Predictors of placebo response in pharmacological and dietary supplement treatment trials in pediatric autism spectrum disorder: a meta-analysis

Citation: Transl Psychiatry (2015) 5, e640; doi:10.1038/tp.2015.143 ORIGINAL ARTICLEPredictors of placebo response in pharmacological and dietarysupplement treatment trials in pediatric autism spectrumdisorder: a meta-analysis A Masi1, A Lampit2, N Glozier1, IB Hickie1 and AJ Guastella1 Large placebo responses in many clinical trials limit our capacity to identify effective therapeutics. Although it is often assumed thatcore behaviors in children with autism spectrum disorders (ASDs) rarely remit spontaneously, there has been limited investigationof the size of the placebo response in relevant clinical trials. These trials also rely on caregiver and clinical observer reports asoutcome measures. The objectives of this meta-analysis are to identify the pooled placebo response and the predictors of placeboresponse in pharmacological and dietary supplement treatment trials for participants with a diagnosis of ASD. Randomizedcontrolled trials (RCTs) in pediatric ASD, conducted between 1980 and August 2014, were identified through a search of Medline,EMBASE, Web of Science, Cochrane Database of Systematic Reviews and clinicaltrials.gov. RCTs of at least 14 days duration,comparing the treatment response for an oral active agent and placebo using at least one of the common outcome measures, wereincluded. Analysis of 25 data sets (1315 participants) revealed a moderate effect size for overall placebo response (Hedges' g = 0.45,95% confidence interval (0.34–0.56), Po0.001). Five factors were associated with an increase in response to placebo, namely: anincreased response to the active intervention; outcome ratings by clinicians (as compared with caregivers); trials of pharmacologicaland adjunctive interventions; and trials located in Iran. There is a clear need for the identification of objective measures of change inclinical trials for ASD, such as evaluation of biological activity or markers, and for consideration of how best to deal with placeboresponse effects in trial design and analyses.
Translational Psychiatry (2015) 5, e640; doi:10.1038/tp.2015.143; published online 22 September 2015 spontaneously in children with severe ASD, randomized controlled Autism spectrum disorder (ASD) is characterized by core deficits in trials (RCTs) have found that up to 30% of child ASD participants social communication and interaction, and the presence of respond to placebo treatments.Outcome measures for children restricted, repetitive patterns of behavior, interests or activities.
with ASD continue to be dependent on observer and informant Prevalence is estimated to be as high as 1 in There are ratings.Although it is widely recommended that both currently no medication treatments approved for the core independent and caregiver ratings are employed to reduce rating symptoms of ASD. The US Food and Drug Administration has biases, it is unclear how observer and informant ratings areindependently influenced by placebo effects and impact on the approved two atypical antipsychotics for children with ASD, evaluation of treatment outcome of trials in ASD. In a double- risperidone and aripiprazole, for irritability symptoms, including blinded, placebo-controlled randomized trial treating children tantrums, aggression and self-injury behaviors. Established phar- with autistic disorder, results for parent-rated outcome measures macological and dietary supplement interventions have also been were nonsignificant, whereas statistically significant improve- trialed as treatments for behavioral symptoms, such as repetitive ments were reported for clinician-rated scales.Conversely, in behavior, aggression, hyperactivity and and for social an RCT assessing the effects of oxytocin on social behaviors in impairment.However, little evidence exists to support the adolescents with ASD, parental beliefs moderated outcome, efficacy for most of these treatments.Notwithstanding the lack regardless of whether the child was actually assigned the active of established evidence for medications, it has been estimated drug condition.
that at least 25% of children with ASD take at least one Previous reviews in psychiatric patient populations have identified trial design factors and patient characteristics that The assessment of treatment response within clinical trials moderate the placebo response within clinical trials. In schizo- presents a major challenge to establishing efficacious interven- phrenia, shorter duration of illness, greater baseline symptom tions to treat core symptoms of ASD and associated social and severity, younger age and trials of shorter duration were behavioral impairments. Inconsistent results from clinical trials for associated with greater placebo response,and more recent core social and communication impairment in ASD have been a trials were associated with a greater placebo Antidepres- noted feature that has limited drug development.Although it is sant trials in adults showed response to placebo for outcomes often assumed that core behaviors are unlikely to remit rated by observers was significantly greatly than outcomes 1Autism Clinic for Translational Research, Brain and Mind Centre, Central Clinical School, Faculty of Medicine, University of Sydney, Camperdown, NSW, Australia and2Regenerative Neuroscience Group, Brain and Mind Centre, Central Clinical School, Faculty of Medicine, University of Sydney, Camperdown, NSW, Australia. Correspondence: DrAJ Guastella, Brain and Mind Centre, Central Clinical School, Faculty of Medicine, University of Sydney, 100 Mallett Street, Camperdown, NSW 2050, Australia.
E-mail: Received 12 June 2015; revised 4 August 2015; accepted 9 August 2015 Predictors of placebo response in autism 424 records identified through 23 additional records identified database searching through other sources 5 duplicate records removed 378 records excluded: Title and abstract scan Non-English (N=6) Diagnosis (N=151) Publication type (N=109) 442 records screened Trial design (N=65) Number of participants (N=47) 28 full-text articles excluded: 64 full-text articles Outcome measure (N=23) assessed for eligibility Intervention type (N=2) Eligibility
36 studies included in 10 full-text articles excluded: qualitative synthesis Insufficient information available on raw data 26 Studies included in quantitative synthesis Included
Figure 1. Flow of information through the stages of the meta-analysis, including reasons for excluding a full-text article.
completed by patients,and in pediatric trials higher baseline keywords ((‘autism' or ‘asperger' or ‘pervasive developmental disorder') severity was associated with lower placebo response.Similarly, AND (‘placebo') AND (‘randomized')). After removal of duplicates, two in a secondary analysis of baseline factors in a multi-site RCT in reviewers (AM and Kerribeth Szolusha) independently screened search ASD, lower symptom severity at baseline predicted increased results based on title and abstract. The full text of remaining studies response to placebo.
identified as meeting inclusion criteria, as described below, were then There are few treatment options in ASD. It is imperative that reviewed and agreement reached between researchers (Kerribeth Szolusha design of, and recruitment for, RCTs is well informed. To our and AM) on eligibility of each study. The reference lists of eligible studies knowledge, there has been no systematic or meta-analytic review were searched for studies meeting inclusion criteria. A flowchart detailingthe stages of the assessment of studies was constructed according to evaluating the placebo response and its moderators in ASD to aid identification of strategies to control these factors. Specifically, Eligible studies included published, peer-reviewed articles reporting whether the type of observer rating the outcome measure used to results from double-blind RCTs comparing treatment response between report treatment response has an impact on response to placebo active agent and placebo using either parallel or crossover designs with needs to be clarified. The aims of this study are to undertake a at least 10 participants per arm, for at least 14 days. Participants were aged systematic review and meta-analysis of RCTs of pharmacological 3 to 20 years and diagnosed with autistic disorder, Asperger's syndrome and dietary supplement treatments for symptoms associated or pervasive developmental disorder according to the Diagnostic and with the core deficits and associated symptoms in children with Statistical Manual of Mental Disorders III or IV, Autism Diagnostic Interview- ASD in order to evaluate the placebo response effect size and Revised or Autism Diagnostic Observation Schedule. Interventions were determine patient and trial characteristics that may predict pharmacological or dietary supplement treatments, taken orally and placebo response. Given prior considerations of how placebos compared against placebo. Studies reported means and s.d. for each group can influence caregiver perceptions and behaviors, we hypo- at baseline and end point (defined as when the intervention was last thesized that the mean change pre-post treatment with placebo given). A recent review identified the most commonly used outcome would be greater for parent or caregiver raters compared with measures assessing treatment response in highlighting 289 unique clinician raters.
measurement tools used to record response/outcome. Only three toolswere used more than 5% of the time across all studies to measurecognitive/behavioral symptoms/skills: Aberrant Behavior Checklist (ABC), MATERIALS AND METHODS Clinical Global Impression rating scales (CGI) and the Vineland AdaptiveBehavior Scales. The ABC, CGI and the Childhood Autism Rating Scale were The systematic review and meta-analysis were undertaken and reported in the three most commonly used outcome measurement tools in accordance with the PRISMA statement (Preferred Reporting Items for pharmacological treatment trials. Therefore, trials using the ABC, CGI, Systematic Reviews and Meta-Analysis).
Vineland Adaptive Behavior Scales and Childhood Autism Rating Scale asoutcome measures to assess treatment response were included. In Data sources and study selection addition, the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) MEDLINE, EMBASE, Web of Science, Cochrane Database of Systemic and the CY-BOCS modified for Pervasive Developmental Disorders Reviews and clinicaltrials.gov databases were searched for articles (CY-BOCS-PDD) were included as a measure of change in repetitive published in English from January 1980 to August 31 2014 using the behavioBoth primary and secondary outcomes were considered.
Translational Psychiatry (2015), 1 – 9 Predictors of placebo response in autismA Masi et al exception of one where the upper end of the age range Baseline and endpoint data for outcome measures assessing treatment was 20 years. presents study characteristics from the response in active intervention and placebo groups were extracted into an placebo-controlled trials. Nine studies reported the target of the excel spreadsheet (mean, s.d. and sample size for each group and time active intervention as whereas seven studies point). Two reviewers (AM and Kerribeth Szolusha) independently reported the target of intervention as The remain- extracted all the data and ensured accuracy. In crossover design trials ing studies reported the target of intervention as only data for the first phase were extracted. When continuous data were repetitive disruptive symptoms,autism severity, reported in formats other than means and s.d., we contacted the authors aggressionand the core symptoms of autism.There were 107 to request raw data.
In order to explore potential moderators of placebo response, we also data points measuring effect size, representing an estimate of extracted the following descriptive variables: type of rater, type of outcome the magnitude of the difference in outcome measure between measure (primary or secondary), type of active intervention, adjunctive baseline and end point, for active intervention and placebo treatment status (defined as a combination of pharmacological agent treatment groups.
approved for use in ASD with another pharmacological agent or dietary Using the Jadad scale, study quality scores varied between 8 supplement not approved for treatment in ASD), baseline severity (reported and 13 with an average score of 11.6 (s.d. = 1.8). In all, 11 out of 25 as ABC-Irritability subscale), number of contact visits for assessment studies scored a maximum of 13 points. Assessment of quality purposes, trial duration, length of washout period, number of study sites, using the Cochrane Risk of Bias Tool found 18 out of 25 studies study location, study quality, publication year, mean age, gender (% males) were judged to be ‘low risk' overall. Supplementary Table S1 and sample size. The type of rater was categorized as clinician (which presents the risk assessment for each study across every domain.
included trained raters and evaluators), caregiver (which included parents)or clinician including caregiver interview. If it was not stated, and authors The proportion of studies within each risk level is shown in had not responded to a request for information, it was assumed that the Supplementary Figure S1.
parent or caregiver of the participant completed the ABC as is The Jadad and the Cochrane Collaboration's tool for assessing Overall effect size of placebo response risk of biaswere used to evaluate methodological quality of each RCTincluded in the meta-analysis. Jadad is an 11-item instrument, with three The size of the placebo response across studies was moderate and items directly related to the control of bias and eight items related to study statistically significant (k = 25, g = 0.45, 95% confidence interval (CI) design and features. The maximum possible score is 13. The Cochrane (0.34–0.56), Po0.001, The level of true heterogeneity Collaboration's risk of bias tool requires an assessment of the risk of bias was moderate (I2 = 62.89%), meaning that only about 40% of the associated with specific features as ‘low risk', ‘high risk' or ‘unclear risk'.
heterogeneity was due to random error. The funnel plot showedsignificant asymmetry (Egger's intercept = 2.85, P = 0.02; Supple- mentary Figure S2). In a trim and fill analysis, the adjusted effect All analyses were performed using Comprehensive Meta-Analysis Version 2 size after imputation of one study was g = 0.42 (95% CI (0.31– (Biostat, Englewood, NJ, USA). The primary outcome was standardized 0.54)). In a subsequent sensitivity analysis, two notable outlier mean difference (SMD, calculated as Hedges' g) from baseline to end point studies were then removed from the analysis.The overall between groups (active treatment and placebo, using a pre-post effect size of placebo remained statistically significant (k = 23, correlation of 0.7) as well as within the placebo group. SMDs of 0.2, 0.5 g = 0.39, 95% CI (0.31–0.46), Po0.001). The resulting heterogene- and 0.8 were considered small, moderate and large, respectivelyIf a ity across the remaining studies was small (I2 = 26.47%) and the study reported baseline and endpoint data for multiple subscales, such as funnel plot did not show significant asymmetry (Egger's the subscales in the ABC,a single effect estimate per study was intercept = 1.01, P = 0.33; Supplementary Figure S3). Nonetheless, calculated based on mean SMD and variance across outcomes.
these two studies were included in all subsequent analyses.
Analysis of placebo response across studies was conducted by pooling combined SMDs using a random-effects model. In order to explorepotential moderators of placebo response, we performed subgroup meta- Moderators of placebo response analyses using a mixed-effects model. A mixed-effects model uses a Potential moderators of placebo response were then investigated random-effects model to combine outcomes within subgroups and a in subgroup analyses Initially, in order to address the xed-effects model to compare subgroups.In addition, we performed proposed hypothesis that the response to placebo would be univariate meta-regressions to investigate the possible impact ofcontinuous moderators on placebo effect size across studies. Cochrane's greater for caregiver ratings compared with clinician ratings, raters Q-statistic was used to test between-subgroup heterogeneity.
were classified based on who completed the outcome measure.
Forest plots were used to identify outliers and potential sources of For ratings categorized as clinician, the ratings were based on heterogeneity. The impact of any identified outlier was assessed by either direct observation by the clinician or on information removing the study reporting the outlier and comparing the subsequent obtained during an interview with the caregiver conducted by the effect size and P-value to the initial result. The I2-statistic was used to clinician, or a combination of both methods. One included assess true heterogeneity across studies (that is, the proportion of an outcome measure rated by teachers, which was excluded from heterogeneity across studies that is not due to random error), with values this analysis on the basis that teachers may not have been of 25, 50 and 75% implying small, moderate and high levels of specifically trained to assess change. There was a significantly heterogeneity, respectively.Small study effect resulting from publication higher placebo response for outcome measures rated by a bias, insufficient reporting of outcomes, selective inclusion of studyparticipants or other sources was assessed by visually inspecting funnel clinician compared with measures rated by a caregiver (Q-statistic plots of SMDs against s.e.and tested using Egger's test of the for between-subgroup heterogeneity = 9.72, df = 1, P = 0.002; intercepts.A trim and fill analysis for random-effects models was used The effect of rater was further explored by separating to estimate the impact of small study effect on pooled the assessments completed by a clinician with input from acaregiver through an interview, from those completed exclusivelyby a clinician or a caregiver. The significant effect for rater remained, with moderate effect size estimates for both the A total of 26 studies were assessed as eligible for quantitative clinician-rated group and the group that was rated by a clinician, analysis after 447 studies were identified in the initial search which included input from a caregiver interview. Effect size One studyreported on secondary outcome measures estimates for ratings completed by a caregiver remained small not included in the initial study, resulting in 25 unique data sets.
The data set comprised 1315 participants (N active treatment = In addition, the effect of rater was investigated for Iran and the 661, N placebo = 654). Male participants comprised 80% of the United States, the two countries where the majority of trials were sample size, and age ranged from 3 to 18 years, with the conducted. A significant difference in efficacy based on clinician Translational Psychiatry (2015), 1 – 9 Predictors of placebo response in autism Translational Psychiatry (2015), 1 – 9 Predictors of placebo response in autismA Masi et al Study name
Hedges'g (95% CI), random
Hedges'g (95% CI)
McCracken et al. 2002 (34) 0.35 (0.14 to 0.57) Shea et al. 2004 (35) 0.62 (0.36 to 0.88) Hellings et al. 2005 (3) 0.73 (0.29 to 1.17) Hollander et al. 2005 (2) 0.62 (0.24 to 0.99) Nagaraj et al. 2006 (51) 0.32 (–0.02 to 0.65) Akhondzadeh et al. 2008 (48) 0.59 (0.23 to 0.94) King et al. 2009 (13) 0.30 (0.12 to 0.48) Marcus et al. 2009 (41) 0.46 (0.23 to 0.68) Akhondzadeh et al. 2010 (38) 1.35 (0.89 to 1.81) Hollander et al. 2010 (42) 0.31 (–0.12 to 0.75) Rezaei et al. 2010 (39) 0.35 (0.01 to 0.68) Bent et al. 2011 (4) 0.15 (–0.25 to 0.55) Hardan et al. 2012 (33) 0.26 (–0.12 to 0.64) Hasanzadeh et al. 2012 (47) 0.62 (0.29 to 0.95) Lemonnier et al. 2012 (49) 0.38 (0.09 to 0.67) Asadabadi et al. 2013 (36) 1.59 (1.05 to 2.14) Fahmy et al. 2013 (32) 0.36 (–0.04 to 0.75) Ghaleiha et al. 2013a (5) 0.90 (0.50 to 1.30) Ghaleiha et al. 2013b (44) 0.23 (–0.08 to 0.53) Ghanizadeh and Moghimi-Sarani 2013 (45) 0.25 (–0.09 to 0.58) Kent et al. 2013 (37) 0.37 (0.11 to 0.63) Klaiman et al. 2013 (50) 0.03 (–0.28 to 0.34) Mohammadi et al. 2013 (40) 0.33 (–0.01 to 0.67) Bent et al. 2014 (46) 0.17 (–0.11 to 0.45) Ghaleiha et al. 2014 (43) 0.53 (0.19 to 0.87) 0.45 (0.34 to 0.56) Worsening symptoms Improving symptoms Figure 2. Forest plot of efficacy of treatment with placebo. The arrow representing the study of Asadabadi et al. 2013 (ref. shows theconfidence interval spread further than the limit for the effect size range (−2.00 to 2.00). CI, confidence interval.
ratings remained for trials located in the United States compared participants (β = 0.01, P = 0.15), trial duration (β = -0.002, P = 0.24), with measures rated by the caregiver (Q = 7.44, df = 1, P = 0.006; the severity of presentation at start of trial (β = 0.00, P = 0.84) and There was a trend toward a significant effect for clinician the study quality assessed using the Jadad scale (β = − 0.03, ratings for trials located in Iran compared with measures rated by P = 0.32) did not demonstrate any significant influence on the a caregiver (Q = 3.44, df = 1, P = 0.06; placebo response.
Trials of pharmacological interventions had a moderate placebo To facilitate the examination of whether response to active effect size significantly greater than the small placebo effect size intervention is a predictor of the level of response to placebo, a seen in trials of dietary supplements (Q = 5.02, df = 1, P = 0.03; further meta-analysis of the efficacy of active intervention was Trials of adjunctive interventions, which included both undertaken. This resulted in a large and statistically significant pharmacological and dietary supplement treatments, also had a effect size for the overall treatment response to the active moderate placebo effect size significantly greater than the small intervention (k = 25, g = 0.96, 95% CI (0.79–1.14), Po0.001; placebo effect size in monotherapy trials (Q = 5.26, df = 1, P = 0.02; Supplementary Figure S4). Heterogeneity across studies was large There was no difference in the placebo effect size for (I2 = 96.45%). Meta-regression revealed the magnitude of placebo primary outcome measures compared with secondary outcome response was significantly influenced by the response to active measures (Q = 3.20, df = 1, P = 0.07).
intervention (β = 0.31, Po0.001, The proportion of We then examined the influence of trial location. A trend in the between-study variation in effect size explained by the response magnitude of placebo response was shown. Trials located in Iran to active intervention was 49%. The ratio of the overall effect sizes reported a moderate placebo effect size compared with a small for the active and placebo treatment groups implies that 47% of effect size for trials located in other countries and the United Sates improvements in the active treatment group were attributable to (Q = 5.64, df = 2, P = 0.06; The placebo response was the placebo effect.
significantly greater in Iran than the United States (Q = 5.27, df = 1,P = 0.02; The impact of continuous modifiers on placebo response rates across studies was then investigated using random-effects meta- This meta-analysis has demonstrated that the response to regression analyses. The year of publication (β = − 0.01, P = 0.49), treatment with placebo across the 25 trials in pediatric ASD is the number of participants in the placebo group (β = 0.00, moderate. This challenges assumptions that have often been P = 0.49), number of contact visits (β = 0.01, P = 0.52), the age of made about the lack of change in core behavioral features in Translational Psychiatry (2015), 1 – 9 Predictors of placebo response in autism P-value for
Outcomes
I2, % (95% CI)
Hedges' g (95% CI)
Hedges' g (95% CI) heterogeneitya
82.55 (73.19 to 88.64) 0.59 (0.48 to 0.70) 58.86 (25.77 to 77.2) 0.33 (0.21 to 0.45) 84.59 (73.33 to 91.09) 0.55 (0.41 to 0.70) Clinician and caregiver interview 83.89 (69.87 to 91.38) 0.59 (0.43 to 0.76) 58.86 (25.77 to 77.2) 0.33 (0.21 to 0.45) Rater - USA Only
66.41 (24.97 to 84.96) 0.51 (0.39 to 0.62) 46.7 (0.00 to 74.33) 0.30 (0.20 to 0.40) Rater - Iran Only
89.39 (80.66 to 94.18) 0.81 (0.53 to 1.09) 51.17 (0.00 to 85.92) 0.34 (–0.07 to 0.75) 77.09 (57.87 to 87.54) 0.60 (0.44 to 0.77) 0 (0.00 to 85.44) 0.43 (0.18 to 0.68) 21.21 (0.00 to 60.39) 0.33 (0.19 to 0.48) 77.09 (57.87 to 87.54) 0.61 (0.43 to 0.78) 21.21 (0.00 to 60.39) 0.33 (0.18 to 0.49) Type of intervention
Dietary supplement 20.68 (0.00 to 64.1) 0.26 (0.07 to 0.45) 65.38 (42.98 to 78.99) 0.52 (0.40 to 0.63) 18.19 (0.00 to 55.16) 0.36 (0.23 to 0.48) 77.09 (57.88 to 87.54) 0.60 (0.44 to 0.77) Worsening symptoms Improving symptoms Figure 3. Subgroup analyses of moderators of placebo response in randomized controlled trials in pediatric ASD. aQ-test for between-groupheterogeneity, mixed-effects model. ASD, autism spectrum disorder; CI, confidence interval.
children with ASD over relatively short periods of time. Five factors Response to active intervention was strongly associated with predicted a greater placebo response: the rater of the outcome the response to placebo. This interesting association has implica- measure, the response to active intervention, the type of active tions for sample size and design of phase-2 and -3 trials testing intervention, an adjunctive treatment and the geographical interventions that have had phase-1 trial success. Larger studies location of the trial. Contrary to the hypothesis, ratings by will be required to detect genuine differences between active clinicians were associated with a stronger placebo effect. Similarly, medications and placebos, if medications are indicating initial a stronger response to the active intervention, the use of a effectiveness from phase-1 study. In addition, this result suggests pharmacological or an adjunctive treatment in a trial, and studies that factors predicting the degree of placebo response in the trial conducted in Iran, also predicted greater placebo response.
may be a major driver of the effect size within the active arm.
The role of the observer and rater of outcome measures used in Placebo response is estimated to contribute up to 50% of the RCTs in pediatric ASD is crucial, as evidenced by the inability to response to pain medication, and up to 75% of the positive effects identify any self-report outcome measures in all the qualifying in trials for antidepressant In treatment trials for studies of this meta-analysis. The significant effect of ratings by patients with unipolar depressive disorder, improvements in clinicians on placebo response may reflect rater bias driven by placebo groups corresponded to 67% of the improvement in underlying beliefs, motivations and enthusiasm for a potential the active treatment groups.Using a similar methodology for efficacious treatment.The potential for overestimation of the trials included in this meta-analysis, 47% of the improvement positive effects by clinicians would be supported by our results.
in the active treatment group could be attributable to the placebo Alternatively, caregiver burden may diminish placebo effects and effect. Factors that may have led to an improvement in both thereby increase the differential between ratings by clinicians and treatment and placebo arms include overall quality of care caregivers. Previously, increased caregiver strain has been found (although we note US trials had the lowest improvement), to be associated with lower placebo response, potentially multiple contact visits with clinicians and raters, the amount of reflecting reduced hopefulness or optimism at the time of the time spent with participants or the amount of additional support child's entry into the Translational Psychiatry (2015), 1 – 9 Predictors of placebo response in autismA Masi et al Figure 4. Placebo response versus response to treatment with active intervention. The equality line has a slope equal to 1, where the responseto placebo is the same as the response to active intervention. The point above the line represents a trial where response to placebo wasgreater than response to treatment with the active intervention. A larger vertical divergence from the equality line represents a largerresponse to active intervention compared with response to placebo. The line labeled PR = 0.1432+0.3134 × AR represents the regression line.
AR, active response; PR, placebo response.
expectation about the potential benefits of an active intervention The number of RCTs meta-analyzed was limited by the small may have influenced the level of response in both groups. Further size of a number of trials that did not meet inclusion criteria, research investigating factors that are differentially associated which subsequently prevented exploration of the interdepen- with response to active intervention and placebo is required.
dence of potential contributors to placebo response. Specifically, Rater expectation may have led to greater improvement in we note that all trials of adjunctive treatments were located in placebo response in RCTs of pharmacological interventions than Iran, and therefore the effect of geography on placebo response in for trials of dietary supplement treatments. This finding is trials of adjunctive treatments could not be investigated. In RCTs consistent with previous analyses of RCTs in major depressive conducted in pediatric major depression, the strongest predictor disorder, where it was proposed that participants in complemen- of placebo response was the number of study sites.Only 4 out of tary and alternative medicine trials, which included dietary 25 studies included in this meta-analysis were multi-site trials, so supplements, may have more modest expectations than partici- the effect of the number of study sites could not be adequately pants in trials of pharmacological The use of investigated. Few trials included a placebo washout-screening risperidone, one of only two pharmacological interventions phase, which prevented an investigation of whether blinded approved for treatment of children with ASD, as the adjunctive randomization to an initial phase of placebo treatment reduces treatment in all included trials, may have influenced rater the observed response to placebo.
expectations and led to a greater improvement in RCTs ofadjunctive treatments. Unlike previous placebo meta-analyses inmood there appeared no temporal trend in the placebo response in RCTs for ASD. In addition, baseline severity This meta-analysis has demonstrated a moderate placebo effect in was also not associated with greater or reduced response to RCTs of pediatric ASD, and identified five key factors that increase placebo, in contrast to the single, but multi-site RCT study by King the placebo effect size: outcome measures completed by clinicians, the level of response to active intervention, a This study has also shown that the level of response to placebo pharmacological active intervention, adjunctive treatments and varied depending on the geographical location of the RCT, with the geographical location of the trial. The impact of these factors response being greater for trials conducted in Iran compared with should be considered in the trial design phase in order to the United States. Differences in participant recruitment proce- minimize the placebo effect, improve the detection of active dures and characteristics, and cultural dynamics may have led to treatment and placebo differences and subsequently improve systematically greater placebo response in studies conducted in identification of efficacious treatments for the symptoms of ASD.
Iran.Alternatively, there may be differences in age of diagnosis Although it is generally accepted that both caregiver and clinician and access to early intervention services across countries that may ratings should be used as baseline and endpoint measures, alter the susceptibility to the effects of expectancy on response to findings also highlight the need for objective measures, such as treatment with placebo. This requires further investigation.
evaluation of biological activity or markers, to ensure compre- The results of this study highlight the urgent need to develop hensive screening and assessment of response to treatment.
valid and objective measures of baseline assessment andtreatment response in ASD. Inclusions based on objectivemeasures, which are differentiated from the primary outcome CONFLICT OF INTEREST variable, are yet to be fully explored and identified. However, there AL received in-kind research support in the form of no-cost software from BrainTrain is preliminary evidence that suggests certain neuropsychological, and HAPPYneuron for projects unrelated to this work. IBH is a Commissioner in physiological or other neurobiological markers, driven by an Australia's National Mental Health Commission. He has led projects for health understanding of underlying biochemical, physiological and professionals and the community supported by governmental, community agency structural changes in ASD, should be considered for screening, and pharmaceutical industry partners (Wyeth, Eli Lily, Servier, Pfizer and AstraZeneca) and baseline and endpoint measures of response to intervention for the identification and management of depression and anxiety. He has received as a means to reduce placebo honoraria for presentations of his own work at educational seminars supported by a Translational Psychiatry (2015), 1 – 9 Predictors of placebo response in autism number of non-government organizations and the pharmaceutical industry 16 Rief W, Nestoriuc Y, Weiss S, Welzel E, Barsky AJ, Hofmann SG. Meta-analysis of the (including Servier, Pfizer, AstraZeneca and Eli Lilly). He is a member of the Medical placebo response in antidepressant trials. J Affect Disord 2009; 118: 1–8.
Advisory Panel for Medibank Private and also a Board Member of Psychosis Australia 17 Bridge JA, Birmaher B, Iyengar S, Barbe RP, Brent DA. Placebo response in ran- Trust. He leads an investigator-initiated study of the effects of agomelatine on domized controlled trials of antidepressants for pediatric major depressive dis- circadian parameters (supported in part by Servier) and has participated in a order. Am J Psychiatry 2009; 166: 42–49.
multicentre clinical trial of the effects of agomelatine on sleep architecture in 18 King BH, Dukes K, Donnelly CL, Sikich L, McCracken JT, Scahill L et al. Baseline depression and a Servier-supported study of major depression and sleep disturbance factors predicting placebo response to treatment in children and adolescents in primary care settings. AL is funded by a NHMRC Project Grant (ID 1084880), IBH is with autism spectrum disorders: a multisite randomized clinical trial. JAMA Pediatr2013; 167: 1045–1052.
funded by an NHMRC Research Fellowship (APP 1046899) and AJG is funded by a 19 Moher D, Liberati A, Tetzlaff J, Altman DG. preferred reporting items for sys- NHMRC career development fellowship (APP1061922) and project grant (1043664).
tematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 2009; The remaining authors declare no conflict of interest.
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20 Bolte EE, Diehl JJ. Measurement tools and target symptoms/skills used to assess treatment response for individuals with autism spectrum disorder. J Autism DevDisord 2013; 43: 2491–2501.
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