Brain Markers of Anxiety Disorders and SSRI Treatment in Children and Adolescents

描述（由申请人提供）：焦虑症是儿童和青少年中非常普遍和致残的疾病，很少缓解和增加成年后抑郁、焦虑、药物滥用和自杀的风险。现有的治疗方法有效时可以降低发病率，但往往收效甚微。一项重要的策略是指导个体患者选择最有可能成功的治疗方法。尽管ssri类药物被广泛用于儿童焦虑症，但人们对这些药物如何发挥其治疗效果知之甚少。这种知识差距阻碍了以生物学为基础、假设驱动的突破的发展，无法指导患者采取个性化的最佳治疗策略。该提案旨在发现神经标记物，可用于了解SSRIs如何发挥其作用并为治疗决策提供信息。来自pi的已发表的工作和初步研究表明，介导恐惧反应的神经回路（特别是杏仁核-腹侧前额叶皮层[vPFC]回路）与焦虑症的病理生理学有关，可能与临床治疗反应有关。SSRI舍曲林是一种广泛使用的一线治疗药物，在对照临床试验的基础上，具有可变的缓解率（汇总估计为63%；范围：55-91%），本研究将对患有焦虑症（AD）的儿童和青少年（年龄范围：7-19岁）和健康对照（HC）的青少年进行杏仁核和杏仁核- vpfc功能的治疗前和治疗后功能MRI （fMRI）。目的是：1)比较儿童和青少年焦虑症（AD）和匹配健康对照（HC）受试者在治疗前的杏仁核反应性和杏仁核-腹侧前额叶皮层功能连通性（“耦合”）对威胁信号的影响；2)比较SSRI类药物舍曲林治疗与安慰剂（PBO）治疗AD青年杏仁核反应性和杏仁核- vpfc功能连通性（耦合）的变化（治疗前后）；3)表征阿尔茨海默青年患者治疗前杏仁核- vpfc功能连通性（和杏仁核反应性）与舍曲林治疗后反应的关系；4)研究发育对杏仁核反应性和杏仁核- vpfc功能连通性的影响，这些影响与AD、治疗变化和治疗反应的预测有关。这种方法是创新的，因为没有研究在安慰剂控制的设计中检查了患有焦虑症的儿童和青少年的脑功能与治疗反应之间的关系。这项工作的预期结果将有助于确定SSRI治疗对脑功能的影响以及调节SSRI治疗反应个体差异的脑机制。总体目标是帮助指导年轻患者接受更有可能成功的治疗，最大限度地减少反复试验的处方，并加快向患者提供有效护理。这项工作也将阐明焦虑相关的大脑目标，为儿童和青少年的新干预。

DESCRIPTION (provided by applicant): Anxiety disorders, highly prevalent and disabling conditions in children and adolescents, rarely remit and increase the risk of subsequent depression, anxiety, substance abuse, and suicide in adulthood. Available treatments when effective can reduce morbidity, but often yield only modest success. One important strategy would be to guide individual patients towards treatments that have the highest likelihood of treatment success. Although SSRIs are widely used for pediatric anxiety disorders, little is known about how these medications exert their therapeutic effects. This knowledge gap precludes the development of biologically-based, hypothesis-driven breakthroughs to guide patients towards individually-tailored, optimal treatment strategies. This proposal seeks to discover neural markers that can be used to understand how SSRIs exerts their effect and to inform treatment decisions. Published work and pilot studies from the PIs indicate that the neural circuitry (particularly amygdala- ventral prefrontal cortex [vPFC] circuitry) that mediates fear responding is relevant to the pathophysiology of anxiety disorders and may be related to clinical treatment response. In the context of a randomized, placebo-controlled clinical trial of the SSRI sertraline, a widely-used first-line treatment with a variable response rate (pooled estimate of 63%; range: 55-91%) based on controlled clinical trials, this study will perform pre- and post-treatment functional MRI (fMRI) of amygdala and amygdala-vPFC function in children and adolescents (age range: 7-19 years) with anxiety disorders (AD) and healthy comparison (HC) youths. The Aims are: 1) Compare amygdala reactivity and amygdala-ventral prefrontal cortex functional connectivity ('coupling') to signals of threat between children and adolescents with anxiety disorders (AD) and matched healthy control (HC) subjects prior to treatment; 2) Compare the change (pre- treatment vs. post-treatment) in amygdala reactivity and amygdala-vPFC functional connectivity (coupling) between AD youths treated with the SSRI sertraline and those treated with placebo (PBO); 3) Characterize the relationship between pre-treatment amygdala-vPFC functional connectivity (and amygdala reactivity) and subsequent sertraline treatment response in AD youths; and 4) Examine the effects of development on amygdala reactivity and amygdala-vPFC functional connectivity in relation to AD, treatment change, and predictor of treatment response. This approach is innovative as no study has examined the relationship between brain function on treatment response in children and adolescents with anxiety disorders in a placebo- controlled design. The expected outcome of this work will be to help identify the effects of SSRI treatment on brain function and the brain mechanisms that mediate individual differences SSRI treatment response. The broad goal is to help to guide young patients towards treatments with higher likelihood of success, minimize trial-and-error prescribing and speed delivery of effective care to patients. This work will also elucidate anxiety- related brain targets for novel interventions in children and adolescents. PUBLIC HEALTH RELEVANCE: Anxiety disorders are highly prevalent, disabling, difficult-to-treat mental disorders that occur in children and adolescence; they can persist through life and increase the risk of subsequent depression, substance abuse, and suicide. Effective, and well-targeted interventions initiated early in the course of anxiety disorders has the potential to alleviate the burden, co-morbidity, and suffering associated with the illness. The primary goal of this research is to identify the effects of medication treatment on brain function and the brain markers of treatment response in order to save young patients costly and lengthy trials of medications that are unlikely to be effective and guide them to towards alternative treatment modalities that have a greater probability of success and/or less risk.