Search strategy results
Through bibliographic searches, we identified 1388 reports after removing duplicates; we excluded 1266 studies on the basis of title and abstract. We retrieved 122 articles in full text for more detailed evaluation, 80 of which we excluded after reading the full text; of the remaining 42 studies, 35 were primary or secondary references referring to 15 RCTs [33-47], 6 were observational studies [48-53], and 1 was a systematic review [54]. See Figure 1 for the flow chart, and Additional file 3 for the full references for included and excluded studies. We reported the methodological quality of included studies in Additional file 4, Additional file 5 and Additional file 6.
Equity
We did not find any study that reported data concerning equity in the use of antipsychotics in children and adolescents with ASD.
Acceptability
Acceptability by parents
Bowker et al. (2011) [48] carried out an online survey to investigate the motivations behind the therapeutic choice of parents of children and adolescents with ASD and their perception of the changes following the therapy undertaken. 970 questionnaires were collected (93% from North America), 96.4% from children and adolescents with ASD, and completed by parents. The survey showed that 77% of subjects had received therapy for ASD during their lifetime, but only 14.6% were on medication at the time the study was conducted. According to the parent's judgment of the effectiveness of the treatment, the area of functioning that benefited most from drug therapy was behavioral (31.9%).
In contrast, a smaller number of parents indicated more notable benefits in the cognitive (16.3%), attention (14.2%), linguistic (12.8%), social (11.3%), and physical (3.5%) areas. Drug therapy was discontinued by 20% of the population. The reasons for discontinuation were mainly lack of efficacy (43% in total and 17% among those who had used antipsychotics at least once) and adverse events (29% in total and 11% among those who had used drug therapy at least once).
The same study reported some factors that parents considered determinant in choosing the type of treatment for their children with ASD, including:
- a) opinions about the causes of the disorder;
- b) parental style;
- c) lifestyle;
- d) socio-economic status;
- e) ease of access to services and care;
- f) impact of the media and the testimonies of other families.
The study concluded that the scientific evidence is not, for parents, decisive for the choice of treatments. Therapies supported by evidence are often underused, while frequently, non-evidence-based treatments are used. Non-evidence-based treatments can be potentially harmful, and the scientific community has a responsibility to explore all possible avenues to help parents to make well-informed decisions.
A survey [50] (n = 96 questionnaires administered), performed in the context of an RCT on the administration of risperidone versus placebo, found the following significant correlations between parent satisfaction and demographic characteristics: a) low income to poor satisfaction with the number of visits (p = 0.003); b) the child's IQ ≥45 and white ethnicity with poor satisfaction to the learning tests (p = 0.043); c) the lower education to poor satisfaction with the behavioral assessment (P = 0.033).
Acceptability by children and adolescent with ASD
We found information on discontinuation due to any cause in 15 RCTs [33-47], and data on discontinuation due to adverse events in 12 RCTs [34-41,44-47]. We evaluated the risk of bias for the included RCTs (Additional file 4). We show forest plots of selected outcomes in Figure 2, Figure 3. Based on visual inspection of funnel plots, we considered that publication bias was not likely (Additional file 7). Results of meta-analyses and certainty of evidence in effect sizes are reported in Table 1.
Figure 2: Forest plots for discontinuation due to any cause
Figure 3: Forest plots for discontinuation due to adverse events
Table 1: Summary of Findings for the comparison antipsychotics versus no antipsychotics: quantitative outcomes for acceptability
Antipsychotics versus no Antipsychotics for children and adolescents with ASD
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Patient or Population: children and adolescents with ASD
Setting: Inpatients and Outpatients
Intervention: Antipsychotics
Control: no Antipsychotics
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Outcomes
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Anticipated absolute effects* (95% CI)
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Relative effect (95% CI)
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№ of participants (studies)
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Certainty of the evidence (GRADE)
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Comments
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Risk with no Antipsychotics
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Risk with Antipsychotics
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Discontinuation due to any cause (Follow up: median 8 weeks)
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244 per 1.000
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149 per 1.000 (117 to 190)
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RR 0.61 (0.48 to 0.78)
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1124 (15 RCT) 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15
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⨁⨁⨁◯ MODERATE b
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Antipsychotics probably reduce the risk of dropout due to any cause
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Discontinuation due to adverse events (Follow up: median 8 weeks)
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39 per 1.000
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39 per 1.000 (22 to 70)
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RR 0.99 (0.55 to 1.79)
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1010 (12 RCT) 2,3,4,5,7,8,9,10,11,13,14,15
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⨁⨁◯◯ LOW a,b
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Antipsychotics may result in little to no difference in the risk of dropout due to adverse events
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*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; SMD: Standardised mean difference; RR: Risk ratio
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GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
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Explanations
- Downgraded by one level because the 95%CI for SMD goes from considerable beneficial effects to undesirable effects.
- Downgraded by one level because most studies showed an unclear risk for selection bias, four studies were at high risk for attrition bias, one study was at high risk for selection bias and one study was at high risk for reporting bias.
References
- Campbell M, Anderson LT, Meier M, Cohen IL, Small AM, Samit C, Sachar EJ.. A comparison of haloperidol and behavior therapy and their interaction in autistic children. J Am Acad Child Psychiatry; 1978.
- Ichikawa H, Mikami K, Okada T, Yamashita Y, Ishizaki Y, Tomoda A, et al. Aripiprazole in the Treatment of Irritability in Children and Adolescents with Autism Spectrum Disorder in Japan: A Randomized, Double-blind, Placebo-controlled Study. Child Psychiatry Hum Dev; 2017.
- Loebel A, Brams M, Goldman RS, Silva R, Hernandez D, Deng L, et al. Lurasidone for the treatment of irritability with autistic disorder. J Autism Dev Disord; 2016.
- Marcus RN, Owen R, Kamen L, Manos G, McQuade RD, Carson WH, Aman MG. A placebo-controlled, fixed-dose study of aripiprazole in children and adolescents with irritability associated with autistic disorder. J Am Acad Child Adolesc Psychiatry; 2009.
- McCracken JT, McGough J, Shah B, Cronin P, Hong D, Aman MG, et al. Risperidone in children with autism and serious behavioral problems. N Engl J Med; 2002.
- NCT00870727. Study of Aripiprazole in the Treatment of Pervasive Developmental Disorders. clinicaltrial.gov; 2009.
- Kent JM, Kushner S, Ning X, Karcher K, Ness S, Aman M, et al. Risperidone dosing in children and adolescents with autistic disorder: a double-blind, placebo-controlled study. Journal of Autism and Developmental Disorders; 2013.
- Luby J, Mrakotsky C, Stalets MM, Belden A, Heffelfinger A, Williams M, Spitznagel E, et al. Risperidone in preschool children with autistic spectrum disorders: an investigation of safety and efficacy. J Child Adoles Psychopharmacol; 2006.
- Hollander E, Wasserman S, Swanson EN, Chaplin W, Schapiro M, Zagursky K, Novotny S.. A double-blind placebo-controlled pilot study of olanzapine in childhood/adolescent pervasive developmental disorder. J Child Adolesc Psychopharmacol; 2006.
- NCT01624675, A Study to Evaluate the Efficacy and Safety of Risperidone (R064766) in Children and Adolescents With Irritability Associated With Autistic Disorder. clinicaltrial.gov; 2012.
- Findling RL, Mankoski R,Timko K,Lears K,McCartney T, McQuade RD, et al. A randomized controlled trial investigating the safety and efficacy of aripiprazole in the long-term maintenance treatment of pediatric patients with irritability associated with autistic disorder. J Clin Psychiatry; 2014.
- Nagaraj R, Singhi P,Malhi P. Risperidone in children with autism: randomized, placebo-controlled, double-blind study. J Child Neurol; 2006.
- Shea S, Turgay A, Carroll A, Schulz M, Orlik H, Smith I, Dunbar F. Risperidone in the treatment of disruptive behavioral symptoms in children with autistic and other pervasive developmental disorders. Pediatrics; 2004.
- Remington G, Sloman L, Konstantareas M, Parker M, Gow R. Clomipramine versus haloperidol in the treatment of autistic disorder: a double-blind, placebo-controlled, crossover study. J Clin Psychopharmacol; 2001.
- Owen R, Sikich L, Marcus RN, Corey-Lisle P, Manos G, McQuade RD, Carson WH, Findling RL. Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Pediatrics. 2009 Dec;124(6):1533-40.doi: 10.1542/peds.2008-3782.
Actual use of antipsychotics in children and adolescents with ASD and predictive factors of their use
Jobski et al. (2017) [54] carried out a systematic review on the use of psychotropic drugs in individuals with ASD, identifying 47 studies that referred to a total of more than 300,000 individuals. In 15 of the 35 studies included in the review, antipsychotics were the most widely administered drugs. About 46% of the children considered across studies were taking psychotropic drugs, with a median prevalence of antipsychotic use of 17%.
About polypharmacological therapy, 22% of the children were taking several psychiatric drugs at the same time; The use of psychopharmacological products increased with age. The authors hypothesized some underlying causes for explaining this phenomenon: a) the development, during growth, of problem behaviors accompanied by an increase in physical strength; b) less reluctance to administer drugs by doctors and parents; (c) having already exhausted attempts at alternative treatments such as behavioral therapies. In addition, the authors noted a trend to switch from stimulants to antipsychotics and antidepressants as age increased, and this trend was attributed to the decrease in symptoms typical of comorbid Attention Deficit/Hyperactivity Disorder, alongside the onset of other problem behaviors such as anxiety, aggression, and depression. Another study [49], conducted in the UK and not included in Jobski et al (2017) systematic review [54], enrolled a cohort of 3482 children and adolescents with ASD; according to the authors, about 10% of the included population was using antipsychotics, mainly risperidone (55%) and aripiprazole (32%), always associated with psychosocial therapy. The authors identified the following socio-demographic predictors of the use of antipsychotics: adolescent age (OR 1.11, 95% CI 1.05 to 1.16), low adaptive functioning inferred from the CGAS scale (OR 0.96, 95% CI 0.95 to 0.97), aggressive and self-harm behaviors (OR 1.85, 95% CI 1.30 to 2.63) and parental concern for symptoms (OR 2.02, 95% CI 1.27 to 3.22). Clinical predictors included hyperactivity (OR 1.44, 95% CI 1.01 to 2.06), depression (OR 2.36, 95% CI 1.37 to 4.09), obsessive-compulsive symptoms (OR 2).31, CI 95 % from 1.16 to 4.61), tics (OR 2.76, CI 95 % from 1.09 to 6.95), intellectual disability (OR 1.68, CI 95 % from 1.11 to 2.53), and obviously psychosis (OR 5.71, CI 95 % from 3.3 to 10.6).
Feasibility
In this section, we summarized barriers and facilitators to the implementation and sustainability of antipsychotics administration using the findings from the three included studies [51-53]. We did not find studies that included children with ASD, but we found three studies considering children with intellectual disabilities and decided to use this evidence to inform this domain.
Among facilitators, the authors identified:
1) Nursing team. Nurses facilitate the monitoring of side effects and routine laboratory controls;
2) Electronic medical records. Electronic medical records are useful tools to assess treatment effects, monitor side effects, and facilitate communication between doctors;
3) Parental or caregiver support.
Among barriers, the authors identified:
1) Electronic medical records. Although perceived by some as facilitators, they are also considered a burden. There is no possibility to follow some parameters of treatment effects and side effects. When the system offers the possibility to monitor specific symptoms or effects of treatment, the possibilities are inflexible and time-consuming;
2) Workloads. The pressure and workloads experienced by health care professionals are barriers to the implementation of antipsychotics;
3) Cost barriers for the choice of drug (e.g. first-generation antipsychotics vs. second-generation antipsychotics);
4) Poor monitoring of metabolic adverse events of antipsychotics.
In Table 2, we summarized the results for all the considered EtD criteria.
Table 2: Summary of Findings for each Evidence to Decision (EtD) framework criterion
EtD Domain
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Results
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Equity
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No included studies
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Acceptability
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4 studies included in the qualitative synthesis, 3 of which specific to both our study population and intervention [49,50,54], one only for the study population [48].
Antipsychotics were among the most prescribed drugs, with a median prevalence of use of 17%. A trend to switch from stimulants to anti-psychotics and anti-depressants as age increased was identified [54].
Socio-demographic predictors of the use of antipsychotics in our population: adolescent age, low adaptive functioning, aggressive and self-harm behaviors, and parental concern for symptoms. Clinical predictors of use: hyperactivity, depression, obsessive-compulsive symptoms, tics, intellectual disability, psychosis [49].
Drug therapy was the most frequently interrupted treatment (20%), mainly due to a lack of efficacy and AEs.
Parents considered as crucial in choosing the treatment: opinions about the causes of the ASD, parental style, lifestyle, socio-economic status, ease of access to services and care, the impact of the media, and the testimonies of other families, but not scientific evidence [48].
Low income, child's IQ ≥45, lower parents’ education correlated to poor satisfaction with the number of visits, learning tests, and behavioral assessment, respectively, in an RCT of risperidone vs. placebo [50].
Quantitative synthesis: antipsychotics in children and adolescents with ASD are acceptable (DO due to any cause: 15 RCTs [33-47], RR 0.61, 95% CI 0.48-0.78, moderate certainty of evidence) and well tolerated (DO due to AEs: 12 RCTs [34-41,44-47], RR 0.99, 95% CI 0.55- 1.79, low certainty of evidence).
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Feasibility
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3 studies investigated the feasibility of administering antipsychotics to the general population (indirect evidence) [51-53].
Facilitators: Nursing team, Electronic medical records, Parental or caregiver support.
Barriers: Electronic medical records, workloads, Cost barriers for the choice of drug, inadequate monitoring of metabolic AEs.
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Legend: AE: Adverse events; ASD: Autism Spectrum Disorder; DO: Dropout; EtD: Evidence to Decision; RCT: Randomized controlled trial;