As expected, reducing the dose by 50 % in the RD group led to clinically significant deterioration in ADHD control. In contrast, children with RD/P group maintained effective ADHD symptom control based on parent IOWA ratings during the four-week period after dose reduction. Control of ADHD symptoms was no different in this group than in the FD group. Parents and children were generally accepting of the treatment. The majority of parents reported treatment benefits and expressed supportive attitudes towards the CPDR treatment.21
A majority of the children found the placebo to be useful. An additional provocative finding is that disclosing the true nature of the placebo did not appear to negate the placebo’s effectiveness.
Although poor ADHD control during washout and Dose Finding contributed to discontinuation, treatment acceptability related to the placebo dose reduction was not cited as a reason for discontinuation. Only one subject discontinued because the child did not wish to swallow an additional placebo. Our published data on the qualitative aspects of the study show that the placebo dose reduction treatment had a high level of acceptability to children and their parents.21
A comparison of retention of subjects in recent ADHD clinical trials shows that our rate of attrition (approximately 25%) is similar or lower than most. For example, in a recent trial of extended-release guanfacine, 113 of 324 (35%) did not complete the study.22
Unlike parents, teachers were blind to treatment status of subjects. Teacher ratings failed to show improvement in ADHD symptom control. This may indicate that parent responses were biased by expectancy. However, we had much more difficulty obtaining responses from teachers, limiting our ability to detect real differences. Our results are consistent with Pliszka et al,23
who reported larger placebo effect on parents’ ratings than on teachers’ ratings.
We hypothesized that CPDR would lead to decreased stimulant-related side effects. We found this to be partially true, in that the side effect rate remained low during dose reduction in the RD/P group. In contrast, side effects increased significantly in the RD group. This was a surprising finding, best explained by the global deterioration in these children as their ADHD became poorly controlled. Indeed, some of the items of the PSERS (sad, tearful; stomach ache; tired, sleepy) may be more indicative of uncontrolled ADHD itself than stimulant side effects.
Placebo effects in ADHD clinical trials are usually measured as changes in rating scales of behavior. The effects on objective measures of behavior are not well established. For this reason, we were eager to determine if CPDR would allow children with ADHD to maintain their performance on a CPT. We found that CPT performance in the three groups were not significantly different at baseline or at post-test. There was a trend for the children in the FD group to show deterioration in CPT performance. This was unexpected, but may reflect the fact that research visits were in the mid-afternoon so as not to interfere with school, and subjects were likely to have done their CPTs at a time when they were “coming off” their dose of stimulant. Rebound effects, irritability and poor CPT performance would be more likely to occur in subjects on higher doses of stimulant medication. It is also possible that the higher doses of stimulant needed for behavioral control impaired cognitive performance.
Research in placebo effects suggests several mechanisms.9
Recent evidence implicates neurochemical and neurophysiological changes due to placebo.24, 25
Positive expectancy –the expectation of treatment benefit leading to behavioral change– has been shown to contribute to stimulant effects,26
although studies using balanced placebo designs have shown a lack of expectancy effects among boys with ADHD treated with stimulants.27, 28
Participation in clinical research may itself be therapeutic.29
Changes in caregiver behavior may be an important participation effect that is especially relevant to treatment of children with developmental disorders.30
Our study does not help to answer important questions about mechanisms of placebo effects. We recognized that establishing both potential conditioned effects (by pairing the placebo with 100% stimulant dose) and potential expectancy effects (describing the placebo as a “dose extender”) negated the possibility that we can determine which of these mechanisms contributed to the resultant effects of the CPDR procedure. However, the primary purpose of this study was proof of a novel treatment concept and preliminary evidence of efficacy. Since a demonstration of efficacy must precede examination of mechanism, we designed our procedure accordingly.
One might consider whether merely a discussion with the parent about the potential benefits of a reduced dosage of the medication would have accomplished the same thing as the use of a placebo. Clinical experience suggests otherwise. Efforts to decrease doses of stimulants very often lead to symptom relapse, even when the parent wants to have the child on a low dose. Moreover, the RD group did poorly, with marked deterioration in ADHD control, despite their parents’ desire to have their children treated with lower doses of stimulant. This suggests that the addition of the open-label placebo was a critical element in the effectiveness of the conditioned placebo dose reduction treatment.
As progress is made in understanding mechanisms of placebo effects, we should remain open to ethical innovative uses of placebo effects that complement established therapeutic approaches. Children with ADHD may be a group of patients who could benefit greatly from such novel treatments.