8-hydroxy-2--deoxyguanosine and Bipolar-Disorder

Oxidative DNA damage has been associated with the pathophysiology of bipolar disorder (BD) as one of the common pathways between increased medical comorbidity and premature aging in BD. Previous evidence shows increased levels of oxidatively induced DNA damage markers, 8-hydroxy-2'-deoxyguanosine (8-OHdG) or its tautomer 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG), in patients with BD in comparison to healthy individuals. With the current research, we aim to analyze data on peripheral (blood or urine) 8-OHdG/8-oxo-dG levels across mood states of BD using a meta-analytical approach.. A literature search was conducted using the databases PubMed, Scopus, and Web of Science to identify eligible studies (January 1989 to July 2022). Relevant studies were systematically reviewed; a random-effects meta-analysis and a meta-regression analysis were conducted.. The current meta-analysis included 12 studies consisting of 808 BD patients (390 in euthymia, 156 in mania, 137 in depression, 16 in mixed episode, 109 not specified) and 563 healthy controls. BD patients that were currently depressed had significantly higher levels of 8-OHdG/8-oxo-dG than healthy controls, while euthymic or manic patients did not differ from healthy controls. A meta-regression analysis showed sex distribution (being female) and older age to be significantly related to increased 8-OHdG/8-oxo-dG levels.. Our findings suggest that 8-OHdG/8-oxo-dG may be a state-related marker of depression in BD and may be affected by older age and female gender.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Affect; Bipolar Disorder; Deoxyguanosine; DNA Damage; Female; Humans; Male; Oxidative Stress

It has been suggested that depressed persons have increased oxidative stress and decreased anti-oxidant defences. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) and F2-isoprostanes, measures of oxidative DNA and lipid damage respectively, are among the most reliable oxidative stress markers, but studies on their association with depression show conflicting results. This meta-analysis quantifies the association between depression and these markers and explores factors that may explain inconsistencies in the results.. A systematic literature search was conducted in PubMed, EMBASE and PsycINFO. Studies assessing the association of 8-OHdG or F2-isoprostanes with elevated depressive symptoms, major depressive disorder (MDD) or bipolar disorder (BD) were pooled in two random-effect models.. The pooled effect size (Hedges' g) for the association of depression with oxidative stress was 0.31 (p=0.01, I(2)=75%) for 8-OHdG (10 studies, 1308 subjects) and 0.48 (p=0.001, I(2)=73%) for F2-isoprostanes (8 studies, 2471 subjects), indicating that both markers are increased in depression. There was no indication of publication bias for either marker. The F2-isoprostane results did not differ by type of depression, biological specimen, laboratory method or quality, however subgroup analyses in the 8-OHdG studies showed significantly stronger associations in plasma/serum vs. urine samples (p<0.01), in measurements performed with immuno-assay vs. chromatography-mass spectrometry (p<0.01) and weaker associations in high quality studies vs. low (p=0.02).. This meta-analysis finds that oxidative stress, as measured by 8-OHdG and F2-isoprostanes, is increased in depression. Larger-scale studies are needed to extend the evidence on oxidative stress in depression, and examine the potential impact of treatment.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers; Bipolar Disorder; Deoxyguanosine; Depression; Depressive Disorder, Major; F2-Isoprostanes; Humans; Oxidative Stress

Persistent cognitive impairments occur in a large proportion of patients with bipolar disorder (BD) but their underlying pathological cellular processes are unclear. The aims of this longitudinal study of BD and healthy control (HC) participants were to investigate (i) the association of brain erythropoietin (EPO) and oxidative stress with cognitive functions and (ii) the changes in brain EPO during and after affective episodes. Participants underwent neurocognitive testing, lumbar punctures for cerebrospinal fluid (CSF) sampling and provided urine spot tests at baseline (all), after an affective episode (patients) and after one year (all). EPO was assayed in the CSF and oxidative stress metabolites related to RNA and DNA damage (8-dihydroguanosine [8-oxo-Guo], 8-hydroxy-2-deoxyguanosine [8-oxo-dG]) were assayed in the CSF and spot urine. Data was available for analyses for 60 BD and 37 HC participants. In unadjusted primary analyses, verbal memory decreased with increasing concentrations of CSF EPO and oxidative stress. In unadjusted explorative analyses, poorer verbal memory and psychomotor speed were associated with higher levels of oxidative stress. However, no associations between cognitive functions and CSF levels of EPO or oxidative stress were observed after adjustment for multiple testing. CSF EPO concentrations were unchanged during and after affective episodes. While CSF EPO correlated negatively with CSF DNA damage marker 8-oxo-dG, this association rendered non-significant after adjusting for multiple testing. In conclusion, EPO and oxidative stress do not seem to be robustly related to cognitive status in BD. Further insight into the cellular processes involved in cognitive impairments in BD is necessary to pave the way for novel therapeutic strategies to improve patients' cognitive outcomes.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Bipolar Disorder; Case-Control Studies; Cognition; Erythropoietin; Humans; Longitudinal Studies; Memory Disorders; Oxidative Stress

Oxidative stress generated nucleoside damage seems to represent key pathophysiological mechanisms of bipolar disorder (BD). Likewise, mood and activity are core features of BD and can be reliably monitored using smartphone-based applications. The aim was to investigate whether oxidative stress generated nucleoside damage could reflect psychopathology in BD using easily available and non-invasive patient-reported smartphone-based symptoms. We included 223 patients newly diagnosed with BD and employed linear mixed-effect regression models to associate baseline measurements of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo) levels with patient-reported smartphone measures of mood, activity, anxiety, stress and sleep duration monitored three days prior to and 30 days after the baseline visit in the longitudinal Bipolar Illness Onset Study. In patients newly diagnosed with BD higher 8-oxoGuo levels were inversely associated with the patient-reported activity level (B = 0.953, 95%CI = 0.909;0.99, p = 0.043) and positively associated with patient-reported anxiety (B = 1.104, 95%CI = 1.022;1.161, p=0.012), perceived stress (B = 1.092, 95%CI = 1.009;1.183, p = 0.014) and sleep duration (B = 1.000, 95%CI = 1.000;1.001, p = 0.001), respectively, in analyses, adjusted for sex and age. The associations between 8-oxoGuo levels and anxiety, perceived stress and sleep duration, respectively, withstood adjustment for sex, age, smoking, BMI and alcohol intake. No associations between 8-oxodG levels and patient-reported smartphone-based data were found and mood was not associated with 8-oxoGuo. Oxidative stress was associated with patient-reported smartphone-based data on activity, anxiety, stress and sleep duration pointing towards that oxidative stress generated nucleoside damage may reflect ongoing psychopathology in BD.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers; Bipolar Disorder; Humans; Nucleosides; Oxidative Stress; Patient Reported Outcome Measures; Smartphone

Enhanced oxidative stress-generated nucleoside damage may contribute to the increased cardiovascular disease mortality in patients with bipolar disorder (BD) but the association has never been investigated. We investigated the associations between oxidative stress-generated damage to DNA (8-oxodG) and RNA (8-oxoGuo), respectively, and three measures reflecting cardiovascular risk; namely, the Framingham 30-year risk score of cardiovascular diseases, the metabolic syndrome, and the insulin resistance index in 360 patients newly diagnosed with BD, 102 of their unaffected relatives (UR) and 197 healthy control individuals (HC). In sex- and age-adjusted models, the 30-year cardiovascular risk score increased by 20.8% (CI = 7.4-35.9%, p = 0.002) for every one nM/mM creatinine increase in 8-oxoGuo and by 15.6% (95% CI = 5.8-26.4%, p = 0.001) for every one nM/mM creatinine increase in 8-oxodG, respectively. Further, insulin resistance index increased by 24.1% (95% CI = 6.7-43%, p = 0.005) when 8-oxoGuo increased one nM/mM creatinine. The associations between cardiovascular measures and oxidative nucleoside damage were more pronounced in patients with BD compared with UR, and HC. Metabolic syndrome was not associated with nucleoside damage. Overall, higher oxidative stress-generated nucleoside damage was associated with a higher cardiovascular risk score and a higher degree of insulin resistance index, and having BD impacted the associations. Further, within patients, treatment with psychotropics seemed to enhance the associations between 30-year CVD risk score and insulin resistance index, respectively, and oxidatively stress-generated nucleoside damage. Our findings support enhanced oxidative stress-generated nucleoside damage as a putative pathophysiological mechanism that may mediate the higher cardiovascular risk observed in patients with BD already at the time of diagnosis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Bipolar Disorder; Cardiovascular Diseases; Case-Control Studies; Creatinine; Heart Disease Risk Factors; Humans; Insulin Resistance; Nucleosides; Oxidative Stress; Risk Factors

Prior studies in bipolar disorders (BD) have suggested that oxidative stress and cellular ageing play a key role in the pathophysiology of BD. Nevertheless, oxidative stress has not been investigated in patients with newly diagnosed BD and in their unaffected first-degree relatives (UR), compared with healthy control individuals (HC).. We investigated the level of systemic oxidative damage to DNA and RNA measured by urinary excretion of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo) levels, respectively, in 360 patients with newly diagnosed BD, 92 of their UR and 197 HC.. Independent of lifestyle and demographic variables, levels of both 8-oxoGuo and 8-oxodG was 17.1% (B = 1.171, 95%CI = 1.125-1.219, p < 0.001) and 21.2% (B = 1.212, 95%CI = 1.145-1.283, p < 0.001) higher, respectively, in patients with BD compared with HC and 13.3% (B = 1.133, 95%CI = 1.069-1.200, p < 0.001) and 26.6% (B = 1.266, 95%CI = 1.167-1.374, p < 0.001) higher, respectively, in UR compared with HC. Neither 8-oxoGuo nor 8-oxodG levels differed between patients with BD and UR. These findings were replicated in patients in full or partial remission and were consistent both in BD type I and II.. Overall, the findings of higher oxidative stress in patients with newly diagnosed BD and their UR suggest that systemic nucleoside damage by oxidative stress is present prior to onset and in the early stages of BD thereby potentially representing trait markers of BD.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Bipolar Disorder; DNA; DNA Damage; Humans; Oxidative Stress; RNA

Previous studies showed significant increases in DNA base damage markers and significant alterations in base excision repair enzymes in patients with unipolar and bipolar depression. We aimed to investigate changes in urine 8-Oxo-2'-deoxyguanosine (8-oxo-dG) and gene expression levels of 8-Oxoguanine DNA glycosylase 1 (OGG1) during a current depressive episode and after remission in bipolar and unipolar disorders.. Twenty-four acutely depressed bipolar (BD), 33 unipolar depression (UD) patients and 61 healthy controls were included in the study. Clinical evaluations, blood and urine sampling were completed at baseline and at remission after eight weeks. The urine 8-oxo-dG levels were assessed by liquid chromatography tandem mass spectrometry and adjusted for urine creatinine levels. The gene expression levels of OGG1 were determined from cDNA extracted from blood samples, using real time-polymerase chain reaction.. At baseline, patients presented significantly higher levels of 8-oxo-dG (p = 0.008), and lower gene expression of OGG1 (p = 0.024) compared to controls. Levels of either 8-oxo-dG or OGG1 expression did not differ between BD and UD. In patients who remitted by the 8th week (n = 30), 8-oxo-dG decreased significantly (p = 0.001), and gene expression levels of OGG1 increased by 2.95 times compared to baseline levels (p = 0.001). All comparisons were adjusted for age, sex, smoking status and body mass index.. Our results suggest that patients with bipolar and unipolar mood disorders present increased 8-oxo-dG and decreased gene expression levels of OGG1 in current depressive episodes, and that these changes might be reversed by the resolution of depressive symptoms. The causal relationship between DNA damage and repair requires further exploration.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Bipolar Disorder; Depressive Disorder; DNA Glycosylases; Female; Gene Expression; Humans; Male; Oxidative Stress; Young Adult

An important step in the development of new drugs for the treatment of bipolar disorder (BD) is the study of the extent to which novel lithium salts whose anionic component has an antioxidant effect can reduce oxidative DNA damage in human blood plasma. Blood incubation was carried out in the presence of lithium salts (1.2 mM) for 1 hour at 37°C. Measurement of 8-OH-dG concentrations in blood plasma was carried out by enzyme immunoassay using a DNA Damage Competitive Elisa Kit (Thermo Fisher Scientific, USA).. In samples without compounds (control), concentrations of 8-OH-dG in the BD-group did not differ from the group of healthy individuals. None of the tested compounds had a significant effect on 8-OH-dG in healthy individuals. In BD patients, Li-PYR significantly reduced levels of plasma 8-OH-dG, while other compounds did not have a noticeable effect.. Lithium pyruvate reduces oxidative DNA damage in the blood of BD patients

Topics: 8-Hydroxy-2'-Deoxyguanosine; Bipolar Disorder; Humans; Lithium; Pharmaceutical Preparations; Plasma; Salts

Bipolar disorder (BD) is a mental disorder characterized by recurrent relapses of affective episodes, cognitive impairment, illness progression, and reduced life expectancy. Increased systemic oxidatively generated nucleoside damage have been found in some neurodegenerative disorders and in BD. As the first, this naturalistic prospective, longitudinal follow-up case-control study investigated cerebrospinal fluid (CSF) oxidative stress markers 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) that relate to RNA and DNA damage, respectively. Patients with BD (n = 86, 51% female) and gender-and-age-matched healthy control individuals (HC; n = 44, 44% female) were evaluated at baseline (T0), during (T1) and after a new affective episode (T2), if it occurred, and after a year (T3). Cerebrospinal and urine oxidative stress markers were analyzed using ultra-performance liquid chromatography-tandem mass spectrometry. CSF-8-oxoGuo was statistically significantly higher by 18% (p = 0.003) in BD versus HC at T0, and by 22% (p = 0) at T3. CSF-8-oxoGuo had increased by 15% (p = 0.042) from T0 to T3, and by 14% (p = 0.021) from T2 to T3 in patients, who experienced an episode during follow-up. CSF-8-oxodG had increased by 26% (p = 0.054) from T0 to T2 and decreased by 19% (p = 0.041) from T2 to T3 in patients, who experienced an episode during follow-up. CSF-8-oxoGuo did not show a statistically significant change in HC during the one-year follow-up. CSF and urine-8-oxoGuo levels correlated moderately. In conclusion, CSF oxidative stress marker of RNA damage 8-oxoGuo showed both state and trait dependence in BD and stability in HC. Central RNA damage may be a potential biomarker for BD.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Biomarkers; Bipolar Disorder; Case-Control Studies; Female; Guanosine; Humans; Longitudinal Studies; Male; Oxidative Stress; Young Adult

Elevated systemic oxidative stress levels of 8-oxoGuo and 8-oxodG have been reported in individuals with severe mental illness (SMI). As no previous studies have addressed the link between local levels of 8-oxoGuo and 8-oxodG in the central nervous system (CNS), measured in cerebrospinal fluid (CSF), and urinary systemic levels, we employed autopsy-based material to elucidate this aspect. Additionally, we investigated the impact of 8-oxoGuo and 8-oxodG levels on the prevalence of somatic co-morbidities. Based on post mortem samples from deceased individuals with SMI (N = 107), we found significantly elevated urinary levels of both 8-oxoGuo and 8-oxodG compared to mentally healthy living controls. While we found an association between urinary and CSF 8-oxodG levels (r = 0.50, P < 0.001), a similar correlation was not evident for 8-oxoGuo (r = 0.15, P = 0.16). Additionally, the two r-values were significantly different (P < 0.001). Neither marker in urine or CSF was associated with obesity-related variables, metabolic syndrome or type 2 diabetes. The post mortem interval did not affect the results, but the agonal phase seemingly introduced bias. This study provided novel insights into the cellular oxidative stress levels in individuals with SMI. We demonstrated that increased oxidative stress locally and systemically is correlated and is a clear phenomenon in SMI. Although post mortem measurements contain some weaknesses, our study indicates DNA as the main site of oxidative stress modifications in the CNS in SMI. This may provide novel opportunities for treatment modalities. Additionally, our study demonstrated the applicability of post mortem material investigating systemic and local 8-oxoGuo and 8-oxodG levels.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Autopsy; Bipolar Disorder; Central Nervous System; Deoxyguanosine; Depression; Female; Guanosine; Humans; Male; Mental Disorders; Middle Aged; Oxidative Stress; Schizophrenia

The mechanisms underlying bipolar disorder (BD) and the associated medical burden are unclear. Damage generated by oxidation of nucleosides may be implicated in BD pathophysiology; however, evidence from in vivo studies is limited and the extent of state-related alterations is unclear. This prospective study investigated for we believe the first time the damage generated by oxidation of DNA and RNA strictly in patients with type I BD in a manic or mixed state and subsequent episodes and remission compared with healthy control subjects. Urinary excretion of 8-oxo-deoxyguanosine (8-oxodG) and 8-oxo-guanosine (8-oxoGuo), valid markers of whole-body DNA and RNA damage by oxidation, respectively, was measured in 54 patients with BD I and in 35 healthy control subjects using a modified ultraperformance liquid chromatography and mass spectrometry assay. Repeated measurements were evaluated in various affective phases during a 6- to 12-month period and compared with repeated measurements in healthy control subjects. Independent of lifestyle and demographic variables, a 34% (P<0.0001) increase in RNA damage by oxidation across all affective states, including euthymia, was found in patients with BD I compared with healthy control subjects. Increases in DNA and RNA oxidation of 18% (P<0.0001) and 8% (P=0.02), respectively, were found in manic/hypomanic states compared with euthymia, and levels of 8-oxodG decreased 15% (P<0.0001) from a manic or mixed episode to remission. The results indicate a role for DNA and RNA damage by oxidation in BD pathophysiology and a potential for urinary 8-oxodG and 8-oxoGuo to function as biological markers of diagnosis, state and treatment response in BD.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Adult; Anticonvulsants; Antidepressive Agents; Antimanic Agents; Antipsychotic Agents; Bipolar Disorder; Case-Control Studies; Deoxyguanosine; DNA; DNA Damage; Female; Guanosine; Humans; Longitudinal Studies; Male; Middle Aged; Oxidation-Reduction; Prospective Studies; RNA; Treatment Outcome; Young Adult

The pathophysiological mechanisms underlying bipolar disorder and its multi-system nature are unclear. Oxidatively generated damage to nucleosides has been demonstrated in metabolic disorders; however, the extent to which this occurs in bipolar disorder in vivo is unknown. We investigated oxidatively generated damage to DNA and RNA in patients with bipolar disorder and its relationship with the affective phase compared with healthy control subjects.. Urinary excretion of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), markers of oxidatively generated DNA and RNA damage, respectively, was measured in 37 rapid cycling patients with bipolar disorder and in 40 age- and gender-matched healthy control subjects. Employing a longitudinal design, repeated measurements of both markers were evaluated in various affective phases in patients with bipolar disorder during a six- to 12-month period and compared with repeated measurements in healthy control subjects.. In linear mixed models, adjusting for demographical, metabolic, and lifestyle factors, the excretion of 8-oxodG and 8-oxoGuo was significantly elevated in euthymic patients with bipolar disorder compared with healthy control subjects, with increases of 40% (p < 0.0005) and 43% (p < 0.0005), respectively. The increased oxidatively generated nucleoside damage was present through all affective phases of the illness, with no significant difference between affective states.. Our results indicate that bipolar disorder is associated with increased oxidatively generated damage to nucleosides. The findings could suggest a role for oxidatively generated damage to DNA and RNA as a molecular mechanism contributing to the increased risk of medical disorders, shortened life expectancy, and the progressive course of illness observed in bipolar disorder.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Biomarkers; Bipolar Disorder; Case-Control Studies; Deoxyguanosine; DNA; DNA Damage; Female; Guanosine; Humans; Longitudinal Studies; Male; Middle Aged; Oxidation-Reduction; RNA; Young Adult

Bipolar disorder (BD) is a major public health problem characterized by progressive functional impairment. A number of clinical variables have been associated with progression of the disease, most notably number of affective episodes and presence of psychotic symptoms, both of which correlate with greater cognitive impairment, lower response rates for lithium, and possibly lower levels of neurotrophic factors. Oxidative damage to cytosine and guanosine (8-OHdG) has been described as a modulator of DNA methylation, but the extent of DNA oxidative damage involvement in BD remains unclear. The aim of this study was to evaluate the extent of DNA oxidative damage to 8-OHdG and 5-methylcytosine (5-HMec), as well as global methylation (5-Mec), in BD patients and healthy controls. Potential association with clinical variables was also investigated. DNA levels of 8-OHdG, 5-HMec and 5-Mec were measured in 50 BD type I patients and 50 healthy controls. DNA 8-OHdG levels were higher in BD patients compared to healthy controls and found to be positively influenced by number of previous manic episodes. BD subjects had lower levels of 5-HMec compared to controls, whereas this measure was not influenced by the clinical features of BD. Number of manic episodes was correlated with higher levels of 8-OHdG, but not of 5-Mec or 5-HMec. Lower demethylation activity (5-HMec) but no difference in global 5-Mec levels was observed in BD. This finding suggests that oxidative damage to 8-OHdG might be a potential marker of disease progression, although further prospective cross-sectional studies to confirm neuroprogression in BD are warranted.

Topics: 5-Methylcytosine; 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Adult; Bipolar Disorder; Cytosine; Deoxyguanosine; DNA; DNA Methylation; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Multivariate Analysis; Oxidation-Reduction; Oxidative Stress; Young Adult