No 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.

Opinion Statement The last decade has seen considerable advances in the treatment of anxiety disorders in children and adolescents and a considerable expansion of the evidence base for psychopharmacologic in this population. The extant data suggest that, for fear-based anxiety disorders (e.g., generalized anxiety disorder, social phobia/social anxiety disorder, and separation anxiety disorder), selective serotonin reuptake inhibitors (SSRIs) and selective serotonin norepinephrine reuptake inhibitors (SSNRIs) are well tolerated and offer considerable benefit. However, the salutary effects of SSRIs and SSNRIs in pediatric anxiety disorders are consistently amplified by the addition of psychotherapy, particularly in individuals with social anxiety disorder. Additionally, several key demographic and clinical factors, including male sex, non-minority status, and better family functioning and younger age predict greater symptomatic improvement in youth with fear-based anxiety disorders. Thus, current data suggest that in addition to several forms of psychotherapy, including cognitive-behavioral therapy (CBT), SSRIs and SSNRIs are efficacious in the treatment of these conditions in youth and that CBT + an SSRI may be associated with greater improvement than would be expected with either treatment as monotherapy. Finally, given that some children and adolescents may exhibit partial response to current pharmacotherapies, benzodiazepines, anti-histamines and other agents may have adjunctive roles, despite a lack of data in terms of large, randomized controlled trials.

Pill placebo-related improvement occurs early in the course of treatment and both clinical factors and expectation predict this improvement. Additionally, probabilistic approaches may refine our understanding and prediction of pill placebo response.

Background Randomized controlled trials consistently support the efficacy of antidepressants in treating youth with generalized anxiety disorder (GAD), although integrated examinations of efficacy, safety, and tolerability of psychotropic medications in GAD specifically are rare. With this in mind, we sought to describe the efficacy, safety and tolerability of psychopharmacologic interventions in youth with GAD. Methods Randomized, double-blind, placebo-controlled, prospective trials of psychopharmacologic interventions in youth with GAD were identified through a PubMed/Medline (1966–2015) search. Both authors manually reviewed trials and, to evaluate comparative efficacy and tolerability across medications, numbers needed to treat (NNT) (based on Pediatric Anxiety Rating Scale (PARS) remission criteria (PARS ≤8 [1]), and number needed to harm (NNH) for selected treatment-emergent adverse events (TEAEs) were calculated. Finally, treatment-emergent suicidality and taper-emergent/post-study adverse events are reported descriptively. Results Five trials that involved 1,186 patients and evaluated four medications were reviewed and efficacy data were extracted with regard to dimensional measures of anxiety. SSRI/SNRIs demonstrated efficacy in the reduction of anxiety symptoms with NNTs ranging from 2.8 to 9.3. TEAEs varied considerably between studies but tended to be mild and generally did not lead to discontinuation. Conclusions Data from five trials of SSRI/SNRI in youth with GAD, many of whom had co-occurring separation and social anxiety disorders, suggest superiority to placebo and favorable tolerability profiles.