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

使用药物遗传学指导剂量提高艾司西酞普兰治疗儿童焦虑症的有效性和安全性

• 批准号: 10456135
• 负责人: Laura B Ramsey
• 金额: $ 54.96万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10456135
• 关键词: Address; Adolescent; Adult; Affect; Age; Agitation; Antidepressive Agents; Anxiety; Anxiety Disorders; Blinded; Body mass index; CYP2C19 gene; CYP2D6 gene; Child; Childhood; Clinical; Data; Development; Disease; Distress; Dose; Drug Kinetics; Effectiveness; Escitalopram; FDA approved; Family Relationship; Genes; Genotype; Guidelines; HTR2A gene; Health Care Costs; Impairment; Major Depressive Disorder; Measures; Medical center; Morbidity - disease rate; Outpatients; Parents; Patients; Pediatric Hospitals; Performance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacogenomics; Plasma; Poly(ADP-ribose) Polymerases; Population; Prediction of Response to Therapy; Prospective Studies; Psychopathology; Quality of life; Randomized; Randomized Controlled Trials; Recommendation; Retrospective Studies; Risk; Safety; Schools; Selective Serotonin Reuptake Inhibitor; Severities; Sleeplessness; Substance Use Disorder; Suicide; Suicide attempt; Testing; Time; Treatment Cost; Variant; Weight Gain; Youth; aged; anxiety symptoms; anxious; base; childhood anxiety; disability; experience; functional disability; high risk; improved; improved outcome; neuropsychiatry; pediatric patients; prospective; psychopharmacologic; psychosocial; randomized trial; receptor; response; serotonin transporter; side effect; social relationships; success; suicidal risk; treatment optimization; treatment response; week trial

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.

项目摘要 焦虑症是青少年最普遍的精神病患者之一，与 功能障碍和症状障碍。如果不进行治疗，它们会导致持续的残疾 成年。此外，近40％的小儿焦虑症患者无法应对第一线 心理药物治疗 - 选择性的5-羟色胺再摄取抑制剂（SSRIS） - 高达70％ 经验治疗限制副作用。确定小儿患者治疗反应的预测因子 提供了（1）优化治疗的机会 和自杀企图以及（3）恢复正常的社会心理功能和生活质量。在这方面，在成年人中， 药物遗传学（PGX）引导的抗抑郁治疗提高了效率，降低了副作用 并降低治疗成本；但是，这些PGX研究涉及成年人几乎只关注 药物选择而不是给药。目前，没有这样的小儿试验。尽管有可用的 PGX剂量指南，针对PGX引导的SSRI剂量的盲人，随机试验从未有过 进行（甚至在成年人中）。与成人相比，SSRI相关的副作用和药代动力学显着 青少年不同。该建议旨在测试PGX引导是否将SSRI的给药给药，Escitalopram， 提高焦虑症青少年的效率和耐受性。我们将测量治疗反应 带有小儿焦虑评分量表（PARS，经过验证的小儿焦虑症状严重程度） 经过12周的依此所治疗。此外，激活和体重增加 - 两个显着的副作用 年轻人中的SSRI-将通过治疗重新激活和自杀评估来评估 在12周试验期间，剖面和体重指数（BMI）。患有焦虑症的青少年（n = 132）将是 随机（1：1）接收（1）标准或（2）PGX引导的依他普兰剂量。我们预计减少 与标准剂量相比，随着时间的推移，PGX引导的给药的PARS分数（即更好的响应）。 此外，我们预计更多的患者会随着标准而体验激活和治疗相关的BMI 与PGX引导的给药相比。此外，我们将研究CYP2C19代谢剂的影响 依他普兰药代动力学的状态，并将确定5-羟色胺转运蛋白（SLC6A4）和 接收器（HTR2A）在治疗反应上的变体。用于治疗小儿焦虑以超越 迫切需要当前的“一定程度适合所有”方法，PGX引导的SSRI给药策略是迫切需要的。这项研究会 为临床医生，患者，父母和付款人提供证据，以确定PGX引导的依他张瘤是否是否 小儿焦虑症的剂量具有临床实用性。