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Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review and meta-regression analysis.

ABSTRACT: BACKGROUND:Placebo response in autism spectrum disorder (ASD) might dilute drug-placebo differences and hinder drug development. Therefore, this meta-analysis investigated placebo response in core symptoms. METHODS:We searched ClinicalTrials.gov , CENTRAL, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (up to July 8, 2018), and PubMed (up to July 4, 2019) for randomized pharmacological and dietary supplement placebo-controlled trials (RCTs) with a minimum of seven days of treatment. Single-group meta-analyses were conducted using a random-effects model. Standardized mean changes (SMC) of core symptoms in placebo arms were the primary outcomes and placebo positive response rates were a secondary outcome. Predictors of placebo response were investigated with meta-regression analyses. The protocol was registered with PROSPERO ID CRD42019125317 . RESULTS:Eighty-six RCTs with 2360 participants on placebo were included in our analysis (87% in children/adolescents). The majority of trials were small, single-center with a duration of 8-12 weeks and published after 2009. Placebo response in social-communication difficulties was SMC = -?0.32, 95% CI [-?0.39, -?0.25], in repetitive behaviors -?0.23[-?0.32, -?0.15] and in scales measuring overall core symptoms -?0.36 [-?0.46, -?0.26]. Overall, 19%, 95% CI [16-22%] of participants were at least much improved with placebo. Caregiver (vs. clinician) ratings, lower risk of bias, flexible-dosing, larger sample sizes and number of sites, less recent publication year, baseline levels of irritability, and the use of a threshold of core symptoms at inclusion were associated with larger placebo response in at least a core symptom domain. LIMITATIONS:About 40% of the trials had an apparent focus on core symptoms. Investigation of the differential impact of predictors on placebo and drug response was impeded by the use of diverse experimental interventions with essentially different mechanisms of action. An individual-participant-data meta-analysis could allow for a more fine-grained analysis and provide more informative answers. CONCLUSIONS:Placebo response in ASD was substantial and predicted by design- and participant-related factors, which could inform the design of future trials in order to improve the detection of efficacy in core symptoms. Potential solutions could be the minimization and careful selection of study sites as well as rigorous participant enrollment and the use of measurements of change not solely dependent on caregivers.

SUBMITTER: Siafis S

PROVIDER: S-EPMC7448339 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review and meta-regression analysis.

Siafis Spyridon S Çıray Oğulcan O Schneider-Thoma Johannes J Bighelli Irene I Krause Marc M Rodolico Alessandro A Ceraso Anna A Deste Giacomo G Huhn Maximilian M Fraguas David D Mavridis Dimitris D Charman Tony T Murphy Declan G DG Parellada Mara M Arango Celso C Leucht Stefan S

Molecular autism 20200826 1

<h4>Background</h4>Placebo response in autism spectrum disorder (ASD) might dilute drug-placebo differences and hinder drug development. Therefore, this meta-analysis investigated placebo response in core symptoms.<h4>Methods</h4>We searched ClinicalTrials.gov , CENTRAL, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (up to July 8, 2018), and PubMed (up to July 4, 2019) for randomized pharmacological and dietary supplement placebo-controlled trials (RCTs) with a minimum of seven days of treatment. Single- ...[more]

PMID: 32847616

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Project description:BackgroundThere is still no approved medication for the core symptoms of autism spectrum disorder (ASD). This network meta-analysis investigated pharmacological and dietary-supplement treatments for ASD.MethodsWe searched for randomized-controlled-trials (RCTs) with a minimum duration of seven days in ClinicalTrials.gov, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (from inception up to July 8, 2018), CENTRAL and PubMed (up to November 3, 2021). The co-primary outcomes were core symptoms (social-communication difficulties-SCD, repetitive behaviors-RB, overall core symptoms-OCS) measured by validated scales and standardized-mean-differences (SMDs). Associated symptoms, e.g., irritability/aggression and attention-deficit/hyperactivity disorder (ADHD) symptoms, dropouts and important side-effects, were investigated as secondary outcomes. Studies in children/adolescents and adults were analyzed separately in random-effects pairwise and network meta-analyses.ResultsWe analyzed data for 41 drugs and 17 dietary-supplements, from 125 RCTs (n = 7450 participants) in children/adolescents and 18 RCTs (n = 1104) in adults. The following medications could improve at least one core symptom domain in comparison with placebo: aripiprazole (k = 6 studies in analysis, SCD: SMD = 0.27 95% CI [0.09, 0.44], RB: 0.48 [0.26, 0.70]), atomoxetine (k = 3, RB:0.49 [0.18, 0.80]), bumetanide (k = 4, RB: 0.35 [0.09, 0.62], OCS: 0.61 [0.31, 0.91]), and risperidone (k = 4, SCM: 0.31 [0.06, 0.55], RB: 0.60 [0.29, 0.90]; k = 3, OCS: 1.18 [0.75, 1.61]) in children/adolescents; fluoxetine (k = 1, RB: 1.20 [0.45, 1.96]), fluvoxamine (k = 1, RB: 1.04 [0.27, 1.81]), oxytocin (k = 6, RB:0.41 [0.16, 0.66]) and risperidone (k = 1, RB: 0.97 [0.21,1.74]) in adults. There were some indications of improvement by carnosine, haloperidol, folinic acid, guanfacine, omega-3-fatty-acids, probiotics, sulforaphane, tideglusib and valproate, yet imprecise and not robust. Confidence in these estimates was very low or low, except moderate for oxytocin. Medications differed substantially in improving associated symptoms, and in their side-effect profiles.LimitationsMost of the studies were inadequately powered (sample sizes of 20-80 participants), with short duration (8-13 weeks), and about a third focused on associated symptoms. Networks were mainly star-shaped, and there were indications of reporting bias. There was no optimal rating scale measuring change in core symptoms.ConclusionsSome medications could improve core symptoms, although this could be likely secondary to the improvement of associated symptoms. Evidence on their efficacy and safety is preliminary; therefore, routine prescription of medications for the core symptoms cannot be recommended. Trial registration PROSPERO-ID CRD42019125317.

Project description:Background: Autism spectrum disorder (ASD) is a developmental disorder characterized by deficits in social interaction, restricted interest and repetitive behavior. Oxidative stress in response to environmental exposure plays a role in virtually every human disease and represents a significant avenue of research into the etiology of ASD. The aim of this study was to explore the diagnostic utility of four urinary biomarkers of oxidative stress. Methods: One hundred and thirty-nine (139) children and adolescents with ASD (89% male, average age = 10.0 years, age range = 2.1 to 18.1 years) and 47 healthy children and adolescents (49% male, average age 9.2, age range = 2.5 to 20.8 years) were recruited for this study. Their urinary 8-OH-dG, 8-isoprostane, dityrosine and hexanoil-lisine were determined by using the ELISA method. Urinary creatinine was determined with the kinetic Jaffee reaction and was used to normalize all biochemical measurements. Non-parametric tests and support vector machines (SVM) with three different kernel functions (linear, radial, polynomial) were used to explore and optimize the multivariate prediction of an ASD diagnosis based on the collected biochemical measurements. The SVM models were first trained using data from a random subset of children and adolescents from the ASD group (n = 70, 90% male, average age = 9.7 years, age range = 2.1 to 17.8 years) and the control group (n = 24, 45.8% male, average age = 9.4 years, age range = 2.5 to 20.8 years) using bootstrapping, with additional synthetic minority over-sampling (SMOTE), which was utilized because of unbalanced data. The computed SVM models were then validated using the remaining data from children and adolescents from the ASD (n = 69, 88% male, average age = 10.2 years, age range = 4.3 to 18.1 years) and the control group (n = 23, 52.2% male, average age = 8.9 years, age range = 2.6 to 16.7 years). Results: Using a non-parametric test, we found a trend showing that the urinary 8-OH-dG concentration was lower in children with ASD compared to the control group (unadjusted p = 0.085). When all four biochemical measurements were combined using SVMs with a radial kernel function, we could predict an ASD diagnosis with a balanced accuracy of 73.4%, thereby accounting for an estimated 20.8% of variance (p < 0.001). The predictive accuracy expressed as the area under the curve (AUC) was solid (95% CI = 0.691-0.908). Using the validation data, we achieved significantly lower rates of classification accuracy as expressed by the balanced accuracy (60.1%), the AUC (95% CI = 0.502-0.781) and the percentage of explained variance (R2 = 3.8%). Although the radial SVMs showed less predictive power using the validation data, they do, together with ratings of standardized SVM variable importance, provide some indication that urinary levels of 8-OH-dG and 8-isoprostane are predictive of an ASD diagnosis. Conclusions: Our results indicate that the examined urinary biomarkers in combination may differentiate children with ASD from healthy peers to a significant extent. However, the etiological importance of these findings is difficult to assesses, due to the high-dimensional nature of SVMs and a radial kernel function. Nonetheless, our results show that machine learning methods may provide significant insight into ASD and other disorders that could be related to oxidative stress.

Dataset Information

Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review and meta-regression analysis.

Publications

Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review and meta-regression analysis.

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