Acute Neurostructural Effects of Escitalopram in Adolescents with Generalized Anxiety Disorder

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Abstract Submission 

Lu Lu¹, Jeffrey Mills², Heidi Schroeder³, Kim Cecil⁴, Qiyong Gong¹, Jeffrey Strawn³

¹Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan, ²Department of Economics, Lindner College of Business, University of Cincinnati, Cincinnati, OH, ³Department of Psychiatry & Behavioral Neuroscience, College of Medicine, University of Cincinnati, Cincinnati, OH, ⁴Department of Radiology, College of Medicine, University of Cincinnati, Cincinnati, OH

Lu Lu  
Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University
Chengdu, Sichuan

Jeffrey Mills  
Department of Economics, Lindner College of Business, University of Cincinnati
Cincinnati, OH

Heidi Schroeder  
Department of Psychiatry & Behavioral Neuroscience, College of Medicine, University of Cincinnati
Cincinnati, OH

Kim Cecil  
Department of Radiology, College of Medicine, University of Cincinnati
Cincinnati, OH

Qiyong Gong  
Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University
Chengdu, Sichuan

Jeffrey Strawn  
Department of Psychiatry & Behavioral Neuroscience, College of Medicine, University of Cincinnati
Cincinnati, OH

Selective serotonin reuptake inhibitors (SSRIs) are effective in treating adolescents with anxiety disorders, including generalized anxiety disorder (GAD), but require weeks to produce clinical improvement (Strawn, Lu et al. 2021). Thus, it is important to reveal its underlying neuromechanism and find biomarkers that could predict its treatment response in the early course. Previous studies has investigated acute neurofunctional effects of SSRIs in adolescents with GAD, and indicated that SSRIs altered connectivity in amygdala-frontal circuit during rest and emotion processing (Lu, Mills et al. 2021, Lu, Li et al. 2022). However, few studies has examined the acute neurostructural effects of SSRIs, and the relationship between neurostructural changes and symptom improvement in adolescents with GAD.

In the context of an 8-week, double-blind, placebo-controlled trial of escitalopram in adolescents with GAD, we enrolled 51 adolescents (aged 12–17 years) with a Pediatric Anxiety Rating Scale (PARS) score ≥15, and a Clinical Global Impression (CGI-Severity) score ≥4. From these, forty-one patients with eligible MR data were included in this study. Patients receiving escitalopram (n=20) and placebo (n=21) did not differ in age, gender, IQ, comorbidity, baseline anxiety severity, intracranial volume, cortical thickness, or amygdala volume at baseline (Figure 1).

High-resolution anatomical images were acquired on a 3-Tesla scanner with a 32-channel phased-array head coil at baseline and 2 weeks after initial treatment. The T1-weighted images were preprocessed and analyzed with FreeSurfer longitudinal pipeline. The escitalopram effect on neurostructure was measured with percent change in cortical thickness and amygdala volume over the first 2 weeks of the trial (percent change = [week 2 – week 0]/2*week 0) with two stage model, and age, sex and intracranial volume as covariates. To further explore escitalopram effect on brain structural covariance, volume of 68 cortical regions (Desikan-Killiany atlas) and 14 subcortical nuclei in each patient at week 0 and 2 were extracted to construct the individual differential structural covariance network (IDSCN) for each patient (Liu, Palaniyappan et al. 2021). The network-based-statistic software was used to compare the IDSCN between patients receiving escitalopram and placebo (5000 iterations, p<0.05). The mixed effects model in R was used to examine the relationship between brain morphometric changes in the first 2 weeks and the trajectory of anxiety improvement using week 0, 1, 2, 4, 6 and 8 PARS scores in patients receiving escitalopram.

Escitalopram-treated adolescents relative to placebo had increased percent change in cortical thickness in bilateral insula (left insula: cluster size=851mm2; Talairach coordinate: x=-33.8, y=12.6, z=-2.9; right insula: cluster size=1048mm2; Talairach coordinate: x=34, y=16.4, z=-4.3; Monte Carlo corrected) (Figure 2A). Escitalopram comparing to placebo increased the percent change in volume in left basal nucleus and right lateral nucleus, and decreased the percent change in volume in right coricoamygdoid transition (Figure 1). Escitalopram-treated adolescents also had a decreased structural covariance network compared to patients received placebo, which comprised 12 connectivity among 13 regions (Figure 2B).

The rate of thickness change in left insula (β=-13.72, p=0.043), right insula (β=-15.58, p=0.0002), and the rate of volume change in right corticoamygdoid transition (β=-0.60, p=0.0002) was associated with trajectory of anxiety improvement in escitalopram group.

Acute treatment with escitalopram altered the rate of neurostructural changes in insula and amygdala, and disrupted the structural covariance among regions associated with default mode, visual, and somatomotor networks. Moreover, these neurostructural changes-within two weeks of starting escitalopram-may represent biomarkers of treatment response.

Psychiatric (eg. Depression, Anxiety, Schizophrenia) ¹

Anatomy and Functional Systems ²

Anxiety

DISORDERS

MRI

PEDIATRIC

Pharmacotherapy

Structures