Supplementary Material for: 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 bipolar disorder, (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 warrented 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.

引言：双相情感障碍（Bipolar disorder, BD）是一类伴随反复发作情感发作且具有强遗传基础的心境障碍，常伴随显著的躯体及精神共病，但其神经生物学机制仍未明确。近期研究证据凸显氧化应激是连接BD与其共病的核心环节，这引发了关于氧化应激究竟是遗传易感性的标志，还是疾病本身继发后果的探讨。本研究针对双相情感障碍易感人群开展的氧化应激相关研究进行了系统综述，并对其中检测氧化DNA损伤的研究开展了荟萃分析。

方法：本研究检索了PubMed、Web of Science、Scopus、Ovid MEDLINE及Cochrane数据库，筛选1946年至2024年3月期间，对比BD患者亲属与健康对照者氧化应激标志物水平的相关研究。纳入研究需满足以下标准：(i) 研究对象为确诊双相情感障碍患者的一级或二级亲属；(ii) 设有健康对照组；(iii) 报告了研究对象的氧化应激参数，包括均值与标准差，或中位数与四分位间距（25%~75%）；(iv) 以英文发表。针对对比BD易感人群8-羟基-2'-脱氧鸟苷（8-hydroxy-2′-deoxyguanosine, 8-OH-dG）及其互变异构体8-氧代-7,8-二氢-2'-脱氧鸟苷（8-oxo-7,8-dihydro-2′-deoxyguanosine, 8-oxo-dG）水平的研究，采用随机效应法开展荟萃分析。采用非随机暴露研究偏倚风险（Risk of Bias in Non-randomized Studies - of Exposure, ROBINS-E）工具评估研究偏倚风险。

结果：本系统综述共纳入11项研究，荟萃分析纳入4项研究。荟萃分析共纳入543名研究对象（BD患者一级亲属238名，健康对照305名）。结果显示，与健康对照相比，BD患者一级亲属体内的8-OH-dG水平显著升高（随机效应模型：Hedges’s g = 0.53，95% CI = 0.36–0.71，p < 0.001）。针对BD患者亲属的其他氧化应激标志物（非氧化DNA损伤类）的相关研究结果有限且稀缺。

结论：本项纳入研究数量有限的荟萃分析结果显示，氧化DNA损伤似乎可作为BD的特质性标志物。该发现或与BD易感人群更高的共病风险及早衰风险相关。不过，仍需开展更大样本量及纵向设计的后续研究以验证上述发现。明确该类标志物在疾病全程中（从易感人群到发病后）的变化规律，将有助于填补我们在理解氧化通路在BD发病风险中作用的认知空白。