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

项目摘要 焦虑症是青少年中最常见的精神疾病之一， 功能障碍和症状性痛苦。如果不治疗，他们会导致持续的残疾， 成年而且，近40%的焦虑症儿科患者在一线治疗时反应不佳 精神药理学治疗-选择性5-羟色胺再吸收抑制剂（SSRIs）-高达70%的人会 会出现限制治疗的副作用确定儿科患者治疗反应的预测因素 提供了一个机会，（1）优化治疗，（2）预防继发性精神病理学的发展 （3）恢复正常的社会心理功能和生活质量。在成年人中， 药物遗传学（PGx）指导的抗抑郁药治疗增加疗效，降低副作用负担 降低治疗成本;然而，这些涉及成人的PGx研究几乎只关注 药物选择而不是剂量。目前，还没有这样的儿科试验。尽管有 成人PGx给药指南，PGx指导SSRI给药的盲法随机试验从未被纳入 （即使是成年人）。与成人相比，SSRI相关的副作用和药代动力学显著 在青少年中有所不同。该提案旨在测试PGx指导的SSRI，艾司西酞普兰， 改善青少年焦虑症患者的疗效和耐受性。我们将测量治疗反应 使用儿科焦虑评定量表（PARS，一种经验证的儿科焦虑症状严重程度测量方法） 艾司西酞普兰治疗12周后此外，激活和体重增加-两个显著的副作用 SSRIs在年轻人中的应用-将通过治疗后出现的激活和自杀评估进行评估 12周试验期间的曲线和体重指数（BMI）。患有焦虑症的青少年（N=132）将被 随机（1：1）接受（1）标准或（2）PGx指导的艾司西酞普兰给药。我们预计会有更大幅度的降价 在PARS分数中随时间的变化（即，与标准给药相比，PGx指导给药的反应更好）。 此外，我们预计更多的患者会经历激活和治疗相关的BMI增加， 与PGx指导给药相比。此外，我们将检查CYP 2C 19代谢物的影响 对艾司西酞普兰药代动力学的影响，并将确定5-羟色胺转运蛋白（SLC 6A 4）和 受体（HTR 2A）变体对治疗反应的影响。对于儿科焦虑症的治疗， 目前的“一刀切”方法，PGx指导的SSRI给药策略是迫切需要的。本研究将 为临床医生、患者、父母和支付者提供证据，以确定PGx指导的艾司西酞普兰是否 在儿科焦虑症中给药具有临床实用性。

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.