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

描述(申请人提供)：焦虑症，在儿童和青少年中非常普遍和致残的情况，很少缓解和增加随后的抑郁，焦虑，药物滥用和成年后自杀的风险。有效的现有治疗方法可以减少发病率，但往往只产生不大的成功。一个重要的战略是引导个别患者接受治疗成功的可能性最高的治疗。尽管SSRI被广泛用于儿童焦虑症，但人们对这些药物如何发挥治疗效果知之甚少。这种知识差距阻碍了以生物学为基础、以假设为驱动的突破的发展，以指导患者走向个性化的、最佳的治疗策略。这项建议旨在发现可用于理解SSRI如何发挥作用并为治疗决策提供信息的神经标记物。PI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-前额叶腹侧皮质[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有关。舍曲林是一种广泛使用的一线药物，缓解率可变(汇集估计为63%；范围：55-91%)。在一项基于对照临床试验的随机、安慰剂对照临床试验的背景下，本研究将对患有焦虑症(AD)和健康对照(HC)的儿童和青少年(年龄范围：7-19岁)进行杏仁核和杏仁核-vPFC功能的治疗前后功能磁共振成像(FMRI)。这些研究的目的是：1)比较焦虑症(AD)儿童和青少年与匹配的健康对照组(HC)治疗前杏仁核反应性和杏仁核-前额叶腹侧皮质功能连接与威胁信号的耦合；2)比较服用SSRI舍曲林和安慰剂(PBO)的AD青少年在杏仁核反应性和杏仁核-vPFC功能连接(耦合)方面的变化(治疗前后)；3)表征AD患者治疗前杏仁核-vPFC功能连接(和杏仁核反应)与随后的舍曲林治疗反应之间的关系；4)研究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素之间的关系。这种方法是创新的，因为还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大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治疗对大脑功能的影响，以及调节个体差异SSRI治疗反应的大脑机制。总体目标是帮助引导年轻患者接受成功率更高的治疗，最大限度地减少反复试错的处方，并加快向患者提供有效护理的速度。这项工作还将阐明儿童和青少年中与焦虑相关的新干预措施的大脑靶点。 公共卫生相关性：焦虑症是发生在儿童和青春期的高度普遍的、致残的、难以治疗的精神障碍；它们可以持续终生，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、共病和痛苦。这项研究的主要目标是确定药物治疗对大脑功能的影响和治疗反应的大脑标记物，以节省年轻患者昂贵而漫长的药物试验，这些药物不太可能有效，并引导他们转向更有可能成功和/或风险更低的替代治疗方式。

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.