Risperidone Treatment of Autistic Disorder: Longer-Term Benefits and Blinded Discontinuation After 6 Months

Abstract

Objective: Risperidone is effective for short-term treatment of aggression, temper outbursts, and self-injurious behavior in children with autism. Because these behaviors may be chronic, there is a need to establish the efficacy and safety of longer-term treatment with this agent.Method: The authors conducted a multisite, two-part study of risperidone in children ages 5 to 17 years with autism accompanied by severe tantrums, aggression, and/or self-injurious behavior who showed a positive response in an earlier 8-week trial. Part I consisted of 4-month open-label treatment with risperidone, starting at the established optimal dose; part II was an 8-week randomized, double-blind, placebo-substitution study of risperidone withdrawal. Primary outcome measures were the Aberrant Behavior Checklist irritability subscale and the Clinical Global Impression improvement scale.Results: Part I included 63 children. The mean risperidone dose was 1.96 mg/day at entry and remained stable over 16 weeks of open treatment. The change on the Aberrant Behavior Checklist irritability subscale was small and clinically insignificant. Reasons for discontinuation of part I included loss of efficacy (N=5) and adverse effects (N=1). The subjects gained an average of 5.1 kg. Part II included 32 patients. The relapse rates were 62.5% for gradual placebo substitution and 12.5% for continued risperidone; this difference was statistically significant.Conclusions: Risperidone showed persistent efficacy and good tolerability for intermediate-length treatment of children with autism characterized by tantrums, aggression, and/or self-injurious behavior. Discontinuation after 6 months was associated with a rapid return of disruptive and aggressive behavior in most subjects.

Withdrawal Confounding in Randomized Controlled Trials of Antipsychotic, Antidepressant, and Stimulant Drugs, 2000–2017

“…It suggests that by not accounting for the withdrawal symptoms of psychiatric drugs in their estimates of symptom differences between drug-discontinued and drug-maintained groups, these RCTs’ results cast doubt on the conclusions researchers draw from them: that the study drug is effective [3, 28, 29], that discontinuation of the study drug leads to an increase or re-emergence of mental disorder or unwanted behavior [25, 30], and that study drugs prevent relapse of mental disorder or are required for long-term treatment [2, 13]. This in turn has potential clinical consequences: mental health professionals should be more cautious in their use of compounds whose evidence base is less rigorous than previously suggested.…”

Efficacy and Tolerability of Pharmacotherapy Options for the Treatment of Irritability in Autistic Children

“…Risperidone treatment was associated with weight gain in short- and longer-term trials,53,56 with these increases being in excess of developmentally expected norms, and which follow a curvilinear trajectory and decelerate over time 82. 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.…”

“…The benefits of up to 6 months of risperidone treatment (mean dosage = 1.96 mg/day), in terms of the mean ABC-I subscale scores and clinician-rated CGI-I scores, were maintained in an open-label extension and double-blind, placebo-controlled, discontinuation trial (n = 63) 56. Efficacy was also maintained in the longer term, according to secondary endpoints, including changes from baseline across most of the other mean ABC subscales,56 and in the parent-rated modified Ritvo–Freeman Real Life Rating Scale, the validated clinician-rated Children’s Yale–Brown Obsessive Compulsive Scale, and the clinician-rated Maladaptive Behavior Domain of the Vineland Adaptive Behavior Scales (MBD-VABS) scores 57…”

“…Efficacy was also maintained in the longer term, according to secondary endpoints, including changes from baseline across most of the other mean ABC subscales,56 and in the parent-rated modified Ritvo–Freeman Real Life Rating Scale, the validated clinician-rated Children’s Yale–Brown Obsessive Compulsive Scale, and the clinician-rated Maladaptive Behavior Domain of the Vineland Adaptive Behavior Scales (MBD-VABS) scores 57…”

ASD: Psychopharmacologic Treatments and Neurophysiologic Underpinnings

“…Their effectiveness is supported by seven randomized controlled trials (RCTs) showing significant differences between risperidone and placebo (Hellings et al 2006; Nagaraj 2006; Pandina et al 2007; McCracken et al 2002; Aman et al 2005; Troost et al 2005; Shea et al 2004) and two for aripiprazole (Owen et al 2009; Marcus et al 2009), with most studies measuring improvement on the irritability subscale of the Aberrant Behavior Checklist. Although two trials of risperidone did not achieve statistical significance in comparison with placebo (Luby et al 2006; Miral et al 2008), several articles reviewing this literature all conclude that the data supporting effectiveness is strong, while cautioning that behavioral intervention should be tried first and that side effects including metabolic abnormalities, weight gain, and potential for extrapyramidal side effects warrant caution in their use (Elbe and Lalani 2012; Parikh et al 2008; Pringsheim and Gorman 2012; Sharma and Shaw 2012).…”