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Fulltext 8-Hydroxy-2'-Deoxyguanosine and Reactive Oxygen Species as Biomarkers of Oxidative Stress in Mental Illnesses: A Meta-Analysis

Goh XX, Tang PY, Tee SF

Psychiatry Investig, 2021 Jul;18(7):603-618.
PMID: 34340273 DOI: 10.30773/pi.2020.0417

OBJECTIVE: Mental illnesses may be caused by genetic and environmental factors. Recent studies reported that mental illnesses were accompanied by higher oxidative stress level. However, the results were inconsistent. Thus, present meta-analysis aimed to analyse the association between oxidative DNA damage indicated by 8-hydroxy-2'-deoxyguanosine (8-OHdG) or 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), which has been widely used as biomarker of oxidative stress, and mental illnesses, including schizophrenia, bipolar disorder and depression. As oxidative DNA damage is caused by reactive oxygen species (ROS), systematic review and meta-analysis were also conducted to analyse the relationship between ROS and these three mental illnesses.
METHODS: Studies from 1964 to 2020 (for oxidative DNA damage) and from 1907 to 2021 (for ROS) in Pubmed and Scopus databases were selected and analysed using Comprehensive Meta-Analysis version 2 respectively. Data were subjected to meta-analysis for examining the effect sizes of the results. Publication bias assessments, heterogeneity assessments and subgroup analyses based on biological specimens, patient status, illness duration and medication history were also conducted.
RESULTS: This meta-analysis revealed that oxidative DNA damage was significantly higher in patients with schizophrenia and bipolar disorder based on random-effects models whereas in depressed patients, the level was not significant. Since heterogeneity was present, results based on random-effects model was preferred. Our results also showed that oxidative DNA damage level was significantly higher in lymphocyte and urine of patients with schizophrenia and bipolar disorder respectively. Besides, larger effect size was observed in inpatients and those with longer illness duration and medication history. Significant higher ROS was also observed in schizophrenic patients but not in depressive patients.
CONCLUSION: The present meta-analysis found that oxidative DNA damage was significantly higher in schizophrenia and bipolar disorder but not in depression. The significant association between deoxyguanosines and mental illnesses suggested the possibility of using 8-OHdG or 8-oxodG as biomarker in measurement of oxidative DNA damage and oxidative stress. Higher ROS level indicated the involvement of oxidative stress in schizophrenia. The information from this study may provide better understanding on pathophysiology of mental illnesses.
Effects of antipsychotics on antioxidant defence system in patients with schizophrenia: A meta-analysis

Goh XX, Tang PY, Tee SF

Psychiatry Res, 2022 Feb 03;309:114429.
PMID: 35150976 DOI: 10.1016/j.psychres.2022.114429

Theory of oxidative stress is suggested in the pathophysiology of schizophrenia. To determine the cause of impaired antioxidant defense system in schizophrenia, a meta-analysis was performed by selecting studies published from 1964 to 2021 from Pubmed and Scopus databases. Data were analysed using Comprehensive Meta-Analysis version 2 and calculated effect sizes were compared between unmedicated and medicated patients with schizophrenia and healthy controls. Heterogeneity, publication bias assessments and subgroup analyses of drug-free and drug-naïve patients, and patients treated with atypical and typical antipsychotics were conducted. Subgroup analysis of confounding factors including age, gender, illness duration and patient status was also conducted. We found that glutathione peroxidase (GPx) was significantly decreased in all patients. Significantly lower catalase (CAT), glutathione (GSH) and albumin (ALB) were found in unmedicated patients only. Both groups showed significantly weakened non-enzymatic antioxidant capacity. Subgroup analyses indicated that weakened non-enzymatic antioxidant capacity may be associated with schizophrenia. Antioxidant status was more impaired in drug-free patients compared with other subgroups. This indicated that antipsychotics may improve antioxidant defense system. Although effect sizes were smaller, future studies may focus on the effect of antipsychotic discontinuation. In overall, schizophrenia was associated with impaired antioxidant defense system especially the non-enzymatic antioxidant system.
Blood-based oxidation markers in medicated and unmedicated schizophrenia patients: A meta-analysis

Goh XX, Tang PY, Tee SF

Asian J Psychiatr, 2022 Jan;67:102932.
PMID: 34839098 DOI: 10.1016/j.ajp.2021.102932

Increased reactive species due to the effect of antipsychotics on oxidative stress may be involved in the development of schizophrenia. However, antipsychotics may have different direct antioxidant effects due to their chemical structures. The present meta-analysis aimed to investigate whether the cause increased oxidant status in schizophrenia patients is due to the illness or induction by antipsychotics. Studies published from 1964 to 2021 were selected from Pubmed and Scopus databases. Data were analysed using Comprehensive Meta-Analysis version 2. Effect sizes were calculated and compared between unmedicated and medicated patients and healthy controls. Heterogeneity and publication bias were assessed. Subgroup analyses were conducted on drug-free and drug-naïve patients, and patients treated with atypical and typical antipsychotics. We found that medicated patients had significantly higher malondialdehyde (MDA), thiobarbituric acid reactive substances (TBARS) and total oxidant status (TOS). Meanwhile, significantly increased plasma/serum MDA and nitric oxide (NO) were observed in unmedicated patients only. Higher lipid peroxidation in the drug-naïve group may be associated schizophrenia. However, both atypical and typical antipsychotics may worsen lipid peroxidation. Antipsychotic discontinuation in the drug-free group led to significantly increased plasma/serum NO, with larger effect size than the atypical antipsychotic group. In conclusion, medicated schizophrenia patients were more suffered from increased oxidative stress. Therefore, future study may focus on the mechanism of action of specific antipsychotic on oxidative stress.
Meta-analysis of soluble tumour necrosis factor receptors in severe mental illnesses

Goh XX, Tang PY, Tee SF

J Psychiatr Res, 2023 Sep;165:180-190.
PMID: 37515950 DOI: 10.1016/j.jpsychires.2023.07.014

Tumour necrosis factor (TNF), as an innate immune defense molecule, functions through binding to TNF receptor 1 (TNFR1) or TNF receptor 2 (TNFR2). Peripheral levels of soluble TNFR1 (sTNFR1) and soluble TNFR2 (sTNFR2) were widely measured in severe mental illnesses (SMIs) including schizophrenia (SCZ), bipolar disorder (BD) and major depressive disorder (MDD) but inconsistencies existed. Hence, the present meta-analysis was conducted to identify the overall association between plasma/serum sTNFR1 and sTNFR2 levels and SMIs. Published studies were searched using Pubmed and Scopus. Data were analysed using Comprehensive Meta-Analysis version 2. Hedges's g effect sizes and 95% confidence intervals were pooled using fixed-effect or random-effects models. Heterogeneity, publication bias and study quality were assessed. Sensitivity analysis and subgroup analysis were performed. Our findings revealed that sTNFR1 level was significantly higher in SMI, particularly in BD. The sTNFR2 level significantly elevated in SMI but with smaller effect size. These findings further support the association between altered immune system and inflammatory abnormalities in SMI, especially in patients with BD. Subgroup analysis showed that younger age of onset, longer illness duration and psychotropic medication raised both sTNFR levels, especially sTNFR1, as these factors may contribute to the activation of inflammation. Future studies were suggested to identify the causality between TNFR pathway and SCZ, BD and MDD respectively using homogenous group of each SMI, and to determine the longitudinal effect of each psychotropic medication on TNFR pathway.