Placebo Response in Pediatric Anxiety Disorders: Implications for Clinical Trial Design and Interpretation

Abstract

Objectives: The characterization and prediction of placebo response in clinical trials of youth with anxiety disorders have received little attention, despite the critical effects of placebo response rate on the success or failure of clinical trials. With this in mind, we sought to examine the factors that predict or influence placebo response in randomized controlled trials of youth with anxiety disorders. Methods: Prospective, randomized, parallel-group controlled trials of psychopharmacologic interventions in pediatric patients with anxiety disorders were identified using a search of PubMed/Medline (1966. Weighted least squares regression models and z-tests were utilized to examine the impact of continuous and categorical variables, respectively, on placebo response. These variables included demographic (e.g., age, percent white, percent female), clinical (e.g., baseline symptom severity), and trial characteristics (sample size, duration, funding). Finally, the relationship between the class of comparator medication and placebo response rate was examined using a multiple comparison for proportions test.Results: The analyses of data from 14 trials involving 2230 patients and 9 medications reveal that higher placebo response rates were associated with a greater number of study sites ( p = 0.013) and fewer patients per site ( p < 0.008), while placebo dropout rates increased with more recent publication ( p = 0.01) and were positively associated with the number of study visits ( p < 0.02). Lower placebo response rates were associated with federally funded studies (z = -4.61, p < 0.001), studies conducted in the United States (z = 1.81, p < 0.035), and with an increased likelihood of detecting a significant effect on the primary outcome (z = 4.58, p < 0.0001). Additionally, studies, in which the majority of patients (>60%) had a diagnosis of social anxiety disorder, exhibited lower placebo response rates ( p < 0.001). Finally, for trials, effect size has decreased over time ( p = 0.004). Conclusions: Important trial-specific factors affect placebo response and placebo dropout in youth with anxiety disorders and have pragmatic implications for the conduct and design of clinical trials and raise the possibility that limiting the number of sites while maximizing the number of patients per site could enhance the ability to detect medication-placebo differences.

Antidepressant Tolerability in Pediatric Anxiety and Obsessive-Compulsive Disorders: A Bayesian Hierarchical Modeling Meta-analysis

“…Second, just as placebo response has received considerable attention in pediatric mood and anxiety disorders, the impact of placebo-related AEs, which affects our ability to quantify medication-related AEs, may vary as a result of patient expectation, clinician-specific factors (eg, experience with the disorder under study, expertise in the clinical trial population) 62 or trial design (eg, capture of AEs). In this regard, by choosing to examine OCD and anxiety disorders (rather than major depressive disorder), we have selected conditions with lower placebo response rates, [62][63][64] which may minimize the influence of high placebo response on AE reporting. Third, although OCD and anxiety disorders were examined independently with the BHM, we also examined AEs in combined OCD and anxiety.…”

Placebo‐like response in absence of treatment in children with Autism

“…One of the most common outcome measurements in pediatric psychiatric research is caregiver report. Yet, recent research has illustrated that placebo response rates are approximately 22% and can range up to 50% in children with ASD [King et al, 2013], with similar rates in childhood depression and anxiety [Bridge, Birmaher, Iyengar, Barbe, & Brent, 2009;Dobson & Strawn, 2016], thus, presenting a significant challenge for treatment research. Nevertheless, continued rigorous research is essential in the search for psychopharmacological and behavioral treatments.…”

Extended Release Guanfacine in Pediatric Anxiety Disorders: A Pilot, Randomized, Placebo-Controlled Trial

“…First, because of the small sample size, this study is underpowered to detect differences in efficacy between groups. Second, the unbalanced randomization may have further attenuated the ability to detect differences between treatment groups and may have inflated the placebo response rate (e.g., due to increased subject or physician expectation of randomization to active drug/treatment efficacy) (Dobson and Strawn 2016). In this regard, recent studies have shown that treatment expectation at baseline predicts placebo response in clinical trials involving antidepressants in adults (Rutherford et al 2016) and youth (Strawn et al 2016).…”