Pediatric Annals

Pharmacologic Therapies Aid Treatment for Autism

Ronald L Lindsay, MD, FAAP; Michael G Aman, PhD

Abstract

Empirical support for most pharmacologic treatments, however, is limited. Psychopharmacologic research is limited in autism and other PDDs by inconsistent findings in small samples that fail to guide clinical practice. Methodological challenges for treatment studies include finding large clinical samples of children and adolescents who have not been exposed to therapeutic agents, identifying target symptoms in a sample of subjects with severe developmental disorders, defining inclusion criteria that are pertinent to clinical practice, matching study design to evaluate both shortand long-term effects, and characterizing subjects in order to identify predictors of treatment response.5

HYPERACTIVE/ADHD SYMPTOMS

A formal diagnosis of attentiondeficit/hyperactivity disorder (ADHD) in addition to autism is not permitted in either of the psychiatric diagnostic systems,6,7 presumably because symptoms are so pervasive in children with autism. However, symptoms of overactivity, inattention, or impulsivity are by no means universal or consistent in presentation in children with autism. Therefore, the ability to employ such a diagnostic label does seem to convey useful information. Additional research is needed to clarify what these symptoms say about etiology and treatment implications.

Two articles have reviewed the evidence regarding use of psychostimulants in children with developmental disabilities, including autism.8,9 Unlike typically-developing children, those with autism appear to have a fairly heterogeneous response to these agents (eg. methylphenidate, amphetamine salts, dextroamphetamine). Occasionally, children with autism show marked irritability, paradoxical increase in hyperactivity, stereotypic behaviors, or agitation. Conversely, some of these children show adequate or exceptionally good clinical responses to stimulants.

We have treated many children with autistic disorders and comorbid ADHD symptoms and have developed theories about which children may respond favorably (eg, extremely withdrawn symptoms, high versus low IQ). Thus far, we have been struck by our inability to predict responses successfully.

The National Institute of Mental Health (NIMH) Research Units on Pediatric Psychopharmacology (RUPP) Autism Network was established in 1997 through a program of competitive contracts designed to study autism and PDDs. This five-site network is now conducting a large controlled trial of methylphenidate in children with PDDs and high parent and teacher ratings on ADHD scales. This study should shed more light on the probability of response, strength of response, and costs of treatment in such children.

In the absence of extensive data, what should the practitioner do? Despite what appears to be an elevated possibility of side effects, psychostimulants still deserve a clinical trial in previously-untreated children with such symptoms. Practitioners should share their uncertainty with parents before treating, start with modest doses, and be prepared to stop stimulant treatment if problems occur. In the case of children displaying moderate stereotypic behavior or self-injury, practitioners might choose to start with a lower dose. However, although it is well to be mindful that adverse effects might occur, they are almost always shortlived, and psychostimulants have a good track record overall.

In the Expert Consensus Guidelines,'0 alpha-2 agonists (guanfacine and Clonidine) and bupropion were designated as second-line treatments for treating patients with ADHD or mental retardation with ADHD. Very little data justifies this recommendation, although it may ultimately be supported by data in such children.

Aman and Langworthy9 reviewed scientific evidence for other agents as well. There is evidence that antipsychotics, both typical and atypical, may reduce ADHD symptoms, particularly the motor manifestations. It is unclear at this time whether attention span is improved. Atypical antipsychotics ordinarily would be preferred to older agents because of reduced likelihood of extrapyramidal symptoms, including tardive dyskinesia. One would ordinarily avoid these agents, because of possible long-term consequences, in any children other than the most severely afflicted.

At the time this article was written, atomoxetine had been recently released…

Autism is a chronic condition with early childhood onset. It is characterized by impaired social relatedness, delayed and deviant language, and restricted patterns of behavior. In addition to the core symptoms, children with autism frequently exhibit behavior disturbances such as hyperactivity, disruptive/irritable behavior, anxiety, self-injurious behavior (SIB), or stereotypies that frequently complicate clinical management.1 Although there is no known cure for autism and other pervasive developmental disorders (PDDs), the appropriate use of medication to control behavioral dysregulation may enhance the individual's function and ability to benefit from educational and behavior modification interventions.

The therapeutic dilemma facing a pediatrician caring for children with autism is to determine the goals for therapeutic intervention. Is it to specifically ameliorate the core symptoms of autism, or to relieve other specific behavioral disturbances? Recent surveys indicate pediatricians use a wide range of medications for treatment of children and adolescents with autism and other PDDs.2,3 One survey reported a 45% prevalence of psychotropic medications,4 which gives some idea how relevant pharmacological treatment is for this population. However, surveys generally indicate a significantly higher prevalence of such medication in adults than in children.2,4

Empirical support for most pharmacologic treatments, however, is limited. Psychopharmacologic research is limited in autism and other PDDs by inconsistent findings in small samples that fail to guide clinical practice. Methodological challenges for treatment studies include finding large clinical samples of children and adolescents who have not been exposed to therapeutic agents, identifying target symptoms in a sample of subjects with severe developmental disorders, defining inclusion criteria that are pertinent to clinical practice, matching study design to evaluate both shortand long-term effects, and characterizing subjects in order to identify predictors of treatment response.5

HYPERACTIVE/ADHD SYMPTOMS

A formal diagnosis of attentiondeficit/hyperactivity disorder (ADHD) in addition to autism is not permitted in either of the psychiatric diagnostic systems,6,7 presumably because symptoms are so pervasive in children with autism. However, symptoms of overactivity, inattention, or impulsivity are by no means universal or consistent in presentation in children with autism. Therefore, the ability to employ such a diagnostic label does seem to convey useful information. Additional research is needed to clarify what these symptoms say about etiology and treatment implications.

Two articles have reviewed the evidence regarding use of psychostimulants in children with developmental disabilities, including autism.8,9 Unlike typically-developing children, those with autism appear to have a fairly heterogeneous response to these agents (eg. methylphenidate, amphetamine salts, dextroamphetamine). Occasionally, children with autism show marked irritability, paradoxical increase in hyperactivity, stereotypic behaviors, or agitation. Conversely, some of these children show adequate or exceptionally good clinical responses to stimulants.

We have treated many children with autistic disorders and comorbid ADHD symptoms and have developed theories about which children may respond favorably (eg, extremely withdrawn symptoms, high versus low IQ). Thus far, we have been struck by our inability to predict responses successfully.

The National Institute of Mental Health (NIMH) Research Units on Pediatric Psychopharmacology (RUPP) Autism Network was established in 1997 through a program of competitive contracts designed to study autism and PDDs. This five-site network is now conducting a large controlled trial of methylphenidate in children with PDDs and high parent and teacher ratings on ADHD scales. This study should shed more light on the probability of response, strength of response, and costs of treatment in such children.

In the absence of extensive data, what should the practitioner do? Despite what appears to be an elevated possibility of side effects, psychostimulants still deserve a clinical trial in previously-untreated children with such symptoms. Practitioners should share their uncertainty with parents before treating, start with modest doses, and be prepared to stop stimulant treatment if problems occur. In the case of children displaying moderate stereotypic behavior or self-injury, practitioners might choose to start with a lower dose. However, although it is well to be mindful that adverse effects might occur, they are almost always shortlived, and psychostimulants have a good track record overall.

In the Expert Consensus Guidelines,'0 alpha-2 agonists (guanfacine and Clonidine) and bupropion were designated as second-line treatments for treating patients with ADHD or mental retardation with ADHD. Very little data justifies this recommendation, although it may ultimately be supported by data in such children.

Aman and Langworthy9 reviewed scientific evidence for other agents as well. There is evidence that antipsychotics, both typical and atypical, may reduce ADHD symptoms, particularly the motor manifestations. It is unclear at this time whether attention span is improved. Atypical antipsychotics ordinarily would be preferred to older agents because of reduced likelihood of extrapyramidal symptoms, including tardive dyskinesia. One would ordinarily avoid these agents, because of possible long-term consequences, in any children other than the most severely afflicted.

At the time this article was written, atomoxetine had been recently released into the market. We are not aware of any published data examining this agent in children with autism, although there have been clinical anecdotes of improvement. This may prove to be a useful secondary treatment to the psychostimulants. Curiously, naltrexone has been shown to be effective for hyperactivity/inattention in a number of studies.9 Whether this agent will gain use among practitioners remains to be seen.

Clomipramine also has been shown to be helpful in at least two studies.9 The main difficulties with this agent are possibilities of cardiac conduction changes, sedation, and lowered seizure threshold. Little evidence supports the use of selective serotonin reuptake inhibitors (SSRIs), antianxiety drugs, or anticonvulsant drugs for ADHD symptoms.

In summary, data are mixed, but some studies support cautious use of stimulants. Atomoxetine, naltrexone, bupropion, antipsychotics, and clomipramine may be viewed as back-up or secondary agents. In some cases, empirical data are lacking, whereas in others, side effects may be a disincentive.

DISRUPTIVE/IRRITABLE BEHAVIOR

Several medications for reducing aggression and self-injurious behavior have also been studied. These include fenfluramine, lithium, naltrexone, and serotonin reuptake inhibitors." Only haloperidol has any consistent data in this respect,12 but concern about shortand long-term side effects with typical antipsychotics causes many clinicians to avoid using haloperidol in children,13

The first project conducted through the NIMH RUPP Autism Network was a study of risperidone in children and adolescents with autism. The primary aims of the study were to evaluate the shortterm efficacy and safety of risperidone in children with autistic disorder and to determine whether observed clinical benefits and safety were stable over time.

The RUPP group divided the study into three phases. Phase 1 was an 8week, double-blind, randomized, parallel-group comparison of risperidone and placebo. Subjects assigned to placebo who did not improve were offered an 8-week open-label trial of risperidone. Phase 2 consisted of a 4month open-label treatment with risperidone for patients who showed improvement in the 8-week acute trial. The subsequent Phase 3 was a randomized, double-blind, placebo-controlled discontinuation study. Target symptoms included tantrums, aggression, selfinjurious behavior, agitation, screaming, emotional rigidity, and repetitive behavior as measured by the Irritability subscale of the Aberrant Behavior Checklist, which was completed by the parent or primary caretaker.14"16 This subscale was selected because of its favorable psychometric properties and because it contains the behaviors of interest. To avoid over-reliance on an informant-based measure, the study also included clinician and laboratory measures as secondary outcomes.

A total of 82 boys and 19 girls, with a mean age of 8.8 (±2.7 years), entered phase 1 of the study and were randomized to risperidone or placebo. Eight weeks of risperidone treatment resulted in a 56.9% reduction on the ABC Irritability score, compared to a 14.1% decrease for the placebo group (P < .0001). The dose range was 0.5 to 3.5 mg per day.

The improvement rate for patients on risperidone was 69.4%, or 34 of 49 patients. For patients on placebo, it was 11.5%, or 6 of 52 patients (P < .0001). There were significant beneficial effects for hyperactivity and stereotypic behavior. Risperidone was associated with an average weight gain of 2.7 kg, compared with 0.8 kg in the control group. Increased appetite, fatigue, drowsiness, tremor and drooling were generally mild but more common in the risperidone group compared with placebo.17

Forty-nine boys and 14 girls, with a mean age 8.6 (±2.8 years), entered phase 2 of the study. Although the average ABC Irritability score showed a statistically significant increase over time (P < 0.02), the absolute change across 4 months was small and not considered clinically significant.

Thirty-two children completed the phase 3 randomized, double-blind, placebo-controlled discontinuation study. Randomization to gradual placebo substitution was associated with a high rate of relapse (62.5%) versus those randomized to continued risperidone. In short, risperidone showed persistent efficacy and excellent tolerability for short- and intermediate-length treatment of children and adolescents with autism characterized by tantrums, aggression, or self-injurious behavior.18

PERSEVERATIVE BEHAVIORS

Perseverative behaviors include repetitive motor activities, such as compulsions, stereotyped movements, self-injury, and even preoccupation with odd or bizarre subjects. In the case of children with high-functioning autism, some are able to describe preoccupation with such activities or topics (eg, all-consuming interest in garage doors).

Perseverative behaviors are extremely common in autism; indeed, a preoccupation with a narrow range of interests and activities is one of the three groups of symptoms necessary to diagnose the disorder.6 At times, perseverative behaviors can be very intrusive on the activities of others. They may interfere with learning, can be stigmatizing, and, in the case of self-injury, can be harmful. Some children with autism become very agitated if prevented from engaging in perseverative behaviors.

The SSRIs and clomipramine are all used to treat true obsessive-compulsive disorder (OCD) in non-autistic psychiatric patients. Many researchers and practitioners in the developmental disabilities field view perseverative behaviors as a variant of OCD. Therefore, a number of researchers have assessed the SSRIs and clomipramine for their ability to suppress such behavior. Aman et al.19 were able to find nine studies and five case reports on clomipramine for this purpose in individuals with developmental disabilities. They also found nine studies and 24 case reports concerning SSRIs. The large majority of the investigations reported benefits to perseverative behavior,19 but most of the trials were done with adults. The situation with children deserves more study.

In the meantime, practitioners may choose to proceed cautiously and in a data-based manner with these agents. Older trials of typical antipsychotics often found reductions in stereotypic behavior.20 In the recent RUPP study, risperidone caused a marked reduction in parent ratings of stereotypic behaviors of subjects with autism and irritable behavior. Even though antipsychotics appear to reduce certain perseverative behaviors, they ordinarily would not be warranted unless the behaviors were causing major disruption.

Self-injury is a category of perseverative behavior that has received a significant degree of study in its own right. Aman and Madrid21 reviewed the literature on atypical antipsychotic treatment in relation to clinical outcomes in patients with developmental disabilities, including individuals with autism. The majority of these studies and case reports indicated improvements with active medication. It is worth mentioning that the primary outcome variable, ABC Irritability subscale, in the NIMH RUPP Autism Network study17 included several items pertinent to self-injury. Another RUPP report indicated substantial symptom reduction when self-injury was identified as a primary outcome variable.22

Aman23 reviewed a range of other psychotropic medicines that have been studied for managing self-injury in patients with developmental disorders. In addition to the agents already mentioned, some positive evidence exists for a therapeutic effect with thioridazine, lithium carbonate, beta blockers, and opiate blockers (especially naltrexone). The Expert Consensus Survey identified atypical antipsychotics, anticonvulstants/mood stabilizers, and antidepressants as potentially helpful in patients with mental retardation.10

ANXIETY ASSOCIATED WITH AUTISM

Children with autism can display anxiety and panic in response to changes in routine or environment.24 Again, there is a paucity of empirical research on pharmacologic treatment for these symptoms. The Expert Consensus Survey identified SSRIs, buspirone, and possibly benzodiazepines as potentially helpful in patients with mental retardation,10 but their use in individuals with autism is less studied.

McDougle et al.25 conducted a 12week, double-blind, placebo-controlled trial of fluvoxamine maléate in 30 adults with autistic disorder. Behavioral ratings were obtained at baseline and after 4, 8, and 12 weeks of treatment. Eight of 15 patients (53%) in the fluvoxamine-treated group were categorized as responders, compared with none of 15 in the placebo group (P = .001). Fluvoxamine was superior to placebo in reducing repetitive thoughts and behavior (P < .001), maladaptive behavior (P < .001), and aggression (P < .03). It was also better at improving some aspects of social relatedness (P < .04), especially language usage (P < .008). Treatment response was not correlated with age level, autistic behavior, or full-scale IQ. Other than mild sedation and nausea in a few patients, fluvoxamine was well tolerated. No dyskinesias, adverse cardiovascular events, or seizures occurred.

Several open-label studies show some benefit for several symptom groups associated with autism. Cook et al.26 conducted an open trial of with fluoxetine, ranging from 20 mg every other day to 80 mg per day. Treatment led to a significant improvement in Clinical Global Impressions ratings of clinical severity in 15 of 23 subjects (65%) with autistic disorder and 10 of 16 subjects (63%) with mental retardation. However, six of 23 patients (26%) with autistic disorder and 3 of 16 patients (19%) with mental retardation had side effects that significantly interfered with function. These predominantly consisted of restlessness, hyperactivity, agitation, decreased appetite, or insomnia.

Steingard et al.27 examined sertaline, an SSRI, in open-label fashion in a clinical sample of nine children who were 6 to 12 years old. The children had autistic disorder and clinically significant transition-induced behavioral deterioration. Eight subjects showed some degree of positive response to treatment at doses of 25 to 50 mg daily. The study was limited, however, by its open-label approach, lack of comparison group, and absence of standardized diagnostic or outcome measures.

Even fewer data supports the use of buspirone in autism. Only two openlabel studies of less than a half-dozen children suggest some efficacy.28,29

SUMMARY

In the absence of other guidelines, practitioners often prescribe by analogy with roles of psychotropic medicines in other psychiatric disorders (eg, the ability of serotonergic antidepressants to reduce compulsive behavior). There is a slow but steady accumulation of data supporting the use of psychotropic medications to manage certain symptoms in children with autism. These data support the use of stimulant medications for attention/hyperactivity symptoms, with willingness to suspend such treatment if a trial is unsuccessful. Risperidone is supported for other disruptive behaviors, especially of an irritable/disruptive nature, but with attention to increases in appetite and weight. SSRIs and atypical antipsychotics may be helpful for a variety of perseverative behaviors, although one would seldom prescribe antipsychotic medication for mild perseverative behavior alone. SSRIs may be useful for anxiety.

Again, there is no compelling evidence that existing pharmacologic treatments have a major role in treating the core symptoms of autism, especially the profound impairments in social interaction and communication. Further welldesigned double-blind studies with significant numbers of subjects and defined target symptoms will provide the data that will guide therapeutic decisions in the future.

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9. Aman MG, Langworthy KS. Pharmacotherapy for hyperactivity in children with autism and other pervasive developmental disorders. J Autism Dev Disord. 2OO0;3O(5):45 1 -459.

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12. Campbell M, Armenteros JL, Malone RP, et al. Neuroleptic-related dyskinesias in autistic children: a prospective, longitudinal study. J Am Acad Child Adolesc Psychiatry. 1997;36(6):835-843.

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16. Marshburn EC, Aman MG. Factor validity and norms for die aberrant behavior checklist in a community sample of children with mental retardation. / Autism Dev Disord. 1992;22(3):357-373.

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18. Research Units on Pediatric Psychopharmacology Autism Network. Risperidone treatment of autistic disorder: longer term benefits and blinded discontinuation after six months. J Dev Behav Pediatr. 2002;23(4):396. Review.

19. Aman MG, Arnold LE, Armstrong SC. Review of serotonergic agents and perseverative behavior in patients with developmental disabilities. Ment Retard Dev Disabil Res Rev. 1999;5:279-289.

20. Campbell M. The effect of neuroleptics on cognition and diagnosis, and their influence on stereotypies. J Ment Defic Res. 1 987;3 1 (Pt 2):220-225.

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22. Arnold LE, Vitiello B, Chuang S, et al. Parent-defined target symptoms respond to risperidone in RUPP Autism Network study: a customer approach to subjecthood in clinical trials. / Am Acad Child Adolesc Psychiatry. In press.

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24. Muris P, Steerneman P, Merckelbach H, Holdrinet I, Meesters C. Comorbid anxiety symptoms in children wiüi pervasive developmental disorders. J Anxiety Disord. 1998;12(4):387-393.

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28. Realmuto GM, August GJ, Garfinkel BD. Clinical effect of buspirone in autistic children. J Clin Psychopharmacol. 1989:9(2): 122- 125.

29. McCormick LH. Treatment with buspirone in a patient with autism. Arch Fam Med. 1997;6(4):368-370.

10.3928/0090-4481-20031001-08

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