Identifying Predictors in the HPA Axis and Inflammatory Pathways for Suicidal Behavior in Youth

确定 HPA 轴和炎症通路中青少年自杀行为的预测因素

• 批准号: 9234320
• 负责人: Nadine M. Melhem
• 金额: $ 70.45万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-17 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234320
• 关键词: Acute; Age; Aggressive behavior; Autopsy; Behavioral; Biological; Biological Markers; Brain; C-reactive protein; Cause of Death; Cessation of life; Child Abuse; Clinical; Cognition; Data; Decision Making; Development; Disease susceptibility; Down-Regulation; Feeling suicidal; Frequencies; Future; Gene Expression; Genes; Glucocorticoid Receptor; Hair; Hospitalization; Hospitals; Hydrocortisone; Impulsivity; Incidence; Inflammation; Inflammatory; Inpatients; Intake; Intervention; Longitudinal Studies; Measures; Memory; Mental disorders; Messenger RNA; Modeling; Monitor; Pathway interactions; Patients; Performance; Pilot Projects; Psychopathology; Race; Reaction; Recording of previous events; Recruitment Activity; Reporting; Research Design; Risk; Sampling; Sleep disturbances; Stress; Suicide; Suicide attempt; TNF gene; Time; Up-Regulation; Youth; accomplished suicide; aged; attentional bias; base; behavior measurement; biological adaptation to stress; high risk; hypothalamic-pituitary-adrenal axis; ideation; improved; inflammatory marker; new therapeutic target; receptor expression; sex; stressor; suicidal behavior; suicidal patient; suicidal risk; suicide attempter; suicide brain; young adult

While suicidal behavior occurs in the context of many psychiatric disorders, relatively few subjects with a psychiatric disorder attempt suicide. One of the most challenging tasks for clinicians is to identify which patients will actually go on to attempt suicide. Studies find no association between clinicians' prediction for a patient and their actual suicidal behavior. Thus, it is critical to identify objective biological signatures for suicidal behavior, the 2nd leading cause of death among youth. In an R21 pilot study, we found that inpatients admitted for their first suicide attempt had lower hair cortisol concentrations (HCC) compared to those admitted for suicidal ideation and healthy controls. HCC provides a retrospective assessment of cortisol levels over the past few months and thus prior to attempt in our R21. Lower HCC were also associated with increased lethality of the attempt within attempters. Suicide attempters also differed by their lower glucocorticoid receptor (GR) mRNA and increased inflammation. In this R01, we propose to recruit a large sample of psychiatric inpatients (n=300), aged 18-30 years, with no prior history of suicidal behavior and enriched for suicidal ideation; and healthy controls (n=50); and follow them at 3, 6, and 12 months from intake. The risk for suicidal behavior is especially high during the first year after psychiatric hospitalization. We will collect biological data on HCC, gene expression in the HPA axis and inflammatory pathways, and systemic markers of inflammation (e.g., C- Reactive Protein, Tumor Necrosis Factor-α); and data on already-established clinical and behavioral predictors for suicidal behavior. We hypothesize that low HCC and downregulation of HPA axis genes together with upregulation of inflammatory genes and increased systemic inflammation at baseline will predict future suicidal behavior. Similarly, the trajectories of these biological alterations over time will be associated with worsening of clinical (impulsivity, aggression, sleep disturbances) and behavioral measures (decision-making, memory, and suicide-specific attentional biases and implicit cognitions). The models combining biological, clinical, and behavioral measures will show better performance in predicting attempts compared to models combining clinical and behavioral measures. We also propose to collect hair samples from subjects, aged 18-30 years, who died by suicide and compare them to those who died from accidental deaths on HCC, which reflects cortisol levels prior to death; we will also compare them on HCC to patients with no ideation, those with ideation, and those who go on to attempt suicide and thus examine the relation of HCC to risk across the full spectrum of suicidal behavior. This study is the first to examine the ability of biological markers in the HPA axis and inflammatory pathways to predict suicidal behavior and to examine them combined with clinical and behavioral predictors. This study will help better identify patients at highest risk who can then be targeted for closer monitoring and interventions; and will improve our understanding of the biological pathways for suicidal behavior, which will guide new therapeutic targets.

虽然自杀行为发生在许多精神疾病的背景下，但具有自杀倾向的受试者相对较少。 对于牧师来说，最具挑战性的任务之一是确定哪些精神疾病试图自杀。 患者实际上会继续尝试自杀 研究发现追随者的预测之间没有关联。 因此，确定自杀的客观生物学特征至关重要。 行为是青少年死亡的第二大原因 在一项 R21 试点研究中，我们发现住院患者入院。 与那些因第一次自杀而入院的人相比，他们的头发皮质醇浓度（HCC）较低 自杀意念和健康对照提供了过去皮质醇水平的回顾性评估。 因此，在我们尝试 R21 之前的几个月，较低的 HCC 也与死亡率增加有关。 自杀未遂者的不同之处在于他们的糖皮质激素受体（GR）较低。 mRNA 和炎症增加 在这个 R01 中，我们建议招募大量精神病住院患者样本。 (n=300)，年龄 18-30 岁，既往没有自杀行为史，且有自杀意念；以及 健康对照（n=50）；并在摄入后 3、6 和 12 个月进行随访。自杀行为的风险为。 在精神病院住院后的第一年尤其高，我们将收集 HCC 的生物学数据， HPA 轴和炎症通路中的基因表达，以及炎症的全身标志物（例如，C- 反应蛋白、肿瘤坏死因子-α）以及已建立的临床和行为预测因子的数据； 我们勇敢地面对低 HCC 和 HPA 轴基因的下调。 基线时炎症基因的上调和全身炎症的增加将预测未来的自杀倾向 类似地，随着时间的推移，这些生物变化的轨迹将与病情恶化相关。 临床（冲动、攻击性、睡眠障碍）和行为测量（决策、记忆和行为） 自杀特异性注意偏差和内隐认知）结合了生物学、临床和认知的模型。 与组合模型相比，行为测量在预测尝试方面将表现出更好的性能 我们还建议收集 18-30 岁受试者的头发样本， 那些因自杀而死亡的人，并将他们与死于 HCC 的意外死亡的人进行比较，这反映了 我们还将 HCC 患者与无意识患者、有意识患者的皮质醇水平进行比较。 以及那些继续尝试自杀的人，从而检查 HCC 与整个风险的关系 这项研究首次检验了 HPA 轴生物标记的能力。 和炎症途径来预测自杀行为，并结合临床和研究来检查它们 这项研究将有助于更好地识别风险最高的患者，然后将其作为治疗目标。 更密切的监测和干预；并将提高我们对自杀的生物学途径的理解； 行为，这将指导新的治疗目标。