Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
MindX Sciences, Indianapolis, IN, USA.
Transl Psychiatry. 2024 Sep 6;14(1):362. doi: 10.1038/s41398-024-03071-y.
Suicidality remains a clear and present danger in society in general, and for mental health patients in particular. Lack of widespread use of objective and/or quantitative information has hampered treatment and prevention efforts. Suicidality is a spectrum of severity from vague thoughts that life is not worth living, to ideation, plans, attempts, and completion. Blood biomarkers that track suicidality risk provide a window into the biology of suicidality, as well as could help with assessment and treatment. Previous studies by us were positive. Here we describe new studies we conducted transdiagnostically in psychiatric patients, starting with the whole genome, to expand the identification, prioritization, validation and testing of blood gene expression biomarkers for suicidality, using a multiple independent cohorts design. We found new as well as previously known biomarkers that were predictive of high suicidality states, and of future psychiatric hospitalizations related to them, using cross-sectional and longitudinal approaches. The overall top increased in expression biomarker was SLC6A4, the serotonin transporter. The top decreased biomarker was TINF2, a gene whose mutations result in very short telomeres. The top biological pathways were related to apoptosis. The top upstream regulator was prednisolone. Taken together, our data supports the possibility that biologically, suicidality is an extreme stress-driven form of active aging/death. Consistent with that, the top subtypes of suicidality identified by us just based on clinical measures had high stress and high anxiety. Top therapeutic matches overall were lithium, clozapine and ketamine, with lithium stronger in females and clozapine stronger in males. Drug repurposing bioinformatic analyses identified the potential of renin-angiotensin system modulators and of cyclooxygenase inhibitors. Additionally, we show how patient reports for doctors would look based on blood biomarkers testing, personalized by gender. We also integrated with the blood biomarker testing social determinants and psychological measures (CFI-S, suicidal ideation), showing synergy. Lastly, we compared that to machine learning approaches, to optimize predictive ability and identify key features. We propose that our findings and comprehensive approach can have transformative clinical utility.
自杀仍然是一个普遍存在的明显危险,特别是对于心理健康患者。缺乏广泛使用客观和/或定量信息,阻碍了治疗和预防工作。自杀是从生活不值得活下去的模糊想法到意念、计划、尝试和完成的严重程度谱。跟踪自杀风险的血液生物标志物为自杀生物学提供了一个窗口,也可以帮助评估和治疗。我们之前的研究是积极的。在这里,我们描述了我们在精神科患者中进行的新的跨诊断研究,从全基因组开始,以扩大识别、优先排序、验证和测试自杀的血液基因表达生物标志物,使用多个独立队列设计。我们使用横断面和纵向方法发现了新的和以前已知的生物标志物,这些标志物可预测高自杀状态和与之相关的未来精神病院住院治疗。整体上调表达的生物标志物是 SLC6A4,即血清素转运体。下调的生物标志物是 TINF2,其突变导致非常短的端粒。顶级生物学途径与细胞凋亡有关。顶级上游调节剂是泼尼松龙。总的来说,我们的数据支持这样一种可能性,即从生物学角度来看,自杀是一种极端的应激驱动的主动衰老/死亡形式。与之一致的是,我们根据临床测量确定的自杀的顶级亚型具有高应激和高焦虑。总体上的最佳治疗匹配是锂、氯氮平和氯胺酮,其中锂在女性中更强,氯氮平在男性中更强。药物再利用生物信息学分析确定了肾素-血管紧张素系统调节剂和环氧化酶抑制剂的潜在用途。此外,我们展示了基于血液生物标志物测试的医生如何为患者提供报告,根据性别进行个性化定制。我们还将血液生物标志物测试的社会决定因素和心理测量(CFI-S、自杀意念)与性别进行了整合,显示出协同作用。最后,我们将其与机器学习方法进行了比较,以优化预测能力并确定关键特征。我们提出,我们的发现和综合方法可以具有变革性的临床实用性。
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