Translate this page into:
Aripiprazole for treating irritability in children & adolescents with autism: a systematic review
Reprint requests: Dr Ahmad Ghanizadeh, Research Center for Psychiatry & Behavioral Sciences, Department of Psychiatry Shiraz University of Medical Sciences, Hafez Hospital, Shiraz, Iran e-mail: ghanizad@sina.tums.ac.ir
-
Received: ,
This is an open access article distributed under the terms of the Creative Commons Attribution NonCommercial ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non commercially, as long as the author is credited and the new creations are licensed under the identical terms.
This article was originally published by Medknow Publications & Media Pvt Ltd and was migrated to Scientific Scholar after the change of Publisher.
Abstract
Background & objectives:
No clear therapeutic benefits of antipsychotics have been reported for the treatment of behavioural symptoms in autism. This systematic review provides an assessment of evidence for treating irritability in autism by aripiprazole.
Methods:
The databases of MEDLINE/PubMed and Google Scholar were searched for relevant articles about the effect of aripiprazole in children with autism. The articles were searched according to the inclusion and exclusion criteria specifed for this review. All the double-blind, controlled, randomized, clinical trials examining the efficacy of aripiprazole for treating children and adolescents with autism were included.
Results:
From the 93 titles identified, 26 were irrelevant and 58 were evaluated for more details. Only five articles met the inclusive criteria. The evidence from precise randomized double blind clinical trials of aripiprazole for the treatment of autism in children and adolescents was convincing enough to recommend aripiprazole. Adverse effects were not very common and were usually mild.
Interpretation & conclusions:
Current evidence suggests that aripiprazole is as effective and safe as risperidone for treating irritability in autism. However, further studies with larger sample size and longer duration are required.
Keywords
aripiprazole
autism
children
clinical trial
irritability
Aripiprazole, 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy}-3,4-dihydro-2(1H)-quinolinone, is an atypical antipsychotic. It is approved for the treatment of bipolar I disorder (in children aged 10-17 yr), schizophrenia (in children aged 13-17 yr)1 and autism in children and adolescents2 by the Food and Drug Administration (FDA). There is strong evidence for its efficacy for treating tic disorder34. In addition, there is some weak evidence for its efficacy for treating attention deficit hyperactivity disorder (ADHD)5. It is a partial agonist of serotonin (5-hydroxy tryptamine, 5-HT) 5-HT1A6 and dopamine D2 receptors7. It is also a 5-HT2A receptor antagonist without considerable affinity at the cholinergic muscarinic receptor2. Its serum half-life in adults is 72 h. Aripirprazole has only one active metabolite, dehydroaripiprazole. The half-life of this metabolite is about 94 hours in adults8.
Autism is a complex neurodevelopmental disorder and its aetiology is not clearly known. At present, two medications including risperidone and aripiprazole are FDA approved for treatment of symptoms associated with autism2. A 14-week, prospective, open-label study including 25 children with irritability and pervasive developmental disorder not otherwise specified and Asperger's disorder reported that aripiprazole had no significant cardiac effects9.
The aim of this systematic review was to evaluate the evidence from clinical trials of therapeutic intervention testing aripiprazole for autism in children and adolescents. A systematic review was conducted in May 2011 to determine the safety and efficacy of aripiprazole for patients with autism spectrum disorders (ASD)10. This study found two randomized controlled trials using aripiprazole for a duration of eight weeks to treat autism in children.
There was no study conducted on adult patients with autism. It was found that aripiprazole improved irritability in children with autism, but increased weight more than placebo9. The current systematic review was aimed to update the evidence for administering aripiprazole for treating autism.
Material & Methods
The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol was used to perform this systematic review11.
Search strategy: Systematic literature searches were conducted to retrieve all randomized clinical trials (RCTs) of aripiprazole for treating pervasive developmental disorder. The databases of MEDLINE, Google Scholar, The Cochrane Library and Web of Science were searched upto 2013. The International Clinical Trials Registry Platform was also searched to find currently ongoing trials.
The terms for conducting the search were “aripiprazole+pervasive developmental disorder”, “autism+aripiprazole”, and “autistic disorder+aripiprazole”. Potentially relevant titles were selected and articles retrieved. A preliminary selection based on the titles was conducted. The references of the articles were also searched to find possible relevant articles. No language limitation was imposed.
Study inclusion criteria: All the randomized controlled clinical trials that investigated the effect of aripiprazole on irritability in pervasive developmental disorders were included. There were no age, publication date, and gender limitations. Any trial using a valid and reliable measurement to assess irritability was included. Intent-to-treat analysis was not an exclusion criterion.
Evaluation of validity: Methodological issues such as method of randomization, blinding of participants, and having any controlled groups were considered.
Data extraction: An extraction data sheet was designed. Study design, sampling, intervention, and adverse effects were extracted.
Results
The number of identified articles was 93 (Figure). Of these, 26 were found to be irrelevant. These studies had not examined the effect of aripiprazole on irritability in autism. The other reasons for exclusion were as follows: not a clinical trial10121314151617181920212223242526272829303132333435363738, not double blind trials3739404142, post-hoc analyses434445, no control group46, case reports474849505152535455, switching risperidone to aripiprazole5657, data re-analysis58, assessed body mass index changes59, prevention of irritability60, and retrospective studies6162636465. One study reported anti-manic effect of aripiprazole in patients with autism spectrum disorder and bipolar disorder66. Another reported lack of any significant effect of aripiprazole on electrocardiographic data in paediatric patients9. A post-hoc analysis reported quality of life of children with autism44.
- Flowchart of trial selection process.
Only five articles met the inclusion criteria6768697071. In these trials, the effect of aripiprazole on patients with autism was investigated. The details of these studies are indicated in the Table. Only one trial compared the safety and efficacy of aripiprazole with another antipsychotic, risperidone, for treating children with autism71.
Only one systematic review was found concerning the effect of aripiprazole for treating autism in the Cochrane Library published in 201210. Searching Web of Science retrieved 83 titles, but these did not add to the titles retrieved from the two databases of PubMed/MEDLINE and Google Scholar.
In progress unpublished studies: There was one unpublished study in progress about the effect of aripiprazole for treating autism (NCT02069977) and there were two other studies that had not started recruiting patients yet (NCT00468130, and NCT00208533).
Discussion
In this systematic review, five published studies on the effect of aripiprazole on autism were reviewed. The best evidence from the randomized placebo controlled clinical trials confirmed that aripiprazole more than placebo reduced irritability in autism. The efficacy and safety of aripiprazole were comparable to risperidone for treating children and adolescents with autism71. All these studies included children and adolescents. Therefore, it is not clear whether these results can be generalized to adult individuals with autism. This systematic review of double-blind controlled RCTs showed convincing evidence of effectiveness and, therefore, supported the recommendations for the use of aripiprazole for treating irritability associated with autism. Other reviews that included open label or retrospective trials also have shown similar results.
Regarding side effects, aripiprazole in children and adolescents seemed to be safe. Many of the adverse effects reported were of mild nature. Serious adverse effects were rare. Because, the number of RCTs is very limited, larger studies need to be conducted to show if it is totally safe. One of the limitations of this review is potential incompleteness of the reviewed evidence. Publication bias cannot be ignored. The four major databases of PubMed/MEDLINE, Google Scholar, the Cochrane Library, and Web of Science were searched. In addition, we also searched International Clinical Trials Registry Platform to find ongoing trials.
In conclusion, the current evidences support the efficacy and safety of aripiprazole for treating irritability in autism in children and adolescents.
References
- Focus on aripiprazole: a review of its use in child and adolescent psychiatry. J Can Acad Child Adolesc Psychiatry. 2009;18:250-60.
- [Google Scholar]
- Issues in the management of challenging behaviours of adults with autism spectrum disorder. CNS Drugs. 2011;25:597-606.
- [Google Scholar]
- Aripiprazole versus risperidone for treating children and adolescents with tic disorder: a randomized double blind clinical trial. Child Psychiatry Hum Dev. 2014;45:596-603.
- [Google Scholar]
- Systemic review of aripiprazole for the treatment of children and adolescents with tic disorders. Neurosciences (Riyadh). 2012;17:200-4.
- [Google Scholar]
- Systematic review of clinical trials of aripiprazole for treating attention deficit hyperactivity disorder. Neurosciences (Riyadh). 2013;18:323-9.
- [Google Scholar]
- The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1A receptor. Eur J Pharmacol. 2002;441:137-40.
- [Google Scholar]
- Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther. 2002;302:381-9.
- [Google Scholar]
- Aripiprazole: an overview of a novel antipsychotic. Psychiatr Danub. 2005;17:67-75.
- [Google Scholar]
- The effects of aripiprazole on electrocardiography in children with pervasive developmental disorders. J Child Adolesc Psychopharmacol. 2012;22:277-83.
- [Google Scholar]
- Aripiprazole for autism spectrum disorders (ASD) Cochrane Database Syst Rev. 2012;5:C D009043.
- [Google Scholar]
- The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62:e1-34.
- [Google Scholar]
- Aripiprazole: in the treatment of irritability associated with autistic disorder in pediatric patients. Paediatr Drugs. 2011;13:197-204.
- [Google Scholar]
- A systematic review of medical treatments for children with autism spectrum disorders. Pediatrics. 2011;127:e1312-21.
- [Google Scholar]
- Aripiprazole for irritability associated with autistic disorder in children and adolescents aged 6-17 years. Ped Health. 2010;4:375-81.
- [Google Scholar]
- Aripiprazole for the treatment of irritability associated with autism. Expert Opin Pharmacother. 2011;12:635-40.
- [Google Scholar]
- Aripiprazole in autism spectrum disorders and fragile X syndrome. Neurotherapeutics. 2010;7:258-63.
- [Google Scholar]
- Atypical antipsychotics in children and adolescents with autistic and other pervasive developmental disorders. J Clin Psychiatry. 2008;69(Suppl 4):15-20.
- [Google Scholar]
- Pharmacologic treatment of behavioral symptoms associated with autism and other pervasive developmental disorders. Curr Treat Options Neurol. 2010;12:529-38.
- [Google Scholar]
- Emerging role of aripiprazole for treatment of irritability associated with autistic disorder in children and adolescents. Adolesc Health Med Ther. 2010;1:105-14.
- [Google Scholar]
- Useful pharmacologic treatment in impaired social interaction in autism spectrum disorders. Seishin shinkeigaku zasshi. 2012;114:934-40.
- [Google Scholar]
- Summary of the comparative effectiveness review on off-label use of atypical antipsychotics. Journal of managed care pharmacy. J Manag Care Pharma. 2012;18(5 Suppl B):S1-20.
- [Google Scholar]
- Review of the pharmacotherapy of irritability of autism. J Can Acad Child Adolesc Psychiatry. 2012;21:130-46.
- [Google Scholar]
- Risperidone or aripiprazole in children and adolescents with autism and/or intellectual disability: A Bayesian meta-analysis of efficacy and secondary effects. Res Autism Spectr Disord. 2013;7:167-75.
- [Google Scholar]
- Psychotropic medications in autism: Practical considerations for parents. J autism dev disord. 2012;42:1249-55.
- [Google Scholar]
- Psychopharmacology of autism spectrum disorders: a selective review. Autism. 2013;17:645-54.
- [Google Scholar]
- Clinical practice pathways for evaluation and medication choice for attention-deficit/hyperactivity disorder symptoms in autism spectrum disorders. Pediatrics. 2012;130(Suppl 2):S125-S38.
- [Google Scholar]
- Efficacy and safety of aripiprazole in child and adolescent patients. Eur child adolesc psychiatry. 2012;21:361-8.
- [Google Scholar]
- Psychotropic medications in children with autism spectrum disorders: a systematic review and synthesis for evidence-based practice. J autism dev disord. 2012;42:1592-605.
- [Google Scholar]
- Atypical antipsychotics in the treatment of children and adolescents with pervasive developmental disorders. Psychopharmacology (Berl). 2014;231:1023-36.
- [Google Scholar]
- Therapies for children with autism spectrum disorders. Comparative effectiveness review. No. 26 AHRQ Publication no. 11-EHC029-EF. Rockville MD: Agency for Healthcare Research and Quality (US); 2011.
- [Google Scholar]
- Psychopharmacological interventions in autism spectrum disorder. Harv rev psychiatry. 2014;22:76-92.
- [Google Scholar]
- An update on medication management of behavioral disorders in autism. Curr psychiatry rep. 2014;16:437.
- [Google Scholar]
- The effectiveness of aripiprazole in the management of problem behaviour in people with intellectual disabilities, developmental disabilities and/or autistic spectrum disorder--a systematic review. Res disabil. 2014;35:711-25.
- [Google Scholar]
- Pharmacological treatments in patients with pervasive developmental disorders: a review. Encephale. 2014;40:188-96.
- [Google Scholar]
- Psychopharmacologic management of serious behavioral disturbance in ASD. Child adolesc psychiatr clin N Am. 2014;23:73-82.
- [Google Scholar]
- Second generation antipsychotics in Asperger's disorder and high functioning autism: a systematic review of the literature and effectiveness of meta-analysis. Curr clin pharmacol. 2013;8:370-9.
- [Google Scholar]
- Aripiprazole in the treatment of irritability in pediatric patients (aged 6-17 years) with autistic disorder: results from a 52-week, open-label study. J Child Adolesc Psychopharmacol. 2011;21:229-36.
- [Google Scholar]
- A prospective open-label study of aripiprazole in fragile X syndrome. Psychopharmacology (Berl). 2011;216:85-90.
- [Google Scholar]
- Aripiprazole in pervasive developmental disorder not otherwise specified and Asperger's disorder: a 14-week, prospective, open-label study. J Child Adolesc Psychopharmacol. 2009;19:265-74.
- [Google Scholar]
- Safety and tolerability of aripiprazole in the treatment of irritability associated with autistic disorder in pediatric patients: results from a 52-week open-label study. Eur Psychiatry. 2011;26(Suppl 1) Abstr P01-317
- [Google Scholar]
- Line-item analysis of the Aberrant Behavior Checklist: results from two studies of aripiprazole in the treatment of irritability associated with autistic disorder. J Child Adolesc Psychopharmacol. 2010;20:415-22.
- [Google Scholar]
- Effect of aripiprazole 2 to 15 mg/d on health-related quality of life in the treatment of irritability associated with autistic disorder in children: a post hoc analysis of two controlled trials. Clin ther. 2012;34:980-92.
- [Google Scholar]
- Aripiprazole treatment of irritability associated with autistic disorder and the relationship between prior antipsychotic exposure, adverse events, and weight change. J Child Adolesc Psychopharmacol. 2013;23:572-6.
- [Google Scholar]
- Clinical observation of aripiprazole in the treatment of autism. Zhongguo dang dai er ke za zhi. 2013;15:294-7.
- [Google Scholar]
- Aripiprazole improves social interaction in Taiwanese children with pervasive developmental disorder. Chang Gung Med J. 2010;33:211-5.
- [Google Scholar]
- Aripiprazole for maladaptive behavior in pervasive developmental disorders. J Child Adolesc Psychopharmacol. 2004;14:455-63.
- [Google Scholar]
- Aripiprazole in an adult with Asperger disorder. Ann Pharmacother. 2003;37:1628-31.
- [Google Scholar]
- Aripiprazole treatment for coprophagia in autistic disorder. J Neuropsychiatry Clin Neurosci. 2010;22(451):s.e33-451.e33.
- [Google Scholar]
- Aripiprazole-induced enuresis in a child with autistic disorder. Arch Neuropsychiatry. 2011;48:164-6.
- [Google Scholar]
- Aripiprazole treatment of Asperger's syndrome in the acute psychiatric setting: case report. Neuropsychiatr Dis Treat. 2007;3:173-6.
- [Google Scholar]
- Aggression and self-injury in a patient with severe autism. Pediatr ann. 2012;41:1-3.
- [Google Scholar]
- Aripiprazole in the treatment of challenging behaviour in adults with autism spectrum disorder. Psychopharmacology (Berl). 2012;223:357-60.
- [Google Scholar]
- Aripiprazole improved obsessive compulsive symptoms in Asperger's disorder. Clin psychopharmacol neurosci. 2011;9:134-6.
- [Google Scholar]
- Switching to aripiprazole in subjects with Pervasive Developmental Disorders showing tolerability issues with risperidone. Prog Neuro-Psychopharmacol Biol Psychiatry. 2012;37:128-31.
- [Google Scholar]
- Effectiveness and tolerability of switching to aripiprazole from risperidone in subjects with autism spectrum disorders: a prospective open-label study. Clin neuropharmacol. 2013;36:151-6.
- [Google Scholar]
- Social Disability in Autism spectrum disorder: results from Research Units on Pediatric Psychopharmacology (RUPP) Autism Network Trials. J Autism Dev Disord. 2013;43:739-46.
- [Google Scholar]
- Body mass index change in autism spectrum disorders: comparison of treatment with risperidone and aripiprazole. J Child Adolesc Psychopharmacol. 2014;24:78-82.
- [Google Scholar]
- 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;75:22-30.
- [Google Scholar]
- Aripiprazole monotherapy in children and young adolescents with pervasive developmental disorders: a retrospective study. CNS Drugs. 2009;23:511-21.
- [Google Scholar]
- Clinical effects and adverse reactions of off-label use of aripiprazole in children and adolescents with developmental disabilities. J Child Adolesc Psychopharmacol. 2006;16:549-60.
- [Google Scholar]
- Long-term aripiprazole in youth with developmental disabilities including autism. J Ment Health Res Intellect Disabil. 2011;4:40-52.
- [Google Scholar]
- A retrospective review of the effectiveness of aripiprazole in the treatment of sensory abnormalities in autism. J Child Adolesc Psychopharmacol. 2012;22:245-8.
- [Google Scholar]
- Drug-refractory aggression, self-injurious behavior, and severe tantrums in autism spectrum disorders: a chart review study. Autism. 2015;19:102-6.
- [Google Scholar]
- Response to second generation antipsychotics in youth with comorbid bipolar disorder and autism spectrum disorder. CNS Neurosci Ther. 2012;18:28-33.
- [Google Scholar]
- Aripiprazole to treat irritability associated with autism: a placebo-controlled, fixed-dose trial. Curr Psychiatry Rep. 2011;13:77-9.
- [Google Scholar]
- Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Pediatrics. 2009;124:1533-40.
- [Google Scholar]
- Safety and tolerability of aripiprazole in the treatment of irritability associated with autistic disorder in pediatric subjects (6-17 years old): results from a pooled analysis of 2 studies. Prim Care Companion CNS Disord. 2011;13:pii-Pcc.10m01008.
- [Google Scholar]
- 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;48:1110-9.
- [Google Scholar]
- A head-to-head comparison of aripiprazole and risperidone for safety and treating autistic disorders, a randomized double blind clinical trial. Child Psychiatry Hum Dev. 2014;45:185-92.
- [Google Scholar]
