Pediatric Pharmacologic Management of Autism-Associated Behavioral Dysregulation

In 2006, risperidone became the first medication approved by the FDA for the treatment of ASD-associated behavioral dysregulation in children and adolescents (≥5 years old). Risperidone is dosed in a weight-based fashion (see Table 1), and there are no established guidelines for children weighing less than 15 kg. Two 8-week randomized, double-blind, placebo-controlled trials of risperidone have demonstrated improvements in behavioral dysregulation (3, 4). The primary outcome of both studies included the irritability subscale of the Aberrant Behavior Checklist, which measures emotional and behavioral symptoms and includes items such as “injures self,” “aggressive,” “temper tantrums,” “irritable,” and “cries and screams inappropriately” (5). A follow-up study showed longer-term efficacy and tolerability of risperidone treatment for 4 months (6), although outcomes for extended treatment durations, as is often the case in clinical settings, are unknown. In a discontinuation phase of the study, continued risperidone treatment resulted in significantly lower behavioral recurrence rates, compared with tapering off risperidone over 4 weeks. The study findings suggest caution when withdrawing effective treatment for target symptoms. In a recent fixed-dose study, risperidone at 1.25 mg or 1.75 mg per day (weight-dependent) was shown again to be efficacious (7), consistent with previous studies with similar doses of risperidone treatment (3–5). However, lower doses at 0.125 mg or 0.175 mg were not found to be effective (7). No inferences can be made about the effectiveness of mid-range doses between 0.175 mg and 1.25 mg, by nature of the study’s design.

Common side effects in the studies included sedation, increased appetite, weight gain, fatigue, drowsiness, dizziness, drooling, tremor, and constipation. Incidence of extrapyramidal symptoms in patients treated with risperidone varied across studies, with one study reporting incidence as high as 27.5%; tremor and hypokinesia were the most common symptoms noted (3).

Aripiprazole was approved by the FDA in 2009 for the treatment of ASD-associated behavioral dysregulation in children and adolescents (ages 6–17). Aripiprazole is dose-independent of weight, with a recommended starting dose of 2 mg daily (see Table 1). Two 8-week, randomized, double-blind, placebo-controlled trials demonstrated efficacy in acute treatment, according to Aberrant Behavior Checklist scores (8, 9). Benefits of long-term treatment of aripiprazole have not been established. In a study of patients who responded to aripiprazole initially, the primary outcome measure of time to behavior recurrence did not significantly differ between those randomly assigned to continue the medication or switch to placebo (10). However, aripiprazole treatment did result in a clinically relevant number needed to treat of 6 (to prevent one additional relapse) in a post hoc analysis. Patients were notably switched from aripiprazole directly to placebo in the study, rather than titrated down in dosage, due to the prolonged 75-hour half-life of aripiprazole.

Common adverse effects in the studies included fatigue, vomiting, somnolence, and tremor (8–10). The FDA has also warned about rare impulse-control problems (e.g., binge eating, gambling) based on 184 case reports of children and adults treated with aripiprazole, although ASD was not specifically mentioned in the treatment indications (11).

One small randomized, double-blind, placebo-controlled trial of olanzapine (treatment group, N=6; control group, N=5) demonstrated improvements in behavioral dysregulation, with weight gain and sedation as notable side effects (13). In a recent trial of lurasidone, double-blind treatment with fixed doses of 20 mg/day (N=50) and 60 mg/day (N=49) did not demonstrate efficacy in treating behavioral dysregulation when compared with placebo (N=51) (14). Although, to our knowledge, no randomized, double-blind, placebo-controlled trials of other atypical antipsychotics exist, quetiapine, ziprasidone, and clozapine have demonstrated benefits in open-label studies and case series (15). Haloperidol has been shown in two randomized, double-blind, placebo-controlled trials to improve general behavioral concerns in children with ASD (e.g., hyperactivity, stereotypies, fidgeting) but not behavioral dysregulation specifically (16, 17).

A pilot randomized, double-blind, placebo-controlled trial (N=33) of N-acetylcysteine, a glutaminergic modulator originally used to treat acetaminophen overdose, showed improvements in behaviors measured by the Aberrant Behavior Checklist (18). A small randomized, double-blind, placebo-controlled study (N=8) of the central alpha-2 agonist clonidine’s effects on inattention, impulsivity, and hyperactivity symptoms incidentally found lower ratings on the Aberrant Behavior Checklist (19). This may suggest promise in the use of clonidine in treatment of behavioral dysregulation, but inferences are limited: Aberrant Behavior Checklist scores were not the primary endpoint, and baseline scores were not provided. To our knowledge, there are no randomized, double-blind, placebo-controlled trials examining the efficacy of antidepressants, but small open-label studies, case reports, and retrospective chart reviews primarily examining stereotypies and repetitive behaviors have suggested secondary benefits in aggression from fluvoxamine, paroxetine, sertraline, citalopram, and escitalopram (15). Evidence on the use of valproate is conflicted, with one study showing significant improvement in Aberrant Behavior Checklist scores and another showing no treatment difference (19). There has been one open-label trial of beta-blockers in eight adults with ASD demonstrating improvements in aggressive behavior (20), but no studies with larger sample sizes, nor any examining children, have been published.