Oxidative Stress In Bipolar Disorder Research Articles

Neuroinflammation and neuroprogression produced by oxidative stress in euthymic bipolar patients with different onset disease times

Bipolar disorder (BD) is associated with systemic toxicity, represented by changes in biomarkers associated with mood episodes, leading to neurological damage, which may reflect cognitive functions and functionality and the progression of the disease. We aimed to analyze the effect of four biomarkers, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and thiobarbituric acid reactive substances (TBA-RS), related to oxidative stress in BD and to correlate them with cognitive functions and functionality. We studied 50 bipolar types I/II patients in the euthymic phase, which was divided into two subgroups with 25 patients each (≤ 3 years and ≥ 10 years of diagnosis, from the first episode of mania) and 25 control patients. To analyze frontal cognitive functions and functionality, we used the Frontal Assessment Battery (FAB) and Functioning Assessment Short Test (FAST) tests, respectively. The scores of the FAST and FAB tests showed an increase and decrease respectively, in both bipolar groups, when compared to the control group, demonstrating impairment in cognitive functions and functionality since the disease onset. In addition, changes occurred in all six domains of the FAST test, and in four domains of the FAB test in bipolar patients when compared to the control group. Regarding oxidative stress biomarkers, we did not find changes in SOD and GSH-Px activities; however, a significant increase in CAT activity and lipid peroxidation was observed in both groups, although the patients were euthymic and medicated. These results allow us to raise the hypothesis that since the beginning of the disease, the euthymic bipolar patient has presented a level of oxidative stress, which gets worse with the evolution of the disease, promoting impairments in the frontal cognitive functions and functionality gradually.

The Effect of Adjunctive Probiotics on Markers of Inflammation and Oxidative Stress in Bipolar Disorder: A Double-blind, Randomized, Controlled Trial.

Bipolar disorder (BD) is a chronic psychiatric illness. Concentrations of inflammatory cytokines are increased in BD. Supplementation with probiotics has shown promising effects in reducing inflammation and producing improvement in clinical symptoms in some psychiatric disorders. Therefore, we designed a clinical trial to assess the effects of adjunctive probiotics on markers of inflammation and oxidative stress in patients with BD. In this 8-week, double-blind, randomized study, 38 patients suffering from BD type I were given a probiotic or placebo capsule each day. Serum levels of interleukin-6 (IL-6), as the primary outcome measure, and of interleukin-10 (IL-10), tumor necrosis factor-α, and malondialdehyde, as the secondary outcome measures, were obtained before and after the intervention. At the end of the study, the 2 groups showed no significant or clinically meaningful differences in the serum concentrations of IL-6 [Hedge g=0.02, 95% confidence interval (CI): -0.6; 0.64, P=0.936], tumor necrosis factor-α (Hedge g=-0.2, 95% CI: -0.82; 0.42, P=0.554), IL-10 (Hedge g=-0.072, 95% CI: -0.071; 0.56, P=0.827), and malondialdehyde (Hedge g=0.27, 95% CI: -0.37; 0.91, P=0.423). This study did not find any significant or conclusive effects of probiotics supplementation on markers of inflammation and oxidative stress in patients with BD. Further studies are needed before a conclusion can be drawn about the efficacy of probiotics in the management of BD.

Concepts of Neuroinflammation and Their Relationship With Impaired Mitochondrial Functions in Bipolar Disorder.

Bipolar disorder (BD) is a chronic psychiatric disease, characterized by frequent behavioral episodes of depression and mania, and neurologically by dysregulated neurotransmission, neuroplasticity, growth factor signaling, and metabolism, as well as oxidative stress, and neuronal apoptosis, contributing to chronic neuroinflammation. These abnormalities result from complex interactions between multiple susceptibility genes and environmental factors such as stress. The neurocellular abnormalities of BD can result in gross morphological changes, such as reduced prefrontal and hippocampal volume, and circuit reorganization resulting in cognitive and emotional deficits. The term “neuroprogression” is used to denote the progressive changes from early to late stages, as BD severity and loss of treatment response correlate with the number of past episodes. In addition to circuit and cellular abnormalities, BD is associated with dysfunctional mitochondria, leading to severe metabolic disruption in high energy-demanding neurons and glia. Indeed, mitochondrial dysfunction involving electron transport chain (ETC) disruption is considered the primary cause of chronic oxidative stress in BD. The ensuing damage to membrane lipids, proteins, and DNA further perpetuates oxidative stress and neuroinflammation, creating a perpetuating pathogenic cycle. A deeper understanding of BD pathophysiology and identification of associated biomarkers of neuroinflammation are needed to facilitate early diagnosis and treatment of this debilitating disorder.

Increased mitochondrial and cytosolic antioxidant enzymes in manic episodes

Background and objectivesAn increasing number of studies have been conducted to investigate the role of oxidative stress in the pathophysiology of bipolar disorder (BD). The aim of our study was to detect the levels of plasma malondialdehyde and the gene expression of antioxidant enzymes in BD patients during manic period and to assess the changes of these markers during the subsequent remission period. MethodsThis study involved 20 drug-free, hospitalized patients with BD type I who met the manic episode diagnostic criteria according to DSM-5, as well as 20 age-sex matched healthy controls. As a marker of lipid damage, malondialdehyde plasma levels were measured by the thiobarbituric acid method; mRNA expression levels of catalase (CAT), glutathione peroxidase (GPx), glutathione synthetase (GS), superoxide dismutase (SOD1) and mitochondrial superoxide dismutase (SOD2) were measured by real-time quantitative PCR from peripheral whole blood samples. ResultsIn a manic episode, the expression levels of CAT, GPx, GS and SOD2 were higher in the patients than the healthy controls. With treatment, only the GPx levels decreased significantly. The malondialdehyde and SOD1 levels did not differ between the patients and controls, and in the patient group, they did not differ between the mania and remission periods. ConclusionThis is the first study that has assessed the mRNA expression levels of antioxidant enzymes in patients with BD type I. The data from this study suggests that there is an increase in the expression of antioxidant enzymes as a response to oxidative stress in BD, and that the gene expression levels of these antioxidant enzymes could be potential biomarkers for manic phase of the disorder.

Serum ischemia modified albumin (IMA) levels of patients with bipolar disorder in remission and healthy controls

Oxidative stress might play an important role in neurological and psychiatric diseases due to the central nervous system sensitivity to reactive oxygen species. Aim of this study is to contribute these data about oxidative stress in bipolar disorder, by detecting IMA levels of bipolar disorder patients in remission and also by comparing these results with healthy controls. Study population consisted of 35 outpatients with bipolar disorder, who being in remission. The patients meeting the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria for bipolar disorder I. 36 healthy subjects were included as control group. Serum ischemia modified albumin levels of all participants were determined and the results were compared between these two groups. The age, gender and ischemia modified albumin levels were not significantly different between bipolar disorder patients and healthy controls. Studies focusing on oxidative stress in bipolar disorder have reached controversial results up till now. The many different markers have been investigated to explain the effects of oxidative stress on bipolar disorders, and this might be reason why there are conflicting results. In addition, the past episodes of patients who were in remission during this study are unclear. Further investigations are needed to be carrying out to illustrate possible changes of oxidative balance in psychiatric disorders, including bipolar disorder.

Evaluation of adiponectin and leptin levels and oxidative stress in bipolar disorder patients with metabolic syndrome treated by valproic acid.

An increased risk for metabolic syndrome (MS) has been described for people with psychotic and mood disorders. The aim of this study was to determine the influence of valproic acid (VPA) treatment on adiponectin, leptin levels and oxidative stress in bipolar disorder (BD). Forty patients with BD receiving VPA monotherapy and 20 healthy control subjects were included in this study. BD patients were divided into two groups with and without MS as group 1 and group 2, respectively. Twenty BD patients diagnosed according to the Diagnostic and Statistical Manual for Mental Disorders (DSM IV) were assessed for MS according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP III) criteria. Adiponectin, leptin, protein carbonyls, sulfhydryl (-SH) and malondialdehyde (MDA) levels were measured in 40 BD patients and 20 control subjects. Serum adiponectin levels were significantly lower in group 1 patients than in group 2 and control subjects ( p<.001). Serum leptin levels were significantly higher in group 1 patients than in group 2 and control subjects ( p<.001). Serum -SH levels were significantly lower in group 2 patients than in group 1 ( p<.001) and control subjects ( p<.05). Serum carbonyl levels were significantly higher in group 1 and group 2 patients than in control subjects ( p<.001). Serum MDA levels were significantly higher in group 1 patients than in group 2 and control subjects ( p<.001). These results provide further evidence that VPA treatment for patients with BD contributed to the metabolic disturbances, such as the decreased serum adiponectin and -SH levels, as well as the increased serum leptin, MDA and carbonyl levels.

P.2.c.007 - Plasma glutathione as a marker of oxidative stress in bipolar disorder

P.2.c.007 - Plasma glutathione as a marker of oxidative stress in bipolar disorder

Evaluation of Oxidative Stress in Bipolar Disorder in terms of Total Oxidant Status, Total Antioxidant Status, and Oxidative Stress Index

Bipolar disorder is one of the most debilitating psychiatric disorders characterized by disruptive episodes of mania/hypomania and depression. Considering the complex role of biological and environmental factors in the etiology of affective disorders, recent studies have focused on oxidative stress, which may damage nerve cell components and take part in pathophysiology. The aim of the present study was to contribute to the data about oxidative stress in bipolar disorder by detecting the total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) levels of manic episode (ME) and euthymic (EU) patients and by comparing these results with those of healthy controls (HCs). The study population consisted of 28 EU outpatients meeting the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for bipolar disorder I and 23 inpatients who were currently hospitalized in a psychiatry ward with the diagnosis of the bipolar disorder ME according to the DSM-5 criteria. Forty-three healthy subjects were included in the study as the control group (HC). Serum TAS, TOS, and OSI levels of all the participants were determined. Statistical analysis of serum TAS, TOS, and OSI levels did not show any significant differences between the ME patients, EU patients, and HCs. Comparison between the bipolar disorder patients (ME+EU) and HC also did not reveal any statistically significant difference between these two groups in terms of serum TAS, TOS, and OSI levels. To date, studies on oxidative stress in bipolar disorder have led to controversial results. In the present study, no statistically significant difference was detected between the oxidative parameters of bipolar disorder patients and HCs. In order to comprehensively evaluate oxidative stress in bipolar disorder, further studies are needed.

Bipolar disorder course, impaired glucose metabolism and antioxidant enzymes activities: A preliminary report

This study aimed to examine the role of oxidative stress in bipolar disorder (BD) by evaluating the relationship among antioxidant enzymes activities, impaired glucose metabolism (IGM) and illness course. We measured the activities of plasma superoxide dismutase (SOD) and glutathione peroxidase (GPx) in individuals with BD (N = 55) and healthy controls (N = 28). Information related to current and past psychiatric/medical history, as well as prescription of any pharmacological treatments was captured. Impaired glucose metabolism was operationalized as pre-diabetes or type 2 diabetes mellitus. Our results showed that, after adjustment for age, gender, alcohol use, smoking and current medication, both BD (p < 0.001) and IGM (p = 0.019) were associated with increased GPx activity, whereas only BD was associated with decreased SOD activity (p = 0.008). We also observed an interaction between BD and IGM on SOD activity (p = 0.017), whereas the difference between BD and controls was only significant in individuals with IGM (p = 0.009). IGM, GPx and SOD activity were independently associated with variables of illness course. Moreover, IGM moderated the association between SOD activity and number of mood episodes (p < 0.001), as a positive correlation between SOD activity and mood episodes was observed only in participants with IGM. In conclusion, BD and IGM are associated with independent and synergistic effects on markers of oxidative stress. The foregoing observations suggest that the heterogeneity observed in previous studies evaluating antioxidant enzymes in BD may be a function of concurrent IGM; and that imbalances in the oxidative system may subserve the association between BD and IGM, as well as its relationship with illness course.

The role of oxidative stress in bipolar disorder: Is DNA damage a potential biomarker of disease severity?

The role of oxidative stress in bipolar disorder: Is DNA damage a potential biomarker of disease severity?

Sodium butyrate has an antimanic effect and protects the brain against oxidative stress in an animal model of mania induced by ouabain

Studies have consistently reported the participation of oxidative stress in bipolar disorder (BD). Evidence indicates that epigenetic regulations have been implicated in the pathophysiology of mood disorders. Considering these evidences, the present study aimed to investigate the effects of sodium butyrate (SB), a histone deacetylase (HDAC)inhibitor, on manic-like behavior and oxidative stress parameters (TBARS and protein carbonyl content and SOD and CAT activities) in frontal cortex and hippocampus of rats subjected to the animal model of mania induced by intracerebroventricular (ICV) ouabain administration.The results showed that SB reversed ouabain-induced hyperactivity, which represents a manic-like behavior in rats. In addition, the ouabain ICV administration induced oxidative damage to lipid and protein and alters antioxidant enzymes activity in all brain structures analyzed. The treatment with SB was able to reversesboth behavioral and oxidative stress parameters alteration induced by ouabain.In conclusion, we suggest that SB can be considered a potential new mood stabilizer by acts on manic-like behavior and regulatesthe antioxidant enzyme activities, protecting the brain against oxidative damage.

An updated meta-analysis of oxidative stress markers in bipolar disorder

Despite its debilitating symptoms, the pathophysiology of bipolar disorder (BD) remains unclear. One consistently compelling finding, however, has been the presence of oxidative stress. In the present investigation, we conducted a meta-analysis of studies that measured oxidative stress markers in BD patients compared to healthy controls. Search terms and selection criteria were determined a priori to identify and include all studies that measured a marker of oxidative stress in BD compared to healthy controls. Eight markers were included: superoxide dismutase, catalase, protein carbonyl, glutathione peroxidase, 3-nitrotyrosine, lipid peroxidation, nitric oxide, and DNA/RNA damage. A meta-analysis of standardized means was conducted using a random-effects model with generic inverse weighting. Between-study heterogeneity, publication bias, and sensitivity analyses were also examined for each marker. Twenty-seven papers were included in the meta-analysis, which comprised a total of 971 unique patients with BD and 886 healthy controls. Lipid peroxidation, DNA/RNA damage, and nitric oxide were significantly increased in BD patients compared to healthy controls. Additionally, the effect size for lipid peroxidation was very high. Publication bias was not detected for any of the markers. The main limitations in this meta-analysis are the high degree of heterogeneity between studies and the small number of studies used in the analysis of some markers. Additionally, the sensitivity analysis indicated that some results are not very robust. The results from this meta-analysis support the role of oxidative stress in bipolar disorder, especially to DNA, RNA, and lipids.

Omega-3 fatty acids alter behavioral and oxidative stress parameters in animals subjected to fenproporex administration

Studies have consistently reported the participation of oxidative stress in bipolar disorder (BD). Evidences indicate that omega-3 (ω3) fatty acids play several important roles in brain development and functioning. Moreover, preclinical and clinical evidence suggests roles for ω3 fatty acids in BD. Considering these evidences, the present study aimed to investigate the effects of ω3 fatty acids on locomotor behavior and oxidative stress parameters (TBARS and protein carbonyl content) in brain of rats subjected to an animal model of mania induced by fenproporex. The fenproporex treatment increased locomotor behavior in saline-treated rats under reversion and prevention model, and ω3 fatty acids prevented fenproporex-related hyperactivity. Moreover, fenproporex increased protein carbonyls in the prefrontal cortex and cerebral cortex, and the administration of ω3 fatty acids reversed this effect. Lipid peroxidation products also are increased in prefrontal cortex, striatum, hippocampus and cerebral after fenproporex administration, but ω3 fatty acids reversed this damage only in the hippocampus. On the other hand, in the prevention model, fenproporex increased carbonyl content only in the cerebral cortex, and administration of ω3 fatty acids prevented this damage. Additionally, the administration of fenproporex resulted in a marked increased of TBARS in the prefrontal cortex, hippocampus, striatum and cerebral cortex, and prevent this damage in the prefrontal cortex, hippocampus and striatum. In conclusion, we are able to demonstrate that fenproporex-induced hyperlocomotion and damage through oxidative stress were prevented by ω3 fatty acids. Thus, the ω3 fatty acids may be important adjuvant therapy of bipolar disorder.

The neurobiology of bipolar disorder: identifying targets for specific agents and synergies for combination treatment

Bipolar disorder (BD) is a chronic psychiatric illness described by severe changes in mood. Extensive research has been carried out to understand the aetiology and pathophysiology of BD. Several hypotheses have been postulated, including alteration in genetic factors, protein expression, calcium signalling, neuropathological alteration, mitochondrial dysfunction and oxidative stress in BD. In the following paper, we will attempt to integrate these data in a manner which is to understand targets of treatment and how they may be, in particular, relevant to combination treatment. In summary, the data suggested that BD might be associated with neuronal and glial cellular impairment in specific brain areas, including the prefrontal cortex. From molecular and genetics: (1) alterations in dopaminergic system, through catechol-O-aminotransferase; (2) decreased expression and polymorphism on brain-derived neurotrophic factor; (3) alterations cyclic-AMP responsive element binding; (4) dysregulation of calcium signalling, including genome-wide finding for voltage-dependent calcium channel α-1 subunit are relevant findings in BD. Future studies are now necessary to understand how these molecular pathways interact and their connection to the complex clinical manifestations observed in BD.

Oxidative Stress in Bipolar Disorder

Research on the complex and multifaceted nature of Bipolar Disorder (BD) pathophysiology has recently expanded to include oxidative stress. Several lines of evidence have reported higher reactive oxygen species production that results in increased oxidative damage in proteins, lipids, and nucleic acids. These findings have been observed in brains and peripheral samples of BD patients, as well as being reproduced in a number of animal model studies. Also discussed in this review is research highlighting antioxidant properties of existing mood stabilizing drugs, with consideration paid to novel therapeutic treatments for BD through the alleviation of oxidative stress. The maladaptive oxidative modifications of cellular macromolecules may be associated with impaired neuroplasticity and the development of functional abnormalities in the brain.

Effects of lithium therapy on Na+–K+-ATPase activity and lipid peroxidation in bipolar disorder

Oxidative stress induced lipid peroxidation along with a reduced Na(+)-K(+)-ATPase activity has been implicated in the pathophysiology of bipolar disorders (BPD). Although, lithium therapy results in significant improvement in the symptoms of the disease, studies regarding its effect on the altered sodium pump activity and lipid peroxidation status have come out with conflicting results. The present study was undertaken to evaluate the status of lipid peroxidation and analyze the role of lithium and Na(+)-K(+)-ATPase activity in its regulation in BPD patients in our region. We measured RBC membrane Na(+)-K(+)-ATPase activity and serum thiobarbituric acid reacting substances (TBARS) level in 73 BPD patients and serum lithium, in addition, in 48 patients receiving lithium therapy among them. Na(+)-K(+)-ATPase activity and serum TBARS level were significantly decreased and increased respectively in all BPD patients compared to age and sex matched healthy controls. Same trend was observed in the BPD patients stabilized on lithium therapy compared to the lithium naive ones. Although, the enzyme activity showed a reciprocal relationship with TBARS in all patients of BPD, a significant positive correlation and dependence of the enzyme activity was evident with serum lithium level only in the lithium stabilized BPD group. BPD patients showed significantly compromised Na(+)-K(+)-ATPase activity and increased lipid peroxidation. Lithium induced improvement in the enzyme activity was associated with significant reduction in lipid peroxidation. Enhancement of the Na(+)-K(+)-ATPase activity by optimum dosage of lithium may be a potential contributing factor for reducing oxidative stress in BPD patients.

Morphometric post-mortem studies in bipolar disorder: possible association with oxidative stress and apoptosis

Despite extensive research in the last decades, the pathophysiology of bipolar disorder (BD) remains unclear. Access to post-mortem brain tissue of subjects who had BD offers an opportunity to investigate neurobiology and this approach has led to some progress, particularly, due to the availability of more sophisticated molecular and cellular biological methodologies and well characterized brain collections over the past decade. Here we review the findings of morphometric post-mortem studies in BD and interpret them in the context of a potential physiopathological mechanism involving oxidative stress and apoptosis. A review of the literature was conducted to identify post-mortem studies that investigated cellular changes such as number, density and size of neurons and glia, in brains of subjects with BD. We found decreased density of neurons and glia and decreased size of neurons in frontal and subcortical areas of the brain. Based on recent studies that found evidence of increased apoptosis and oxidative stress in BD, we hypothesize that the cell abnormalities described are due to an increase in the apoptotic process that can be triggered, through its intrinsic pathway, by the existence of an exacerbated production of reactive oxygen species and oxidative damage in the disease.

Animal model of mania induced by ouabain: Evidence of oxidative stress in submitochondrial particles of the rat brain

The intracerebroventricular (ICV) administration of ouabain (a Na +/K +-ATPase inhibitor) in rats has been suggested to mimic some symptoms of human bipolar mania. Clinical studies have shown that bipolar disorder may be related to mitochondrial dysfunction. Herein, we investigated the behavioral and biochemical effects induced by the ICV administration of ouabain in rats. To achieve this aim, the effects of ouabain injection immediately after and 7 days following a single ICV administration (at concentrations of 10 −2 and 10 −3 M) on locomotion was measured using the open-field test. Additionally, thiobarbituric acid reactive substances (TBARSs) and superoxide production were measured in submitochondrial particles of the prefrontal cortex, hippocampus, striatum and amygdala. Our findings demonstrated that ouabain at 10 −2 and 10 −3 M induced hyperlocomotion in rats, and this response remained up to 7 days following a single ICV injection. In addition, we observed that the persistent increase in the rat spontaneous locomotion is associated with increased TBARS levels and superoxide generation in submitochondrial particles in the prefrontal cortex, striatum and amygdala. In conclusion, ouabain-induced mania-like behavior may provide a useful animal model to test the hypothesis of the involvement of oxidative stress in bipolar disorder.

S29-04 Markers of oxidative stress in bipolar disorder and in schizophrenia

There has been strong evidence in recent years that oxygen free radicals may play an important role in the pathophysiology of schizophrenia and bipolar disorder. More recent evidence of altered antioxidant defenses in major mental illnesses has been accumulating. Much of the focus on antioxidant defense mechanism has been on the key scavenging antioxidant enzymes: Superoxide dismutase (SOD), Catalase (CAT) and Glutathione peroxidase (GSH-Px). Of these, SOD activity has been the most frequently examined.The imbalance between antioxidant and oxidant mechanisms increases what is called oxidative stress, when the oxygen free species react and could damage lipids, proteins, carbohydrates and DNA. Lipids are the main compound of cellular membrane and the oxygen free radicals reaction to them is called lipid peroxidation. Several plasma lipid peroxides, like MDA, are measured by Thiobarbituric acid reactive substances (TBARS). Increased levels of TBARS have been reported in the plasma of drug-free and medicated bipolar disorder and schizophrenic patients. It is hypothesized that psychotic symptoms seen in both disorders might be a consequence of peroxidative injury to membrane phospholipids. Moreover, neuronal functioning is affected by this injury either by changes in membrane fluidity or by alterations in membrane receptors, which can cause neurotransmitter uptake and release impairment and even cell death.