Baseline Factors Predicting Placebo Response to Treatment in Children and Adolescents With Autism Spectrum Disorders

Abstract

IMPORTANCE The finding of factors that differentially predict the likelihood of response to placebo over that of an active drug could have a significant impact on study design in this population. OBJECTIVE To identify possible nonspecific, baseline predictors of response to intervention in a large randomized clinical trial of children and adolescents with autism spectrum disorders. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of citalopram hydrobromide for children and adolescents with autism spectrum disorders and prominent repetitive behavior. Baseline data at study entry were examined with respect to final outcome to determine if response predictors could be identified. A total of 149 children and adolescents 5 to 17 years of age (mean [SD] age, 9.4 [3.1] years) from 6 academic centers were randomly assigned to citalopram (n = 73) or placebo (n = 76). Participants had autistic disorder, Asperger syndrome, or pervasive developmental disorder, not otherwise specified; had illness severity ratings that were moderate or more than moderate on the Clinical Global Impression–Severity scale; and scored moderate or more than moderate on compulsive behaviors measured with the modified Children’s Yale-Brown Obsessive-Compulsive Scale. INTERVENTIONS Twelve weeks of treatment with citalopram (10 mg/5 mL) or placebo. The mean (SD) maximum dose of citalopram was 16.5 (6.5) mg by mouth daily (maximum dose, 20 mg/d). MAIN OUTCOMES AND MEASURES A positive response was defined as having a score of at least much improved on the Clinical Global Impression–Improvement scale at week 12. Baseline measures included demographic (sex, age, weight, and pubertal status), clinical, and family measures. Clinical variables included baseline illness severity ratings (the Aberrant Behavior Checklist, the Child and Adolescent Symptom Inventory, the Vineland Adaptive Behavior Scales, the Repetitive Behavior Scale–Revised, and the Children’s Yale-Brown Obsessive-Compulsive Scale). Family measures included the Caregiver Strain Questionnaire. RESULTS Several baseline predictors of response were identified, and a principal component analysis yielded 3 composite measures (disruptive behavior, autism/mood, and caregiver strain) that significantly predicted response at week 12. Specifically, participants in the placebo group were significantly less likely than participants in the citalopram group to respond at week 12 if they entered the study more symptomatic on each of the 3 composite measures, and they were at least 2 times less likely to be responders. CONCLUSIONS AND RELEVANCE This analysis suggests strategies that may be useful in anticipating and potentially mitigating the nonspecific response in randomized clinical trials of children and adolescents with autism spectrum disorders. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00086645

Escitalopram pharmacogenetics

“…The sample size is modest, which limits our power to exhaustively examine interactions between genotypes and demographic variables, although these were relatively evenly distributed across metabolizer groups and not identified as major contributors to dosing and symptom outcomes. Placebo response measured dichotomously across RCTs of antipsychotics and antidepressants in ASD has ranged from 10–34%, with placebo response more likely in patients with higher levels of disruptive behaviors, mood/autism symptoms, and reported caregiver strain[44]. Due to the open label study design of the present study, we are unable to assess placebo response which may have influenced our ability to detect pharmacogenetic associations with clinical improvement over time.…”

Placebo effects in psychiatry: mediators and moderators

“…The most consistent finding is that a low symptom severity at baseline is a strong predictor of the placebo response in schizophrenia, 24 psychosis, 26 children with autism, 27 obsessive-compulsive disorder, 30 attention-deficit hyperactivity disorder, 32 binge-eating disorder, 34 and depression, 19,37,39–43,47,48 despite the fact that in three studies the opposite was reported for schizophrenia, 23 psychosis, 25 and attention-deficit hyperactivity disorder. 33 …”

Placebo Response and the Company It Keeps

“…However, an expert panel convened by the Eunice Kennedy Shriver National Institute of Child Health and Human Development in 2005 reviewed the then available literature and concluded that a simple, if convenient, dichotomous division at any gestational age is fraught with risk because maturation is a continuum. 1 The gestational age breakdown, although convenient for epidemiological classification, is not always appropriate for clinical management. The panel suggested that the phrase near term should be replaced with late preterm to convey that infants born between 34 and 36 weeks of gestation are immature and vulnerable, needing close monitoring, evaluation, and follow-up examination.…”

“…The genius of the authors has been to "turn the tables" from the usual approach and focus on the placebo group as the primary group, with the active drug group as the comparator. 1 They found that greater initial severity of disruptive behavior, autistic and mood symptoms, and caregiver strain (probably also reflecting to some extent greater problems in the child) decreased the rate of placebo response but did not affect the rate of citalopram response in either direction. The similar responses in the citalopram group to both high and low initial severity is somewhat surprising because the base rate dependency theory 3 would lead us to expect more improvement in the more severe group (at least for the active treatment) because there is more room for improvement (and for regression to the mean).…”

“…Even if the patient does not reach normality, there is more likely to be enough improvement from initial severity to merit a clinical global impression of "much improved" or "very much improved," the responder criterion used in this study. 1 The failure to find such a base rate effect might be interpreted as additional evidence for a lack of therapeutic effect from citalopram. Returning to the authors' focus on the placebo group, we note an even more surprising and more interesting finding.…”