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

描述（由申请人提供）：焦虑症，在儿童和青少年中高度流行和致残的疾病，很少缓解和增加成年后抑郁，焦虑，药物滥用和自杀的风险。有效的现有治疗方法可以降低发病率，但往往只能取得有限的成功。一个重要的策略是指导个体患者接受最有可能成功治疗的治疗。虽然SSRIs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作用知之甚少。这种知识差距阻碍了基于生物学的、假设驱动的突破的发展，从而指导患者采取个性化的、最佳的治疗策略。该提案旨在发现可用于了解SSRIs如何发挥作用并为治疗决策提供信息的神经标记物。PI的已发表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相关，并可能与临床治疗反应相关。在SSRI舍曲林的随机、安慰剂对照临床试验中，舍曲林是一种广泛使用的一线治疗药物，应答率可变（汇总估计值为63%;范围：55 - 91%）基于对照临床试验，本研究将对儿童和青少年的杏仁核和杏仁核-vPFC功能进行治疗前和治疗后功能MRI（fMRI）检查（年龄范围：7 - 19岁）患有焦虑症（AD）的青年和健康对照（HC）青年。目标是：1）比较杏仁核反应性和杏仁核-腹侧前额叶皮层功能连接在治疗前，将患有焦虑症（AD）的儿童和青少年与匹配的健康对照（HC）受试者之间的威胁信号（"耦合"）进行比较;（2）比较变化杏仁核反应性和杏仁核-vPFC功能连接（治疗前vs.治疗后）（偶联）在用SSRI舍曲林治疗的AD青年和用安慰剂（PBO）治疗的AD青年之间; 3）表征治疗前杏仁核-vPFC功能连接之间的关系，（和杏仁核反应性）和随后的舍曲林治疗反应在AD青年;和4）检查发育对杏仁核反应性和杏仁核-vPFC功能连接的影响，与AD，治疗变化，和治疗反应的预测因子。这种方法是创新的，因为没有研究在安慰剂对照设计中检查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介导个体差异SSRI治疗反应的脑机制。其总体目标是帮助指导年轻患者接受更有可能成功的治疗，尽量减少试错处方，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。 公共卫生相关性：焦虑症是一种发生在儿童和青少年中的高度流行、致残、难以治疗的精神障碍;它们可以持续一生，并增加随后抑郁、药物滥用和自杀的风险。在焦虑症病程早期开始的有效和有针对性的干预措施有可能减轻与疾病相关的负担、合并症和痛苦。这项研究的主要目标是确定药物治疗对脑功能的影响和治疗反应的大脑标志物，以节省年轻患者昂贵和冗长的药物试验，这些药物不太可能有效，并引导他们转向具有更大成功概率和/或更低风险的替代治疗方式。

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.