Pharmacotherapy of emotional and behavioral symptoms associated with autism spectrum disorder in children and adolescents

Abstract

Autism spectrum disorder (ASD) is characterized by impairment in social communication and restricted patterns of behavior. Although there is no pharmacological treatment approved by the US Food and Drug Administration (FDA) for the core symptoms of ASD, there is mounting support in the literature for the management of behavioral symptoms associated with this developmental disorder, in particular, irritability and hyperactivity. Aripiprazole and risperidone are currently approved by the FDA for the treatment of irritability in youth with ASD. Though not FDA-approved, methylphenidate and guanfacine are effective for the management of hyperactivity in children with ASD. Selective serotonin reuptake inhibitors are often used in clinical practice to target anxiety and compulsions; however, there is little evidence to support its use in this population. There is a great need for further research on the safety and efficacy of existing psychotropic medications in youth with ASD, as well as the development of new treatment modalities for the core and associated behavioral symptoms.

Introduction

Autism spectrum disorder (ASD) is a developmental disorder that appears in early childhood and is characterized by persistent deficits in social interaction, as well as restricted, repetitive patterns of behavior, interests, or activities.¹ These core symptoms of ASD are frequently associated with emotional and behavioral disturbances, including anxiety, irritability, labile mood, inattention, hyperactivity, and sleep problems, which may lead to functional impairment and significant emotional and economic burden for caregivers.^2,3 In 2012, the Center for Disease Control and Prevention reported 1 out of 68 children were affected by ASD.⁴

The treatment for ASD is often multimodal and can include early intensive behavior therapy (applied behavior analysis), speech therapy, occupational and physical therapy, social skills training, special education, and vocational training, among other nonpharmacological interventions. Although there is no cure for ASD, early behavior interventions often improve a child's functioning and outcome.⁵ Currently, there are no medications approved for the management of core symptoms of ASD; however, a psychopharmacological approach may be beneficial in the treatment of associated symptoms that can substantially and adversely impact the life of a person with ASD⁶

Currently, there are only two medications, risperidone and aripiprazole, that are approved by the US Food and Drug Administration (FDA) for the management of symptoms associated with ASD. However, it has been reported that close to half of the insured children with ASD are receiving psychopharmacological interventions with stimulants, α-agonists, antipsychotics, and antidepressants.⁷ It is important to remember that many families seek out natural remedies, supplements, and chelating agents, which all have the potential to cause adverse effects and interact with the prescribed medications.⁸ Therefore, it is essential to inquire about the use of any complementary and alternative therapies utilized by families, provide psychoeducation, and recommend evidence-based approaches for the management of symptoms associated with ASD. In this article, we provide an overview of the current literature on psychopharmacological interventions in treating ASD and comorbid conditions.

Antipsychotics

Risperidone is approved by the FDA for the treatment of irritability associated with autistic disorder in youth aged 5 to 16 years. Youth with ASD receiving risperidone showed an over 50% reduction in the irritability score of the Aberrant Behavior Checklist (ABC-I).^9-12 The magnitude of the response was greater with moderateto-severe irritability and lethargy associated with ASD.¹³

The efficacy of risperidone was maintained long term during a 4-month open-label treatment.¹⁴ During the double-blind, placebo-substitution withdrawal part of this study, over 60% of youth relapsed on placebo compared with 12.5% on risperidone. However, symptom improvement with risperidone came at the expense of weight gain, which averaged 5.1 kg. Another open-label extension study demonstrated a decrease in irritability over the course of 21 months.^10,15 Interestingly, treatment with risperidone was not associated with an improved Clinical Global Impressions-Severity (CGIS) score, possibly due to it being dichotomized to “improved” or “not improved” and therefore not able to detect subtle changes.

Adequate dosing of risperidone was explored in a double-blind, placebo-controlled study of 96 children, ages 5 to 17 years.¹¹ In this study, higher doses of risperidone (1.75 mg/day for >45 kg) contributed to greater change in the ABC-I than lower doses (0.175 mg/day for >45 kg).

Aripiprazole is also approved by the FDA for the treatment of irritability associated with autistic disorder in children and adolescents between the ages of 6 and 17 years. Two large-scale randomized, placebo-controlled studies of children and adolescents taking aripiprazole reported significantly lower scores on the ABC-I and the Clinical Global Impressions—Improvement (CGI-I) scale on active medication than on placebo.^16,17 Post hoc analysis of the aforementioned studies revealed an association of aripiprazole with improved quality of life in the areas of emotional, social, and cognitive functioning.¹⁸

Aripiprazole did not separate from placebo in a randomized, relapse-prevention trial of 85 children, evaluating long-term treatment effects.¹⁹ In phase 1 of this trial, subjects received flexible doses of aripiprazole (2 to 15 mg/day) for 13 to 26 weeks. Those who achieved more than a 25% decrease in ABC-I and were stable for 12 weeks were randomized to continue active treatment for an additional 16 weeks or were switched to placebo. Although there was no statistically significant difference between the two groups, a post hoc analysis revealed a number needed to treat of 6 to prevent 1 additional relapse. Therefore, aripiprazole may be helpful in long-term management of some patients.

In an open-label flexible-dose study of 330 children and adolescents aged 6 to 17 years, where aripiprazole was continued for 52 weeks following two 8-week randomized placebo-controlled trials, the treatment with aripiprazole significantly reduced ABC-I scores in de novo subjects and in those previously receiving placebo.²⁰ Improvement was maintained for those patients who received aripiprazole during the first 8 weeks of treatment. Aripiprazole was generally well tolerated, and common side effects included weight gain, vomiting, insomnia, and dyslipidemia.²¹ The most frequent serious adverse event was aggression. Younger children with higher baseline weight were more likely to gain additional weight when taking aripiprazole.²²

Aripiprazole was directly compared with risperidone in a 2-month double-blind, randomized trial.²³ Both medications decreased the ABC-I scores. Although aripiprazole reduced the symptoms of irritability faster than risperidone, the overall effects on the ABC-I scores were similar in both groups.

Weight gain is often a common concern for patients and families when choosing an antipsychotic medication. Although aripiprazole is usually not associated with significant weight gain in typically developing youths,²⁴ increases in body mass index were similar for aripiprazole and risperidone in children with ASD.²⁵

Several small studies of olanzapine suggest potential benefits in the management of children with ASD. Olanzapine improved symptoms of irritability in a 3-month open-label study of 25 youth aged 6 to 16 years.²⁶ A double-blind, placebo-controlled study of 11 children aged 6 to 14 suggested an overall improvement in global functioning, but at the expense of weight gain.²⁷ The effectiveness of olanzapine was compared with that of haloperidol in an open-label study of 12 children with ASD.²⁸ Both groups improved on the Children's Psychiatric Rating Scale (CPRS Autism Factor) and the CGI-I. Side effects included drowsiness and weight gain for both interventions.

The effectiveness of paliperidone for irritability in children with ASD was evaluated in an 8-week, open-label study of 25 subjects aged 12 to 21 years.²⁹ Significant improvement in irritability was noted in 84% of patients. Side effects included an average weight increase of 2.2 kg and an elevated level of prolactin.

Quetiapine was not effective and was poorly tolerated in the treatment of youth with ASD in two small open-label studies.^30,31 However, in an open-label trial of 11 adolescents aged 13 to 17 years, quetiapine was well tolerated, and a significant decrease in aggressive behavior and sleep disturbances was noted.³² Ziprasidone is an antipsychotic with a putative reduced propensity for weight gain; improved global functioning attributed to this agent in two studies suggests it may be promising for the management of children with ASD.^33,34

Lurasidone did not prove to be beneficial in reducing irritability associated with ASD in a randomized, double-blind, placebo-controlled trial of 150 children and adolescents.³⁵ However, there was an improvement in global functioning on lurasidone 20 mg/day, though not on 60 mg/day. The reasons for the lack of response to the higher dose of lurasidone used in this trial are not yet clear.

There is more evidence to support the use of risperidone and aripiprazole for the treatment of irritability associated with ASD than observed with other second-generation antipsychotics. However, paliperidone and olanzapine may be promising medications in this population. Reports of quetiapine are small and show mixed results, whereas lurasidone is not beneficial in the management of irritability in youth with ASD. To our knowledge, there are no published studies of asenapine in the treatment of behavior symptoms associated with ASD.

Anticonvulsants and lithium

Divalproex was beneficial in reducing irritability in a small, randomized, placebo-controlled trial of children with ASD³⁶; however, an earlier double-blind, randomized trial failed to show separation from placebo on the ABC-I.³⁷ An open-label trial of levetiracetam suggested improvements in emotional lability and aggressive behaviors³⁸; however, a randomized, placebo-controlled trial did not find any benefit in the management of repetitive behaviors, impulsivity, and hyperactivity.³⁹

Monotherapy with topiramate has no demonstrated benefit in the treatment of youth with ASD⁴⁰; however, it reduced the ABC-I score when added to risperidone.⁴¹ Lamotrigine was not effective in reducing irritability, a finding based on a double-blind, placebo-controlled study of 27 boys aged 3 to 11 years.⁴²

Although there are no randomized placebo-controlled trials of lithium in children with ASD, a retrospective chart review of 30 children and adolescents with ASD revealed improvements in functioning in subjects with elevated mood and euphoria.⁴³

The current evidence for divalproex in the management of irritability in subjects with ASD is mixed. There is no evidence to support the use of levetiracetam or lamotrigine in the management of ASD. Topiramate may be beneficial as an adjunct to risperidone. Lithium may be helpful in the management of elevated mood symptoms.

Antidepressants

It has been our experience that antidepressants have been commonly prescribed to treat children with ASD with the hope of targeting repetitive behaviors and anxiety symptoms. However, there is insufficient data to support the use of antidepressants in this population. A randomized, placebo-controlled study of citalopram in children and adolescents aged 5 to 17 years failed to find a positive response on the CGI-I scale or the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS).⁴⁴ In addition, subjects experienced increased adverse events, such as increased energy levels, impulsiveness, hyperactivity, stereotypy, and insomnia. A study of fluoxetine was conducted in this population; although the study is unpublished, an Autism Speaks press release about the study indicated that fluoxetine was not effective in reducing repetitive behaviors.⁴⁵ An open-label 10-week study of fluvoxamine in 18 children and adolescents suggested a partial response in some individuals, but not in the group as a whole.⁴⁶ A Cochrane review did not find enough evidence to support the use of selective serotonin reuptake inhibitors (SSRIs) in children with ASD.⁴⁷ In addition, there is an increased risk of side effects with SSRI treatment in children with ASD.

Psychostimulants

Methylphenidate has been shown to reduce the symptoms of hyperactivity and inattention in youth with ASD. However, the effect sizes were lower and the rates of adverse events higher than in youth without ASD.^48-50 A recently published study, where subjects were randomized to low (10 mg/day) or medium (30 mg/day) doses of an extended-release liquid formulation of methylphenidate, reported significant decreases on ABC subscales of irritability and hyperactivity.⁵¹ Interestingly, the side effects of rebound hyperactivity and aggression at the end of the day decreased in the medium-dose group only. To our knowledge, there are no published trials of methodological rigor regarding the use of amphetamines in children with ASD.

α₂-Agonists

Guanfacine is effective in reducing hyperactivity in children with ASD.⁵² In a double-blind, placebo-controlled trial of an extended-release formulation of guanfacine, 50% of youth on active treatment improved on the CGI-I scale, compared with 9.4% on placebo.⁵³ Low blood pressure was noted for the first 4 weeks of treatment but returned to baseline at week 8. A gene variant in a multidrug-resistance protein (MDR1) may have an effect on the treatment response to guanfacine in children with ASD.⁵⁴ The studies of clonidine suggest a benefit in reducing hyperactivity symptoms and improving sleep in children with ASD.^55,56 In general, α-agonists show promise in the management of hyperactivity in children with ASD; however, larger-scale studies of clonidine are needed to establish its efficacy in this population.

Norepinephrine reuptake inhibitors

Atomoxetine is an alternative to stimulants and α-agonists in treating patients with ASD and associated hyperactivity.^57,58 In a 10-week randomized, placebo-controlled trial, where the treatment with atomoxetine was compared with parent training, placebo, and a combination of atomoxetine with parent training, response rates were higher in a combination treatment group.⁵⁹ The response was maintained by 60% of subjects in a 24-week extension study.⁶⁰

Oxytocin

Over the past decade, oxytocin has been investigated as a potential agent modulating social responsiveness and communication in subjects with ASD. Although early trials, which involved single-dose administration, were promising, more recent evidence has provided mixed results.⁶¹ A double-blind, placebo-controlled trial of two doses of oxytocin (12 or 24 international units [IU] for 5 days daily, depending on the weight of a child) revealed no separation from placebo in the areas of emotion recognition or social interaction.⁶² Similarly, higher doses of 18 or 24 IU twice daily for 8 weeks did not produce improvement in scores on the Social Responsiveness Scale (SRS) and the CGI-I scale.⁶³ Alternatively, in a study with very young children between the ages of 3 and 8, significant improvements in social behaviors were observed on the parent ratings after administration of oxytocin for 5 weeks.⁶⁴ It is possible that variable efficacy of oxytocin in these trials was due to considerable methodological differences or unequal effect of oxytocin across the person's life cycle. Whereas oxytocin may be a promising agent, larger-scale studies utilizing similar dosing administration of the medication and outcome measures are warranted.

Glutamatergic and γ-aminobutyric acid receptor-modulating agents

Arbaclofen, a selective γ-aminobutyric-acid B receptor (GABA_B) agonist, improved scores from the irritability and lethargy/social withdrawal subscales of ABC, as well as the SRS scores in an 8-week open-label study of 32 children with ASD.⁶⁵ N-acetylcysteine (NAC), a glutamatergic modulator and an antioxidant, has been shown to reduce irritability associated with ASD as an adjunct to risperidone,^66,67 whereas monotherapy with NAC delivered mixed results.^68-70 In addition, NAC did not improve social impairment.⁶⁹ D-Cycloserine was considered a promising agent after it showed improvements in social withdrawal.⁷¹ Although these findings were not corroborated in follow-up studies,⁷² cycloserine may still be beneficial in maintaining the effects of social skills training.⁷³

A number of other medications have been beneficial when used in adjunction with risperidone. Memantine, riluzole, and amantadine may help reduce irritability and other behavioral measures when combined with risperidone.^74-76 A significant decrease in ABC-I scores was noted in a small randomized, double-blind trial of 44 children aged 4 to 12 years who received pioglitazone in addition to risperidone for 10 weeks.⁷⁷

In an 8-week randomized trial of youth aged 4 to 17 years, memantine was directly compared with risperidone.⁷⁸ Both medications significantly reduced irritability, social withdrawal, inappropriate speech, and hyperactivity; however, there was no statistically significant difference between the two groups. More patients in the risperidone group were “very much improved,” a finding based on the Clinical Global Impression, Improvement score (CGI-I). Memantine did not demonstrate improvement on the SRS in a 12-week randomized, placebo-controlled study with a 48-week open-label extension.⁷⁹

Other agents

Secretin has been studied extensively for the treatment of core symptoms of ASD; however, a Cochrane review concluded that there is no evidence for its effectiveness, and it should not be recommended for the management of ASD.⁸⁰ Effectiveness of monotherapy with buspirone has been investigated in a small randomized, placebo-controlled trial of children with ASD aged 2 to 6 years.⁸¹ Although the composite score of the Autism Diagnostic Observation Schedule (ADOS) did not change between groups, there was a significant improvement noted in the restricted and repetitive behavior score of the ADOS with buspirone 2.5 mg twice daily. A combination of buspirone and risperidone was more effective in reducing the ABC-I score than a combination of risperidone and placebo during 8 weeks of treatment.⁸²

Conclusions

Despite the recent advances in the pharmacotherapy of ASD, current evidence-based options for treatment remain limited. There is no evidence that any of the reviewed medications have a significant impact on social withdrawal, which is one of the characteristic symptoms of this developmental disorder. However, there are more options available for the management of associated symptoms. The treatment of irritability has received the most attention. Two second-generation antipsychotics—risperidone and aripiprazole—have the highest level of evidence for the treatment of irritability associated with ASD and are approved by the FDA for this purpose. Olanzapine and paliperidone may be beneficial, but larger trials are needed to establish safety and efficacy. Lurasidone is not effective, and quetiapine showed mixed results; they are therefore not recommended in the treatment of irritability in ASD. Trials involving mood stabilizers and lithium have generally not been sufficiently powered. The evidence for monotherapy with divalproex is mixed. Lithium has been effective in children with ASD exhibiting manic symptoms.

A number of medications may be effective when used in combination with an antipsychotic, such as risperidone. NAC, memantine, riluzole, amantadine, and buspirone reduced irritability in children with ASD when given in adjunction to risperidone.

Attention-deficit/hyperactivity disorder (ADHD) symptoms are also prevalent in youth with ASD and lead to significant functional impairment. Methylphenidate has been reported to be effective in managing hyperactivity; however, the effect size in children with ASD is generally lower and the rates of adverse effects higher than in typically developing youth. Surprisingly, there are little data regarding the use of amphetamines in youths with ASD. Guanfacine extended release has been shown to be effective in the management of comorbid ADHD. The studies evaluating the effect of clonidine are generally small but, overall, show some benefit.

Stereotypy and repetitive behaviors are challenging to address with psychopharmacologic agents. Antidepressants did not show significant benefit in this area. Moreover, children with ASD tend to experience more activating side effects with antidepressants, and their use for treating stereotypy is not recommended.

As outlined in this review, clinical trials have provided some evidence that a number of pharmacological interventions are not beneficial in the management of ASD and associated symptoms. There could be several factors affecting the results of these studies. In general, these trials may not be sufficiently powered to detect the effect of the medication. In addition, the studies show considerable methodological differences, utilize a variety of rating scales, and have different baseline scores, which could all contribute to the statistical analysis showing lack of effectiveness. The effect of the medications across the life span of a child with ASD is yet to be determined; it may be possible that earlier psychopharmacological interventions would be more beneficial. In addition, behavioral management is an essential factor in managing a child with autism; however, it is not included in most of the clinical trials.

Despite the interest and major advances in the autism field, more research is needed to establish efficacy and safety of the pharmacological and behavioral interventions in the management of ASD and comorbid conditions. Several clinical trials are currently addressing this need. An online search for active studies on clinicaltrials.gov produced 225 hits, including medication, behavior interventions, and psychotherapeutic treatment options. More studies are needed to evaluate the safety and efficacy of long-term treatment of ASD in youth, as well as comparative trials of existing medications. ASD is a heterogeneous group of developmental conditions, and there may be subgroups that could benefit from more targeted pharmacologic interventions. Further understanding of genetics and pathophysiology of ASD could lead to the development of novel treatment options that could directly address the core symptoms of autism.