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Journal ArticleDOI

Intravenous secretin for autism spectrum disorders (ASD).

TL;DR: There is no evidence that single or multiple dose intravenous secretin is effective and as such currently it should not be recommended or administered as a treatment for ASD.
Abstract: BACKGROUND: In 1998 secretin, a gastrointestinal hormone, was suggested as an effective treatment for autism spectrum disorders (ASD) based on anecdotal evidence. OBJECTIVES: To assess whether intravenous secretin improves the core features of ASD, other aspects of behaviour or function such as self-injurious behaviour, and the quality of life of affected individuals and their carers. We also assessed whether secretin causes harm. This is an updated version of our review of this topic originally published in 2005. SEARCH METHODS: We searched CENTRAL (2010 Issue 1), MEDLINE (1950 to January 2010) , EMBASE (1980 to 2010 Week 2), PsycINFO (1806 to 2010 Week 2), CINAHL (1938 to January 2010), ERIC (1966 to January 2010), Sociological Abstracts (1952 to January 2010). Sociofile and HealthStar were searched in March 2005 when this review was first published, but were not available for this update. Records were limited to studies published since 1998 as this is when secretin was first proposed as a possible treatment for ASD. We searched reference lists of trials and reviews; we also contacted experts and trialists to find unpublished studies. SELECTION CRITERIA: Randomised controlled trials of intravenous secretin compared to a placebo treatment in children or adults diagnosed with ASD, where at least one standardised outcome measure was reported. DATA COLLECTION AND ANALYSIS: Sixteen studies met the inclusion criteria but for two of these, conducted by Repligen, the only available multisite data were reported in press releases. All outcome data from the other 14 trials were continuous. Where trials used cross-over designs, we conducted analysis on results from the first treatment phase. Where mean change from baseline was reported, we used this in preference to post-treatment scores for meta-analyses or forest plots. Meta-analysis was able to be attempted for only one outcome (Childhood Autism Rating Scale). Insufficient data were available to conduct sensitivity or subgroup analyses to assess the impact of study quality, clinical differences in the intervention or clinically relevant differences between groups, such as age or presence of gastrointestinal symptoms. MAIN RESULTS: Over 900 children were recruited for the secretin trials. Twenty-five established standardised outcome measures were reported to assess core features of ASD, communication, behaviour, visuospatial skills, affect and adverse events. One standardised measure of global impression was also used. No more than four studies used any one outcome measure similarly. When duration from the start of the intervention to outcome assessment was known, outcomes were reported at between three and six weeks. Meta-analysis of data was not possible but there is now consistency of findings, with RCTs of the efficacy of secretin in autism not showing improvements for core features of ASD. AUTHORS' CONCLUSIONS: There is no evidence that single or multiple dose intravenous secretin is effective and as such currently it should not be recommended or administered as a treatment for ASD. Further experimental assessment of secretin's effectiveness for ASD can only be justified if there is new high-quality and replicated scientific evidence that either finds that secretin has a role in neurotransmission in a way that could benefit all children with ASD or identifies important subgroups of children with ASD who could benefit from secretin because of a proven link between the action of secretin and the known cause of their ASD, or the type of problems they are experiencing.

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Journal ArticleDOI
TL;DR: Cyclic AMP is a potentially useful biochemical marker to distinguish autism comorbid with FX from autism per se and the cAMP cascade may be a viable therapeutic target for both FX and autism.

53 citations

Journal ArticleDOI
TL;DR: It is demonstrated that HBOT delivered at 24% oxygen at 1.3 atmospheric pressure does not result in a clinically significant improvement of the symptoms of Autistic Disorder.

50 citations

Journal ArticleDOI
TL;DR: It is indicated that intravenous secretin had no effects in a 5-week period on the language and behavior of 20 children with autism and gastrointestinal symptoms, and no relationship was found between parental reports of change and observable improvement in the sample.
Abstract: Background. Autism is a severe developmental disorder with poorly understood etiology. A recently published case series describes 3 autistic children with gastrointestinal symptoms who underwent endoscopy and intravenous administration of secretin and were subsequently noted by their parents to demonstrate improved language skills over a 5-week period. This report sparked tremendous public interest, and investigators at several sites moved quickly to design controlled trials to test the efficacy of secretin as a therapy for autistic children. However, this is the first effort specifically designed to replicate the initial reported findings in terms of patient age, presenting symptoms, and drug administration. Objective. To rigorously apply the scientific method by assessing the reproducibility of the reported effects of intravenous secretin on the language of young children with autism and gastrointestinal symptoms. Methods. We performed a single-blinded, prospective, open-label trial by conducting formal language testing and blinded behavioral rating both before and repeatedly after a standardized infusion of secretin. We selected autistic children who were similar in age and profile to those described in the published retrospective case review. Inclusion criteria for study participation included age (3–6 years), confirmed diagnosis of autism, and reported gastrointestinal symptoms (16 had chronic diarrhea, 2 had gastroesophageal reflux, and 2 had chronic constipation). Twenty children (18 male) were admitted to the Pediatric Clinical Research Center at the University of California, San Francisco after administration of the Preschool Language Scale-3 (PLS-3). A 3 CU/kg dose of secretin (Secretin-Ferring) was administered intravenously (upper endoscopy was not performed). Behavioral ratings were derived using the Autism Observation Scale applied to a 30-minute time sample of the child9s behavior consisting of a videotape of the PLS-3 (structured setting) and a second free play session with a standard set of developmentally appropriate toys. Participants then returned for follow-up evaluations, with readministrations of the PLS-3 at 1, 2, 3, and 5 weeks9 postinfusion, and videotaping of each session for later blinded review by 2 independent observers using the Autism Observation Scale, uninformed about week of posttreatment. We also surveyed parents of our study children about their impressions of the effects of secretin using a 5-point Likert scale for parents to rate changes seen in their child. Results. With a total study completion rate across all participants of 96%, repeated measures analyses of variance revealed no significant increases in children9s language skills from baseline across all 5 study time periods after a single infusion of secretin. Similarly, neither significant decreases in atypical behaviors nor increases in prosocial behaviors and developmentally appropriate play skills emerged. Furthermore, no relationship was found between parental reports of change and observable improvement in the sample. Despite the objective lack of drug effect, 70% of parents in our study reported moderate to high change in their child9s language and behavior. Furthermore, 85% of parents reported that they felt that their child would obtain at least some additional benefits from another infusion of secretin. Conclusions. The results of our pilot study indicate that intravenous secretin had no effects in a 5-week period on the language and behavior of 20 children with autism and gastrointestinal symptoms. The open-label, prospective design of our study with blinded reviews of patients both before and after secretin administration follows the scientific method by seeking to reproduce an observed phenomenon using validating and reliable outcome measures. Pilot studies remain a mandatory step for the design of future randomized, clinical trials investigating potential treatments for children with autism.

49 citations

Journal ArticleDOI
TL;DR: A literature review was undertaken to compare and contrast the OMERACT conceptual framework with others within and outside rheumatology and reinforced the need for clear methods and standards for core set development.
Abstract: Objective. The usefulness of randomized control trials to advance clinical care depends upon the outcomes reported, but disagreement on the choice of outcome measures has resulted in inconsistency and the potential for reporting bias. One solution to this problem is the development of a core outcome set: a minimum set of outcome measures deemed critical for clinical decision making. Within rheumatology the Outcome Measures in Rheumatology (OMERACT) initiative has pioneered the development of core outcome sets since 1992. As the number of diseases addressed by OMERACT has increased and its experience in formulating core sets has grown, clarification and update of the conceptual framework and formulation of a more explicit process of area/domain core set development has become necessary. As part of the update process of the OMERACT Filter criteria to version 2, a literature review was undertaken to compare and contrast the OMERACT conceptual framework with others within and outside rheumatology. Methods. A scoping search was undertaken to examine the extent, range, and nature of conceptual frameworks for core set outcome selection in health. We searched the following resources: Cochrane Library Methods Group Register; Medline; Embase; PsycInfo; Environmental Studies and Policy Collection; and ABI/INFORM Global. We also conducted a targeted Google search. Results. Five conceptual frameworks were identified: the WHO tripartite definition of health; the 5 Ds (discomfort, disability, drug toxicity, dollar cost, and death); the International Classification of Functioning (ICF); PROMIS (Patient-Reported Outcomes Measurement System); and the Outcomes Hierarchy. Of these, only the 5 Ds and ICF frameworks have been systematically applied in core set development. Outside the area of rheumatology, several core sets were identified; these had been developed through a limited range of consensus-based methods with varying degrees of methodological rigor. None applied a framework to ensure content validity of the end product. Conclusion. This scoping review reinforced the need for clear methods and standards for core set development. Based on these findings, OMERACT will make its own conceptual framework and working process more explicit. Proposals for how to achieve this were discussed at the OMERACT 11 conference.

48 citations

Journal ArticleDOI
TL;DR: It is suggested that currently available pharmacological agents have at best only a modest benefit for the treatment of RRBs in ASD with the most evidence supporting antipsychotic medications.
Abstract: Objective To examine the efficacy of pharmacological treatments for restricted and repetitive behaviors (RRB) in autism spectrum disorders (ASD). Method We searched PubMed, Embase, and CENTRAL to identify all double-blind, randomized, placebo-controlled trials that examined the efficacy of pharmacological agents in the treatment of ASD and measured RRB as an outcome. Our primary outcome was the standardized mean difference in rating scales of RRB. Results We identified 64 randomized, placebo-controlled trials involving 3,499 participants with ASD. Antipsychotics significantly improved RRB outcomes compared to placebo (standardized mean difference [SMD] = 0.28, 95% CIs = 0.08−0.49), z = 2.77, p = .01) demonstrating a small effect size. Larger significant positive effects on RRB in ASD were seen in individual studies with fluvoxamine, buspirone, bumetanide, divalproex, guanfacine, and folinic acid that have not been replicated. Other frequently studied pharmacological treatments in ASD including oxytocin, omega-3 fatty acids, selective serotonin reuptake inhibitors (SSRI), and methylphenidate did not demonstrate significant benefit in reducing RRB compared to placebo (oxytocin: SMD = 0.23, 95% CI = −0.01 to 0.47, z = 1.85, p = .06; omega-3 fatty acids: SMD = 0.19, 95% CI = −0.05 to 0.43, z = 1.54, p = .12; SSRI: SMD = 0.09, 95% CI = −0.21 to 0.39, z = 0.60, p = .56; methylphenidate: SMD = 0.18, 95% CI = −0.11 to 0.46, z = 1.23, p = .22). Conclusion The results of the present meta-analysis suggest that currently available pharmacological agents have at best only a modest benefit for the treatment of RRB in ASD, with the most evidence supporting antipsychotic medications. Additional randomized controlled trials with standardized study designs and consistent and specific assessment tools for RRB are needed to further understand how we can best help ameliorate these behaviors in individuals with ASD.

47 citations

References
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Journal ArticleDOI
13 Sep 1997-BMJ
TL;DR: Funnel plots, plots of the trials' effect estimates against sample size, are skewed and asymmetrical in the presence of publication bias and other biases Funnel plot asymmetry, measured by regression analysis, predicts discordance of results when meta-analyses are compared with single large trials.
Abstract: Objective: Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses. Design: Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30% of the trial); analysis of funnel plots from 37 meta-analyses identified from a hand search of four leading general medicine journals 1993-6 and 38 meta-analyses from the second 1996 issue of the Cochrane Database of Systematic Reviews . Main outcome measure: Degree of funnel plot asymmetry as measured by the intercept from regression of standard normal deviates against precision. Results: In the eight pairs of meta-analysis and large trial that were identified (five from cardiovascular medicine, one from diabetic medicine, one from geriatric medicine, one from perinatal medicine) there were four concordant and four discordant pairs. In all cases discordance was due to meta-analyses showing larger effects. Funnel plot asymmetry was present in three out of four discordant pairs but in none of concordant pairs. In 14 (38%) journal meta-analyses and 5 (13%) Cochrane reviews, funnel plot asymmetry indicated that there was bias. Conclusions: A simple analysis of funnel plots provides a useful test for the likely presence of bias in meta-analyses, but as the capacity to detect bias will be limited when meta-analyses are based on a limited number of small trials the results from such analyses should be treated with considerable caution. Key messages Systematic reviews of randomised trials are the best strategy for appraising evidence; however, the findings of some meta-analyses were later contradicted by large trials Funnel plots, plots of the trials9 effect estimates against sample size, are skewed and asymmetrical in the presence of publication bias and other biases Funnel plot asymmetry, measured by regression analysis, predicts discordance of results when meta-analyses are compared with single large trials Funnel plot asymmetry was found in 38% of meta-analyses published in leading general medicine journals and in 13% of reviews from the Cochrane Database of Systematic Reviews Critical examination of systematic reviews for publication and related biases should be considered a routine procedure

37,989 citations

Journal ArticleDOI
TL;DR: It is concluded that H and I2, which can usually be calculated for published meta-analyses, are particularly useful summaries of the impact of heterogeneity, and one or both should be presented in publishedMeta-an analyses in preference to the test for heterogeneity.
Abstract: The extent of heterogeneity in a meta-analysis partly determines the difficulty in drawing overall conclusions. This extent may be measured by estimating a between-study variance, but interpretation is then specific to a particular treatment effect metric. A test for the existence of heterogeneity exists, but depends on the number of studies in the meta-analysis. We develop measures of the impact of heterogeneity on a meta-analysis, from mathematical criteria, that are independent of the number of studies and the treatment effect metric. We derive and propose three suitable statistics: H is the square root of the chi2 heterogeneity statistic divided by its degrees of freedom; R is the ratio of the standard error of the underlying mean from a random effects meta-analysis to the standard error of a fixed effect meta-analytic estimate, and I2 is a transformation of (H) that describes the proportion of total variation in study estimates that is due to heterogeneity. We discuss interpretation, interval estimates and other properties of these measures and examine them in five example data sets showing different amounts of heterogeneity. We conclude that H and I2, which can usually be calculated for published meta-analyses, are particularly useful summaries of the impact of heterogeneity. One or both should be presented in published meta-analyses in preference to the test for heterogeneity.

25,460 citations

Book
23 Sep 2019
TL;DR: The Cochrane Handbook for Systematic Reviews of Interventions is the official document that describes in detail the process of preparing and maintaining Cochrane systematic reviews on the effects of healthcare interventions.
Abstract: The Cochrane Handbook for Systematic Reviews of Interventions is the official document that describes in detail the process of preparing and maintaining Cochrane systematic reviews on the effects of healthcare interventions.

21,235 citations

Book
01 Jun 1991

12,618 citations


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