;64:468–75. Bulut M, Selek S, Gergerlioglu HS, Savas HA, Yilmaz HR, Yuce M, et al. Malondialdehyde levels in adult attention-deficit hyperactivity disorder. J Psychiatry Neurosci 2008;32: 435–8. Erel O. A novel automated method to measure total antioxidant response against potent free radical reactions. Clin Biochem 2004a;37:112–9. Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem 2004b;37: 277–85. Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem 2005;38:1103–11. Frey BN, Andreazza AC, Kunz M, Gomes FA, Quevedo J, Salvador M, Goncalves CA, Kapczinski F, et al. Increased oxidative stress and DNA damage in bipolar disorder: a twin-case report. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:283–5. Gergerlioglu HS, Savas HA, Bulbul F, Selek S, Uz E, Yumru M. Changes in nitric oxide level and superoxide dismutase activity during antimanic treatment. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:697–702. Guemouri L, Artur Y, Herbeth B, Jeandel C, Cuny G, Siest G. Biological variability of superoxide dismutase, glutathione peroxidase and catalase in blood. Clin Chem 1991;37: 1932–7. Guy W. Assessment Manual for Psychopharmacology — Revised. Rockville, MD, U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, NIMH Psychopharmacology Research Branch, Division of Extramural Research Programs; 1976. p. 218–22.
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Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p n p
Oxidative imbalance in bipolar disorder subtypes: A comparative study Mehmet Yumru a, Haluk A. Savas a,⁎, Aysun Kalenderoglu a, Mahmut Bulut a, Hakim Celik b, Ozcan Erel b a b
Psychiatry Department, Gaziantep University, Medical Faculty, Gaziantep, Turkey Biochemistry Department, Harran University, Medical Faculty, Sanliurfa, Turkey
a r t i c l e
i n f o
Article history: Received 18 November 2008 Received in revised form 6 June 2009 Accepted 6 June 2009 Available online 12 June 2009 Keywords: Bipolar disorder Oxidative stress Total antioxidant status Total oxidant status
a b s t r a c t Objective: The oxidants are related with the membrane-associated pathologies in the central nervous system and may have an important role in neuropsychiatric disorders. Several studies were performed on the effects of free radicals in bipolar disorder. However, there are no studies investigating the effects of free radicals both in the subtypes of BD (Bipolar disorders I and II) and in antidepressant induced mania (AIM). In this study, we aimed to investigate the status of oxidative metabolism in BD and its subtypes. Methods: 94 bipolar patients (BD I–II and AIM) diagnosed according to DSM IV and as control group 41 healthy subjects were included to the study. The total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI) were examined in the properly obtained plasma samples of subjects and healthy controls included in the study. Results: The patients' TAS, TOS and OSI were significantly higher than the controls. TAS is negatively correlated with the number of previous total episodes in BD I. The BD I group appeared to have higher TOS compared to BD II group. Conclusions: Oxidative balance is impaired in bipolar disorder. Antioxidant levels may be increased compensatorily in response to increased oxidant levels. Another important result of our study was that in the comparison of the three disease subtypes BD I group was found to have higher TOS compared to the BD II group. This finding is compatible with the literature on BD I and may be associated with the more severe course of BD I. © 2009 Elsevier Inc. All rights reserved.
1. Introduction Oxidative stress is an excessive exposure to oxidants and/or reduction in antioxidant capacity. In biological systems atoms or molecules that contain one or more unshared electrons are called “oxidants” or “free radicals”. The oxidants impair the cell structure, extracellular matrix, cilia functions and the genetic structure by causing DNA damage (Guemouri et al., 1991). The body has developed several defense mechanisms to prevent the formation of free radicals and the damage they cause. Free radicals have a role in the pathogenesis of several diseases including atherosclerosis, neurodegenerative diseases, cancer, allergy, diabetes and cataract and therefore are one of the most studied topics (Guemouri et al., 1991). Our studies on the role of oxidative stress in the course and treatment of psychiatric disorders demonstrated that oxidative balance is impaired in schizophrenia, autistic disorder, bipolar disorder, depression, panic disorder and adult attention deficit-hyperactivity disorder; in certain diseases this imbalance persisted even during remission. This imbalance
Abbreviation: BD, Bipolar Disorder; AIM, Antidepressant induced mania; TOS, Total oxidant status; TAS, Total antioxidant status; OSI, Oxidative stress index; CGI, Clinical global impression; NO, Nitric oxide, SOD, Superoxide dismutase. ⁎ Corresponding author. Tel.: +90 342 3606060. E-mail address: [email protected] (H.A. Savas). 0278-5846/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2009.06.005
is associated with some specific signs and in certain diseases it improves with treatment (Gergerlioglu et al., 2007; Herken et al., 2006; Kuloglu et al., 2002a; Savas et al., 2006; Selek et al., 2008a; Sogut et al., 2003; Yanik et al., 2003). There are various assumptions as to how this impairment emerges. For instance, the oxidants may react with the membrane-associated proteins and impair enzymes or uptake of neurotransmitters involved in the normal process leading to a tendency to develop the disease. The oxidants are related with the membrane-associated pathologies in the central nervous system and may have an important role in neuropsychiatric disorders (Berk et al., 2008a; Kuloglu et al., 2002a; Ng et al., 2008). Some of the specific oxidants may lead to “adverse” increases in other components of the metabolism which may lead to specific symptoms of psychiatric disorders. For instance, the increased nitric oxide levels may lead to such an effect via the glutamate pathway in manic patients presenting with the psychotic symptom as delusion (Gergerlioglu et al., 2007). Also, N-acetyl cysteine (orally bioavailable precursor of glutathione) was found to be an effective augmentation strategy for depressive symptoms in bipolar disorder (Berk et al., 2008b). According to the results of these studies, there exists an impaired oxidative balance in psychiatric disorders. In certain diseases, this impairment may improve even with clinical response to treatment, whereas the oxidative imbalance persists in moderate or severe
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psychiatric disorders. The information regarding oxidative imbalance still does not explain the entire psychiatric pictures; however, they do enlighten some certain topics including the presence of alternative treatment, more specific monitorisation of treatment response with biological markers and screening of specific markers in plasma samples. Several studies were performed on the effects of free radicals in bipolar disorder (BD) (Gergerlioglu et al., 2007; Hoekstra et al., 2006; Sadeghipour et al., 2007; Savas et al., 2006; Selek et al., 2008a). Recently published meta analysis has shown oxidative stress markers may play a role in the pathophysiology of bipolar disorder (Andreazza et al., 2008). However, there are no studies investigating the effects of free radicals both in the subtypes of BD (Bipolar disorders I and II) and in antidepressant induced mania (AIM). AIM is classified as “BD III” by some authors (Akiskal and Pinto, 1999). Comparison of oxidative metabolism in the subtypes of BD, may prove its result in the clinical appearance between subtypes showing the biological sign of differentiation. In this study, we aimed to investigate the status of oxidative metabolism in BD and its subtypes. 2. Method 2.1. Subjects The study population consisted of 94 patients who referred to the Mood Disorders Unit of Gaziantep University Department of Psychiatry between the dates of 15.11.2006–15.05.2007 and met the inclusion and exclusion criteria of the study. The control group is formed of 41 healthy subjects who were chosen among the doctors and hospital staff. The inclusion criteria of the study included euthymic patients diagnosed with bipolar disease according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition, (DSM IV) (American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 2004) and a control group without any present or previous psychiatric disorder. BD I was accepted with at least one or more manic/mixed episodes. Major depressive episodes with spontaneous hypomania were assigned to BD II. AIMs were accepted when all the following criteria were met: 1. Antidepressant use for at least 3 days in the last 2 weeks, 2. Onset of symptoms within 16 weeks after beginning antidepressants (Tamada et al., 2004). The exclusion criteria were: Patients having concomitant psychiatric or other medical diseases in the non-euthymic episode of the bipolar disease, hypertension, diabetes or other serious medical conditions including endocrinopathies, patients with or have history of alcohol and/or substance abuse, and patients that receive any antioxidant agents (e.g. vitamin E and C). Seventeen patients were excluded for not conforming to the exclusion criteria. Among the 314 patients registered to the Mood Disorders Unit, 94 euthymic patients who had received a diagnosis of bipolar disease and attended a visit at the clinic between the above stated dates were included. Patients were evaluated by a psychiatrist (MY) according to the DSM IV criteria. All patient records in the Mood Disorders observation form were examined; sociodemographic parameters including age and sex and concomitant diseases and present medications as well as smoking status were noted. Clinical global impression (CGI) Scale (Guy, 1976), Young mania rating scale (YMRS) (Young et al., 1978) and Hamilton depression rating scale (Ham-D) (Hamilton, 1960) were applied to patients to determine disease severity. All of the patients were euthymic for at least 2 months, as confirmed by a HAM-D b8, YMRS b6 and CGI equal or less than 2. The control group included healthy and volunteer 41 persons from hospital staff. The sociodemographic parameters including age and sex as well as smoking status of them were also noted. The control group consisted of individuals who had no history of medication or non-medication drug use in the last 6 weeks and no history or family history of psychiatric disorders.
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Ethics committee approval was obtained for the study. Written informed consent was obtained from all participants. 2.2. Instrument 2.2.1. Gaziantep mood disorders observation form Mood Disorders Unit of the Gaziantep University Department of Psychiatry is a clinic that follows up and treats patients with mood disorders on one day of the week since 2000. Each patient receives routine follow-up at this unit and side effect scales as well as Gaziantep Mood Disorders Observation Form are used to record the height, weight and laboratory results. Data regarding the patients were obtained via this form. 2.3. Biochemical analysis Blood samples of the patient and control groups were drawn from the antecubital vein following a 12-h period of fasting. The blood samples were transferred to tubes and in the presence of ice their plasma were separated by centrifuging at 3000 rpm for 5 min to be in process within 6 h. The plasma were stored at − 80 °C for determination of the total antioxidants status (TAS) and total oxidants status (TOS). TAS and TOS were measured and oxidative stress index (OSI) was calculated in the Biochemistry Laboratory of Harran University. 2.3.1. Measurement of total antioxidant status (TAS) This is a full-automatic method designed by Erel et al. (2004a) and measures the total antioxidant capacity of the body against powerful free radicals. Fe2+-o-dianisidine complex gives a Fenton type reaction with the hydrogen peroxide to form the OH radical. This powerful reactive oxygen species reacts with the colorless o-dianisidine molecule at the reducting low pH and leads to the formation of yellow–brown dianisidyl radicals. Dianisidyl radicals participate in further oxidation reactions resulting in more color formation. However, antioxidants in the samples suppress these oxidation reactions and inhibit color formation. This reaction is measured spectrophotometrically in automatic analysers ( Erel, 2004b). 2.3.2. Measurement of total oxidant status (TOS) This is a full-automatic colorimetric method developed by Erel et al. (2005). The oxidants in the sample oxidize the ferrous ion-odianisidine complex to ferric ion. The glycerol in the media accelerates this reaction about three fold. Ferric ions form a colored compound with xylenol orange in the acidic media. This color is associated with the amount of oxidant in the sample and is measured spectrophotometrically (Erel, 2005). 2.3.3. Calculation of the oxidative stress index (OSI) Oxidative stress index (OSI) was calculated by dividing the total oxidants status (TOS) with the total antioxidants status (TAS) (Kosecik et al., 2005). 2.4. Apparatus A Cecil 3000 spectrophotometer with a temperature controlled cuvette holder (Cecil) and an Aeroset automated analyzer (Abbott) were used (Erel, 2004a). 2.5. Statistical analysis SPSS (Statistical Package for Social Sciences) for Windows 13.0 was used to perform the statistical analysis and p b 0.05 was considered statistically significant. The Chi-Square test was used for the comparison of parameters with two variables such as sex and in ratios. The
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Table 1 The sociodemographic and clinical features of the patient and control groups. Patient
Control
BD I
BD II
AIM
N (%)
N (%)
N (%)
Sex Male Female Total
22 (48.9) 23 (51.1) 45 (100)
5 (22.7) 17 (77.3) 22 (100)
14 (51.9) 13 (48.1) 27 (100)
41 (43.6) 53 (56.4) 94 (100)
p N 0.05
Occupation Employed Unemployed
17 (37.8) 28 (62.2)
5 (22.7) 17 (77.3)
12 (44.4) 15 (55.6)
34 (36.2) 60 (63.8)
p N 0.05
Family history Yes No
11 (24.4) 34 (75.6)
4 (18.2) 18 (81.8)
7 (25.9) 20 (74.1)
22 (23.4) 72 (76.6)
p N 0.05
Smoking status Yes No
Statistic
Total N (%) 22 (53.7) 19 (46.3) 41 (100)
χ2 = 1.1, p = 0.34
20 (21.3) 74 (78.7)
9 (22.0) 32 (78.0)
χ2 = 0.0, p = 1.00
31.4 ± 7.1
31.0 ± 11.1
p N 0.05
Mean ± SD Age 31.0 ± 6.3
31.5 ± 6.8
31.8 ± 8.6
4.9 ± 3.5
4.6 ± 2.4
1.2 ± 0.5
p b 0.01
24.2 ± 6.6
25.8 ± 6.4
30.8 ± 8.6
p b 0.01
Number of episodes Age of onset BD: Bipolar disorder. AIM: Antidepressant induced mania. SD: Standard deviation.
parameters were assumed to have a normal distribution and the student's t-test was used to evaluate the difference between the groups, and ANOVA and post-hoc analysis were used as LSD. Pearson's relation analysis was performed to evaluate the relationship between the variables. Multiple linear regression analysis was performed to evaluate the relationship between biochemical and multiple clinical variables (such as age, sex, and age of onset). 3. Results 3.1. Sociodemographic and clinical data Summaries of the sociodemographic and clinical features of the patient and control groups are presented in Table 1. No significant differences were determined between the two groups in terms of sociodemographic data. The total number of episodes was 3.8 ± 3.1 and the mean age of disease onset was 26.5 ± 7.6 years in the patient group. In the AIM
Fig. 1. Total antioxidants status in patient and control groups (µmol Trolox Eqv./L). TAS: Total antioxidant status. BD: Bipolar disorder. AIM: Antidepressant induced mania. ⁎p b 0.05. ⁎⁎p N 0.05.
group, the number of episodes was lower than the other patient groups (BD I-II) (p b 0.05). However, the age of disease onset was found to be statistically significantly higher than the other patient groups (p b 0.05). 3.2. Oxidative data The oxidative parameters of the patient and control groups are given in Figs. 1 and 2. The TAS of the patient group was found to be statistically significantly higher than that of the control group (t = 35.7, p b 0.01) (Fig. 1). In the patient group, the total level of oxidants were also higher than those of the control group (t = 4.3, p b 0.01) (Fig. 2). OSI values were significantly higher in the patient group compared to the control group (t = 3.2, p b 0.01). Plasma oxidative parameters and OSI values between the disease subtypes showed that there were no significant differences among the three groups of diagnosis in terms of TAS, TOS and OSI (F = 0.48, p N 0.05, F = 2.62, p N 0.05, F = 2.13, p N 0.05). The post-hoc analysis revealed that BD I and BD II differed significantly in terms of TOS. The
Fig. 2. Total oxidant status in patient and control groups (µmol H2O2 Eqv./L). TOS: Total oxidant status. BD: Bipolar disorder. AIM: Antidepressant induced mania. ⁎p b 0.05. ⁎⁎p N 0.05.
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BD I group appeared to have higher TOS compared to BD II group (p = 0.03). No relations were determined in the patient group between TAS, TOS and OSI values, the number of episodes, and age of onset. The comparison of disease subtypes and control groups separately is as follows: BD I-control: The two groups did not differ in terms of age, sex and smoking status. The BD I group had significantly higher TAS, TOS and OSI (t = 32.6, p b 0.01; t = 4.7, p b 0.01; t = 3.8, p b 0.01). In addition, a negative relationship was determined between the number of episodes and TAS in BD I (r = 0.37, p = 0.01). In other words, in BD I, TAS reduces as the number of episodes increases. BD II-control: There were more females in the BD II group compared to the control group (a2 = 5.5, df = 1, p = 0.03). There were no significant differences between the groups in terms of age (t = 0.2, p N 0.05). TAS was found to be significantly higher in the BD II group compared to the control group (t = 25.9, p b 0.01). The two groups did not differ significantly in terms of TOS and OSI. The oxidative parameters and clinical features also were not associated in the BD II group. Antidepressant induced mania-control: The two groups did not differ in terms of age, sex and smoking status. The AIM group had significantly higher TAS, TOS and OSI (t = 26.0, p b 0.01; t = 5.3, p b 0.01; t = 4.2, p b 0.01). The oxidative parameters and clinical features were not associated in the AIM group. 4. Discussion Although the distribution of sex by subtypes in the patients' group revealed more females in BD II group, no significant differences were observed between the three groups in terms of sex. Although statistically not significant, the fact that there were more female patients in BD II seems to comply with the literature (Akiskal and Pinto, 1999). The number of episodes was lower and age of disease onset was higher in the group of AIM. This may be associated with the delayed establishment of diagnosis in AIM. One of the most important findings of the study is that TOS is higher in the BD patients compared to the control group. There are several studies that have shown increased levels of oxidants in psychiatric diseases (Sogut et al., 2003; Zoroglu et al., 2003). In recent studies performed in our clinic, NO and malondialdehyde (MDA) were found to be increased in adult attention deficit and hyperactivity disorders (Bulut et al., 2008; Selek et al., 2008b. In another study performed recently in our clinic however, patients with panic disorder were found to have higher NO levels, though statistically not significant. The higher NO levels in the study decreased significantly with antidepressant therapy (Herken et al., 2006). Similar findings were also obtained in our study performed on patients with major depression (Herken et al., 2007). In another study of ours on patients with schizophrenia, NO and adrenomedullin levels were found to be higher compared to the control group (Zoroglu et al., 2002). One study demonstrated that the NO metabolite nitrite was higher in schizophrenia patients (Yanik et al., 2003). Several studies in our clinic have also been performed on BD. In the first study of our clinic on this topic, BD patients in manic episode were found to have higher NO levels compared to the control group (Savas et al., 2002). Again in BD I, another study performed on patients in manic episode revealed higher NO levels. This study indicates that the arginine-NO pathway might have a role in the pathogenesis of BD (Yanik et al., 2004a). In a recent study of ours on the three different episodes of BD, increased NO levels were determined in the euthymic, manic and depressive episodes (Gergerlioglu et al., 2007; Savas et al., 2006; Selek et al., 2008a). In our study regarding the bipolar depressive episode, it was observed that the increased NO levels decrease to normal after the treatment (Selek et al., 2008a). In another
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study, NO levels were also found to be increased, though not significantly, and they reduced with treatment in major depressive disorder (Herken et al., 2007). Other studies in literature on BD and antioxidants focus more on BD I. In this study, TOS were found to be higher in the patient group consisting of BDs I and II and AIM patients compared to the control group. In the comparison of BD subtypes individually with the control group, however, patients with BD I and AIM were found to have higher TOS whereas no differences were determined for patients with BD II. To our knowledge, there are no studies in the literature investigating the oxidant levels in BD II and AIM. Another important result of our study was that in the comparison of the three disease subtypes BD I group was found to have higher TOS compared to the BD II group. This finding may be associated with the more severe course of BD I. In our study, no relationship was found between the BD subtypes and the number of previous episodes and TOS. However, in our previous study on BD I euthymic patients, we had found a positive correlation between NO levels and number of previous episodes (Savas et al., 2006). The causal relationship between psychiatric disorders and increased oxidants is yet unclear. It is not known whether the increased oxidants cause psychiatric disorders or psychiatric disorders lead to increases in oxidants. However, the presence of signs of oxidative stress even in the euthymic episodes of BD and the reduction in the level of oxidants with treatment in some psychiatric disorder suggest that oxidants may lead to psychiatric disorders (Herken et al., 2006; Savas et al., 2006; Yanik et al., 2003). The second result of the study is the increased antioxidant levels. Similarly to studies on oxidants, studies on psychiatric disorders also included various investigations regarding specific antioxidants. In schizophrenia, the antioxidant superoxide dismutase (SOD) was found to be increased in drug-free period and decreased with treatment (Yao et al., 1998; Yu et al., 2003). In one study performed on patients with attention deficit-hyperactivity disorder, SOD was found to be decreased (Selek et al., 2008b). In the study by Kuloglu et al. (2002c), patients with BD and schizophrenia were observed to have increased SOD levels. Studies performed on BD I patients reported decreased SOD levels during the depressive episode, normalized even if it increased with treatment, whereas it was demonstrated to increase in the euthymic and manic episodes. Authors have interpreted the increased SOD in euthymic and manic episodes as a reactive increase (Savas et al., 2006; Selek et al., 2008a). In another study the authors had found increased SOD levels during depressive and manic episodes (Kunz et al., 2008). In our study, the increased TAS in BD compared to the control is possibly a response of the body to increased oxidants. In the comparison of the BD subtypes with the controls, however, all subtypes were found to have higher TAS. To our knowledge there are no studies in the literature investigating the antioxidant levels in BD II and AIM. Our findings regarding BD I seemed compatible with the literature (Savas et al., 2006; Gergerlioglu et al., 2007). There was no significant difference in TAS levels among the subtypes in patients group. This finding suggests no different patterns of antioxidative system among the subtypes. In addition, a negative correlation was determined between the total number of episodes in BD I and TAS. This means that in BD I, TAS decreases with the increasing number of episodes. Similarly, another recently published study has shown that previous number of manic episodes and levels of the antioxidant SOD were inversely correlated in patients with BD I (Gergerlioglu et al., 2007). These results may indicate that the oxidative balance may shift towards oxidants in the long term. The third result of our study was the increased OSI in patients with BD. OSI is an index obtained by dividing TOS with TAS and is used as a parameter for evaluation of the oxidative stress (Kuloglu et al., 2002a,b). Both antioxidant–oxidant sides of the oxidative metabolism may be assessed with OSI and antioxidants and oxidants may be compared. Despite the compensatory increase to balance the antioxidants, the increased OSI levels compared to the controls indicate the impairment of
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the system in favor of oxidants. The compensatory increase in TAS cannot balance the metabolism. There is an overt oxidative stress in BD and internal regulatory mechanisms are inadequate to balance the oxidative stress. However, Yanik et al. (2004b) performed a similar study with biochemical design in major depression and found that oxidant levels were reduced whereas OSI was increased. Two recently published studies have also shown that oxidative stress is increased in BD (Frey et al., 2007; Machado-Vieira et al., 2007). In this study, our findings regarding OSI comply with those of the previous oxidative stress studies in BD. The limitation of our study occurs by the result of ignoring the effects of the mood stabilizators and other drugs about oxidative balance. However, the most important feature of our study is that it is the first study comparing BD subtypes with the control group separately and as a whole. 5. Conclusion As a conclusion, there is a gradual increase in oxidants in BD; however, the compensatory increase in antioxidants is not enough to maintain the balance. The resulting oxidative stress leads to impairments in various cellular structural elements and functional compounds which are thought to play an important role in the development of the disease. References Akiskal HS, Pinto O. The evolving bipolar spectrum. Prototypes I, II, III, and IV. Psychiatr Clin North Am 1999;22:517–34. Andreazza AC, Kauer-Sant'anna M, Frey BN, Bond DJ, Kapczinski F, Young LT, et al. Oxidative stress markers in bipolar disorder: a meta-analysis. J Affect Disord 2008;111:135–44. American Psychiatric Association: Diagnostic and statistical manual of mental disorders 4th edition, 2004. American Psychiatric Association, Washington D.C. Berk M, Ng F, Dean O, Dodd S, Bush AI. Glutathione: a novel treatment target in psychiatry. Trends Pharmacol Sci 2008a;29:346–51. Berk M, Copolov DL, Dean O, Lu K, Jeavons S, Schapkaitz I, et al. N-acetyl cysteine for depressive symptoms in bipolar disorder—a double-blind randomized placebocontrolled trial. Biol Psychiatry 2008b;64:468–75. Bulut M, Selek S, Gergerlioglu HS, Savas HA, Yilmaz HR, Yuce M, et al. Malondialdehyde levels in adult attention-deficit hyperactivity disorder. J Psychiatry Neurosci 2008;32: 435–8. Erel O. A novel automated method to measure total antioxidant response against potent free radical reactions. Clin Biochem 2004a;37:112–9. Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem 2004b;37: 277–85. Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem 2005;38:1103–11. Frey BN, Andreazza AC, Kunz M, Gomes FA, Quevedo J, Salvador M, Goncalves CA, Kapczinski F, et al. Increased oxidative stress and DNA damage in bipolar disorder: a twin-case report. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:283–5. Gergerlioglu HS, Savas HA, Bulbul F, Selek S, Uz E, Yumru M. Changes in nitric oxide level and superoxide dismutase activity during antimanic treatment. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:697–702. Guemouri L, Artur Y, Herbeth B, Jeandel C, Cuny G, Siest G. Biological variability of superoxide dismutase, glutathione peroxidase and catalase in blood. Clin Chem 1991;37: 1932–7. Guy W. Assessment Manual for Psychopharmacology — Revised. Rockville, MD, U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, NIMH Psychopharmacology Research Branch, Division of Extramural Research Programs; 1976. p. 218–22.
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