Placebo Effect in Clinical Trials in Autism: Experience from a Pregnenolone Treatment Study.

PURPOSE

The placebo effect is a significant limitation in subjective report, particularly when using informant-based outcome measures. In autism spectrum disorder (ASD), this effect is particularly complex due to high expectations for positive treatment outcomes. Therefore, interventional research in ASD needs to account for and remediate the placebo response.

METHODS

This preliminary pilot report examines placebo effect in a single-blind, two-week placebo lead-in that preceded the double-blind phase of a randomized controlled trial. The trial assessed pregnenolone, an endogenous neurosteroid, for reducing irritability in adolescents and young adults (ages 14-25) with ASD. The Aberrant Behaviors Checklist (ABC) irritability subscale (ABC-I) was the primary outcome measure used to identify correlates of the placebo effect (IQ, age, sex, and baseline symptom severity). Paired, 2-tailed t-tests compared outcome measures at baseline and following the lead-in.

RESULTS

Twenty-five participants (23 males, 2 females; mean age 18.5 ± 3.1 years) have completed the trial to date. The two-week lead-in resulted in a 30.2% decrease in irritability symptoms (t(24) = 5.090(24), p < 0.001; Cohen's d = 1.018) across all participants. The remaining ABC subscales also decreased significantly. The magnitude of change in ABC-I was correlated (r=0.488, p = 0.013) with baseline ABC-I score, but not sex, IQ, or age.

CONCLUSION

Findings from this preliminary pilot trial provide evidence of a significant placebo effect in a clinical trial for ASD, further highlighting the challenges that this phenomenon presents for interventional research. A single-blind placebo lead-in within ASD clinical trials is a recommended approach to both account and mitigate for the placebo effect.