Pharmacogenetically Guided Escitalopram Treatment for Pediatric Anxiety Disorders: Protocol for a Double-Blind Randomized Trial

Current pharmacologic treatments for pediatric anxiety disorders (e.g., selective serotonin reuptake inhibitors (SSRIs)) frequently use “one size fits all” dosing strategies based on average responses in clinical trials. However, for some SSRIs, including escitalopram, variation in CYP2C19 activity produces substantial variation in medication exposure (i.e., blood medication concentrations). This raises an important question: would refining current SSRI dosing strategies based on CYP2C19 phenotypes increase response and reduce side effect burden? To answer this question, we designed a randomized, double-blind trial of adolescents 12–17 years of age with generalized, separation, and/or social anxiety disorders (N = 132). Patients are randomized (1:1) to standard escitalopram dosing or dosing based on validated CYP2C19 phenotypes for escitalopram metabolism. Using this approach, we will determine whether pharmacogenetically-guided treatment—compared to standard dosing—produces faster and greater reduction in anxiety symptoms (i.e., response) and improves tolerability (e.g., decreased risk of treatment-related activation and weight gain). Secondarily, we will examine pharmacodynamic variants associated with treatment outcomes, thus enhancing clinicians’ ability to predict response and tolerability. Ultimately, developing a strategy to optimize dosing for individual patients could accelerate response while decreasing side effects—an immediate benefit to patients and their families. ClinicalTrials.gov Identifier: NCT04623099.

Anxiety Is Associated With DPPIV Alterations in Children With Selective Mutism and Social Anxiety Disorder: A Pilot Study

Background: Both selective mutism (SM) and social anxiety disorder (SAD) are severe pediatric anxiety disorders with the common trait of behavioral inhibition (BI). The underlying pathophysiology of these disorders remains poorly understood, however converging evidence suggests that alterations in several peripheral molecular pathways might be involved. In a pilot study, we investigated alterations in plasma molecular markers (dipeptidyl peptidase-4 [DPPIV], interleukin-6 [IL-6], tumor necrosis factor-β [TNF-β] and neuropeptide-Y [NPY]) in children with SM, SAD, and healthy controls, as well as the correlation of these markers to symptom severity.Methods: We included 51 children and adolescents (aged 5–18 years; n = 29 girls): n = 20 children in the SM-, n = 16 in the SAD- and n = 15 in the control-group (CG). Peripheral blood samples were analyzed for DPPIV, IL-6, TNF-β, and NPY concentrations. Diverse psychometric measures were used for BI, anxiety, and mutism symptoms.Results: Lower DPPIV-levels were correlated with more anxiety symptoms. However, we could not find a difference in any molecular marker between the patients with SAD and SM in comparison to the CG.Conclusion: DPPIV is proposed as relevant marker for child and adolescent anxiety. Investigating the pathophysiology of SM and SAD focusing on state and trait variables as anxiety or BI might help better understanding the underlying mechanisms of these disorders. Further studies with especially larger cohorts are needed to validate the current pilot-findings.

Frequency and Correlates of Fathers' Accommodation in Pediatric Anxiety Disorders

Previous studies investigating family accommodation (FA) in pediatric anxiety disorders have primarily relied on mothers' reports, while data on FA by fathers remains scarce. We examined the frequency and correlates of fathers' FA of anxious children and compared fathers’ and mothers’ reports of FA. Participants were 69 parents of treatment-seeking children and adolescents with a primary anxiety disorder. FA was highly prevalent amongst fathers, with the majority of fathers participating in symptom-related behaviors and modifying family routines due to child anxiety. Fathers' accommodation levels were significantly correlated with fathers' reports of child internalizing symptoms, child externalizing symptoms, and fathers' own anxiety symptoms. Fathers’ and mothers’ reports of FA were moderately correlated, whereas their reports of their respective distress related to the need to accommodate were only weakly correlated. Fathers reported a significantly lower frequency of FA than did mothers. These findings highlight the importance of obtaining reports from both fathers and mothers when assessing FA. Results are particularly relevant to family-focused and parent-based interventions designed to address and reduce FA amongst parents of clinically anxious children.