This article provides an overview of the psychopharmacologic management of irritability, hyperactivity, and repetitive behaviors in children and adolescents with autism spectrum disorder. A review of the current literature on medications used to treat these conditions with emphasis on randomized controlled trials is presented.
Autism is a neurodevelopmental disorder with core symptom domains of impairment in social interactions and communication, and restricted, repetitive behaviors and interests. The disorder was initially described by Kanner in 1943. In his seminal paper he described these children to be born without the ability to make social relationships and identified some characteristic features including limited ability to develop relationships, language delays, aloofness, lack of imagination, and persistence on sameness. Bleuler had already used the term “autism” in 1912 to describe “self-absorption” or “withdrawal from reality” as one of the pathognomonic features of schizophrenia. Rutter later identified four core symptom clusters in autistic disorder: (1) social impairment, (2) language disturbances, (3) insistence on sameness, and (4) onset before 30 months of age. These criteria, with modifications and changes, were later incorporated into the Diagnostic and Statistical Manual of Mental Disorders (DSM)-III systems of classification.
DSM-IV text-revision (TR) identifies five disorders under the category of autism spectrum disorder (ASD): (1) autistic disorder, (2) Asperger syndrome, (3) childhood disintegrative disorder, (4) Rett syndrome, and (5) pervasive developmental disorder not otherwise specified. DSM-V, scheduled for publication in 2013, has proposed the following changes to this category. Rett syndrome will be excluded from DSM-V; childhood disintegrative disorder, Asperger syndrome, and pervasive developmental disorder not otherwise specified will be merged into a single diagnosis of autistic disorder; and diagnostic criteria for autistic disorder will be changed as follows: the domains of “social interaction” and “communication” will be merged into “social/communication deficits,” and “restricted interests” will be renamed “fixed interests/repetitive behaviors.” In the social/communication domain, DSM-V will require all of the following criteria to be met: deficits in nonverbal and verbal communication, lack of social reciprocity, and lack of peer relationships. In the fixed interests/repetitive behaviors domain, DSM-V will require any two of the following three criteria to be met: (1) stereotypic behaviors or unusual sensory symptoms, (2) adherence to routines, and (3) restricted interests.
There continues to be a possibility of further changes in the proposed DSM-V criteria until its publication in 2013. Until that time, it is advisable for clinicians to continue using the DSM-IV-TR criteria to diagnose and document ASD.
ASDs are associated with numerous comorbidities and disabling symptoms including aggression and self-injurious behaviors (SIB). Behavioral and pharmacologic interventions are the mainstay of treatment. This article summarizes the current state of knowledge on the pharmacotherapy of ASDs.
Medications are usually not the first-line treatment to target the core symptoms of autism, which respond to intensive behavioral interventions. Instead, pharmacotherapy in these individuals is limited to the management of the comorbid symptoms of aggression, hyperactivity, impulsivity, inattention, obsessions, anxiety, depression, and repetitive behaviors. Studies have reported a 9% to 10% prevalence rate of comorbid psychiatric disorders in this population. One recent study has found 70% of their ASD sample to have at least one comorbid psychiatric disorder and 41% with two or more comorbid disorders. The same study also reported social anxiety disorder, attention-deficit/hyperactivity disorder (ADHD), and oppositional defiant disorder to be the three most common comorbid disorders. Treatment of these associated symptoms is necessary when they cause psychosocial dysfunction and impairment in the individual’s life. What follows is a review of the symptom-specific treatments of these disorders.
Aggression
Aggressive symptoms in autism are common, and if severe, they can be an indicator of poor long-term prognosis. Aggression, as a term, is commonly used to define a broad range of behaviors including intentional or unintentional violence toward others, SIB, sexual offenses, fire setting, and defiance toward caretakers. Identifying the triggers and nature of the behavior aids in the treatment because behavioral interventions can be effectively implemented to target these symptoms. Recent studies have identified the effectiveness of combined use of medications with intensive behavioral treatments. In one recent study, the authors sought to identify the cumulative benefit of these treatments. After implementation of intensive behavioral interventions while keeping medication use stable, the authors noticed substantial reduction in the number of average aggressive behaviors. The addition of neuroleptic medications enhanced the success of behavioral interventions in managing aggression. Some of the causes of aggression that need to be identified before the initiation of pharmacotherapy Box 1 .
Impaired understanding of actions and consequences
Impaired ability to communicate and express wants and needs
Impaired coping skills
Conflict with peers and authority figures
Psychosocial dysfunction
Undiagnosed pain, constipation, underlying seizures, hypoglycemia
Psychiatric factors: Psychosis, depression, mania, suicidal or homicidal ideation
Evaluating the intensity of aggression is an important initial step of management. An understanding of the target behavior including the predictors of aggression helps in selecting appropriate treatment settings. Less serious events warrant further evaluation in an outpatient setting for implementation of behavioral plans and psychopharmacology. More serious events, however, warrant an immediate assessment in an urgent care or emergency room setting with goals to maintain safety and to prevent further deterioration in functioning. Once the medical and psychosocial factors are considered in the differential diagnosis, and believed not to be the contributing factor, consideration can be given to psychopharmacologic agents to target the aggressive behaviors.
There are limited evidence-based psychopharmacologic options to treat the aggressive symptoms in autistic individuals, because few studies have used aggression and SIB as primary outcome measures. Given the limitations in the medical literature on this matter, medications usually are directed at the underlying neurobiologic deficits that are believed to trigger those symptoms. Briefly, dopaminergic, adrenergic, serotonergic, and opioid systems are thought to be associated with aggression. One review of 21 trials covering 12 medications found only methylphenidate and risperidone to be effective; however, this review was published before the 2009 Food and Drug Administration (FDA) approval of aripiprazole for the treatment of irritability associated with autism.
Antipsychotics
Both first- and second-generation antipsychotic (neuroleptic) medications can be used to manage aggressive symptoms in autism and have shown efficacy across different studies. Among this group, haloperidol and risperidone have extensive literature support for their use in this population, and in 2006 risperidone received FDA approval for the treatment of irritability and aggression in children with autism aged 5 to 16 years. Haloperidol has been shown to reduce social isolation and stereotypes while improving learning, anger-related behaviors, hyperactivity, and tasks of language acquisition. Chlorpromazine and fluphenazine also have shown efficacy, although sedation, dystonic reactions, and withdrawal dyskinesias have limited their effectiveness. Because of the different mechanisms of action, atypical antipsychotics have slightly lower propensity of causing extrapyramidal symptoms and are considered to be the first choice for the management of aggression and SIB. Nevertheless, when prescribed at high dose, these medications are as prone to cause extrapyramidal symptoms as the conventional antipsychotics.
Three randomized controlled trials (RCTs) of the use of risperidone in autistic disorders have shown its efficacy in controlling irritability and aggression and these results are consistent across other studies. Initial studies on the short- and long-term effects of risperidone were published by the Research Units on Pediatric Psychopharmacology Autism Network (RUPPAN). During their 8-week trial, 101 individuals were evaluated for irritability, aggression, and SIB using the Aberrant Behavior Checklist (ABC) and then randomized for risperidone or placebo. At a mean dose of 1.8 mg/day, the risperidone group was found to have 57% reduction in their ABC scores compared with 14% in the placebo group. Reduction in the stereotype and hyperactivity subscales of ABC was more pronounced, but no statistically significant improvement in core symptoms of social withdrawal and inappropriate speech subscales was noticed. During the long arm of the trial, subjects who initially responded to risperidone were enrolled in an open-label continuation phase for an additional 16 weeks followed by 8 weeks of randomized double-blind placebo-controlled discontinuation phase. During the open-label continuation phase, most of the initial responders (51 of 63) continued to remain stable without any worsening of symptoms. The mean irritability score (ABC-I) showed 59% reduction from the rating at the initiation of trial. In the second phase of this trial, 36 individuals were initially enrolled, whereas 32 completed this phase. Among 32 that were randomized to continued risperidone treatment (N = 16) and to placebo (N = 16), 62.5% (N = 10) from the placebo group relapsed compared with 12.5% (N = 2) from the risperidone group whose symptoms worsened. The median time to relapse was 34 days for placebo group compared with 57 days for the risperidone group. The results of this study underscore the need for long-term medication management in individuals with autism.
Fewer studies have evaluated the efficacy of risperidone among preschool children with ASD. A 3-year-long open-label naturalistic study reviewed the clinical outcomes of risperidone monotherapy among 53 children with ASD, ages ranging from 3.6 to 6.6 years, at a mean dose of 0.55 mg/day. Improvement in behavior and affect regulation was noticed in 47.2% of the children who continued to take risperidone throughout the study period. For the remaining 52.8% of subjects who discontinued the medication, side effects including increased appetite, elevated prolactin levels without clinical symptoms, and lack of efficacy were major concerns. In a double-blind, placebo-controlled trial, researchers evaluated the safety and effectiveness of risperidone among 24 preschool children aged 2.5 to 6 years who were also undergoing applied behavioral analysis. The Childhood Autism Rating Scale and the Gilliam Autism Rating Scale were the primary outcome measures. The group was randomized to risperidone (0.5–1.5 mg/day) or placebo for 6 months. The risperidone group tolerated the medication well except for sedation, hypersalivation, and increased appetite, which were noted to be the most common adverse effects. Findings suggest superior improvements in global measurements of autism symptoms in the risperidone group compared with the placebo group but no specific change in the core autistic symptoms of language, stereotypes, social deficits, and restricted interests was found in the study sample.
Efficacy of olanzapine is suggested by a few open-label trials and case reports. One double-blind placebo-controlled trial of olanzapine among 11 children aged 6 to 14 years has shown promise at a mean dose of 10 mg/day. On the Clinical Global Impression-Improvement Rating (CGI-I) scale, 50% of the olanzapine group showed improvement compared with 20% of the placebo group. Sedation and weight gain were the main side effects among the study sample.
Aripiprazole has recently received FDA approval for its use in the treatment of irritability in autistic children aged 6 to 17 years. Two double-blind, placebo-controlled trials have shown aripiprazole to be efficacious in the treatment of aggression associated with ASD. In the first 8-week trial, 98 subjects aged 6 to 17 years were randomly assigned to flexible-dose aripiprazole (5–15 mg/day) or placebo treatment. The ABC and the CGI-I irritability subscale were the primary outcome measure. Among the sample, 76.5% of subjects completed the trial, and the aripiprazole group showed greater improvement in the ABC and the CGI irritability subscale across weeks 1 through 8. The remaining 10.6% of the aripiprazole group discontinued the medication because of side effects including extrapyramidal symptoms. Aripiprazole treatment was associated with a greater than 7% increase in weight compared with the placebo. At the end of the study, fasting blood glucose and lipid values were comparable across both groups without any statistically significant increase in the aripiprazole group. Suicide-related adverse events were common in the placebo group compared with the aripiprazole group. In the second 8-week parallel group trial, 218 children and adolescents with aggressive behaviors were randomized to flexible-dose aripiprazole or placebo. This study found all aripiprazole doses to be effective in reducing the mean ABC irritability subscales. Sedation and weight gain were the most common side effects and on average, the aripiprazole group gained 1.3 kg through the 8-week trial.
No RCTs are available for ziprasidone and quetiapine, but open-label trials have shown efficacy in individuals with autism. In the most recent open-label trial, 12 adolescents were treated with ziprasidone with doses ranging from 20 to 160 mg/day. Authors noted 75% of their sample to be treatment responders according to the parameters on CGI-I. On ABC, irritability and hyperactivity subscales showed improvement. Ziprasidone was found to be weight neutral, but the mean QTc increase was 14.7 milliseconds among the sample.
Movement disorders including tardive dyskinesia are an important limiting factor in the use of the older first-generation antipsychotic medications. Recent studies have documented a lower risk of tardive dyskinesia with second-generation antipsychotics compared with first-generation medications. A recent review has noted a 0.35% incidence rate of tardive dyskinesia among children with atypical antipsychotics compared with 7.7% in adults using conventional antipsychotics. All of the antipsychotics pose the risk of metabolic syndrome that is characterized by elevations in weight, blood pressure, and lipids and glucose. Because of the complex array of side effects, it is recommended to periodically check the patient’s weight, waist circumference, blood pressure, and fasting blood glucose and lipid levels. Counseling about nutrition and activity levels needs to be included in the treatment sessions.
Selective Serotonin Reuptake Inhibitors
The serotonergic system has been implicated in the pathogenesis of aggression since 1961 when researchers noticed elevated blood 5-HT levels in six children among a cohort of 23 individuals with autism. Depletion of dietary tryptophan, a precursor of 5-HT, has been found to worsen autistic symptomatology. Considering these findings, theoretically selective serotonin reuptake inhibitor (SSRI) medications seem to be the best possible choice to treat either the core or comorbid symptoms of autism. Unfortunately, at this time there is no clear evidence suggesting the efficacy of these medications for aggressive behaviors in autism. Altogether there are seven RCT involving fluoxetine, citalopram, and fluvoxamine with various outcome measures suggesting no specific evidence of the benefits of SSRI use for aggression in children with autism.
α 2 -Agonists
Adrenergic stimulation has been postulated in the pathophysiology of tics, ADHD, and aggression in children. Individuals with autism have difficulty in filtering out unwanted stimuli and are easily hyperaroused suggesting underlying adrenergic stimulation. Clonidine and guanfacine are two available α-agonists that have different side effect profiles and are efficacious in the treatment of aggression. In clinical practice, these agents have been used effectively in the management of irritability and mild aggression particularly in the children with associated impulsive and hyperactive behaviors. One small, double-blind, placebo-controlled crossover study, involving eight children and adolescents with ADHD-like symptoms has showed improvement in the measures of aggression and SIB. Sedation and hypotension seemed to be the most common adverse effects. Guanfacine, a longer acting α 2 -agonist with less sedative potential, was effective in only 23.8% of the patients in a retrospective analysis of 80 children aged 3 to 18 years old.
Psychostimulants
Psychostimulants are effective in the treatment of individuals in whom the aggression is associated with impulsivity and hyperactivity. In others, when aggression is not comorbid with hyperactive and impulsive behaviors, these medications show modest results and seem to cause worsening in irritability, insomnia, and paradoxic aggression. Methylphenidate is among the most studied psychostimulant in children and adolescents with autism; two RCTs show aggression as an outcome measure. In the first controlled trial, 10 children aged 7 to 10 years were administered methylphenidate, 10 mg twice a day for 1 week, and 20 mg twice a day for the next week. Methylphenidate was significantly more effective in improving the primary outcome measures of aggression and SIB measured with ABC-I. The other controlled trial of 13 children with ADHD and autism studied the efficacy of flexible-dose methylphenidate (0.3–0.6 mg/kg in twice a day and three times a day dosing). Subjects showed improvement on aggression subscales of the IOWA Conners’. Higher methylphenidate dose was associated with more side effects of irritability and social withdrawal.
Mood Stabilizers
The adult and pediatric literature has supported the role of mood stabilizers in aggressive symptoms associated with mania and conduct disorders. Because of these effects on overt aggression it was thought that mood stabilizers play an efficacious role in the management of aggression associated with autism. This possibility, however, is based only on anecdotal reports. Except for one positive trial in an autistic sample, published RCTs of divalproex sodium, lamotrigine, and levetiracetam have not supported this notion.
In a trial of divalproex sodium 30 individuals with autism, aged 6 to 20 years, with aggression and SIB were randomized to 20 mg/kg daily dose of divalproex versus placebo. After 8 weeks, no significant differences were found among the groups on the aggression subscale of ABC-I and on the Overt Aggression Scale. Increased appetite was the major side effect in the divalproex group. In the most recent RCT, 27 subjects with ASD at a mean age of 9.46 years were randomized to divalproex sodium versus placebo for 12 weeks. Primary outcome measures were ABC-I and CGI-I. Medication was titrated on the basis of weight to achieve a minimum plasma level of 50 μg/ml. The authors found an overall improvement of 62.5% in the divalproex group as compared with 9% in the placebo group. Worsening aggression in two subjects from the active group was the only major side effect noticed.
Open-label trials of lamotrigine also have shown efficacy in improving behavioral problems in individuals with autism. The only RCT of lamotrigine was conducted in 27 subjects with autism aged 3 to 11 years who were randomized to lamotrigine, 5 mg/kg/d, versus placebo over 8 weeks. After initial titration, the optimal dose of lamotrigine was maintained for 4 weeks. This phase was followed by 2 weeks tapering down and 4 weeks medication-free period. No significant differences were found among groups on the primary outcome measure of ABC-I.
Levetiracetam is another mood stabilizer that has shown promise in open-label trials but the only RCT has not supported its use for aggression.
Risperidone, methylphenidate, and clonidine had the most published support for efficacy in the treatment of irritability, aggression, and SIB in individuals with ASD. Mood stabilizers also have good clinical support for use in this population, but further studies are needed to replicate these effects.
Hyperactivity and impulsivity in ASD
Hyperactive, impulsive, and inattentive behaviors in individuals with autism usually represent a comorbid diagnosis of ADHD, despite the DSM-IV qualifier that autism and ADHD should not be diagnosed concurrently. These symptoms are increasingly prevalent in individuals with autism and in one study, authors noted the incidence of ADHD in ASDs to be as high as 74%. Genetic factors play an important role in the transmission of this disorder and D 2 and D 4 dopamine receptor and dopamine transporter genes have been implicated in the pathophysiology.
The diagnosis of comorbid ADHD is easier to establish in individuals with high-functioning rather than low-functioning autism. The usual initial presentation is of a child who fidgets, needs constant reminders, is disruptive and impulsive in the classroom, displays poor frustration tolerance, and gets irritable and aggressive. It is important to rule out any medical causes of hyperactivity including hyperthyroidism that can mimic these behaviors. Depression, anxiety, and cognitive deficits with resultant limited coping skills also can mimic these behaviors and need to be considered in the differential diagnosis.
There is evidence of shared genetic influence in the pathophysiology of these disorders. It is a common clinical perception that these disorders are relatively difficult to treat if they coexist. Children tend to have more side effects from the medications used, and the treatment response is usually suboptimal. Standard medications that improve symptoms in children with either diagnosis alone tend to cause numerous side effects including irritability, dysphoria, and behavioral disinhibition. The dopaminergic system has been implicated in the pathophysiology and so is a natural target for pharmacologic management. Perhaps because of the mutually exclusionary criterion in the DSM-IV-TR that the diagnosis of ADHD and ASD should not be made concurrently, fewer studies have looked into the management of these patients in which both disorders coexist. Table 1 summarizes the evidence for the use of psychostimulants and α-agonists based on a recent review.
| Medications | Efficacy | Literature Support | Common Side Effects |
|---|---|---|---|
| Psychostimulants | |||
| Methylphenidate | Effective | Many double-blind placebo-controlled trials and open-label studies Research Units of Pediatric Psychopharmacology (RUPP): effective at doses of 0.25–0.5 mg/kg; 49% subjects were labeled as responders; 18% withdrew from the study because of side effects. Posey et al : methylphenidate at doses of 0.125–0.50 mg/kg; subjects from the original RUPP study. Hyperactivity and impulsivity improved more than inattention. | Irritability, dysphoria, worsening aggression |
| Nonstimulants | |||
| Atomoxetine | Effective | Many open-label trials. Only double-blind placebo-controlled crossover trial in 16 children with pervasive developmental disorder and ADHD. Atomoxetine group, 56% responders; placebo group, 25% responders. | Sedation, irritability, constipation, nausea |
| α-Agonists | |||
| Clonidine | Mixed results | Two double-blind placebo-controlled cross-over studies. Mixed results with both showing improvement in parent-rated end points. | Sedation the most common side effect |
| Guanfacine | Effective | Open-label trial and one retrospective chart review. | Irritability and agitation |
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