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2/2 - Inflammation and Stress Response in Familial and Nonfamilial Youth Suicidal Behavior

2/2 - 家族和非家族青少年自杀行为中的炎症和压力反应

基本信息

批准号：
10550199
负责人：
Joseph John Mann
金额：
$ 35.75万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-18 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10550199
关键词：
Accident and Emergency department Acute Admission activity Age Autoreceptors Binding Biological Blood specimen Brain Cause of Death Cells Chronic Chronic stress Clinical Clinical Data Complex Detection Event Family history of Feeling suicidal Frequencies Funding Future Genes Hair Hospitals Hydrocortisone Inflammation Inflammatory Inpatients Insula of Reil Interleukin-6 Knowledge Kynurenine Ligands Longitudinal Studies Machine Learning Measures Messenger RNA Methods Mitochondria Mitochondrial DNA Mood Disorders Near-Infrared Spectroscopy Neurocognitive Outpatients Parents Pathogenesis Pathway interactions Patients Peripheral Phenotype Plasma Positron-Emission Tomography Production Recording of previous events Reporting Respiration Risk Risk Behaviors Risk Factors Salivary Sampling Serotonin Severities Site Stress Suicide Suicide attempt TNF gene Time Tryptophan Universities Work Youth aged biological adaptation to stress clinical risk cytochrome c cytochrome c oxidase cytokine follow-up glial activation high risk hypothalamic-pituitary-adrenal axis improved indexing mitochondrial dysfunction neuroinflammation novel offspring oxidation peripheral blood predicting response psychosocial recruit resilience response social stress suicidal suicidal adolescent suicidal behavior suicidal risk transmission process young adult

项目摘要

Suicide is 2nd leading cause of death in the US youth, and rates have risen 33% in 17 years. Clinical risk factors alone have disappointing predictive power and biological predictors show promise but rarely separated into long- term and short-term predictors due to the challenge of detecting biological profiles shortly before suicide behavior (SB). We propose a novel pragmatic approach of examining biological risk profiles immediately after an acute suicidal crisis and then separating them into familial and nonfamilial risk profiles. Our collaborative work indicates a stress responsive biological phenotype associated with more lethal and familial SB where inflammation activates the kynurenine pathway depleting brain serotonin by shunting tryptophan away from serotonin toward kynurenine synthesis. Inflammation and neuroinflammation can potentially result from HPA axis and mitochondrial dysregulations. We also find HPA axis dysregulation and inflammation to be more pronounced in those with SB and family history of SB. We hypothesize familial factors to be mostly long-term and nonfamilial factors to be mostly short-term risk factors. We propose to examine short-term or proximal biological risk profiles for suicidal behavior (SB) in stress response and inflammatory pathways, peripherally and in the brain, and examine familial and nonfamilial biological mechanisms for SB in young adults. We will recruit 120 young adult psychiatric inpatients or outpatients, aged 18-30 years, 80 at high-risk for SB defined as those presenting to the emergency department (ED) or admitted for suicidal ideation (SI) with a plan and intent or SB in the last two weeks; and 40 at lower risk with no SB or SI with plan/intent in past 3 months. Groups will be frequency-matched on familial risk. We will collect: 1) clinical data; 2) hair to measure hair cortisol concentrations (HCC); 3) conduct the Trier Social Stress Task (TSST) to measure cortisol, peripheral inflammation (cytokines, kynurenine metabolites) and circulating cell free mitochondrial DNA (ccf-mtDNA); 4) PET imaging using [11C]ER176 ligand to measure neuroinflammation; and 5) near-infrared spectroscopy (NIRS) to measure in PFC oxidation state of cytochrome-c-oxidase (oxCOX), a brain marker of mitochondrial function. Patients will be followed up at 1, 3, and 12 months. The year post-hospital/ED discharge is a high-risk period for SB and the first 3 months is the highest risk period. We hypothesize high-risk patients will show higher [11C]ER176 PET binding and lower oxCOX at baseline. They will also show lower HCC and higher cortisol response to stress and higher inflammation and ccf-mtDNA prior and in response to stress at baseline. Offspring of attempters will show more severe biological profiles due to the contribution of short and longer-term risk factors. We will also examine the relationships between peripheral and brain measures and explore whether they predict SB. This study will improve our understanding of familial and nonfamilial biological mechanisms for SB to better separate long-term and short- term risk biological phenotypes, which will help guide risk detection and novel just-in-time approaches.

自杀是美国年轻人的第二大死因，17年来自杀率上升了33%。临床危险因素