Evaluating Oxidative Stress Markers in At-Risk Individuals for Bipolar Disorder: A Systematic Review and Meta-Analysis

Introduction: Bipolar disorder (BD), a mood disorder with recurrent affective episodes and a strong genetic basis is frequently associated with significant comorbidities, both physical and psychiatric, yet its neurobiology remains unclear. Recent evidence underscores oxidative stress as a pivotal factor linking BD to its comorbidities, prompting an investigation into whether this is a sign of a genetic vulnerability or a consequence of the disease. In this study, we systematically reviewed oxidative stress studies conducted on individuals at risk for BD. We performed a meta-analysis on studies examining oxidative DNA damage in these individuals. Methods: The literature was searched across the databases PubMed, Web of Science, Scopus, Ovid MEDLINE, and Cochrane to locate studies of oxidative stress markers in relatives of patients with BD compared with healthy controls (from 1946 to March 2024). Studies were considered for inclusion based on the following criteria: (i) involvement of first- or second-degree relatives of individuals diagnosed with BD, (ii) presence of a healthy control group, (iii) reporting of oxidative stress parameters for relatives, including mean and standard deviation or median and interquartile range (25-75%) values, and (iv) publication in the English language. Studies comparing the levels of 8-hydroxy-2 '-deoxyguanosine (8-OH-dG) or its tautomer 8-oxo-7,8-dihydro-2 '-deoxyguanosine (8-oxo-dG) in individuals at risk for BD with healthy controls were evaluated using a meta-analysis with the random-effects method. The risk of bias was evaluated using the Risk of Bias in Non-Randomized Studies of Exposure (ROBINS-E) tool. Results: Eleven studies were included in the systematic review and four studies for the meta-analysis. The meta-analysis included 543 individuals (first-degree relatives of individuals with BD = 238, control = 305). 8-OH-dG levels were found to be increased in first-degree relatives of individuals with BD compared to healthy controls (random effects: Hedges's g = 0.53, 95% CI = 0.36-0.71, p < 0.001). Findings of oxidative stress markers other than oxidative DNA damage in relatives of individuals with BD are limited and scarce. Conclusion: In this meta-analysis, which consists of a limited number of studies, oxidative DNA damage seems to be a trait marker for BD. This finding could be associated with increased comorbidity and a higher risk of premature aging in individuals at risk for BD. However, further studies with larger sample sizes and longitudinal designs are warranted to confirm findings. Clarifying the changes in these markers from individuals at risk for the disorder throughout the course of the illness would help bridge the gap in understanding the role of oxidative pathways in the risk of BD.