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In vivo imaging of a neural marker of suicidal behavior in Bipolar Disorder

双相情感障碍自杀行为神经标志物的体内成像

基本信息

批准号：
10307146
负责人：
Irina Esterlis
金额：
$ 78.74万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10307146
关键词：
Acute Advisory Committees Age Animal Model Autopsy Behavior Behavioral Behavioral Mechanisms Bipolar Disorder Brain Brain region Brain scan Chronic Data Detection Development Disease Exhibits Face Feeling suicidal Functional Magnetic Resonance Imaging Functional disorder Genes Glutamates High Prevalence Impulsive Behavior Impulsivity Individual Knowledge Left Life Measures Methods Molecular Molecular Target Moods Patient Self-Report Patients Persons Pharmaceutical Preparations Play Positron-Emission Tomography Prefrontal Cortex Prevalence Prevention Proteins Psychiatry Recording of previous events Reflex action Regulation Research Research Domain Criteria Rewards Risk Risk Reduction Role Scaffolding Protein Severities Sex Behavior Sex Differences Suicide Suicide attempt Suicide prevention Symptoms Synaptic plasticity System Time Woman cognitive process cognitive testing comparison control comparison group completed suicide design disorder risk effective therapy emotion regulation endophenotype experience high risk improved in vivo in vivo imaging innovation insight interdisciplinary approach men monoamine mood regulation neural neuromechanism neurotransmission new therapeutic target novel pre-clinical receptor reducing suicide response reward processing sex suicidal behavior suicidal risk suicide attempter suicide mortality suicide rate trait treatment strategy

项目摘要

PROJECT SUMMARY: Bipolar disorder (BD) is associated with a suicide attempt rate of up to 50% and completion rate of up to 20%, making prevention and treatment of suicidal behavior in BD one of the most critical challenges that Psychiatry faces. Women with BD have much higher rate of suicide attempts (SA) than men, and completion rates are on the rise. The RDoC Suicide Task Force revealed several endophenotypes that may distinguish attempters versus non-attempters including reward responsiveness and response inhibition. Further, evidence from fMRI studies indicates that attempters and non-attempters have different brain responses to reward and inhibition tasks. Alterations have been observed in the dlPFC and OFC, and these are also the brain regions highly associated with the suicide-related endophenotypes. Unfortunately, the molecular mechanisms underlying suicidal behavior are not well elucidated and current medications are often ineffective in reducing the rates of suicide completion. In order to provide more effective treatments for the highly prevalent suicidal behavior in BD, it is necessary to elucidate the molecular mechanisms that underlie its associated features, so that they can be targeted with new treatments in men and women with BD. We have exciting new preliminary evidence supporting the involvement of cortical metabotropic glutamatergic receptors (mGluR5s) in suicidal behavior. mGluR5 aid in regulation of other glutamatergic receptors, neurotransmission and synaptic plasticity, which are all critical to healthy mood regulation and cognitive processes. Modulation of mGluR5 was shown to play a role in reward processing and impulsivity, and mGluR5 associated genes and proteins have been implicated in suicide specifically. Our novel in vivo data suggest that higher dlPFC and OFC mGluR5 availability may be a trait marker of suicidal behavior in BD and may therefore aid with the identification of patients at higher risk for completed suicide. We built upon this knowledge and developed an innovative multidisciplinary approach to studying this novel mechanism in suicidal behavior. State of the art positron emission tomography (PET) methods will be used to measure prefrontal cortical mGluR5 levels in groups of individuals with BD who have and have not attempted suicide in the past. The relationships between mGluR5 levels and suicide-related endophenotypes will be assessed. Importantly, we will examine the role of sex in the association between severity of dysregulation in mGluR5 and suicide related endophenotypes, with the hypothesis that women will exhibit a greater extent of dysregulation in mGluR5 as compared to men. Further, we hypothesize that individuals in the BD attempt group will have the greatest dysregulation in mGluR5, and that this will be associated with greatest deficits in the related endophenotypes. These results may lead to a breakthrough in determining a mechanism that may be important in the pathophysiology of suicidal behavior, and one that can be targeted for critically-needed improved detection, treatment and prevention of suicide in BD and potentially other high-risk disorders.

项目总结：双相情感障碍（BD）与高达50%和50%的自杀企图率相关