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

项目总结：双相情感障碍（BD）与高达50%的自杀企图率相关， 完成率高达20%，使预防和治疗自杀行为在BD的最 精神病学面临的重大挑战。BD女性的自杀企图率（SA）远高于 男性，毕业率正在上升。RDoC自杀工作组揭示了几种内在表型 这可能会区分奖励者和非奖励者，包括奖励反应和反应。 抑制作用此外，来自fMRI研究的证据表明，运动员和非运动员具有不同的 大脑对奖励和抑制任务的反应。在dlPFC和OFC中观察到改变， 这些也是与自杀相关的内在表型高度相关的脑区域。可惜 自杀行为背后的分子机制尚未得到很好的阐明，目前的药物治疗往往 在降低自杀完成率方面无效。为了提供更有效的治疗， BD中自杀行为的高度流行，有必要阐明其背后的分子机制， 相关的功能，使他们可以有针对性的新的治疗方法在男性和女性的BD。我们有 令人兴奋的新的初步证据支持参与皮质代谢型多巴胺能受体 （mGluR5s）在自杀行为中的作用。mGluR5有助于调节其他谷氨酸能受体、神经传递 和突触可塑性，这些都对健康的情绪调节和认知过程至关重要。调制 mGluR5被证明在奖励处理和冲动中起作用，mGluR5相关基因和 蛋白质与自杀有着密切的关系。我们的新的体内数据表明，较高的dlPFC和 OFC mGluR5可用性可能是BD自杀行为的特征标记，因此可能有助于 确定自杀未遂风险较高的患者。我们建立在这些知识和开发一个 创新的多学科方法来研究自杀行为中的这种新机制。现有技术 正电子发射断层扫描（PET）方法将用于测量前额叶皮质mGluR5水平， 过去曾尝试自杀或未尝试自杀的BD患者群体。之间的关系 将评估mGluR5水平和自杀相关内源性表型。重要的是，我们将研究 性别在mGluR5失调严重程度和自杀相关内表型之间的相关性， 假设与男性相比，女性在mGluR5中表现出更大程度的失调。 此外，我们假设BD尝试组中的个体将具有最大的失调， mGluR5，并且这将与相关内表型的最大缺陷相关。这些结果 可能导致在确定一种机制方面的突破，这种机制可能在疾病的病理生理学中很重要。 自杀行为，和一个可以有针对性的急需改进的检测，治疗和 预防BD和其他潜在高危疾病中的自杀。

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.