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.

尽管自杀行为发生在许多精神疾病的背景下，但相对较少的受试者 精神障碍尝试自杀。临床医生最挑战的任务之一是确定哪个 患者实际上会继续自杀。研究发现临床医生对 病人及其实际的自杀行为。这一点至关重要的是要确定自杀的客观生物学特征 行为，年轻人的第二大死亡原因。在一项R21试点研究中，我们发现住院患者允许 因为他们的第一次自杀尝试具有较低的头发皮质醇浓度（HCC） 自杀的想法和健康控制。 HCC过去对皮质醇水平进行回顾性评估 几个月，因此在我们的R21尝试之前。较低的HCC也与杀伤性升高有关 试图在Attempter中。自杀式植物的较低糖皮质激素受体（GR）也有所不同 mRNA和增加感染。在此R01中，我们建议招募大量的精神病患者 （n = 300），年龄18-30岁，没有自杀行为的先前历史，并且以自杀的想法丰富；和 健康对照（n = 50）;并从摄入量3、6和12个月关注它们。自杀行为的风险是 在精神科住院后的第一年，尤其是高。我们将在HCC上收集生物学数据， HPA轴和炎症途径中的基因表达以及炎症的全身标志物（例如，C- 反应性蛋白质，肿瘤坏死因子-α）；以及有关已经建立的临床和行为预测因素的数据 用于自杀行为。我们假设HPA轴基因的低HCC和下调以及 炎症基因的上调和基线时的全身性炎症增加将预测未来的自杀 行为。同样，随着时间的推移，这些生物学改变的轨迹将与遗憾有关 临床（冲动，侵略性，睡眠障碍）和行为测量（决策，记忆和 自杀特异性的注意偏见和隐性认知）。结合生物学，临床和 与组合模型相比，行为措施将在预测尝试方面表现更好 临床和行为措施。我们还建议从18-30岁的受试者那里收集头发样本， 他们因自杀而死，并将其与因HCC意外死亡而死亡的人进行比较，这反映了 死亡前皮质醇水平；我们还将在HCC上与不知道的患者进行比较， 构想，以及那些继续尝试自杀并因此检查HCC与全面风险的关系的人 自杀行为的频谱。这项研究是第一个检查HPA轴上生物标记的能力的研究 以及预测自杀行为的炎症途径并检查它们与临床和 行为预测因素。这项研究将有助于更好地识别风险最高的患者，然后将其作为目标 密切的监控和干预措施；并将提高我们对自杀生物学途径的理解 行为，这将指导新的治疗靶标。