Acute Neurofunctional Effects of Escitalopram in Pediatric Anxiety: A Double-Blind, Placebo-Controlled Trial

Abstract

Objective: Amygdala-ventrolateral prefrontal cortex (VLPFC) circuitry is disrupted in pediatric anxiety disorders, yet how selective serotonin reuptake inhibitors (SSRIs) affect this circuitry is unknown. We examined the impact of the SSRI escitalopram on functional connectivity (FC) within this circuit, and whether early FC changes predicted treatment response in adolescents with generalized anxiety disorder (GAD).

Method: Resting-state functional magnetic resonance (MR) images were acquired before and after 2 weeks of treatment in 41 adolescents with GAD (12-17 years of age) who received double-blind escitalopram or placebo for 8 weeks. Change in amygdala-based whole-brain FC and anxiety severity were analyzed.

Results: Controlling for age, sex, and pretreatment anxiety, escitalopram increased amygdala-VLPFC connectivity compared to placebo (F = 17.79, p = .002 FWE-corrected). This early FC change predicted 76.7% of the variability in improvement trajectory in patients who received escitalopram (p < .001) but not placebo (p = .169); the predictive power of early amygdala-VLPFC FC change significantly differed between placebo and escitalopram (p = .013). Furthermore, this FC change predicted improvement better than baseline FC or clinical/demographic characteristics. Exploratory analyses of amygdala subfields' FC revealed connectivity of left basolateral amygdala (BLA) -VLPFC (F = 19.64, p < .001 FWE-corrected) and superficial amygdala-posterior cingulate cortex (F = 22.92, p = .001 FWE-corrected) were also increased by escitalopram, but only BLA-VLPFC FC predicted improvement in anxiety over 8 weeks of treatment.

Conclusion: In adolescents with GAD, escitalopram increased amygdala-prefrontal connectivity within the first 2 weeks of treatment, and the magnitude of this change predicted subsequent clinical improvement. Early normalization of amygdala-VLPFC circuitry might represent a useful tool for identifying future treatment responders as well as a promising biomarker for drug development.

Clinical trial registration information: Neurofunctional Predictors of Escitalopram Treatment Response in Adolescents With Anxiety; https://www.clinicaltrials.gov/; NCT02818751.

Keywords: MRI; antidepressant; anxiety disorders; clinical trial; selective serotonin reuptake inhibitor (SSRI).

Copyright © 2021 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

FIGURE 1

CONSORT Diagram

FIGURE 2. Treatment-by-Time Interaction in Amygdala- and Amygdala Subdivision-based Functional Connectivity (FC) in Adolescents with Generalized Anxiety Disorder.

Note: In the box and whisker plots, the horizontal line inside the box represents the median FC strength, the bottom and top edges reflect interquartile range (25th and 75th percentiles, respectively) and the whiskers extend to the furthest datum within 1.5 times the interquartile range. BLA, basolateral amygdala; FC, functional connectivity; L, left; PCC, posterior cingulate cortex; SFA, superficial amygdala; VLPFC, ventrolateral prefrontal cortex. *, p<0.05; **, p<0.001.