Acute neurofunctional effects of escitalopram during emotional processing in pediatric anxiety: a double-blind, placebo-controlled trial.

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.

Attention Alterations in Pediatric Anxiety: Evidence From Behavior and Neuroimaging.

BACKGROUND: Pediatric anxiety disorders involve greater capture of attention by threatening stimuli. However, it is not known if disturbances extend to nonthreatening stimuli, as part of a pervasive disturbance in attention-related brain systems. We hypothesized that pediatric anxiety involves greater capture of attention by salient, nonemotional stimuli, coupled with greater activity in the portion of the inferior frontal gyrus (IFG) specific to the ventral attention network (VAN). METHODS: A sample of children (n = 129, 75 girls, mean 10.6 years of age), approximately half of whom met criteria for a current anxiety disorder, completed a task measuring involuntary capture of attention by nonemotional (square boxes) and emotional (angry and neutral faces) stimuli. A subset (n = 61) completed a task variant during functional magnetic resonance imaging. A priori analyses examined activity in functional brain areas within the right IFG, supplemented by a whole-brain, exploratory analysis. RESULTS: Higher clinician-rated anxiety was associated with greater capture of attention by nonemotional, salient stimuli (F1,125 = 4.94, p = .028) and greater activity in the portion of the IFG specific to the VAN (F1,57 = 10.311, p = .002). Whole-brain analyses confirmed that the effect of anxiety during capture of attention was most pronounced in the VAN portion of the IFG, along with additional areas of the VAN and the default mode network. CONCLUSIONS: The pathophysiology of pediatric anxiety appears to involve greater capture of attention to salient stimuli, as well as greater activity in attention-related brain networks. These results provide novel behavioral and brain-based targets for treatment of pediatric anxiety disorders.