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

儿童和青少年焦虑症的脑标志物和 SSRI 治疗

• 批准号: 8240081
• 负责人: Christopher Stephen Monk
• 金额: $ 46.01万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240081
• 关键词: Adolescence; Adolescent; Adult; Affect; Aftercare; Age; Amygdaloid structure; Anger; Anxiety; Anxiety Disorders; Biological Markers; Brain; Caring; Child; Childhood; Clinical; Clinical Treatment; Clinical Trials; Comorbidity; Controlled Clinical Trials; Coupling; Cues; Data; Development; Exhibits; Face; Fright; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Individual; Individual Differences; Intervention; Knowledge; Life; Mediating; Mental Depression; Mental disorders; Modality; Morbidity - disease rate; Neurobiology; Outcome; Patients; Pattern; Pharmaceutical Preparations; Pilot Projects; Placebo Control; Placebos; Play; Prefrontal Cortex; Probability; Process; Publishing; Randomized; Research; Risk; Role; Selective Serotonin Reuptake Inhibitor; Separation Anxiety; Sertraline; Severities; Signal Transduction; Social Phobia; Speed; Substance abuse problem; Suicide; Symptoms; Therapeutic Effect; Time; Work; Youth; affective neuroscience; alternative treatment; base; clinical care; common treatment; comparison group; depressive symptoms; design; effective therapy; innovation; neural circuit; neuromechanism; novel; public health relevance; relating to nervous system; response; success; treatment response; treatment strategy

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.

描述（由申请人提供）：焦虑症是儿童和青少年中非常普遍的致残性疾病，很少缓解，并且会增加成年后抑郁、焦虑、药物滥用和自杀的风险。有效的可用治疗方法可以降低发病率，但通常只能取得有限的成功。一项重要的策略是指导个体患者接受最有可能成功的治疗。尽管 SSRI 广泛用于治疗儿童焦虑症，但人们对这些药物如何发挥治疗作用知之甚少。这种知识差距阻碍了基于生物学、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。 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（特别是杏仁核腹侧前额皮质 [vPFC] 回路）与焦虑症的病理生理学相关，并且可能与临床治疗反应相关。 SSRI 舍曲林是一种广泛使用的一线治疗药物，基于对照临床试验，反应率可变（汇总估计为 63%；范围：55-91%），在一项随机、安慰剂对照临床试验的背景下，本研究将对儿童和儿童的杏仁核和杏仁核-vPFC 功能进行治疗前和治疗后功能性 MRI (fMRI)。 患有焦虑症（AD）的青少年（年龄范围：7-19岁）和健康对照（HC）青少年。目标是： 1) 在治疗前将杏仁核反应性和杏仁核-腹侧前额皮质功能连接（“耦合”）与患有焦虑症（AD）的儿童和青少年以及匹配的健康对照（HC）受试者之间的威胁信号进行比较； 2) 比较接受 SSRI 舍曲林治疗的 AD 青少年和接受安慰剂 (PBO) 治疗的 AD 青少年杏仁核反应性和杏仁核-vPFC 功能连接（耦合）的变化（治疗前与治疗后）； 3) 描述 AD 青少年治疗前杏仁核-vPFC 功能连接（和杏仁核反应性）与随后舍曲林治疗反应之间的关系； 4) 检查发育对杏仁核反应性和杏仁核-vPFC 功能连接与 AD、治疗变化和治疗反应预测因子的影响。这种方法具有创新性，因为还没有研究在安慰剂对照设计中检验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介导 SSRI 治疗反应个体差异的大脑机制。总体目标是帮助指导年轻患者接受更有可能成功的治疗，最大限度地减少处方试错并加快为患者提供有效的护理。这项工作还将阐明与焦虑相关的大脑目标，以用于儿童和青少年的新干预措施。 公共卫生相关性：焦虑症是儿童和青少年中非常普遍、致残且难以治疗的精神障碍；它们可能会持续一生，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有效且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以及治疗反应的大脑标志物，以便为年轻患者节省昂贵且漫长的不太可能有效的药物试验，并指导他们采用成功概率更大和/或风险更低的替代治疗方式。