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 (rs=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.
Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by difficulties in social functioning, along with restricted and repetitive patterns of behavior and/or interests (APA, 2013). Beyond core features, individuals with ASD often experience elevated levels of irritability, emotion regulation difficulties, and a range of internalizing and externalizing symptoms (Cai et al., 2018; McGuire et al., 2016; Robertson & Baron-Cohen, 2017). Irritability is defined as a mood state characterized by annoyance, anger, and outbursts or tantrums that can have significant negative impact on both concurrent and long-term outcomes (Holtzman et al., 2015). Though outward expression of irritability can vary in severity and manifestation, it is often associated with lower cognitive functioning, greater severity of ASD symptoms, and sleep problems (Hill et al., 2014). Severe irritability can result in aggressive behaviors towards others, a strong predictor of stress in the family (Baker et al., 2002). Kanne and Mazurek found as many as 68% of parents of children with ASD report aggressive behaviors towards caregivers (Kanne & Mazurek, 2011). Irritability may also manifest in the form of self-injurious behavior (SIB) like head banging and hand biting. SIB is complex, often chronic, and a key point of distress for individuals with ASD and their families (Flowers et al., 2020). Given the significant burden of irritability and associated behaviors, there is a clear need for well-designed trials targeting this complex mood state in ASD.
One central challenge for optimizing clinical trials in ASD, and neuropsychiatric disorders generally, is the propensity for a placebo effect in randomized, controlled trials. In fact, a recent systematic review and meta-analysis found that symptom improvement following placebo treatment is observed across nine psychiatric conditions (not including ASD), with major depressive disorder and generalized anxiety disorder exhibiting the largest effect sizes (Cohen’s d = 1.4 and 1.23, accordingly) (Bschor et al., 2024). These observations indicate that placebo response is pervasive across psychiatric research and likely contributes to the limited success of psychopharmacological drug development in the field (Rutherford & Roose, 2013).
ASD clinical trials are no exception to this trend. In a recent systematic review and meta-regression analysis of ASD trials, 20% of participants showed improvement with placebo alone, and baseline measures of irritability were positively associated with a larger placebo response in social communication abilities (Siafis et al., 2020). In three large balovaptan trials, elevated baseline symptom severity also predicted a greater, positive placebo response (Jacob et al., 2022). In contrast, a multisite trial of citalopram in ASD found that higher baseline symptom severity was negatively correlated with placebo response (King et al., 2013). While some evidence is emerging, a comprehensive understanding of the placebo effect and the clinical characteristics predicting this response is lacking and further research is warranted.
The need to adequately account for placebo effect in psychiatric interventional research has motivated innovation in clinical trial design. There are several novel options, such as placebo lead-in (Homma & Daimon, 2023) sequential parallel comparison (Chen et al., 2014) and sequential enrichment designs (Chen et al., 2011) depending on research objectives, logistical constraints, and patient populations. While each approach seeks to detect true drug efficacy, a placebo lead-in is generally considered the most straight forward and simple design due to its minimal addition to trial duration. A single-blind placebo lead-in involves all participants receiving a placebo before being randomized to a treatment arm, allowing investigators to account for the placebo effect and when appropriate, exclude placebo responders during the analyses.
In the present pilot study, we implemented a single-blind placebo lead-in into a trial examining the tolerability and efficacy of pregnenolone for targeting irritability in ASD. Pregnenolone is an endogenous neurosteroid that is hypothesized to reduce irritability in ASD by enhancing inhibitory neurotransmission and has previously demonstrated efficacy when used in conjunction with risperidone (Ayatollahi et al., 2020). This current randomized controlled trial builds on additional evidence from a previous open-label study suggesting pregnenolone’s utility in treating irritability in ASD (Fung et al., 2014). However, the focus of the current report is to evaluate a placebo lead-in design in an ASD clinical trial in order to measure the magnitude of the placebo effect across symptom domains and to identify potential correlates of this effect, like baseline symptom severity, sex, and IQ.
Methods
Study Design
The overall trial design consisted of a two-week single-blind placebo lead-in for all participants, followed by a twelve-week, randomized controlled trial of pregnenolone. Participants met with the lead investigator biweekly. The goal was to examine the tolerability and efficacy of pregnenolone for reducing irritability in autistic individuals aged fourteen to twenty-five years old. The study started in August of 2015 and is still ongoing after being temporarily disrupted by the COVID-19 pandemic. The study is being conducted in an outpatient clinic located in a large medical center affiliated with a university. Participants were recruited using public fliers, through collaboration with the Simons Powering Autism Research (SPARK) recruitment initiative (Simons Foundation), and in collaboration with our home university clinical research recruitment program. Following a discussion with research clinical staff, informed consent was signed by the adult participants, legal guardians, or both. Legal guardians provided consent for minors and for participants with intellectual disability. For participants who were minors, assent was obtained when intellectual ability permitted. This investigation was approved by our Institutional Review Board at the authors’ home institution (NCT01881737). An investigational new drug application (#109191) was filed with the Food and Drug Administration. The full trial protocol is available upon request. Preliminary analyses in this report include participants who completed the study by June 2024.
Participants
To date, fifty-eight individuals (48 males and 10 females) signed consent for this study, and twenty-five participants (23 males and 2 females; mean age 18.5 ± 3.1 years; range 14–24 years, including 10 minors; 17 Caucasians, 3 Asians, 1 Unknown, 2 Other, and 2 two or more races) have been randomized and completed the trial. 13 participants (12 male, 1 female) were randomized to the active group, and 12 participants (11 male, 1 female) were in the placebo group. Participants of all intellectual abilities were included. Inclusion criteria required (a) outpatients between fourteen and twenty-five years of age with Tanner stage of IV or V (Tanner, 1962); (b) male and female participants who were physically healthy; (c) diagnosis of ASD based on the DSM-5, expert clinical evaluation, Autism Diagnostic Interview– Revised (ADI-R) (Lord et al., 1994), and either Autism Diagnostic Observation Schedule (ADOS) (Lord et al., 2000) or Childhood Autism Rating Scale (CARS-2) (Schopler et al., 1980); (d) an Aberrant Behavior Checklist– Irritability subscale (ABC-I) (Schmidt et al., 2013) score ≥ 18 and Clinical Global Impressions-Severity subscale (CGI-S) (Guy, 1976) ≥ 4; (e) stable concomitant medications for at least two weeks; and (f) no planned changes in psychosocial interventions or medications during the trial. Exclusion criteria were (a) DSM-5 diagnosis of schizophrenia, schizoaffective disorder, or alcohol use disorder; (b) prior adequate trial of pregnenolone; (c) active medical problems, including unstable seizures (> 2 in past month) (Kokate et al., 1999), significant physical illness; (d) pregnant or sexually active female participants who do not adhere to use an appropriate form of external contraception throughout the trial (Kancheva et al., 2007); and (e) participants taking steroid medications. Randomization was done by an independent investigator who generated a randomization list. The study coordinator was not involved in the randomization or in any of the clinical ratings. Parents, caretakers and study investigators were blinded to participants’ status. Subjects were randomly assigned (1:1) to either placebo or active. The randomization was stratified based on sex (male vs. female) and IQ [high (IQ = 70 and above) vs. low (IQ = 69 and below)].
Pharmacological Intervention
The trial consisted of a two-week placebo lead-in followed by a twelve-week, double-blind phase, and an optional open-label phase for participants randomized to placebo. Participants were assigned (1:1) to placebo or active pregnenolone groups by gender and cognitive function.
Assessments
The Aberrant Behavior Checklist (ABC) was completed at baseline, after the placebo-lead in, and at each biweekly visit for the duration of the study. The ABC is a widely used assessment tool in autism research completed by the caregiver and subdivided into five subscales– irritability, hyperactivity, lethargy/withdrawal, stereotypy, and inappropriate speech. The Clinical Global Impression-Severity and Improvement (CGI-S/I) scales were also completed biweekly, and the Stanford-Binet Intelligence Scales 5th Edition (SB5) (Roid & Pomplun, 2012) or Developmental Profile 4th Edition (DP-4) (Alpern, 2020) were used to evaluate cognitive function at the start of the trial. Safety measures were based on electrocardiogram (EKG) and laboratory tests, including comprehensive metabolic panel, complete blood count with differential, cholesterol panel, and routine urinalysis for all participants, as well as a urine pregnancy test for female participants (Fung et al., 2014). The Dosage Record Treatment Emergent Symptom Scale– DOTES was used to assess adverse events systematically (Guy, 1976).
Statistical Analyses
Data analysis was conducted with IBM’s Statistical Package for Social Sciences (SPSS-29). Paired, 2-tailed student t-tests were performed to compare primary and secondary outcome measures between baseline and the end of the lead-in phase. Significant differences, p > 0.05, were attributed to the placebo effect and effect sizes for these differences are represented as Cohen’s d. Bivariate analysis using Spearman correlation coefficients was utilized to identify correlates of the placebo response. Data is available upon request.
Results
All participants in the trial completed the placebo lead-in and their data were combined for the current analyses. The effect of pregnenolone across the 14-week trial is the subject of a later publication. At the end of the single-blind placebo lead-in, there was a significant 30.2% decrease in irritability symptoms on the ABC-I (t(24) = 5.090(24), p < 0.001; Cohen’s d = 1.012) (Fig. 1). Similar reductions were also observed across other ABC subscales (Table 1). Interestingly, CGI-S and CGI-I scores showed no change during the lead-in. Of 25 participants, only 1 was ‘minimally improved,’ and 1 ‘much worse,’ but 23 showed ‘no change.’
Fig. 1
Single-Blind Placebo Lead-In: Individual differences in ABC-I score between baseline and Visit 1, two weeks later
Single-Blind placebo Lead-In: average change in aberrant behavior checklist (ABC) scores between baseline and visit 1, two weeks later (N = 25)
Subscale
Avg. Percent Decrease (%)
T-Score
P-value
Cohen’s d
Irritability (ABC-I)
30.2
5.09
< 0.001
1.02
Lethargy (ABC-L)
26.7
3.25
0.002
0.65
Stereotypy (ABC-S)
31.4
3.75
< 0.001
0.77
Hyperactivity (ABC-H)
32.3
4.65
< 0.001
0.95
Inappropriate Speech (ABC-IS)
33.5
4.11
< 0.001
0.82
The association between clinical characteristics and the placebo effect was also examined. Age, sex, and IQ did not correlate with the magnitude of change in any ABC subscales. Change in some of the ABC subscale scores moderately correlated with their relative baseline scores (ΔABC-I, rs=0.488, p = 0.013; ΔABC-L, rs=0.511, p = 0.009; ΔABC-H, rs=0.432, p = 0.035). Finally, upon examination of only the control group over the course of the 14-week trial, the placebo effect was found to diminish by over 88% following the first two weeks, as shown in Fig. 2.
Fig. 2
Duration of ABC-I Placebo Response; ABC Aberrant Behavior Checklist; SBPLI Single blind placebo lead-in
In the present study, the two-week single-blind placebo lead-in resulted in a significant decrease in the primary outcome of irritability, as well as lethargy, stereotypy, hyperactivity, and inappropriate speech. The initial severity of irritability also correlated with changes at the end of the lead-in, mirroring previous reports that baseline irritability may predict symptom improvement in ASD (Siafis et al., 2020). Additionally, the placebo effect observed in this preliminary analysis of autistic patients aligns with reports in other neuropsychiatric disorders (Bschor et al., 2024; Siafis et al., 2020).
The use of placebo, including an added placebo-lead in, in randomized controlled trials is a subject of ethical debate, specifically as it relates to withholding efficacious treatment from individuals with autism. While there are no approved treatments for core symptoms of ASD, risperidone and aripiprazole are both approved to treat irritability in autism and should not be withheld from individuals in the context of an RCT studying irritability (Iffland et al., 2023). Accordingly, given that participants meet a threshold of irritability symptoms at screening, the current study permits individuals to continue ongoing medications, including risperidone and aripiprazole, and/or behavioral interventions throughout the study, as long as any concomitant interventions have been stable for at least two weeks before the start of the study. In addition, participants in the placebo arm of the trial are given the option to participate in an open-label extension of pregnenolone treatment following the 14-week blinded phase, ensuring individuals get access to the potential benefit of pregnenolone. These study protocols ensure participants maintain access to evidence backed treatments for irritability, while also offering the opportunity to try pregnenolone, regardless of treatment group randomization.
The robust placebo response observed in this study across five primary symptom domains of aberrant behavior highlights the value of placebo lead-in in ASD clinical trials for autistic patients. Notably, improvements in irritability, hyperactivity, and lethargy positively correlated with baseline severity, suggesting potential utility in predicting placebo response. It is essential to build an understanding of the clinical profiles that might predict placebo effect and to elucidate the factors that might have a general and specific impact on this response. For example, irritability and hyperactivity have been associated with executive dysfunction (Tsai et al., 2020) and better executive control has been linked to increased adaptive functioning and daily living skills (Udhnani et al., 2020; Yon-Hernández et al., 2023). Despite this, higher baseline adaptive functioning has predicted placebo response in ASD clinical trials (Curie et al., 2023; Tobe et al., 2023). Taken together, these findings underscore the complex interplay among cognitive abilities and symptom severity that may influence placebo response. Additional studies are needed to further characterize the influence of these variables in ASD trials.
In the present pilot trial, the parent-reported ABC-I showed a strong placebo effect, unlike the clinician-measured CGI. However, the CGI rater was aware of the assignment during the lead-in phase. Several factors have, over the years been implicated in the placebo effect. Evidence from the literature indicates this response is directly influenced by rater expectations (Curie et al., 2023; Jones et al., 2017). While Masi et al. (2015) found clinician ratings to be linked to greater placebo effect, other studies have demonstrated caregiver-ratings to be more vulnerable (Siafis & Leucht, 2023; Tobe et al., 2023). Additionally, some symptom domains might be less vulnerable to the placebo effect than others (e.g., restricted repetitive behaviors) (Siafis & Leucht, 2023). Finally, conclusions from 3 large balovaptan trials indicated that placebo response was predicted by several characteristics including greater baseline symptom severity, online recruitment of participants, and less experienced or non-academic trial sites (Jacob et al., 2022). In summary, further research is needed to appreciate the different factors influencing the placebo response including the patient-informant dynamics, symptom domains, method of recruitment, sites characteristics, and clinical profiles.
The magnitude of the placebo effect, as measured in the current study, was most pronounced in the first two weeks of the trial. In fact, in the control group, the average parent-reported irritability decreased over 88% during the initial, two-week lead-in. The placebo group’s parent-reported irritability appeared to stabilize in the succeeding two-week intervals. This initial drop-off in magnitude suggests a two-week lead-in might be sufficient in most cases to identify the placebo response. Given the advantages of the innovative trial design outlined in this short report, a placebo lead-in, in our estimation, is a worthwhile addition to pharmacological clinical trials.
This study has several limitations, including a small sample size, the short duration of the placebo lead in phase, and lack of assessment of placebo response on other symptom domains using additional instruments. Despite these limitations, this investigation provides additional evidence describing the placebo effect in clinical trials for autistic patients and supports the inclusion of a single-blind placebo lead-in in the design of ASD trials. Importantly, findings suggest that a single-blind placebo lead-in should not be very long, and a period of two weeks might be enough to identify placebo responders and/or mitigate this effect. Further research is needed to gain more insight on the variables implicated in placebo effect to first identify the different characteristics of this response and then to develop study designs that will outsmart this challenge.
Acknowledgments
The authors are grateful to all the families in the Simons Foundation Powering Autism Research (SPARK) program, the SPARK clinical sites, and the SPARK staff. They appreciate obtaining access to recruit participants through SPARK research match on the Simons Foundation Autism Research Initiative (SFARI) database.
Declarations
Conflict of interest
Lawrence Fung and John Hegarty are associate editors of JADD but were not involved in the editorial process. The remaining authors report no conflicts-of-interest.
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