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: 7991966
• 负责人: Christopher Stephen Monk
• 金额: $ 65.48万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991966
• 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; young adult

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）：儿童和青少年的焦虑症，高度普遍和致残的状况，很少招募并增加了后来的抑郁症，焦虑，药物滥用和自杀的风险。有效的治疗方法可以降低发病率，但通常只会获得适度的成功。一种重要的策略是指导个别患者进行治疗成功可能性最高的治疗。尽管SSRI被广泛用于小儿焦虑症，但这些药物如何发挥其治疗作用知之甚少。这种知识差距排除了基于生物学的，假设驱动的突破的发展，从而指导患者采取单独量身定制的最佳治疗策略。该提案试图发现可用于了解SSRI如何施加其作用并为治疗决定提供的神经标记。 PIS发表的工作和试验研究表明，介导恐惧反应的神经回路（尤其是杏仁核腹前额叶皮层[VPFC]电路）与焦虑症的病理生理学有关，并且可能与临床治疗反应有关。在SSRI Sertraline的随机，安慰剂对照的临床试验中，这是一种基于对照临床试验的广泛使用的一线治疗（汇总估计值为63％；汇总估计值为63％；范围：55-91％），这项研究将在AMI（fmri and freatialtial MRI（fmri）和Amygdala the Amyy和Amyysa的功能中，青少年（年龄范围：7-19岁）患有焦虑症（AD）和健康比较（HC）青年。目的是：1）将杏仁核反应性和杏仁核 - 腹前额叶皮层功能连通性（“耦合”）与患有焦虑症的儿童和青少年之间的威胁信号（AD）和匹配的健康控制受试者（HC）受试者； 2）比较杏仁核反应性和杏仁核VPFC功能连接性（偶联）的变化（治疗前与治疗后的变化）与SSRI舍曲林治疗的AD年轻人与接受安慰剂（PBO）治疗的AD年轻人之间的变化； 3）表征杏仁核-VPFC功能连接性（以及杏仁核反应性）与随后的静脉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功能连通性与AD，治疗变化以及治疗反应预测指标的影响。这种方法具有创新性，因为尚无研究检查在安慰剂控制设计中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是帮助确定SSRI治疗对脑功能的影响以及介导个体差异SSRI治疗反应的大脑机制。广泛的目标是帮助指导年轻患者取得更高的成功治疗，最大程度地减少对患者有效护理的试验开处方和速度提供有效护理。这项工作还将阐明与焦虑相关的大脑目标，以实现儿童和青少年的新干预措施。 公共卫生相关性：焦虑症是高度普遍，残疾，难以治疗的精神障碍，发生在儿童和青春期中；他们可以持续生活，并增加随后的抑郁症，药物滥用和自杀的风险。在焦虑症的早期开始，有效且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。这项研究的主要目的是确定药物治疗对脑功能的影响以及治疗反应的大脑标志物，以节省年轻患者的代价高昂且冗长的药物试验，这些药物不太可能有效，并指导他们朝着成功和/或更少风险的替代治疗方式迈向替代治疗方式。