Pediatric Drugs

, Volume 9, Issue 5, pp 343–354 | Cite as


A Review of its Use in the Treatment of Irritability Associated with Autistic Disorder in Children and Adolescents
Adis Drug Evaluation



Risperidone (Risperdal®), a psychotropic atypical antipsychotic agent, is thought to act via dopamine D2 and serotonin (5-HT [5-hydroxytryptamine])2A receptor antagonism. The clinical efficacy of oral risperidone in the treatment of bipolar mania and schizophrenia in adult patients is well established. In the US, risperidone is also approved for the treatment of irritability associated with autistic disorder in children and adolescents aged 5–16 years, for the treatment of schizophrenia in adolescents aged 13–17 years and, as monotherapy, for the short-term treatment of acute manic and mixed episodes associated with bipolar I disorder in children and adolescents aged 10–17 years.

Oral risperidone treatment was better than placebo treatment in reducing irritability and other behavioral symptoms associated with autistic disorder in children and adolescents in two well designed short-term trials, with these benefits maintained in those receiving risperidone for up to 6 months. The drug had a clinically manageable tolerability profile, with most adverse events being of mild to moderate intensity. There are some aspects of treatment, such as weight gain, somnolence, and hyperglycemia, that require monitoring, and the long-term safety of risperidone in children and adolescents with autistic disorder remains to be fully determined. With these issues in mind, risperidone offers a valuable emerging option for the treatment of irritability associated with autistic disorder in children and adolescents.

Pharmacologic Properties

Although the mechanism of action of risperidone, a benzisoxazole derivative, is unknown, its pharmacodynamic effects are thought to be mediated via dopamine D2 and serotonin 5-HT2A receptor antagonism. Risperidone and its active metabolite 9-hydroxyrisperidone have high in vitro binding affinity for these receptors, which results in significant inhibition of both serotonin and dopamine, with the pharmacologic effects of risperidone attributed to the combined effects of risperidone plus 9-hydroxyrisperidone. The neurotransmitter binding profile of risperidone may provide the putative mechanisms for its antipsychotic effects and generally lower incidence of adverse effects relative to older antipsychotic agents.

Risperidone is absorbed rapidly and has a high bioavailability (70%). In autistic children, peak plasma levels of risperidone and 9-hydroxyrisperidone were achieved ≈1 and 1–4 hours post dose. The drug is 90% plasma protein bound and undergoes extensive hepatic metabolism, largely via cytochrome P450 (CYP) 2D6-mediated hydroxylation to 9-hydroxyrisperidone, and to a small extent via N-dealkylation. In autistic children, the mean terminal half-lives of risperidone and 9-hydroxyrisperidone were ≈2 and 11–16 hours, which were 30–35% lower than those in adults. Risperidone and its metabolites are eliminated largely via the urine and partly via the feces.

Dosage adjustments are required in patients with moderate to severe renal impairment due to reduced clearance, and in patients with hepatic impairment due to an increase in the free fraction of the drug. Coadministration of CYP2D6 and/or CYP3A inhibitors (e.g. clozapine and fluoxetine) may interfere with the conversion of risperidone to 9-hydroxyrisperidone, whereas coadministration of inducers (e.g. carbamazepine and rifampin [rifampicin]) may decrease the combined plasma concentrations of the drug and its metabolite.

Therapeutic Efficacy

In two 8-week, randomized, double-blind trials (n = 101 and 55) in autistic children and adolescents (aged 5–17 years), patients receiving oral risperidone (mean modal dosage of 1.37–1.96 mg/day) had significantly greater improvements from baseline in irritability scores than those receiving placebo (primary endpoint). In modified intent-to-treat analyses, parent-rated mean Aberrant Behavior Checklist-Irritability Subscale (ABC-IS) scores were reduced by 56.9% and 65.0% from baseline in the risperidone groups versus a decrease of 14.1% and 34.7%, respectively, in the placebo groups. There were also significantly greater improvements from baseline for some of the other ABC subscale mean scores (Stereotypic behavior, lethargy/social withdrawal, and/or hyperactivity/noncompliance subscales) in risperidone groups than in placebo groups and a significantly higher proportion of patients in risperidone groups achieved a positive response. Other secondary endpoints also favored risperidone treatment in one or both of these short-term trials, including those for repetitive behavior and measures of relatedness and impaired communication (assessed using the parent-rated modified Ritvo-Freeman Real Life Rating Scale [RFRLRS], the validated clinician-rated Children’s Yale-Brown Obsessive Compulsive Scale [CYBOCS], and the clinician-rated Maladaptive Behavior Domain of Vineland Adaptive Behavior Scales [MBD-VABS]), scores for the conduct problem, hyperactive, and overly sensitive subscales of the parent-rated Nisonger Child Behavior Rating Form, and the score for hyperactivity on the visual analog scale for the most troublesome symptoms.

The benefits of up to 6 months’ risperidone treatment (mean modal dosage of risperidone was 1.96 mg/day), in terms of mean ABC-IS scores (no clinically relevant change) and clinician-rated Clinical Global Impression-Improvement scores (coprimary endpoints), were maintained in an open-label extension and double-blind, placebo-controlled, discontinuation trial (n = 63). Efficacy was also maintained in the longer term, according to secondary endpoints, including changes from baseline in most other mean ABC subscales, and in RFRLRS, CYBOCS, and MBD-VABS scores. In addition, patients receiving risperidone showed significant improvements in adaptive behavior for areas of communication, daily living skills, and socialization. Of note, significantly fewer patients in the risperidone-treatment group than in the placebo-treatment group relapsed during the placebo-controlled discontinuation phase; as a consequence, the discontinuation phase was stopped early.


Risperidone had a clinically manageable tolerability profile in children and adolescents with autistic disorder receiving up to 6 months’ treatment in short- and longer-term clinical trials. Most treatment-emergent adverse events were of mild to moderate intensity, with most resolving spontaneously or being effectively managed with dosage adjustments. In short-term trials, very few patients discontinued treatment due to an adverse event. In a pooled descriptive analysis of short-term clinical trials, the most common treatment-emergent adverse events (i.e. those occurring in >10% of patients receiving risperidone [n = 76] and at a rate that was at least twice that in the placebo group [n = 80]) were somnolence, increased appetite, fatigue, upper respiratory tract infection, increased saliva, constipation, dry mouth, tremor, and dystonia. The most common of these was somnolence, which was generally transient in nature.

There was a higher incidence of adverse events associated with extrapyramidal symptoms in the risperidone group than in the placebo group in a pooled analysis of short-term trials evaluating risperidone treatment. In clinical trials, tardive dyskinesia occurred in 2 of 1885 children and adolescents with autistic disorder or other psychiatric disorders receiving risperidone, with these cases resolving upon discontinuation of treatment. Risperidone treatment was associated with weight gain in short- and longer-term trials, with these increases being in excess of developmentally expected norms. There was no correlation between serum leptin levels and weight gain in 63 children and adolescents with autistic disorder receiving risperidone for up to 6 months. In double-blind trials, 49% of children and adolescents receiving risperidone had elevated serum prolactin levels compared with 2% of patients in the placebo group. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. In addition, when long-standing hyperlactinemia is associated with hypogonadism, patients of both genders may experience a decrease in bone density. In a retrospective analysis of pooled data from five clinical trials in 572 evaluable children (aged 5–15 years) with disruptive behavior disorders, there were no statistically or clinically relevant effects on growth, or the onset or progression of puberty with risperidone treatment for up to 1 year.


  1. 1.
    Fombonne E. Epidemiology of autistic disorder and other pervasive developmental disorders. J Clin Pyschiatry 2005; 66Suppl. 10: 3–8Google Scholar
  2. 2.
    Filipek PA, Accardo PJ, Ashwal S, et al. Practice parameter: screening and diagnosis of autism: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Child Neurology Society [online]. Available from URL: [Accessed 2007 Sep 3]
  3. 3.
    Scahill L, Koenig K, Carroll DH, et al. Risperidone approved for the treatment of serious behavioral problems in children with autism. J Child Adolesc Psychiatric Nurs 2007; 20(3): 188–90CrossRefGoogle Scholar
  4. 4.
    Parr J. Autism. Clin Evid 2005; 14: 275–84PubMedGoogle Scholar
  5. 5.
    Rapin I. The autistic-spectrum disorders. N Engl J Med 2002; 347(5): 302–3PubMedCrossRefGoogle Scholar
  6. 6.
    Morgan S, Taylor E. Antipsychotic drugs in children with autism. BMJ 2007; 334(7603): 1069–70PubMedCrossRefGoogle Scholar
  7. 7.
    Posey DJ, McDougle CJ. The pharmacotherapy of target symptoms associated with autistic disorder and other pervasive developmental disorders. Harv Rev Psychiatry 2000; 8(2): 45–63PubMedGoogle Scholar
  8. 8.
    Barnard L, Young AH, Pearson J, et al. A systematic review of the use of atypical antipsychotics in autism. J Psychopharmacol 2002; 16(1): 93–101PubMedCrossRefGoogle Scholar
  9. 9.
    Jesner OS, Aref-Adib M, Coren E. Risperidone for autism spectrum disorder. Cochrane Database Syst Rev 2007; (3): CD005040Google Scholar
  10. 10.
    Fenton C, Scott LJ. Risperidone: a review of its use in the treatment of bipolar mania. CNS Drugs 2005; 19(5): 429–44PubMedCrossRefGoogle Scholar
  11. 11.
    Bhana N, Spencer CM. Risperidone: a review of its use in the management of the behavioural and psychological symptoms of dementia. Drugs Aging 2000; 16(6): 451–71PubMedCrossRefGoogle Scholar
  12. 12.
    Swainston Harrison T, Goa K. Long-acting risperidone: a review of its use in schizophrenia. CNS Drugs 2004; 18(2): 113–32CrossRefGoogle Scholar
  13. 13.
    L.P. Janssen. Risperdal® (risperidone): US prescribing information [online]. Available from URL: [Accessed 2007 Sep 24]
  14. 14.
    Stahl S. Describing an atypical antipsychotic: receptor binding and its role in pathophysiology. Primary Care Companion to J Clin Psychiatry 2003; 5Suppl. 3: 9–13Google Scholar
  15. 15.
    Schotte A, Janssen PFM, Gommeren W, et al. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology 1996; 124(1-2): 57–73PubMedCrossRefGoogle Scholar
  16. 16.
    Eli Lilly and Company. Zyprexa® (olanzapine tablets): US prescribing information [online]. Available from URL: [Accessed 2007 Sep 24]
  17. 17.
    Pfizer. Geodon® (ziprasidone HCL) capsules: US prescribing information [online]. Available from URL:,020919s0141bl.pdf [Accessed 2007 Sep 24]
  18. 18.
    Novartis. Clozaril® (clozapine) tablets: US prescribing information [online]. Available from URL: [Accessed 2007 Sep 24]
  19. 19.
    AstraZeneca. Seroquel® (quetiapine fumarate) tablets: US prescribing information [online]. Available from URL: [Accessed 2007 Sep 24]
  20. 20.
    Bristol-Myers Squibb Company. Abilify® (aripiprazole) tablets, Abilify® Discmelt™ (aripiprazole) orally disintegrating tablets and Abilify® (aripiprazole) oral solution: US prescribing information [online]. Available from URL:,021713s008,021729s0011bl.pdf [Accessed 2007 Sep 24]
  21. 21.
    Kapur S, Seeman P. Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics?: a new hypothesis. Am J Psychiatry 2001; 158(3): 360–9PubMedCrossRefGoogle Scholar
  22. 22.
    Baptista T, Kin NMKNY, Beaulieu S, et al. Obesity and related metabolic abnormalities during antipsychotic drug administration: mechanisms, management and research perspectives. Pharmacopsychiatry 2002; 35(6): 205–19PubMedCrossRefGoogle Scholar
  23. 23.
    Casaer P, Walleghem D, Vandenbussche I, et al. Pharmacokinetics and safety of risperidone in autistic children [abstract no. 29]. Pediatr Neurol 1994; 11(2): 89CrossRefGoogle Scholar
  24. 24.
    Heykants J, Huang ML, Mannens G, et al. The pharmacokinetics of risperidone in humans: a summary. J Clin Psychiatry 1994; 55(5 Suppl.): 13–7PubMedGoogle Scholar
  25. 25.
    Pandina GJ, Bossie CA, Youssef E, et al. Risperidone improves behavioral symptoms in children with autism in a randomized, double-blind, placebo-controlled trial. J Autism Dev Disord 2007; 37(2): 367–73PubMedCrossRefGoogle Scholar
  26. 26.
    McCracken JT, McGough J, Shah B, et al. Risperidone in children with autism and serious behavioral problems (Research Units of Pediatric Psychopharmacology Autism Network). N Engl J Med 2002; 347(5): 314–21PubMedCrossRefGoogle Scholar
  27. 27.
    Risperidone treatment of autistic disorder: longer-term benefits and blinded discontinuation after 6 months (Research Units on Pediatric Psychopharmacology Autism Network). Am J Psychiatry 2005; 162(7): 1361–9Google Scholar
  28. 28.
    McDougle CJ, Scahill L, Aman MG, et al. Risperidone for the core symptom domains of autism: results from the study by the Autismn Network of the Research Units on Pediatric Psychopharmacology. Am J Psychiatry 2005; 162(6): 1142–8PubMedCrossRefGoogle Scholar
  29. 29.
    Lindsay RL, Arnold LE, Aman MG, et al. Dietary status and impact of risperidone on nutritional balance in children with autism: a pilot study. J Intellect Dev Disabil 2006; 31(4): 204–9PubMedCrossRefGoogle Scholar
  30. 30.
    Arnold LE, Vitiello B, McDougle C, et al. Parent-defined target symptoms respond to risperidone in RUPP autism study: customer approach to clinical trials. J Am Acad Child Adolesc Psychiatry 2003; 42(12): 1443–50PubMedCrossRefGoogle Scholar
  31. 31.
    Williams SK, Scahill L, Vitiello B, et al. Risperidone and adaptive behavior in children with autism. J Am Acad Child Adolesc Psychiatry 2006; 45(4): 431–9PubMedCrossRefGoogle Scholar
  32. 32.
    Aman MG, Arnold LE, McDougle CJ, et al. Acute and long-term safety and tolerability of risperidone in children with autism. J Child Adolesc Psychopharmacol 2005; 15(6): 869–84PubMedCrossRefGoogle Scholar
  33. 33.
    Martin A, Scahill L, Anderson GM, et al. Weight and leptin changes among risperidone-treated youths with autism: 6-month prospective data. Am J Psychiatry 2004; 161(6): 1125–7PubMedCrossRefGoogle Scholar
  34. 34.
    Dunbar F, Kusumakar V, Daneman D, et al. Growth and sexual maturation during long-term treatment with risperidone. Am J Psychiatry 2004; 161(5): 918–20PubMedCrossRefGoogle Scholar
  35. 35.
    Anderson GM, Scahill L, McCracken JT, et al. Effects of short- and long-term risperidone treatment on prolactin levels in children with autism. Biol Psychiatry 2007; 61(4): 545–50PubMedCrossRefGoogle Scholar
  36. 36.
    American Academy of Pediatrics Committee on Children with Disabilities. Technical report: the pediatrician’s role in the diagnosis and management of autistic spectrum disorder in children. Pediatrics 2001; 107(5): 1–18Google Scholar
  37. 37.
    Filipek PA, Steinberg-Epstein R, Book TM. Intervention for autistic spectrum disorders. Neurotherapeutics 2006; 3(2): 207–16CrossRefGoogle Scholar
  38. 38.
    American Academy of Child and Adolescent Psychiatry. Summary of the practice parameters for the assessment and treatment of children, adolescents, and adults with autism and other pervasive developmental disorders. J Am Acad Child Adolesc Psychiatry 1999; 38(12): 1611–5CrossRefGoogle Scholar
  39. 39.
    Chavez B, Chavez-Brown M, Sopko MA, et al. Atypical antipsychotics in children with pervasive developmental disorders. Pediatr Drugs 2007; 9(4): 249–66CrossRefGoogle Scholar
  40. 40.
    Lilienfeld SO. Scientifically unsupported and supported interventions for childhood psychopathology: a summary. Pediatrics 2005; 115(3): 761–4PubMedCrossRefGoogle Scholar
  41. 41.
    Volkmar FR, Pauls D. Autism. Lancet 2003; 362(9390): 1133–41PubMedCrossRefGoogle Scholar
  42. 42.
    Shea S, Turgay A, Carroll A, et al. Risperidone in the treatment of disruptive behavioral symptoms in children with autistic and other pervasive developmental disorders. Pediatrics 2004; 114(5): e634–41PubMedCrossRefGoogle Scholar
  43. 43.
    Luby J, Mrakotsky C, Stalets MM, et al. Risperidone in preschool children with autistic spectrum disorders: an investigation of safety and efficacy. J Child Adolesc Psychopharmacol 2006; 16(5): 575–87PubMedCrossRefGoogle Scholar
  44. 44.
    Haddad PM, Wieck A. Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management. Drugs 2004; 64(20): 2291–314PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  1. 1.Wolters Kluwer Health / AdisMairangi Bay, North Shore 0754, AucklandNew Zealand
  2. 2.Wolters Kluwer HealthConshohockenUSA

Personalised recommendations