Pediatric Pharmacologic Management of Autism-Associated Behavioral Dysregulation

Autism spectrum disorder (ASD) is a developmental disorder characterized by persistent impairments in social communication and interactions, in addition to restricted and repetitive patterns of behavior and interests. A surveillance summary by the Centers for Disease Control and Prevention from 2008 estimated the prevalence of ASD in the United States to be one in every 68 children, as defined by the DSM-IV-TR criteria for autism, Asperger’s syndrome, and pervasive developmental disorder not otherwise specified (1). Early behavioral and educational interventions (e.g., applied-behavioral analysis, Early Start Denver Model, speech therapy) are recommended as primary treatment modalities, as they have been well documented to mitigate the core features of ASD, maximize patients’ functional independence, and improve quality of life (2). These approaches aim to promote communication, socialization, play, daily living skills, and academic achievements, while decreasing maladaptive behaviors.

Psychotropic medications are sometimes used in patients with ASD to treat various symptoms, including hyperactivity, inattention, impulsivity, comorbid anxiety or depression, obsessive behaviors, and sleep disturbances. Medications can also be helpful in decreasing aggression, irritability, self-injurious behaviors, and tantrum behaviors, which will be addressed collectively as “behavioral dysregulation” in the present article. Psychotropic medications should be considered after behavioral and environmental interventions have been inadequate or if the child poses a safety risk (2). The benefits and risks of medications must be weighed carefully by the psychiatrist on a case-by-case basis. Important considerations include the impact of behavioral dysregulation on the child’s ability to learn and socialize, as well as the child’s general health and safety. The psychiatrist must provide psychoeducation to caretakers, emphasizing that medications, similar to behavioral and educational modalities, will not “cure” autism but rather aim to improve the patient’s overall functioning.

The only medications that have been approved by the Food and Drug Administration (FDA) for ASD-associated behavioral dysregulation in the pediatric population are risperidone and aripiprazole. While there are no established mechanisms explaining treatment efficacy, the dopaminergic and serotonergic pathways are likely contributory, given links to impulsive aggression and known actions of atypical antipsychotics on dopamine D₂ receptors and serotonin receptors. The safety and effectiveness of these two psychotropic medications in children under 5 years old have not yet been established. There are also no FDA-approved medications for ASD-associated behavioral dysregulation in adults. However, various pharmacological treatments, such as other antipsychotics, anticonvulsants, alpha-2 agonists, mood stabilizers, selective serotonin reuptake inhibitors, and beta blockers, have been studied and are used off-label in children and adults.

FDA-Approved Pharmacotherapies

Risperidone

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

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).

Advanced-Management Considerations

When deciding between risperidone and aripiprazole, psychiatrists should balance side-effect profiles with existing evidence and the patient’s clinical response. To our knowledge, there has only been one head-to-head study of these two medications to date, which showed comparable safety and efficacy of treatment over a 2-month period (12). Risperidone has some evidence, albeit limited, for longer-term efficacy, but poses greater theoretical risk of sedation, metabolic effects, as well as dose-related extrapyramidal symptoms and hyperprolactinemia. On the other hand, aripiprazole may lead to increased activation and akathisia and may be associated with rare impulse-control problems. Atypical antipsychotics, as a class, are known to have metabolic side effects (i.e., weight gain, dyslipidemia, insulin resistance), with long-term cardiovascular risks. Other less common adverse effects of antipsychotics to consider include dystonic reactions, tardive dyskinesia, and neuroleptic malignant syndrome, all of which parents should be educated about before consenting for treatment.

Off-Label Pharmacotherapies

Other Antipsychotics

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).

Other Agents

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.

Conclusions

Children and adolescents with ASD often suffer from behavioral dysregulation that affects their lives, as well as the lives of their families. There are only two FDA-approved pharmacologic treatments in this population and limited evidence for off-label options. Even less is known about treatment in adults, and there are no formally approved treatments at this time. There is no hard and fast rule on when to start medications, or which medication to choose. Pharmacological management decisions rely on clinical acumen and consideration of the amount of evidence for efficacy, as well as the side-effect profile and tolerability of any given treatment. Further research is required to better guide the treatment of ASD-associated behavioral dysregulation in an evidence-based fashion.

Key Points/Clinical Pearls