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Acute Neurofunctional Effects of Escitalopram in Pediatric Anxiety: A Double-Blind, Placebo-Controlled Trial
Lu Lu1, Jeffrey A Mills2, Hailong Li3
1West China Hospital of Sichuan University, Chengdu, China; University of Cincinnati, Ohio.
Insights
Selective serotonin reuptake inhibitors (SSRIs) like escitalopram enhance amygdala-prefrontal cortex connectivity in adolescents with generalized anxiety disorder (GAD). Early functional connectivity changes predict treatment response, offering a potential biomarker for anxiety treatment.
Area of Science:
- Neuroscience
- Psychiatry
- Medical Imaging
Background:
- Pediatric anxiety disorders involve disrupted amygdala-ventrolateral prefrontal cortex (VLPFC) circuitry.
- The impact of selective serotonin reuptake inhibitors (SSRIs) on this circuitry in adolescents is not well understood.
Purpose of the Study:
- To investigate the effect of escitalopram on functional connectivity (FC) within the amygdala-VLPFC circuit in adolescents with generalized anxiety disorder (GAD).
- To determine if early changes in FC predict treatment response to escitalopram.
Main Methods:
- Resting-state functional magnetic resonance imaging (fMRI) was used to assess whole-brain FC in 41 adolescents with GAD before and after 2 weeks of double-blind escitalopram or placebo treatment.
- Changes in amygdala-based FC and anxiety severity were analyzed over an 8-week treatment period.
Main Results:
- Escitalopram significantly increased amygdala-VLPFC connectivity compared to placebo after 2 weeks.
- This early FC improvement predicted treatment response in escitalopram-treated patients, outperforming baseline FC and clinical factors.
- Specifically, left basolateral amygdala (BLA)-VLPFC connectivity increases predicted anxiety improvement.
Conclusions:
- Escitalopram enhances amygdala-prefrontal connectivity in adolescents with GAD within the first two weeks of treatment.
- The magnitude of this early functional connectivity change serves as a predictor of subsequent clinical improvement.
- This early normalization of amygdala-VLPFC circuitry may identify treatment responders and act as a biomarker for drug development.
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.
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