Impact of antipsychotics in children and adolescents with autism spectrum disorder: a systematic review and meta-analysis.

BACKGROUND: The net health benefit of using antipsychotics in children and adolescents with ASD is unclear. This review was performed to provide the evidence necessary to inform the Italian national guidelines for the management of ASD. METHODS: We performed a systematic review of randomized controlled trials (RCTs) comparing antipsychotics versus placebo for the treatment of ASD in children and adolescents. For efficacy, acceptability and safety we considered outcomes evaluated by the guideline panel critical and important for decision-making. Continuous outcomes were analyzed by using standardized mean difference (SMD), and dichotomous outcomes by calculating the risk ratio (RR), with their 95% confidence interval (95% CI). Data were analyzed using a random effects model. We used the Cochrane tool to assess risk of bias of included studies. Certainty in the evidence of effects was assessed according to the GRADE approach. RESULTS: We included 21 RCTs with 1,309 participants, comparing antipsychotics to placebo. Antipsychotics were found effective on "restricted and repetitive interests and behaviors" (SMD - 0.21, 95% CI - 0.35 to - 0.07, moderate certainty), "hyperactivity, inattention, oppositional, disruptive behavior" (SMD - 0.67, 95% CI - 0.92 to - 0.42, moderate certainty), "social communication, social interaction" (SMD - 0.38, 95% CI - 0.59 to - 0.16, moderate certainty), "emotional dysregulation/irritability" (SMD - 0.71, 95% CI - 0.98 to - 0.43, low certainty), "global functioning, global improvement" (SMD - 0.64, 95% CI - 0.96 to - 0.33, low certainty), "obsessions, compulsions" (SMD - 0.30, 95% CI - 0.55 to - 0.06, moderate certainty). Antipsychotics were not effective on "self-harm" (SMD - 0.14, 95% CI - 0.58 to 0.30, very low certainty), "anxiety" (SMD - 0.38, 95% CI - 0.82 to 0.07, very low certainty). Antipsychotics were more acceptable in terms of dropout due to any cause (RR 0.61, 95% CI 0.48 to 0.78, moderate certainty), but were less safe in terms of patients experiencing adverse events (RR 1.19, 95% CI 1.07 to 1.32, moderate certainty), and serious adverse events (RR 1.07, 95% CI 0.48 to 2.43, low certainty). CONCLUSIONS: Our systematic review and meta-analysis found antipsychotics for children and adolescents with ASD more efficacious than placebo in reducing stereotypies, hyperactivity, irritability and obsessions, compulsions, and in increasing social communication and global functioning. Antipsychotics were also found to be more acceptable, but less safe than placebo.

Introduction and methods of the evidence-based guidelines for the diagnosis and management of autism spectrum disorder by the Italian National Institute of Health.

BACKGROUND: Autism Spectrum Disorder (ASD) is a neuro-developmental disorder that affects communication and behavior with a prevalence of approximately 1% worldwide. Health outcomes of interventions for ASD are largely Participant Reported Outcomes (PROs). Specific guidelines can help support the best care for people with ASD to optimize these health outcomes but they have to adhere to standards for their development to be trustworthy. OBJECTIVE: The goal of this article is to describe the new methodological standards of the Italian National Institute of Health and novel aspects of this guideline development process. This article will serve as a reference standard for future guideline development in the Italian setting. METHODS: We applied the new standards of the Italian National Institute of Health to the two guidelines on diagnosis and management of children/adolescents and adults with ASD, with a focus on the scoping, panel composition, management of conflict of interest, generation and prioritization of research questions, early stakeholders' involvement, and PROs. Recommendations are based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Evidence-to-Decision frameworks. RESULTS: Following a public application process, the ISS established two multidisciplinary panels including people with ASD and/or their caregivers. Seventy-nine research questions were identified as potentially relevant for the guideline on children and adolescents with ASD and 31 for the one on adults with ASD. Questions deemed to have the highest priority were selected for inclusion in the guidelines. Other stakeholders valued their early involvement in the process which will largely focus on PROs. The panels then successfully piloted the development of recommendations using the methodological standards and process set by the ISS with a focus on PROs. CONCLUSIONS: In this article, we describe the development of practice guidelines that focus on PROs for the diagnosis and management of ASD based on novel methods for question prioritization and stakeholder involvement. The recommendations allow for the adoption or adaptation to international settings.

Impact of polyunsaturated fatty acids on patient-important outcomes in children and adolescents with autism spectrum disorder: a systematic review.

BACKGROUND: Recent randomized controlled trials (RCTs) claimed PUFAs to be effective for autism spectrum disorder (ASD) but international guidelines have not considered yet this body of evidence. Our aim was to assess the effectiveness of PUFAs in children and adolescents with ASD, for the Italian national guidelines on the management of ASD in children and adolescents. METHODS: We performed a systematic review and meta-analysis of RCTs comparing PUFAs versus placebo or a healthy diet for the treatment of ASD in children and adolescents. The outcomes considered were deemed by the guideline panel to be highly relevant to children and adolescents with ASD and to their caregivers. The outcomes included hyperactivity, quality of sleep, self-harm, aggression, irritability, anxiety, attention, adaptive functioning, social interaction, restricted and repetitive interests and behavior, communication, hyperactivity and disruptive behaviors coexistent with core symptoms. The risk of bias of the included studies was assessed with the Cochrane tool, and the rating of the confidence in the effect estimates according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: We included 9 studies with 405 participants. The strength of evidence ranged from low to very low. Six studies included preschoolers and school-age children, three studies included both children and adolescents. The majority of participants were males (83.8%), with a mean age of 6.7 years. PUFAs were superior compared to placebo in reducing anxiety in individuals with ASD (SMD -1.01, 95% CI - 1.86 to - 0.17; very low certainty of evidence). Moreover, PUFAs worsened quality of sleep compared to a healthy diet (SMD 1.11, 95% CI 0.21 to 2.00; very low certainty of evidence). PUFAs were not better than placebo in reducing aggression, hyperactivity, adaptive functioning, irritability, restricted and repetitive interests and behaviors and communication. Effects on some critical outcomes such as sleep, self-harm and disruptive behavior are currently unknown. The main limitations were the small number of participants included in the RCTs and the dosage which varied greatly (from 200 mg/day to 1540 mg/day), making it difficult to address causal inference. CONCLUSIONS: PUFAs did not show evidence of effect in children and adolescents with ASD and the certainty of evidence as measured with the GRADE was low to very low. Further research is needed on this topic because the available evidence is inconclusive.

Acceptability, equity, and feasibility of using antipsychotics in children and adolescents with autism spectrum disorder: a systematic review.

BACKGROUND: It is unclear whether the administration of antipsychotics to children and adolescents with autism spectrum disorders (ASD) is acceptable, equitable, and feasible. METHODS: We performed a systematic review to support a multidisciplinary panel in formulating a recommendation on antipsychotics, for the development of the Italian national guidelines for the management of ASD. A comprehensive search strategy was performed to find data related to intervention acceptability, health equity, and implementation feasibility. We used quantitative data from randomized controlled trials to perform a meta-analysis assessing the acceptability and tolerability of antipsychotics, and we estimated the certainty of the effect according to the GRADE approach. We extracted data from systematic reviews, primary studies, and grey literature, and we assessed the risk of bias and methodological quality of the published studies. RESULTS: Antipsychotics were acceptable (dropouts due to any cause: RR 0.61, 95% CI 0.48-0.78, moderate certainty of evidence) and well tolerated (dropouts due to adverse events: RR 0.99, 95% CI 0.55-1.79, low certainty of evidence) by children and adolescents with ASD. Parents and clinicians did not raise significant issues concerning acceptability. We did not find studies reporting evidence of reduced equity for antipsychotics in disadvantaged subgroups of children and adolescents with ASD. Workloads, cost barriers, and inadequate monitoring of metabolic adverse events were indirect evidence of concerns for feasibility. CONCLUSION: Antipsychotics in children and adolescents with ASD were likely acceptable and possibly feasible. We did not find evidence of concern for equity.

Clinical practice guidelines in Brazil - developing a national programme.

In Brazil, governmental and non-governmental organisations develop practice guidelines (PGs) in order to optimise patient care. Although important improvements have been made over the past years, many of these documents still lack transparency and methodological rigour. In order to conduct a critical analysis and define future steps in PG development in Brazil, we carried out a structured assessment of strengths, weaknesses, opportunities and threats (SWOT analysis) for the development of a national guideline programme. Participants consisted of academia, methodologists, medical societies and healthcare system representatives. In summary, the PG development process has improved in Brazil and current investments in methodological research and capacity-building are ongoing. Despite the centralised processes for public PGs, standardised procedures for their development are not well established and human resources are insufficient in number and capacity to develop the amount of trustworthy documents needed. Brazil's capacity could be strengthened and initial efforts have been made such as the adoption of standards proposed by world-renowned institutions in PG development and enhancement of the involvement of key stakeholders. Further steps involve the alignment between health technology assessment and PG processes for synergy and the development of a national network to promote the interaction between groups involved in the development of PGs. The lessons learned from this paper could be used to foster debate on guideline development, especially for countries facing similar threats on this topic.

Prevalence of co-occurring conditions in children and adults with autism spectrum disorder: A systematic review and meta-analysis.

This systematic review estimates the prevalence of co-occurring conditions (CCs) in children and adults with autism. A comprehensive search strategy consulting existing guidelines, diagnostic manuals, experts, carers, and autistic people was developed. PubMed and PsycInfo databases from inception to May 2022 were searched. PROSPERO registration: CRD42019132347. Two blind authors screened and extracted the data. Prevalence estimates for different CCs were summarized by using random effects models. Subgroup analyses were performed for age groups (children/adolescents vs adults) and study designs (population/registry-based vs clinical sample-based). Of 19,932 studies, 340 publications with about 590,000 participants were included and meta-analyzed to estimate the prevalence of 38-point prevalence, 27-lifetime, and 3 without distinction between point and lifetime prevalence. Point prevalence of developmental coordination disorder, sleep-wake problem, gastrointestinal problem, ADHD, anxiety disorder, overweight/obesity, feeding and eating disorder, elimination disorder, disruptive behavior, and somatic symptoms and related disorder were the most frequent CCs. Prevalence differed depending on the age group and study design. Knowing specific CCs linked to autism helps professional investigations and interventions for improved outcomes.

Formulations of desensitizing toothpastes for dentin hypersensitivity: a scoping review.

OBJECTIVE: This study aimed to review evidence from randomized controlled trials (RCTs) to describe: 1) the active ingredients and desensitizing toothpaste brands; 2) the evaluation of these active ingredients over time, and 3) the fluoride and abrasive content in the formulations designed to treat dentin hypersensitivity (DH). METHODOLOGY: In total, 138 RCTs and their tested toothpastes were included. Searches were updated up to August 19, 2021. Formulations, reported brands, active ingredients over time, and type of fluoride (ionizable or ionic fluoride) and abrasive (calcium or silica-based) were analyzed (PROSPERO #CRD42018086815). RESULTS: Our trials assessed 368 toothpaste formulations, including 34 placebo (9%), 98 control toothpastes with fluoride (27%), and 236 (64%) with active ingredients to treat DH. We tested the following active ingredients: potassium compounds (n=68, 19%), calcium sodium phosphosilicate (CSP) (n=37, 10%), strontium compounds (n=28, 8%), arginine (n=29, 8%), stannous fluoride (SnF2) (n=21, 6%), hydroxyapatite (n=9, 2%), potassium combined with another active ingredient (n=19, 5%), inorganic salt compounds (n=11, 3%), citrate (n=5, 1%), formaldehyde (n=3, 1%), herbal (n=4, 1%), copolymer (n=1, 0.5%), and trichlorophosphate (TCP) (n=1, 0.5%). The number of toothpaste formulations increased since 1968, with the greatest increment after 2010. Most toothpastes described their type of fluoride as sodium monofluorphosphate (MFP) (n=105, 29%) and NaF (n=82, 22%), with silica-based (n=84, 23%) and calcium-based (n=64, 17%) abrasives. CONCLUSION: Patients and dentists enjoy an increasing number of brands and active ingredients to decide what desensitizing toothpaste to use. The most common types of fluoride are MFP and NaF.

Formulations of desensitizing toothpastes for dentin hypersensitivity: a scoping review

Abstract Objective: This study aimed to review evidence from randomized controlled trials (RCTs) to describe: 1) the active ingredients and desensitizing toothpaste brands; 2) the evaluation of these active ingredients over time, and 3) the fluoride and abrasive content in the formulations designed to treat dentin hypersensitivity (DH). Methodology: In total, 138 RCTs and their tested toothpastes were included. Searches were updated up to August 19, 2021. Formulations, reported brands, active ingredients over time, and type of fluoride (ionizable or ionic fluoride) and abrasive (calcium or silica-based) were analyzed (PROSPERO #CRD42018086815). Results: Our trials assessed 368 toothpaste formulations, including 34 placebo (9%), 98 control toothpastes with fluoride (27%), and 236 (64%) with active ingredients to treat DH. We tested the following active ingredients: potassium compounds (n=68, 19%), calcium sodium phosphosilicate (CSP) (n=37, 10%), strontium compounds (n=28, 8%), arginine (n=29, 8%), stannous fluoride (SnF2) (n=21, 6%), hydroxyapatite (n=9, 2%), potassium combined with another active ingredient (n=19, 5%), inorganic salt compounds (n=11, 3%), citrate (n=5, 1%), formaldehyde (n=3, 1%), herbal (n=4, 1%), copolymer (n=1, 0.5%), and trichlorophosphate (TCP) (n=1, 0.5%). The number of toothpaste formulations increased since 1968, with the greatest increment after 2010. Most toothpastes described their type of fluoride as sodium monofluorphosphate (MFP) (n=105, 29%) and NaF (n=82, 22%), with silica-based (n=84, 23%) and calcium-based (n=64, 17%) abrasives. Conclusion: Patients and dentists enjoy an increasing number of brands and active ingredients to decide what desensitizing toothpaste to use. The most common types of fluoride are MFP and NaF.