Stress homeostatic mediators are the most consistently anomalous biomarkers observed in suicide and may therefore point to a common ‘core biology’ of stress susceptibility, and suicidal behaviour. Previously reported meta-analyses have demonstrated aberrant levels of stress cortisol and inflammatory cytokines in suicide patients compared to controls, and significant associations between the stress regulator FK506-binding protein 51 (FKBP5) gene and suicidal behaviour. Although these independent studies were investigated as separate entities in suicide, stress mediators interact in a dynamic system, collectively giving rise to system changes physiologically, and ultimately psychologically and behaviourally. It is therefore important to study the dynamic network these stress mediators. Network meta-analysis allows for the simultaneous comparison of more than two biological mediators, and for comparisons to be made between mediators that have not been directly compared before, using previously reported, pooled meta data. Such network approaches may help study the complex biological phenomena of suicide and may provide better prediction of biological risk of suicidal states.

Methods

This study aimed to establish the comparative relationships between key stress mediators in suicidal patients compared to non-suicidal controls using a random-effects network meta-analysis approach.. The key stress mediators included cortisol, six inflammatory markers (interleukin-6 (IL-6), interleukin-4 (IL-4), interleukin-2 (IL-2), tumour necrosis factor-a (TNF-α), interferon (IFN-y) and transforming growth factor β (TGF-β), and the FKBP5 single nucleotide polymorphism (SNP) allele. Data was derived from three previously published meta-analysis. The study population comprised of 1348 suicidal patients, defined as suicide attempters, completers, or patients with severe suicidal ideation, and 1750 non-suicidal controls, defined as healthy controls and psychiatric patients without suicidal ideation or previous attempts.

Results

Pair-wise indirect effects of stress mediators in suicide compared to controls demonstrated that relative to the effect of the FKBP5 risk SNP allele on suicide risk, the magnitude of differences (suicide vs control) for the levels of IL-2 (SMD −0.72; 95% CI, −0.135 to −0.09 and IL-4 (SMD −0.71; 95% CI, −1.34 to −0.08) were significantly smaller (with 95% confidence intervals not crossing the null). The comparative relationships between stress mediators in suicidal behaviour demonstrates that the dynamic stress network relationship is dysregulated in suicide patients when compared to controls.

Conclusions

This model suggests that a genetic stress susceptibility with downstream abnormal cortisol stress axis functioning, together with anomalous interactions between the inflammatory system, may be one of the neurobiological correlates of suicide behaviour. This biological state may leave the individual physiologically susceptible and unable to cope with environmental stressors, which is consistent with the stress-diathesis hypothesis of suicide behaviour.

中文翻译：

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自杀行为中压力介质的网络荟萃分析

压力稳态介质是在自杀中观察到的最一致的异常生物标志物，因此可能指向压力易感性和自杀行为的共同“核心生物学”。先前报道的荟萃分析表明，与对照组相比，自杀患者的应激皮质醇和炎性细胞因子水平异常，并且应激调节因子 FK506 结合蛋白 51 ( FKBP5) 基因和自杀行为。尽管这些独立研究被作为独立的自杀实体进行调查，但压力介质在动态系统中相互作用，共同引起生理上的系统变化，最终导致心理和行为上的变化。因此，研究这些压力介质的动态网络非常重要。网络荟萃分析允许同时比较两个以上的生物介质，并允许在以前未直接比较的介质之间进行比较，使用先前报告的汇总元数据。这种网络方法可能有助于研究自杀的复杂生物学现象，并可以更好地预测自杀状态的生物学风险。

方法

本研究旨在使用随机效应网络荟萃分析方法建立自杀患者与非自杀对照组的关键压力介质之间的比较关系。关键压力介质包括皮质醇、六种炎症标志物（白细胞介素 6（IL- 6)、白细胞介素-4(IL-4)、白细胞介素-2(IL-2)、肿瘤坏死因子-α(TNF-α)、干扰素(IFN-γ)和转化生长因子β(TGF-β)，和FKBP5 _单核苷酸多态性（SNP）等位基因。数据来自三个先前发表的荟萃分析。研究人群包括 1348 名自杀患者，定义为自杀未遂者、完成者或有严重自杀意念的患者，以及 1750 名非自杀对照，定义为健康对照和没有自杀意念或先前尝试的精神病患者。

结果

与对照组相比，自杀压力介质的成对间接影响表明，相对于FKBP5风险 SNP 等位基因对自杀风险的影响，IL-2 水平的差异幅度（自杀与对照组）（SMD -0.72； 95% CI，-0.135 至 -0.09 和 IL-4（SMD -0.71；95% CI，-1.34 至 -0.08）显着更小（95% 置信区间不跨越零值）。自杀行为表明，与对照组相比，自杀患者的动态压力网络关系失调。

结论

该模型表明，与下游异常皮质醇应激轴功能的遗传应激易感性以及炎症系统之间的异常相互作用可能是自杀行为的神经生物学相关性之一。这种生物状态可能使个体在生理上容易受到影响，无法应对环境压力，这与自杀行为的压力素质假说一致。