Dataset Information

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.

SUBMITTER: Lu L

PROVIDER: S-EPMC8333264 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Lu Lu L Mills Jeffrey A JA Li Hailong H Schroeder Heidi K HK Mossman Sarah A SA Varney Sara T ST Cecil Kim M KM Huang Xiaoqi X Gong Qiyong Q Ramsey Laura B LB DelBello Melissa P MP Sweeney John A JA Strawn Jeffrey R JR

Journal of the American Academy of Child and Adolescent Psychiatry 20210204 10

<h4>Objective</h4>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).<h4>Method</h4>Resting-state functional magnetic resonance (MR) images wer ...[more]

PMID: 33548492

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Project description:Anxiety disorders are the most common mental disorders in adolescents. However, only 50% of pediatric patients with anxiety disorders respond to the first-line pharmacologic treatments-selective serotonin reuptake inhibitors (SSRIs). Thus, identifying the neurofunctional targets of SSRIs and finding pretreatment or early-treatment neurofunctional markers of SSRI treatment response in this population is clinically important. We acquired pretreatment and early-treatment (2 weeks into treatment) functional magnetic resonance imaging during a continuous processing task with emotional and neutral distractors in adolescents with generalized anxiety disorder (GAD, N = 36) randomized to 8 weeks of double-blind escitalopram or placebo. Generalized psychophysiological interaction analysis was conducted to examine the functional connectivity of the amygdala while patients viewed emotional pictures. Full-factorial analysis was used to investigate the treatment effect of escitalopram on amygdala connectivity. Correlation analyses were performed to explore whether pretreatment and early (week 2) treatment-related connectivity were associated with treatment response (improvement in anxiety) at week 8. Compared to placebo, escitalopram enhanced emotional processing speed and enhanced negative right amygdala-bilateral ventromedial prefrontal cortex (vmPFC) and positive left amygdala-right angular gyrus connectivity during emotion processing. Baseline amygdala-vmPFC connectivity and escitalopram-induced increased amygdala-angular gyrus connectivity at week 2 predicted the magnitude of subsequent improvement in anxiety symptoms. These findings suggest that amygdala connectivity to hubs of the default mode network represents a target of acute SSRI treatment. Furthermore, pretreatment and early-treatment amygdala connectivity could serve as biomarkers of SSRI treatment response in adolescents with GAD. The trial registration for the study is ClinicalTrials.gov Identifier: NCT02818751.

Project description:ObjectiveThe purpose of this study was to evaluate the extended efficacy, safety, and tolerability of escitalopram relative to placebo in adolescents with major depressive disorder (MDD).MethodsAdolescents (12-17 years) who completed an 8-week randomized, double-blind, flexible-dose, placebo-controlled, lead-in study of escitalopram 10-20 mg versus placebo could enroll in a 16-24-week, multisite extension trial; patients maintained the same lead-in randomization (escitalopram or placebo) and dosage (escitalopram 10 or 20 mg/day, or placebo) during the extension. The primary efficacy was Children's Depression Rating Scale-Revised (CDRS-R) change from the lead-in study baseline to treatment week 24 (8-week lead-in study plus 16-week extension); the secondary efficacy was Clinical Global Impressions-Improvement (CGI-I) score at week 24. All efficacy analyses used the last observation carried forward (LOCF) approach; sensitivity analyses used observed cases (OC) and mixed-effects model for repeated measures (MMRM). Safety was evaluated via adverse event (AE) reports and the clinician-rated Columbia-Suicide Severity Rating Scale (C-SSRS).ResultsFollowing lead-in, 165 patients enrolled in the double-blind extension (82 placebo; 83 escitalopram); 40 (48.8%) placebo and 37 (44.6%) escitalopram patients completed treatment. CDRS-R total score improvement was significantly greater for escitalopram than for placebo (p=0.005, LOCF; p=0.014; MMRM). Response rates (CDRS-R ≥ 40% reduction from baseline [adjusted and unadjusted] and CGI-I ≤ 2) were significantly higher for escitalopram than for placebo (LOCF); remission rates (CDRS-R ≤ 28) were 50.6% for escitalopram and 35.7% for placebo (p=0.002). OC analyses were not significantly different between groups. The most frequent escitalopram AEs (≥ 5% and more frequent than placebo) were headache, nausea, insomnia, vomiting, influenza-like symptoms, diarrhea, and urinary tract infection. Most AEs were mild/moderate and not related to the study drug. AEs suggestive of self-harm occurred in 5.7% and 7.1% of placebo and escitalopram patients. Occurrence of suicidal behavior and/or suicidal ideation assessed by C-SSRS was 10.9% (14/128) for placebo and 14.5% (19/131) for escitalopram.ConclusionsExtended use of escitalopram was generally safe and resulted in modest improvement in efficacy in adolescents with MDD.

Project description:Objective: To characterize executive function in adolescents with generalized anxiety disorder (GAD) and its relationship to treatment. Methods: Using data from a double-blind, placebo-controlled trial of escitalopram in adolescents (N = 51) 12-17 years of age with GAD, we used the self-report version of the Behavior Rating Inventory of Executive Function (BRIEF-SR) to assess executive function, at baseline, and examined its relationship to treatment response as measured by the Pediatric Anxiety Rating Scale (PARS). Results: For all baseline subscores of the BRIEF-SR, T-scores were significantly elevated in adolescents with GAD compared to an age- and sex-matched normative healthy sample. In escitalopram-treated patients, baseline BRIEF-SR scores for Emotional Control (β = 0.256, 95% credibility interval [CrI]: 0.367 to 0.146, p < 0.001), Working Memory (β = 0.204, CrI: 0.2952 to 0.1134, p < 0.001), Planning/Organizing (β = -0.223, CrI: -0.1021 to -0.3436, p = 0.004), and Task Completion (β = -0.152, CrI: 0.075 to 0.228, p = 0.002) predicted the trajectory of improvement in PARS score over the 8-week trial. For youth who received placebo, only the Inhibit score was significantly, but weakly, associated with response trajectory (β = -0.081, CrI: -0.0167 to -0.1461, p = 0.015). For adolescents who had clinically significant impairment in Emotional Control, Working Memory, Planning/Organizing, and Task Completion (i.e., T-score >65), the trajectory of improvement significantly differed from patients without scores in the clinically significant range. Conclusions: Taken together, these findings point to the potential value of assessing executive function in youth with anxiety disorders as one strategy for guiding treatment selection. These data suggest that executive function may predict treatment response to psychopharmacologic treatment and point to numerous avenues for further personalizing treatment.

Dataset Information

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

Objective

Method

Results

Conclusion

Clinical trial registration information

Publications

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

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