Does placebo response differ between objective and subjective measures in children with attention-deficit/hyperactivity disorder?

Postgrad Med. 2010 Sep;122(5):52-61. doi: 10.3810/pgm.2010.09.2201.


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.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adrenergic Uptake Inhibitors / administration & dosage
  • Atomoxetine Hydrochloride
  • Attention Deficit Disorder with Hyperactivity / drug therapy*
  • Central Nervous System Stimulants / administration & dosage
  • Child
  • Delayed-Action Preparations
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Male
  • Methylphenidate / administration & dosage
  • Neuropsychological Tests*
  • Placebo Effect*
  • Propylamines / administration & dosage
  • Severity of Illness Index


  • Adrenergic Uptake Inhibitors
  • Central Nervous System Stimulants
  • Delayed-Action Preparations
  • Propylamines
  • Methylphenidate
  • Atomoxetine Hydrochloride