Neurobiological Underpinnings of Two Suicidal Subtypes

 描述(申请人提供)：2011年，41,146名美国人死于自杀，超过了2010年令人震惊的38,364人。自杀行为(死亡/未遂)与神经生物学、神经认知和行为因素有关，但综合的、多模式的研究很少。通常，对理解未来风险至关重要的前瞻性研究集中在单一预测因素和单一结果上，这意味着SB是同质的。然而，某人是复杂和多种多样的：它可以是冲动的，也可以是有条不紊地计划的；无论是否暴力，对生活事件的反应 或者在没有明显的压力源暗示不同的亚型的情况下发生。作为分离这些亚型的第一步，我们的模型在我们的试点数据的支持下，假设了两种假定的SB表型与不同的自杀意念(SI)模式相关。我们发现了一种不同的自杀意念模式，通常发生在有创伤病史的个体中，他们对环境应激源的反应具有攻击性，显著的皮质醇反应和可变的SI，部分原因是前额叶区域难以参与影响调节。相反，我们假设当SI升高但波动很小时，它与钝化的5-羟色胺能功能有关，并且 更大的认知控制导致更有计划和更致命的某人。Conte Center(CC)P50-MH090964对严重抑郁症的SB进行横断面研究。我们试图跟踪这个队列和一个新登记的抑郁症患者样本，为期2年，这是最高风险期。基线CC评估意味着显著节省成本，并最大限度地利用丰富的数据集，包括：RA的点减攻击模式、使用我们的新激动剂进行PET成像、用于量化5-HT1ABPF的[11C]CUMI-101，以及MRI扫描仪中的认知情绪调节任务。我们将实施Stroop和持续绩效任务，以评估认知控制，并使用临床和生态瞬时评估(EMA)前瞻性地量化SI和SB、生活事件和抑郁症。主要创新是：(1)前瞻性、多模式设计；(2)描述两种不同的SB亚型，这可能产生更稳健的预测因子；(3)评估情绪调节，可以预测SI和SB；(4)使用EMA实时描述SI的起源；(5)实验室评估，以表征自杀亚组的轨迹。影响：在大的一般人群样本中，大多数自杀未遂者报告了SI(NESARC[94.2%]；NLAES[86.8%])，然而&GT；50%的自杀者之前没有SB。因此，以前的SB作为未来SB的预测因子是有限的，尤其是自杀死亡，因此更好地理解SI对于提高对SB的预测和理解是至关重要的。关键是，如果变量SI是冲动自杀企图的先兆，那么描述与之相关的不同的生物学和临床特征，可能有助于描述不同的风险模式。最终，它可能会在未来帮助 确定某人的不同表情/表型的风险人群。此外，未来的研究可能会检验针对可变SI的影响调节的药物或心理干预的优点，与针对持续性SI的抗抑郁药物或认知治疗的优点。

 DESCRIPTION (provided by applicant): In 2011, 41,146 Americans died by suicide, surpassing the alarming 2010 toll of 38,364. Suicidal behavior (SB) (deaths/attempts) is linked to neurobiological, neurocognitive and behavioral factors, but integrative, multimodal studies are rare. Often, prospective studies, crucial to understanding future risk, have focused on single predictors and a single outcome, implying that SB is homogeneous. Yet, SB is complex and heterogeneous: it can be impulsive or methodically planned; violent or not, reactive to life events or occur despite no obvious stressors suggesting different subtypes. As a first step towards disentangling these subtypes, our model, supported by our pilot data, posits 2 putative phenotypes of SB associated with different patterns of suicidal ideation (SI). We have identified a variable pattern of suicidal ideation typically occurring in individuals with a trauma history wh react to environmental stressors with aggression, pronounced cortisol response and variable SI, in part due to difficulty engaging prefrontal regions in affect regulation. In contrast, we posit tat when SI is elevated but with little fluctuation, it is linked to blunted serotonergic function, and greater cognitive control leading to more planned and lethal SB. The Conte Center (CC) P50-MH090964, conducts cross-sectional studies of SB in Major Depression. We seek to follow this cohort and a newly enrolled sample of depressed patients for 2 years, the highest risk period. Baseline CC assessments mean significant cost savings and maximize use of a rich dataset including: Point-Subtraction Aggression Paradigm for RA, PET imaging with our new agonist, [11C]CUMI-101 to quantify 5-HT1A BPF, and a cognitive emotion regulation task in the MRI scanner. We will administer Stroop and Continuous Performance Tasks to assess cognitive control and prospectively quantify SI and SB, life events and depression using clinical and Ecological Momentary Assessments (EMA). Key innovations are: (1) prospective, multi-modal design to (2) delineate 2 distinct SB subtypes, which may yield more robust predictors; (3) assessment of emotion regulation which may predict SI and SB; (4) use of EMA to delineate origins of SI in real time; (5) Laboratory assessments to characterize trajectories of suicidal subgroups. Impact: In large general population samples, most suicide attempters report SI (NESARC [94.2%]; NLAES [86.8%]), yet >50% of suicides had no prior SB. Thus, prior SB is limited as a predictor of future SB, especially suicide death, so better understanding of SI is crucial to improving prediction and understanding of SB. Critically, if variable SI is a harbinger f impulsive suicide attempts, then delineation of distinct biological and clinical features associate with it or not, may help delineate different risk patterns. Ultimately, it may aid in prospectively identifying those at risk for different expressions/phenotypes of SB. Moreover, future studies could examine the merits of pharmacologic or psychological interventions targeting affect regulation for variable SI, versus antidepressants or cognitive treatments for sustained SI.