Improving the Effectiveness and Safety of Escitalopram in Pediatric Anxiety Disorders Using Pharmacogenetically-guided Dosing

项目总结 焦虑症是青少年中最常见的精神疾病之一，与 功能受损和症状性窘迫。如果不治疗，它们会导致永久性残疾 成人期。此外，近40%的患有焦虑症的儿科患者对第一线没有反应 精神药物治疗-选择性5-羟色胺再摄取抑制剂(SSRIs)-高达70%的人会 体验治疗--限制副作用。确定儿科患者治疗反应的预测因素 提供机会(1)优化治疗，(2)阻止继发性精神病理学的发展 以及(3)恢复正常的心理社会功能和生活质量。在这方面，在成年人中， 药物遗传学(PGx)指导的抗抑郁药物治疗提高疗效，减少副作用负担 并降低治疗成本；然而，这些涉及成年人的PGx研究几乎完全集中在 选择药物而不是剂量。目前，还没有这样的儿科试验。尽管有可用的 成人PGx剂量指南，PGx引导的SSRI剂量的盲法随机试验从未被 进行(即使是在成年人中)。与成人相比，SSRI相关副作用和药代动力学显著 在青少年中有所不同。这项建议旨在测试PGx引导下的SSRI，爱司匹兰， 提高焦虑症青少年的疗效和耐受性。我们将测量治疗反应 使用儿科焦虑量表(PARS，一种经过验证的儿科焦虑症严重程度测量工具) 艾司西普兰治疗12周后。此外，激活和体重增加--两个显著的副作用 青少年中的SSRI-将通过治疗紧急激活和自杀评估进行评估 12周试验期间的个人资料和体重指数(BMI)。患有焦虑症的青少年(N=132)将 随机(1：1)接受(1)标准剂量或(2)PGx引导下的艾司匹林剂量。我们预计会有更大幅度的削减 与标准剂量相比，使用PGx引导剂量时，随着时间的推移(即更好的反应)，PARS得分。 此外，我们预计更多的患者将经历激活和治疗相关的BMI增加 给药与PGx引导给药的比较。此外，我们还将检查CYP2C19代谢物对 埃司替普兰药代动力学的研究现状，并将确定5-羟色胺转运体(SLC6A4)和 受体(HTR2A)变体对治疗反应的影响。为了治疗儿科焦虑症 目前“一刀切”的方法、PGx引导的SSRI给药策略是迫切需要的。这项研究将 为临床医生、患者、父母和付款人提供证据，以确定PGx引导的艾司匹林 给药治疗儿童焦虑症具有临床实用价值。

PROJECT SUMMARY Anxiety disorders are among the most prevalent psychiatric conditions in adolescents and are associated with functional impairment and symptomatic distress. When untreated, they result in persistent disability into adulthood. Moreover, nearly 40% of pediatric patients with anxiety disorders fail to respond to the first-line psychopharmacologic treatment—selective serotonin reuptake inhibitors (SSRIs)—and up to 70% will experience treatment-limiting side effects. Identifying predictors of treatment response in pediatric patients provides an opportunity to (1) optimize treatment, (2) forestall the development of secondary psychopathology and suicide attempts and (3) restore normal psychosocial function and quality of life. In this regard, in adults, pharmacogenetically (PGx)-guided antidepressant treatment increases efficacy, decreases side effect burden and reduces treatment costs; however, these PGx studies involving adults focus almost exclusively on medication selection rather than dosing. Currently, there are no such pediatric trials. Despite the availability of PGx dosing guidelines for adults, blinded, randomized trials of PGx-guided SSRI dosing have never been conducted (even in adults). Compared to adults, SSRI-related side effects and pharmacokinetics significantly differ in adolescents. This proposal aims to test whether PGx-guided dosing of the SSRI, escitalopram, improves efficacy and tolerability in adolescents with anxiety disorders. We will measure treatment response with the Pediatric Anxiety Rating Scale (PARS, a validated measure of pediatric anxiety symptom severity) after 12 weeks of escitalopram treatment. Additionally, activation and weight gain—two significant side effects of SSRIs in youth—will be assessed with the Treatment Emergent Activation and Suicidality Assessment Profile and body mass index (BMI) during the 12 week trial. Adolescents with anxiety disorders (N=132) will be randomized (1:1) to receive (1) standard or (2) PGx-guided escitalopram dosing. We expect greater reduction in PARS scores over time (i.e., better response) with PGx-guided dosing compared to standard dosing. Further, we expect more patients to experience activation and treatment-related BMI increases with standard dosing compared to PGx-guided dosing. Additionally, we will examine the influence of CYP2C19 metabolizer status on escitalopram pharmacokinetics and will determine the impact of serotonin transporter (SLC6A4) and receptor (HTR2A) variants on treatment response. For treatment of pediatric anxiety to move beyond the current "one-size fits all" approach, PGx-guided SSRI dosing strategies are urgently needed. This study will provide clinicians, patients, parents, and payers the evidence to determine whether PGx-guided escitalopram dosing in pediatric anxiety disorders has clinical utility.