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

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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.