McGrath Joseph C, Gong Jared, Hegarty John P, Fung Lawrence K, Uljarevic Mirko, Hardan Antonio Y
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
J Autism Dev Disord. 2025 Jul 18. doi: 10.1007/s10803-025-06951-4.
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.
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.
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.
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.
安慰剂效应是主观报告中的一个重大限制，尤其是在使用基于报告者的结局指标时。在自闭症谱系障碍（ASD）中，由于对积极治疗结果的高度期望，这种效应尤为复杂。因此，ASD的干预性研究需要考虑并纠正安慰剂反应。
本初步试验报告研究了在一项随机对照试验的双盲阶段之前进行的为期两周的单盲安慰剂导入期内的安慰剂效应。该试验评估了孕烯醇酮（一种内源性神经甾体）对降低患有ASD的青少年和青年（14 - 25岁）的易怒情绪的作用。异常行为检查表（ABC）易怒性子量表（ABC - I）是用于确定安慰剂效应相关因素（智商、年龄、性别和基线症状严重程度）的主要结局指标。配对双尾t检验比较了基线时和导入期后的结局指标。
截至目前，25名参与者（23名男性，2名女性；平均年龄18.5 ± 3.1岁）完成了试验。两周的导入期使所有参与者的易怒症状减少了30.2%（t(24) = 5.090(24)，p < 0.001；科恩d值 = 1.018）。其余ABC子量表也显著下降。ABC - I的变化幅度与基线ABC - I得分相关（r = 0.488，p = 0.013），但与性别、智商或年龄无关。
这项初步试验的结果为ASD临床试验中显著的安慰剂效应提供了证据，进一步凸显了这一现象给干预性研究带来的挑战。ASD临床试验中的单盲安慰剂导入期是一种推荐的方法，可用于考虑并减轻安慰剂效应。
