Predictors of Placebo Response in Randomized Controlled Trials of Psychotropic Drugs for Children and Adolescents with Internalizing Disorders

Cohen, David; Consoli, Angèle; Bodeau, Nicolas; Purper-Ouakil, Diane; Deniau, Emmanuelle; Guilé, Jean-Marc; Donnelly, Craig L.

doi:10.1089/cap.2009.0047

Cited by 50 publications

(56 citation statements)

References 39 publications

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“…Among the patient characteristics frequently accused of driving the placebo response are sex (with larger placebo responses in women) and (younger) age. Although these factors were shown to be relevant in some trials (Thijs et al, 1990;Freeman and Rickels, 1999;Rheims et al, 2008;Cohen et al, 2010;Yildiz et al, 2011;Agid et al, 2013;Arakawa et al, 2015), a recent review (Weimer et al, 2015a) of 75 systematic reviews and metaanalyses including more than 1500 trials, 150,000 patients, and 40 medical indications revealed that age and sex were not significant predictors of placebo responses in RCT, despite occasional evidence from experimental research (Aslaksen et al, 2007;Weimer et al, 2013b).…”

Section: B Influence Of Patient Characteristicsmentioning

confidence: 99%

Neuro-Bio-Behavioral Mechanisms of Placebo and Nocebo Responses: Implications for Clinical Trials and Clinical Practice

Schedlowski¹,

Enck²,

Rief³

et al. 2015

Pharmacol Rev

268

257

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Section: B Influence Of Patient Characteristicsmentioning

confidence: 99%

Neuro-Bio-Behavioral Mechanisms of Placebo and Nocebo Responses: Implications for Clinical Trials and Clinical Practice

Schedlowski¹,

Enck²,

Rief³

et al. 2015

Pharmacol Rev

268

257

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“…Placebo response-the degree of symptomatic improvement in patients receiving placebo relative to those treated with the active medication-represents a particularly problematic issue in child and adolescent psychiatry. In this regard, some studies note placebo response rates of 40%-50% (Bridge et al 2009;Emslie et al 2014), although there is some suggestion that placebo response in pediatric patients may vary as a function of disorder (Cohen et al 2010). Increasing, but variable, placebo response rates in clinical trials involving youth with anxiety disorders may result in an efficacious treatment not being statistically superior to placebo.…”

Section: Introductionmentioning

confidence: 99%

“…Increasing, but variable, placebo response rates in clinical trials involving youth with anxiety disorders may result in an efficacious treatment not being statistically superior to placebo. In fact, some contend that the placebo response rate is key to detecting drug versus placebo differences within a trial and, in terms of clinical practice, to better detect those children and adolescents who would truly benefit from medication (Cohen et al 2010). Consequently, high placebo response rates in pediatric patients may result in effective treatments being abandoned and may further limit the psychopharmacologic armamentarium for youth with anxiety disorders.…”

Section: Introductionmentioning

confidence: 99%

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

Dobson

2016

Journal of Child and Adolescent Psychopharmacology

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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.

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“…In contrast, when placebo response rate was >30%, only 1 in 5 antidepressants showed significant separation. A review of controlled trials of psychotropic drugs for children and adolescents with internalizing disorders found that, as in adults, the magnitude of placebo response was the most powerful predictor of the outcome of a trial, rather than the response of the active treatment itself (Cohen, et al 2010). This makes sense, considering the wide variation in the percentage of responders to active compounds in most studies with children and adolescents with internalizing disorders: 36-71% (MDD), 21-65% (OCD), and 56-91% (AD) (Bridge et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Comparison Among Clomipramine, Fluoxetine, and Placebo for the Treatment of Anxiety Disorders in Children and Adolescents

Costa

Morais²,

Zanetta³

et al. 2013

Journal of Child and Adolescent Psychopharmacology

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Objective: The purpose of this study was to test the efficacy of clomipramine and fluoxetine, controlled by placebo, and compare their action in children and adolescents with anxiety disorders. Method: Thirty subjects (ages 7-17 years), who were diagnosed with generalized anxiety disorder and/or separation anxiety disorder and/or social phobia, were submitted to a 12 week double-blind, randomized, placebo-controlled trial of clomipramine and fluoxetine. The instruments included: the Schedule for Affective Disorders and Schizophrenia, the Multidimensional Anxiety Scale for Children, the Children's Depression Inventory, the Clinical Global Impressions, and the Children's Global Assessment Scale. Results: All groups (clomipramine [n = 9], fluoxetine [n = 10], placebo [n = 11]) showed a significant improvement after 12 weeks of treatment. There were significant differences between the fluoxetine and placebo groups in some ratings of anxiety severity and impairment. No significant differences were observed between clomipramine and placebo groups or between fluoxetine and clomipramine groups. Conclusions: Treatment with placebo showed an unusual high response rate. Clomipramine showed similar efficacy compared with fluoxetine, although it was not superior to placebo.

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Predictors of Placebo Response in Randomized Controlled Trials of Psychotropic Drugs for Children and Adolescents with Internalizing Disorders

Abstract: Predictors of placebo response in internalizing disorders of youths parallel those in adult studies, with the exception of race. These predictors should be considered when designing placebo-controlled trials in youths to enhance findings of true drug-placebo differences.

Cited by 50 publications

References 39 publications

Neuro-Bio-Behavioral Mechanisms of Placebo and Nocebo Responses: Implications for Clinical Trials and Clinical Practice

Neuro-Bio-Behavioral Mechanisms of Placebo and Nocebo Responses: Implications for Clinical Trials and Clinical Practice

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

Comparison Among Clomipramine, Fluoxetine, and Placebo for the Treatment of Anxiety Disorders in Children and Adolescents

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