Does Placebo Response Differ between Objective and Subjective Measures in Children with Attention-Deficit/Hyperactivity Disorder?

Abstract

Placebo response complicates the interpretation of treatment response in both clinical practice and clinical trials in youth with attention-deficit/hyperactivity disorder (ADHD). In a pilot study comparing subjective ADHD symptom rating scales with scores obtained using the Quotient™ ADHD System (an objective computerized technology for assessment of hyperactivity, inattention, and impulsivity in ADHD), it was found that agreement between these 2 measures was not as strong as anticipated. This observation prompted us to evaluate placebo responses associated with subjective and objective assessments. Eligible study participants aged 6 to 14 years with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ADHD diagnosis based on clinician interviews were randomized to 1 of 2 treatment sequence groups (placebo, low dose, and medium dose; or low dose, medium dose, and placebo) using either atomoxetine HCl or osmotic controlled-release (OROS) methylphenidate HCl as the active treatment in a 3-week, triple-blind (subject, parent, rater) trial. Subjects were exposed to placebo and different medication doses to evaluate the comparative sensitivity of objective and subjective measures in assessing changes in clinical condition. Placebo response was defined using 3 thresholds: any improvement, > 25% improvement, or > 40% improvement from baseline on Quotient™ Global Scaled Score (QGSS) or the ADHD Rating Scale (ADHD-RS) Total score from baseline to the visit when placebo was administered. Lin's concordance correlation coefficient was used to measure agreement between baseline and placebo scores for the objective and subjective assessments. Of 30 subjects with placebo and baseline scores, 80%, 47%, and 27% met the 3 response thresholds (ie, any, > 25%, or > 40% improvement, respectively) on the ADHD-RS Total score compared with 27%, 7%, and 0% on the QGSS. Lin's concordance correlation coefficient was 0.81 and 0.39 for the QGSS and the ADHD-RS Total score, respectively. Although larger trials are warranted, we tentatively conclude that using objective measures and higher response thresholds may enhance assay sensitivity in clinical trials and hence limit necessary patient enrollments to rule out type II statistical error.

Baseline Severity of Parent-Perceived Inattentiveness Is Predictive of the Difference Between Subjective and Objective Methylphenidate Responses in Children with Attention-Deficit/Hyperactivity Disorder

“…In previous studies comparing subjective ADHD symptom rating scales, with scores obtained using an objective neuropsychological test for the assessment of hyperactivity, inattention, and impulsivity, it was found that agreement between these two measurements was not as strong as anticipated (Manor et al 2008;Sumner et al 2010). These results prompted us to find potential predictors associated with differences between subjective perceptions and objective measurements in children with ADHD treated with MPH.…”

“…Parent and teacher ratings appear to be influenced by the identity of the person reporting the behavior, rather than by the reported behavior itself. The accuracy of subjective assessments is often questioned because they are prone to the placebo effect (Sumner et al 2010). Another difficulty lies in differentiating between the behavioral response (decreases in the hyperactive-impulsive symptoms) and improvement in attention.…”

Clinical Gains from Including Both Dextroamphetamine and Methylphenidate in Stimulant Trials

“…Cb-CPTs consistently demonstrate responsiveness to the effect of stimulants (Rapport et al 1987;Pelham et al 1990;Tabori-Kraft et al 2007;Teicher et al 2008;Fernandez-Jaen et al 2009), and an absence of practice effects is reported (Fernandez-Jaen et al 2009). Recent studies show that cb-CPTs combined with motion tracking systems (MTS) also serve as responsive measures of attention and motor activity in clinical trials (Tabori-Kraft et al 2007;Teicher et al 2008), vulnerability to placebo effects is low (Sumner et al 2010), and a degree of ecological validity has been demonstrated (Teicher et al 2008). …”

“…Because ADHD rating forms are vulnerable to placebo (Waschbusch et al 2009) and source (Gomez et al 2003) effects, the inclusion of objective test measures in clinical trials has been recommended by several authors (Teicher et al 2008;Waschbusch et al 2009;Sumner et al 2010). Computer-based continuous performance tests (cb-CPT) are a large family of laboratory tests measuring attention; they are administered in a diversity of forms.…”

The Groundskeeper Gaming Platform as a Diagnostic Tool for Attention-Deficit/Hyperactivity Disorder: Sensitivity, Specificity, and Relation to Other Measures

“…Of particular relevance are continuous performance tests (CPTs), of which many are available (e.g., Corkum and Siegel 1993;Riccio and Reynolds 2001;Homack and Riccio 2006), the Quotient ADHD system (Sumner et al 2010), which pairs a type of CPT with recording of motor activity, and the Neuropsychiatric EEG-Based Assessment Aid (NEBA) quantitative EEG assessment (Snyder et al 2015). CPTs are frequently used in neuropsychological testing, but have less than optimal sensitivity and specificity for diagnosing ADHD.…”