Escitalopram in Adolescents With Generalized Anxiety Disorder: A Double-Blind, Randomized, Placebo-Controlled Study

Abstract

Background: Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat pediatric anxiety disorders, including generalized anxiety disorder (GAD); however, their efficacy and tolerability are difficult to predict. This study evaluated the efficacy and tolerability of escitalopram in adolescents with GAD (DSM-IV-TR) and the impact of variants in HTR2A and serotonin transporter (SLC6A4) genes and cytochrome P450 2C19 (CYP2C19) phenotypes on response as well as CYP2C19 phenotype on escitalopram pharmacokinetics from February 2015 through November 2018.

Methods: Patients were treated with escitalopram (forced titration to 15 mg/d, then flexible titration to 20 mg/d) (n = 26, mean ± SD age: 14.8 ± 1.7 years) or placebo (n = 25, mean ± SD age: 14.9 ± 1.6 years) for 8 weeks. Outcomes were the change in scores on the Pediatric Anxiety Rating Scale (PARS) and Clinical Global Impressions (CGI) scales as well as vital signs and adverse events. Plasma escitalopram and desmethylcitalopram area under the curve during 24 hours (AUC0-24) and maximum concentration (Cmax) were determined and compared across CYP2C19 phenotypes.

Results: Escitalopram was superior to placebo for mean ± SD baseline-to-endpoint change in PARS (-8.65 ± 1.3 vs -3.52 ± 1.1, P = .005) and CGI scores, and increasing CYP2C19 metabolism was associated with decreases in escitalopram Cmax (P = .07) and AUC0-24 (P < .05). Vital signs, corrected QT interval, and adverse events were similar in patients who received escitalopram and placebo.

Conclusions: Escitalopram reduces anxiety symptoms, and pharmacogenetics variables influence the trajectory and magnitude of improvement. Variation in CYP2C19 metabolism accounts for significant differences in escitalopram pharmacokinetics, raising the possibility that CYP2C19 phenotype should be considered when prescribing escitalopram.

Trial registration: ClinicalTrials.gov identifier: NCT02818751.

Conflict of interest statement

CONFLICT OF INTEREST: Dr. Strawn has received research support from the National Institutes of Health (NIMH/NIEHS) as well as Allergan, Neuronetics and Otsuka. He has received material support from and provided consultation to Myriad Genetics and receives royalties from the publication of two texts (Springer) and serves as an author for UpToDate and an Associate Editor for Current Psychiatry. Drs. Strawn and Mills receive research support from the Yung Family Foundation. Dr. Desta reports no biomedical conflicts of interest. Dr. Ramsey has received research support from the National Institutes of Health (NICHD) and BTG, International Ltd. Kim Cecil receives research support from the NIH. Dr. DelBello receives research support from NIH, PCORI, Acadia, Allergan, Janssen, Johnson and Johnson, Lundbeck, Otsuka, Pfizer, and Sunovion. She is also a consultant, on the advisory board, or has received honoraria for speaking for Alkermes, Allergan, Assurex, CMEology, Janssen, Johnson and Johnson, Lundbeck, Myriad, Neuronetics, Otsuka, Pfizer, Sunovion, and Supernus. Ethan Poweleit reports no biomedical conflicts of interest. Heidi Schroeder reports no biomedical conflicts of interest. Sarah Mossman reports no biomedical conflicts of interest. Sara Varney reports no biomedical conflicts of interest.

© Copyright 2020 Physicians Postgraduate Press, Inc.

Figures

FIGURE 1.. Study Flow.

During the study, all patients and study staff remained unaware of trial group assignments. Of 134 referrals, 79 were enrolled and 51 were randomized.

Figure 2:

(A) Change Over Time in PARS Score for Escitalopram Versus Placeboa; Change From Baseline to Endpoint by CYP2C19 Phenotype in (B) Maximum Concentration (Cmax), (C) Area Under the Curve (AUC), and (D) Metabolite:Parent Drug Ratiob; and Difference in (E) Cmax and (F) AUC Between Patients With and Without Activation Symptoms aValues shown as mean ±SD. bBoxplots for parts B, C, and D show median (IQR) and minimum and maximum values. cBoxplots for parts E and F show median (IQR) and minimum and maximum values and outliers. Abbreviations: CYP2C19=cytochrome P450 2C19, IM=intermediate metabolizer, IQR=interquartile range, NM=normal metabolizer, PM=poormetabolizer, RM=rapid metabolizer, UR=ultrarapaid metabolizer.