Psychopharmacology of autism spectrum disorders: A selective review

Abstract

While there is no cure for autism spectrum disorder, psychopharmacologic agents are often used with behavioral and educational approaches to treat its comorbid symptoms of hyperactivity, irritability, and aggression. Studies suggest that at least 50% of persons with autism spectrum disorder receive psychotropic medications during their life span. This selective review examines recent studies about the use of psychotropic medications in persons with autism spectrum disorder. The aim was to focus on randomized controlled trials conducted from 1990 to 2010 on this topic. A comprehensive literature search was performed using PubMed and Cochrane databases. Out of 105 studies identified for the review, only 24 were randomized controlled trials. Thus, despite the common use of these medications in autism spectrum disorder, more controlled studies are needed to determine their long-term efficacy and safety.

Keywords

autism psychopharmacology comorbidity

Introduction

Although autism was first described about 70 years ago, it took almost 25 years for researchers to start systematically examining the use of medications as part of its treatment. For several years after the publication of Kanner’s (1943) initial report, the main method of treatment was psychodynamic psychotherapy and the chief focus of intervention was the supposedly flawed parent–child relationship (e.g. see Bettelheim, 1967). However, even during that period, occasional reports continued to describe the use of medications. For example, at least 3 of the 11 patients described by Kanner (1971) were taking psychotropic medications at the time of his follow-up study.

Among the earliest studies to explore the role of medications in autism, those by Campbell et al. (1978, 1990) deserve particular mention. These studies not only provided preliminary evidence for the efficacy and safety of commonly used psychotropic drugs of the day, such as haloperidol, but also showed that none of the agents affected the core symptoms of the disorder. While most of the studies focused on antipsychotic agents, such as chlorpromazine and trifluoperazine, a few also examined the use of stimulants and tricyclic antidepressants (e.g. Campbell et al., 1971). Studies published before 1980 often included a wide variety of severely disturbed children under the umbrella of autism, including those with so-called childhood schizophrenia and bipolar disorder (Fish et al., 1966; Jorgensen, 1979).

Today, psychopharmacologic agents are often used for the control of the comorbid symptoms of autism spectrum disorder (ASD), such as hyperactivity, depression, and aggressive behavior that occur in up to half of the affected individuals (Baghdadli et al., 2003) affecting their quality of life and long-term outcome. In the United States, about a quarter of children and adolescents with ASD, between the ages of 3 and 14 years, are placed on psychotropic medications. A web-based registry study found that out of 5181 children with ASD, 35% had been placed on at least one psychotropic medication, most commonly stimulants, neuroleptics, and/or antidepressants (Rosenberg et al., 2010). The same study also found that those with older age, intellectual disability, and psychiatric comorbidity were more likely to be prescribed psychotropic medications. Multiple medication use also tends to be common. In a cross-sectional study of Medicaid claims in 60,641 children with autism, Mandell et al. (2008) found that 56% had used at least one psychotropic medication and that 20% of them had been prescribed more than three medications concurrently during the course of a year (Mandell et al., 2008). Although several reviews of the pharmacotherapy of autism have been published recently, few have focused on randomized controlled trials (RCTs), which is the main purpose of this review.

Method

A comprehensive literature search was performed using PubMed and Cochrane Databases focusing on RCTs of psychopharmacologic agents conducted from 1990 to 2010. Only English language publications were considered. The following classes of psychopharmacologic agents were included: antipsychotic medications, antidepressants, and central nervous system stimulants, as these are the most commonly used classes of drugs used in persons with ASD (Mandell et al., 2008). In addition, because of their common use for behavioral control in this population, anticonvulsants, and two other medications, atomoxetine (a norepinephrine reuptake inhibitor) and clonidine (an alpha-2 adrenergic agonist), were also included. Drugs such as naltrexone and lithium, which are not commonly used in persons with ASD, were excluded.

Results

Out of 105 studies identified by the literature search, 24 met the inclusion criteria. The classes of drugs and the number of controlled studies identified were as follows: antipsychotic agents and antidepressants, seven each; stimulants, four; alpha-2 adrenergic agents, two; anticonvulsants, three; and norepinephrine reuptake agents, one.

Antipsychotic drugs

Antipsychotic drugs, so-called because of their specific effect on treating symptoms of psychosis, have had a long association with autism. Because autism was conceptualized as an early manifestation of schizophrenia, antipsychotic drugs such as chlorpromazine, thioridazine, and haloperidol, were among the first medications to be tried and studied systematically in children with autism (Campbell et al., 1978; 1990).

Haloperidol

Although atypical antipsychotic agents, such as risperidone and aripiprazole, have now become the drugs of choice for the treatment of aggressive and disruptive behaviors in persons with ASD, haloperidol remains a useful alternative for those persons who either do not tolerate or do not respond to the atypical agents. Remington et al. (2001) conducted a double-blind placebo-controlled crossover study comparing haloperidol, clomipramine, and placebo. Differences were found between haloperidol and placebo on the Aberrant Behavior Checklist–Irritability (ABC-I) and the ABC–Hyperactivity subscale scores (p < 0.05). However, no differences were detected for the Stereotypic Behavior, Lethargy, or Inappropriate Speech subscales of the ABC.

Risperidone

McDougle et al. (1998) conducted a 12-week RCT of risperidone in 31 adults with ASD and found that the drug was more effective than placebo as measured by ratings on the Clinical Global Impressions (CGI). McCracken et al. (2002), as part of the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network, conducted a double-blind placebo-controlled study to determine the efficacy and safety of risperidone in children with autism and behavioral symptoms such as irritability, hyperactivity, and aggression. Risperidone was administered to 101 children with the disorder at a mean dose of 1.8 mg/day for 8 weeks. At the end of the study period, the medication caused significant reduction in the symptoms, as measured by the mean Irritability subscale score of the ABC-I (risperidone vs. placebo, 56.9% vs. 14.1%).

Shea et al. (2004) conducted the second RCT of risperidone in 80 children using a double-blind placebo-controlled design, again over a period of 8 weeks. Risperidone was administered at a mean dose of 1.17 mg/day. Over the duration of the study, subjects receiving risperidone had approximately twice the mean decrease in ABC-I subscale score compared to those receiving placebo.

Troost et al. (2005) conducted another RCT of risperidone using a standardized measure of aggression in children and adolescents with ASD. After an initial 24-week open-label phase, 24 responders entered an 8-week double-blind, placebo-controlled, parallel-group discontinuation study. For subjects who remained on risperidone, the mean dose was 1.81 mg/day. Significantly more subjects relapsed in the placebo group (67%) compared to those who continued to receive risperidone (25%). Over the duration of the discontinuation phase, subjects who received placebo also showed a significantly greater increase in ABC-I subscale score (60%) compared to those who received risperidone (14%).

Aripiprazole

Aripiprazole is the most recent drug to receive approval from the Food and Drug Administration (FDA) in the United States for the treatment of irritability in persons with autism. Although several open-label studies of aripiprazole exist, only two randomized placebo-controlled studies have been done in this population. Owen et al. (2009) examined 98 patients who were randomly assigned to receive one of three aripiprazole doses (5, 10, or 15 mg/day) or placebo. Results showed that all aripiprazole doses were more effective than placebo for improving mean ABC-I subscale scores (5 mg, p < 0.05; 10 mg, p < 0.01; 15 mg, p = 0.001). Differences between the dose groups were not evaluated and the active groups were found to have higher rates of discontinuation, extra-pyramidal side effects, and weight gain. A larger 8-week double-blind placebo-controlled study of aripiprazole in 210 children and adolescents with ASD was conducted by Marcus et al. (2009), again using the ABC-I subscale and CGI–Improvement (CGI-I) subscale scores as primary outcome measures. Similar to the study conducted by Owen et al. (2009), significant improvement in CGI-I ratings over placebo was reported in the treatment groups. However, aripiprazole was found to be associated with significant weight gain in comparison with placebo. Subsequently, based on a detailed post hoc analysis of the items of the ABC from both the studies, Aman et al. (2010) proposed that aripiprazole was particularly effective for irritability associated with temper tantrums.

Antidepressants

Antidepressants are used in persons with ASD not only for clinical depression, which becomes increasingly common after puberty (Ghaziuddin et al., 2002), but also for the management of irritability and aggression (Aman et al., 2005). Although seldom prescribed today, the older tricyclic antidepressants were often used in the treatment of hyperactivity and impulsivity in the past (Campbell et al., 1971). However, the most commonly used antidepressants in ASD are the selective serotonin receptor inhibitors (SSRIs) such as fluoxetine and sertraline (Aman et al., 2005).

Fluvoxamine

There have been two double-blind placebo-controlled studies of fluvoxamine in persons with ASD. The first, conducted by McDougle et al. (1996), was a 12-week study of fluvoxamine in 30 adults. This study reported significant improvement in repetitive thoughts and behaviors, maladaptive behaviors, aggression, and overall behavioral symptoms. The second, conducted by Sugie et al. (2005), was a 12-week double-blind placebo-controlled crossover study of fluvoxamine in 18 children with ASD, which also examined the correlation between the response to fluvoxamine and the serotonin transporter gene promoter region polymorphism. When those with minimal improvement on the CGI were included in the analysis, 10 (56%) patients were categorized as positive responders. However, when only those with “excellent response” on the CGI were examined, the figure fell down to only 5 (18%). In addition, a positive response occurred more frequently in those with the long (l) allele than in those with the short (s) allele of the serotonin transporter gene (Sugie et al., 2005).

Clomipramine

Gordon et al. (1993) conducted a double-blind comparison of clomipramine, desipramine, and placebo and found that clomipramine was superior to both desipramine and placebo on ratings for stereotypes and compulsive behaviors as measured by the Children’s Psychiatric Rating Scale. The response to clomipramine was not correlated with age, sex, or IQ of the subjects (Gordon et al., 1993). However, as mentioned in section “Antipsychotic drugs,” Remington et al. (2001) compared the effects of haloperidol, clomipramine, and placebo in a double-blind placebo-controlled crossover study. The objective of the study was to see if clomipramine would be better tolerated than haloperidol and also prove more effective for the control of stereotypic behavior. In the 36 patients (mean age 16.3 years) who could complete the full 7-week trial, haloperidol was found to be more effective than clomipramine and also better tolerated. No significant differences were found between placebo and clomipramine on the ABC-I and ABC–Hyperactivity subscales. In addition, no differences were detected for Stereotypic Behavior, Lethargy, or Inappropriate Speech between clomipramine and placebo (Remington et al., 2001).

Fluoxetine

Two double-blind placebo-controlled studies have examined the use of fluoxetine in ASD. The first, conducted by Buchsbaum et al. (2001), was a 16-week placebo-controlled crossover study in six adults. Significant improvement was reported on the Child Yale–Brown Obsessive–Compulsive Scale (CY-BOCS) Obsessions subscale (though not on the Compulsions subscale) as well as on the Hamilton Anxiety Scale and the CGI–Autism Scale. However, the number of patients included was small and side effects were not systematically studied. The second, conducted by Hollander et al. (2005), was a larger study in 45 children. During this study, participants received either fluoxetine or placebo in two 8-week phases separated by a 4-week washout phase. Fluoxetine was started at 2.5 mg daily and titrated up to 0.8 mg/kg/day over a 2-week period with a mean dose of 9.9 ± 4.3 mg daily. Fluoxetine was found to be superior to placebo (p = 0.004) in decreasing CY-BOCS repetitive behaviors. No significant difference in CGI-I was found between groups though a trend toward greater improvement in the fluoxetine group was noted. In addition, no significant differences were observed in the side effects, such as agitation, anorexia, weight gain, anxiety, diarrhea, insomnia, and sedation. Moreover, no increased suicidal risk was found in the fluoxetine group based on the suicide subscale of the Overt Aggression Scale–Modified (OAS-M; Hollander et al., 2005).

Citalopram

In a recent multicenter double-blind placebo-controlled study of citalopram in 149 children with ASD, King et al. (2009) found no significant differences in CGI-I subscale score between the citalopram group (32.9%) and the placebo group (34.2%). In addition, no significant differences were found between the groups on the CY-BOCS pervasive developmental disorder (PDD) Scale and on all the six subscale scores of the parent-rated Repetitive Behavior Scale–Revised. The citalopram group reported increased activation, hyperactivity, diarrhea, insomnia, and stereotypic behavior. The overall conclusion was that citalopram was not effective in reducing repetitive behaviors in persons with ASD. Another important finding of the study was the high placebo response. About 30% of cases treated with a placebo had a positive response suggesting the need for caution, while interpreting the results of psychopharmacological studies in ASD (King et al., 2009).

Stimulants, norepinephrine reuptake inhibitors, and alpha-2 adrenergic agonists

These medications are often used for the control of attention deficit hyperactivity disorder (ADHD)-like symptoms in persons with ASDs. The most commonly used agents are the stimulants, such as methylphenidate (Ritalin) and a mixture of amphetamine and dextroamphetamine (Adderall). Norepinephrine reuptake inhibitors such as atomoxetine (Strattera) and alpha-2 adrenergic agonists, such as clonidine (Catapres) are also used, often as second-line drugs or in combination with stimulants. These are discussed in the following sections.

Methylphenidate

There is a long history of the use of stimulants, such as methylphenidate, in children and adolescents with autism. The results have often been equivocal with some of the older studies warning of a possible deterioration in symptoms. Recent clinical experience, however, suggests an increasing use of these medications, often with positive results. For example, Handen et al. (2000) conducted a three-way placebo-controlled crossover trial of 13 prepubertal patients involving placebo and two different doses (0.3 and 0.6 mg/kg) of methylphenidate for 7 days. A total of 62% of patients, on at least one of the doses of methylphenidate, were deemed responders based on a 50% reduction in the Hyperactivity Index scores on the Conners’ Teachers Scale compared to those taking placebo. Adverse event data were not systematically collected though both groups reported poor appetite and irritability.

The RUPP Autism Network (RUPP, 2005) conducted the largest trial thus far with methylphenidate. In total, 72 patients from multiple sites completed the trial in three different phases over a period of 13 weeks. Children were initially given a 1-week test dose to assess tolerability and were then randomized to a 4-week crossover trial with methylphenidate doses of 0.125, 0.25, or 0.5 mg/kg per dose, administered three times a day. Outcome data found that 35 (49%) children enrolled in the study responded best (based on the CGI and the ABC–Hyperactivity subscale scores) to one of the three active doses of methylphenidate. Parent ratings indicated the greatest benefit of methylphenidate compared with placebo at 0.25 mg/kg per dose, while teacher ratings indicated the greatest benefit at 0.5 mg/kg per dose.

There have also been two studies of methylphenidate primarily studying aggression (using the ABC-I) in children and adolescents with autism. Quintana et al. (1995) conducted the first study in 10 prepubertal children with autism. This study was conducted over 4 weeks using a double-blind, placebo-controlled, crossover design. Methylphenidate was administered in divided doses equaling 20 and 40 mg/day. Compared to placebo, methylphenidate produced significant improvements in ABC-I mean endpoint scores. Unlike previously mentioned studies of atypical antipsychotics in the treatment of aggression, no significant differences were found in the rates of side effects between methylphenidate and placebo.

More recently, Handen et al. (2000) conducted a trial of methylphenidate in 13 prepubertal autistic children over 7 days using a double-blind placebo-controlled, crossover design. Methylphenidate was administered in low (0.3 mg/kg per dose) and high (0.6 mg/kg per dose) doses two to three times daily. In addition to the ABC-I, this study included an additional outcome measure, the aggression subscale of the Inattention/Overactivity With Aggression (IOWA) Conners’ Teacher Rating Scale. Compared to placebo, subjects who received methylphenidate showed significant improvement on both the outcome measures.

Norepinephrine reuptake inhibitors

Atomoxetine is a norepinephrine (noradrenaline) reuptake inhibitor used for the treatment of ADHD. There has been one randomized placebo-controlled crossover trial of atomoxetine in children with ASD (Arnold et al., 2006). This 6-week trial included 16 children on the autistic spectrum, though the majority of the patients completed only 3 weeks of each test condition. Atomoxetine was found to be superior to placebo on the hyperactivity subscale of the ABC, which was used as the primary outcome measure. However, it was not found to have any significant effect on the nine inattentive symptoms based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria of ADHD (APA, 1994).

Alpha-2 adrenergic agonists

There have been two placebo-controlled trials conducted of clonidine, though only one has been found to show improvement in hyperactivity in patients with ASD. Jaselskis et al. (1992) studied eight children with significant levels of hyperactivity, randomizing them to 7 weeks of either placebo or oral clonidine. They found that both the parent ratings on the Conners’ Abbreviated Parent–Teacher Questionnaire and teacher ratings on the ABC–Hyperactivity subscale favored clonidine over placebo, but clonidine was associated with a significant increase in drowsiness compared to placebo. In a double-blind placebo-controlled study to examine the efficacy of transdermal clonidine in autism, Fankhauser et al. (1992) administered either clonidine or placebo to nine males with autism (5–33 years of age). The treatment group showed significant improvement in social relationships and overall behavior. Again, drowsiness and fatigue were more common with clonidine than with placebo.

Anticonvulsants

In persons with ASD, anticonvulsants are often used not only to control seizures, which occur in about 30% of cases of autism, but also to treat aggression, mood swings, and hyperactivity, even when seizures do not occur. A few recent studies have examined the use of valproate (Anagnostou et al., 2006; Hellings et al., 2005; Hollander et al., 2006, 2010), lamotrigine (Belsito et al., 2001), and levetiracetam (Wasserman et al., 2006). While the latter two have not been found to be effective (Belsito et al., 2001; Wasserman et al., 2006), there is some evidence that valproate might be of benefit.

Hellings et al. (2005) conducted one of the first double-blind placebo-controlled studies of valproate in persons with ASD. In this 8-week study, 30 participants (6–20 years of age) with ASDs and significant aggression were randomized to either valproate or placebo. Participants receiving valproate were titrated to 20 mg/kg/day dosing and then maintained on trough levels between 70 and 100 µg/mL. Subsequent mean trough blood levels in the treatment arm were found to be 75.5 µg/mL at week 4 and 77.8 µg/mL at week 8. However, no significant treatment difference was found on primary or secondary outcome measures of ABC-I (p = 0.65), CGI-I (p = 0.16), and OAS (p = 0.96). In addition, significant side effects were noted in the treatment arm, including increased appetite, skin rash, and increased serum ammonia level; the latter was associated with parent report of slurred speech and mild cognitive slowing in one participant.

A small double-blind placebo-controlled study of divalproex sodium was conducted by Hollander et al. (2006). In this study, 13 individuals with ASD were randomized to either sodium valproate or placebo. Significant improvement was found in repetitive behaviors in the sodium valproate group as measured by the CY-BOCS (p = 0.037). Hollander et al. (2010) subsequently studied the effectiveness of valproate in 55 children (mean age 9.46 ± 2.46, mean nonverbal IQ 63.3 ± 23.9) in a 12-week randomized double-blind placebo-controlled trial using the ABC-I subscale scores and the CGI-I subscale as primary outcome measures. A total of 62.5% of the children receiving valproate were classified as responders (in contrast to only 9% children receiving placebo). However, secondary outcome measures including the CY-BOCS, the Vineland Adaptive Behavioral Scale, the Young Mania Rating Scale, CGI-Autism, and the OAS-M demonstrated no statistically significant differences between the groups, although CGI-I responders tended to have higher valproate blood levels than CGI-I nonresponders.

Discussion

The main finding of this review is that despite the common use of medications in persons with ASD, few controlled studies have been undertaken, consistent with the findings of other reviews on this topic (Dinca et al., 2005; McPheeters et al., 2011). Only 24 of the 105 studies were RCTs. Of the seven studies in the antipsychotic group, four examined the role of risperidone, two of aripiprazole, and one of haloperidol. Among antidepressants, two studies examined the use of fluvoxamine, fluoxetine, and clomipramine and one focused on citalopram. Similarly, only three controlled studies of anticonvulsants were identified, all examining the use of sodium valproate. Moreover, studies generally supported the role of psychotropic medications in the treatment of the comorbid symptoms of autism, with the notable exception of the citalopram study (King et al., 2009).

Taken together, therefore, the findings suggest that while psychotropic medications are effective in some patients with ASD, several reasons underscore the need for caution. First, the symptoms of the disorder are not only difficult to measure but also tend to change over time; in addition, they are often complicated by comorbid conditions such as intellectual disability, aggressive behavior, epilepsy, and so on. Second, most of the studies have either used modest-sized samples or excluded patients with additional disorders. Third, relatively little is known about the long-term side effects of medications such as the atypical antipsychotic agents (Anderson et al., 2007; Haddad and Sharma, 2007).

In summary, despite their widespread use, there exist no medications that are specific to the core symptoms of autism. At best, medications result only in a modest symptomatic response (Bailey et al., 1996). As Kanner (1971) remarked over 40 years ago, “No one as yet has succeeded in finding a therapeutic setting, drug, method, or technique that has yielded the same or similar ameliorative and lasting results for all children” (p. 145). However, when used judiciously with educational and behavioral interventions, psychotropic medications can play an integral role in the care and habilitation of persons with ASD across their life span.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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