Daray Federico M, Chiapella Luciana Carla, Grendas Leandro Nicolás, Casiani Romina Isabel Álvarez, Olaviaga Alejandro, Robetto Josefina, Prokopez Cintia Romina, Carrera Silva Eugenio Antonio, Errasti Andrea Emilse, Neupane Sudan Prasad
Instituto de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, Piso 9, Ciudad Autónoma de Buenos Aires, C1121ABG, Argentina.
Instituto de Medicina Experimental (IMEX), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Academia Nacional de Medicina, Ciudad Autónoma de Buenos Aires, Argentina.
Mol Psychiatry. 2024 Dec;29(12):3874-3892. doi: 10.1038/s41380-024-02587-5. Epub 2024 May 27.
Previous meta-analyses have documented the association of immune-inflammatory pathways with the pathophysiology of Major Depressive Episode (MDE), as reflected by alterations in peripheral blood immune cell counts. However, it remains unclear whether these immunological changes are distinct in individuals experiencing suicidal ideation (SI) or suicidal behavior (SB), beyond the context of an MDE. This systematic review and meta-analysis aimed to examine peripheral immune cell profiles across samples with SI/SB and compare them to healthy controls or patients with MDE. A systematic literature search was conducted in MEDLINE, Embase, and PsycINFO for articles published from inception until June 12, 2023. Two independent reviewers screened the articles for inclusion, extracted data, and assessed the risk of bias using the Newcastle-Ottawa scale. Meta-analyses were performed using a random-effects model to calculate standardized mean differences (SMDs) and 95% confidence intervals (CIs) for immune cell counts or ratios between groups with and without SI/SB. Heterogeneity across studies was assessed using the restricted maximum-likelihood estimator for tau statistic and I-statistic and tested by the Q test. Publication bias was evaluated using the Egger´s test and funnel plots. Meta-regression analyses were conducted to explore the potential moderating effects of age, gender, current or lifetime SI/SB, and the type of self-harming behavior (SI or SB). The study was registered with PROSPERO (CRD42023433089). The systematic review included 30 studies, with data from 19 studies included in the meta-analyses comprising 139 unique comparisons. Eleven different cell populations or ratios were included, comprising 1973 individuals with SI/SB and 5537 comparison subjects. White blood cell (WBC) and neutrophil counts were higher in individuals with SI/SB than in controls (WBC: SMD = 0.458; 95% CI = 0.367-0.548; p value ≤ 0.001; I = 0.002% and; Neutrophils: SMD = 0.581; 95% CI = 0.408-0.753; p < 0.001), indicating an inflammatory process. The neutrophil-to-lymphocyte ratio (NLR) emerged as a potential marker, demonstrating a notable elevation in individuals with SI/SB (SMD = 0.695; 95% CI = 0.054-1.335; p value = 0.033; I = 94.281%; Q test p value ≤ 0.001). The elevated NLR appears to be primarily driven by the increase in neutrophil counts, as no significant differences were found in lymphocyte counts between groups. Comparisons among participants with and without SI/SB and depression revealed similar trends with increased NLR, monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) observed in depressed individuals with SI/SB compared to those without SI/SB. Broad alteration in the peripheral immune cell populations and their ratios were observed in individuals with SI/SB, indicating an immune activation or dysfunction. Notably, these immunological changes were also evident when comparing MDE individuals with and without SI/SB, suggesting that such immune dysfunction associated with suicidality cannot be solely attributed to or explained by depressive symptoms. The NLR, MLR, and PLR ratios, in combination with novel immune cellular and protein biomarkers, open new avenues in understanding the immunological underpinnings of SI/SB. These findings highlight the potential utility of immune markers as part of a multi-modal approach for risk stratification and therapeutic monitoring in SI/SB.
既往的荟萃分析记录了免疫炎症通路与重度抑郁发作(MDE)病理生理学之间的关联,这在外周血免疫细胞计数的改变中有所体现。然而,在MDE背景之外,这些免疫变化在有自杀意念(SI)或自杀行为(SB)的个体中是否独特仍不清楚。本系统评价和荟萃分析旨在研究有SI/SB的样本中的外周免疫细胞谱,并将其与健康对照或MDE患者进行比较。在MEDLINE、Embase和PsycINFO中进行了系统的文献检索,以查找从创刊至2023年6月12日发表的文章。两名独立的审阅者筛选文章以纳入研究、提取数据,并使用纽卡斯尔-渥太华量表评估偏倚风险。使用随机效应模型进行荟萃分析,以计算有和没有SI/SB的组之间免疫细胞计数或比率的标准化平均差(SMD)和95%置信区间(CI)。使用tau统计量和I统计量的受限最大似然估计器评估研究间的异质性,并通过Q检验进行检验。使用Egger检验和漏斗图评估发表偏倚。进行了荟萃回归分析,以探讨年龄、性别、当前或终生的SI/SB以及自我伤害行为类型(SI或SB)的潜在调节作用。该研究已在PROSPERO(CRD42023433089)注册。该系统评价纳入了30项研究,荟萃分析纳入了19项研究的数据,包括139项独特的比较。纳入了11种不同的细胞群体或比率,包括1973名有SI/SB的个体和5537名对照受试者。有SI/SB的个体的白细胞(WBC)和中性粒细胞计数高于对照组(WBC:SMD = 0.458;95%CI = 0.367 - 0.548;p值≤0.001;I = 0.002%;中性粒细胞:SMD = 0.581;95%CI = 0.408 - 0.753;p < 0.001),表明存在炎症过程。中性粒细胞与淋巴细胞比率(NLR)成为一个潜在标志物,在有SI/SB的个体中显著升高(SMD = 0.695;95%CI = 0.054 - 1.335;p值 = 0.033;I = 94.281%;Q检验p值≤0.001)。NLR升高似乎主要由中性粒细胞计数增加驱动,因为两组之间淋巴细胞计数未发现显著差异。有和没有SI/SB及抑郁症的参与者之间的比较显示出类似趋势,与没有SI/SB的抑郁症个体相比,有SI/SB的抑郁症个体中观察到NLR、单核细胞与淋巴细胞比率(MLR)和血小板与淋巴细胞比率(PLR)升高。在有SI/SB的个体中观察到外周免疫细胞群体及其比率的广泛改变,表明免疫激活或功能障碍。值得注意的是,在比较有和没有SI/SB的MDE个体时,这些免疫变化也很明显,这表明与自杀倾向相关的这种免疫功能障碍不能仅仅归因于或由抑郁症状来解释。NLR、MLR和PLR比率,结合新的免疫细胞和蛋白质生物标志物,为理解SI/SB的免疫基础开辟了新途径。这些发现突出了免疫标志物作为SI/SB风险分层和治疗监测的多模式方法一部分的潜在效用。
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