Antipsychotics in the treatment of autism (original) (raw)
Antagonism at 5-HT receptors is thought to underlie, at least in part, the reported advantages of atypical antipsychotics over conventional agents, namely the reduced propensity to cause EPS (55). In addition, atypical antipsychotics are generally considered more effective than conventional antipsychotics for improving the negative symptoms of schizophrenia such as anhedonia, avolition, and apathy (56). These negative symptoms have similarities to the social impairment characteristic of autism. Therefore, the atypical antipsychotic risperidone was postulated to have potential efficacy for treating core symptoms in autism (57). As discussed below, these hopes have not been fully realized.
This section will review the atypical antipsychotics most commonly prescribed for autism. These include risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole (Table 2). Only a few case reports of clozapine treatment in autism have been published (58–60). Clozapine is rarely used clinically because it has the potential to cause life-threatening agranulocytosis and requires frequent weekly to biweekly venipuncture to monitor white blood cell counts. Cognitively impaired children and adults with high degrees of irritability frequently do not tolerate venipuncture well. Due to the absence of any known advantages to clozapine over other atypical antipsychotics for these symptoms, its use is limited.
Atypical antipsychotics commonly used to treat severe behavioral symptoms in PDDs
Risperidone. The first placebo-controlled trial of risperidone conducted in autism involved 31 adults (mean age, 28.1 years) with autism or PDD NOS (13). Risperidone (mean dose, 2.9 mg/d) was significantly more efficacious than placebo, with 8 of 14 (57%) subjects being categorized as responders on the Clinical Global Impression–Improvement (CGI-I) scale versus 0 of 16 in the placebo group. Specifically, risperidone was efficacious for reducing interfering repetitive behavior as well as aggression toward self, others, and property. Significant differences between risperidone and placebo were not captured on scales measuring social relatedness to people and language. In 13 of 15 (87%) subjects randomized to risperidone, at least one adverse effect was observed — although this included mild, transient sedation in 5 subjects — compared with 5 of 16 (31%) subjects given placebo (agitation in all 5 cases). Weight gain occurred in a minority (2 of 14; 14%) of risperidone-treated subjects and was significantly less than that reported in the pediatric trials discussed below.
A double-blind, placebo-controlled study of risperidone in children and adolescents with autism was completed by the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network (15). A total of 101 children (mean age, 8.8 years) was randomly assigned to receive 8 weeks of risperidone or placebo. At baseline, all patients had significant irritability, aggression, or self injury as rated by an Aberrant Behavior Checklist (ABC) (61) Irritability subscale score of 18 or greater. Treatment with risperidone for 8 weeks (mean dose, 1.8 mg/d) resulted in a 57% reduction in the Irritability subscale score of the ABC as compared with a 14% decrease in the placebo group. Of the risperidone-treated subjects, 69% were categorized as treatment responders, compared with 12% of those given placebo. Risperidone was associated with an average weight gain of 2.7 kg, as compared with 0.8 kg with placebo. Drooling was more commonly reported with risperidone than placebo, but standardized measures of acute EPS and TD were not significantly different between groups.
The RUPP study (15) also examined the other 4 subscales of the ABC, which included social withdrawal, stereotypy, hyperactivity, and inappropriate speech. Risperidone led to greater reduction on all these scales, but the reduction in social withdrawal and inappropriate speech were only significant at the P = 0.03 level (not significant following Bonferroni correction for multiple analyses). To further analyze the efficacy of risperidone on the core symptoms of autism in this group of highly irritable patients, McDougle et al. (62) examined secondary outcome measures that included a modified Ritvo-Freeman Real Life Rating Scale (R-F RLRS) (63) and modified Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) (64). On the R-F RLRS, significant improvement was seen on the following subscales: sensory motor behaviors, affectual reactions, and sensory responses. However, there was no significant change on the social relationship to people or language subscales. Risperidone was more efficacious than placebo in reducing interfering repetitive behavior on the CY-BOCS.
A companion study to the initial 8-week acute risperidone trial by the RUPP Autism Network has also been completed (65). In this study, 63 subjects who responded to 8 weeks of acute treatment continued on open-label risperidone for an additional 4 months. During this open-label continuation phase, the mean risperidone dose remained stable and there was no clinically significant worsening of target symptoms. Drug use was discontinued by 2 subjects (8%) due to loss of efficacy and by 1 subject due to adverse effects. Subjects gained an average of 5.6 kg of body weight during the total 6-month course of risperidone treatment. Subsequently, 32 subjects who continued to be classified as responders after the 16-week extension were randomized to continued risperidone versus gradual substitution with placebo (over the course of 3 weeks). In subjects randomized to placebo, 10 of 16 (62.5%) showed significant worsening of symptoms, compared with 2 of 16 subjects (12.5%) who continued on risperidone, suggesting that risperidone treatment beyond 6 months is needed to prevent relapse. This relapse with drug withdrawal has also been confirmed in another placebo-controlled discontinuation study of risperidone in PDD (66).
A second multicenter, placebo-controlled study of risperidone in children with PDD has been conducted in Canada (16). A total of 79 children (mean age, 7.5 years) was randomized to either risperidone (mean dose, 1.2 mg/d) or placebo for 8 weeks. No specific entry criteria were reported other than a diagnosis of PDD and a Childhood Autism Rating Scale (CARS) (67) score exceeding 30. However, the average baseline ABC Irritability subscale score of 20 suggests that these children were, on average, highly symptomatic at study entry. Risperidone was associated with a 64% reduction in ABC irritability subscale scores versus 31% in the placebo group. On the CGI-I, 21 of 40 (53%) risperidone-treated subjects were “much” or “very much” improved compared with 7 of 39 (18%) placebo-treated subjects. Significant improvement was seen on all subscales of the ABC (P < 0.05), but the greatest magnitude of improvement was observed for irritability and hyperactivity. Social withdrawal decreased by 63% in the risperidone group compared with 40% for placebo (P < 0.01). Weight gain following 8 weeks of risperidone was 2.7 kg compared with 1.0 kg for placebo. EPS as measured by standardized rating scales were equal in both groups.
These 2 studies of risperidone in children with autism produced similar results in terms of efficacy and adverse events. These studies eventually led to FDA approval of risperidone for the treatment of irritability in children and adolescents with autism aged 5–16 years. In addition, there is evidence that risperidone is efficacious for hyperactivity, repetitive behavior, and perhaps social withdrawal in children with PDD exhibiting high levels of baseline irritability.
Other investigators have studied risperidone in samples that included even younger children. Risperidone is occasionally needed in very young children due to the severity of the irritability and agitation, which can be extreme (68). Nagaraj et al. (69) recently published a study that included children as young as 2 years using doses of 1 mg/d. In this study of 40 children (aged 2–9 years), risperidone was highly efficacious as measured by ratings on the CARS and the Children’s Global Assessment Scale. Luby et al. (70) also found some evidence for efficacy in a study of 24 children under the age of 6 years. However, these investigators found risperidone (dose range, 0.5–1.5 mg/d) only minimally efficacious compared with placebo at 6 months, possibly owing to group differences at baseline or sample size. In this latter study, high degrees of irritability were not required for study entry. This too may have limited observed improvement.
Olanzapine. To date, 3 prospective open-label trials of olanzapine in PDD have been published. In a 12-week study of olanzapine (mean dose, 7.8 mg/d; dose range, 5–20 mg/d) in children, adolescents, and adults (age range, 5–42 years) with autism and other PDDs, 6 of 8 (75%) patients who entered a 12-week, open-label trial were responders based on the CGI-I (71). Significant improvements in overall symptoms of autism, motor restlessness/hyperactivity, social relatedness, affectual reactions, sensory responses, language usage, self injury, aggression, irritability or anger, anxiety, and depression were observed. Significant changes in repetitive behaviors did not occur for the group. The drug was generally well tolerated, with the most significant adverse effects being increased appetite and weight gain in 6 patients. The mean weight for the group increased 8.4 kg during the course of the 12-week trial.
In another open-label study, 12 children with autism (mean age, 7.8 years) were randomized to 6 weeks of open-label treatment with olanzapine or haloperidol (72). Mean final dosages were 7.9 mg/d for olanzapine and 1.4 mg/d for haloperidol. In the olanzapine group, 5 of 6 (83%) subjects were rated as responders; 3 of 6 (50%) in the haloperidol group were rated as responders. Weight gain from baseline to the end of treatment was significantly higher in the olanzapine group (mean, 4.1 kg) compared with the haloperidol group (mean, 1.5 kg).
In a third study, 25 children (mean age, 11.2 years) with PDD were treated with olanzapine (mean dose, 10.7 mg/d) for 3 months (73). In contrast to the other 2 studies, olanzapine was effective in only 3 (12%) subjects. The reason for the lower response rate is unclear, but could have been the relatively low level of disruptive behavior at baseline. In this study, the mean baseline ABC Irritability subscale score was 11, which is low compared with the baseline values in the 2 largest studies of risperidone in children with PDD: 20 and 26. The other 2 olanzapine investigations discussed above had specific entry criterion based on degree of disruptive behavior.
One small placebo-controlled study of olanzapine has been published (74). In this study, 11 patients with PDD were randomized to olanzapine (mean dose, 10 mg/d) or placebo for 8 weeks. Of subjects receiving olanzapine, 3 of 6 (50%) were judged treatment responders on the CGI-I, compared with 1 of 5 (20%) subjects receiving placebo. Mean weight gain was 7.5 pounds compared with 1.5 for placebo.
Quetiapine. Four open-label studies or case series have reported on the use of quetiapine in treating PDD. In the first of these, 6 children and adolescents (aged 6–15 years) with autism were treated with quetiapine (mean dose, 225 mg/d) during a 16-week open-label trial (75). Quetiapine was poorly tolerated by 4 subjects, 3 of whom terminated early due to sedation and 1 due to a seizure. The 2 subjects who finished the study were classified as responders on the CGI-I. Increased appetite and weight gain were also reported. The investigators concluded that quetiapine was poorly tolerated and generally ineffective in this diagnostic group.
Another open-label trial of quetiapine in PDD enrolled 9 adolescents (aged 12–17 years) with autism (76). Subjects were treated with quetiapine (mean dose, 292 mg/d) for 12 weeks. The trial was completed by 6 of 9 subjects (67%), with 2 of 9 (22%) judged responders on the CGI-I. Two subjects discontinued quetiapine early, 1 due to sedation and 1 to increased agitation/aggression. Overall, adverse effects reported for the group included sedation, weight gain, agitation, and aggression.
Retrospective studies published recently have been slightly more optimistic as to the efficacy of quetiapine in PDD. In 1 case series (77), 20 patients (aged 5–28 years) were treated with quetiapine (mean dose, 249 mg/d) over an average of 60 weeks (range, 4–180 weeks). Of these 20 patients, 8 (40%) were judged responders to quetiapine based on a CGI-I performed at the time of clinic visits. Adverse effects occurred in 50% of patients, but only led to drug discontinuation in 15% of cases.
In another case series (78), quetiapine (mean dose, 477 mg/d) was effective in treating 6 of 10 (60%) patients (aged 5–19 years) with PDD as judged by the CGI-I. Significant improvement was also found on the Conduct, Hyperactivity, and Inattention subscales of the Conners Parent Scale (79). Adverse effects were mild and included sedation, sialorrhea, and weight gain.
At first glance, the response rate in these uncontrolled studies of quetiapine is lower than that reported with risperidone. The highest response rate in any of these studies was 60%. In the study by Hardan et al. (78), somewhat higher doses of quetiapine were reached compared with the other 3 studies. Controlled trials of quetiapine are needed to more accurately determine its efficacy and appropriate dosing in the treatment of autism and other PDDs.
Ziprasidone. There have been 2 published studies that examined the effectiveness of ziprasidone in PDD. In the first study (80), ziprasidone (mean dose, 59 mg/d) was associated with “much” or “very much” improvement on the CGI-I in 6 of 12 (50%) children and adolescents (mean age, 11.6 years) with PDD following an average treatment duration of 14 weeks. Improvement was seen in symptoms of aggression, agitation, and irritability. Transient sedation was the most common side effect. No cardiovascular side effects were observed. On average, patients lost weight during treatment with ziprasidone, but this could have been secondary to being switched from other drugs that had caused excessive weight gain. Mean change in body weight for the group was –5.8 ± 12.5 pounds (range, –35 to 6 pounds): 5 patients lost weight, 5 had no change, 1 gained weight, and 1 had no follow-up weight beyond the baseline measure.
In the second study (81), 10 adults with autism and mental retardation living in a residential setting were switched to ziprasidone from other atypical antipsychotics (clozapine, risperidone, and quetiapine), most commonly because of excessive weight gain. At 6 months after the switch, they had lost a significant amount of weight, averaging 9.5 pounds. The changes in maladaptive behavior were not significantly different, and the authors reported that 6 patients improved, 1 was unchanged, and 3 decompensated. The potential for QTc interval prolongation with ziprasidone on electrocardiography led to a warning in the full prescribing information (82). The drug should not be given to individuals with cardiac arrhythmias or long QT syndrome or who take other medications that can prolong the QTc interval.
Aripiprazole. Aripiprazole is the newest atypical antipsychotic available in the United States. This drug differs from other atypicals because it is a partial DA D2 and 5-HT1A agonist in addition to being a 5-HT2A antagonist (83). In 1 case series (84), 5 patients (mean age, 12.2 years) received aripiprazole (mean dose, 12 mg/d) for an average duration of 13 weeks. All 5 subjects (100%) were deemed responders on the CGI-I. Significant improvement was noted in a variety of interfering behavioral symptoms, including aggression, self injury, and irritability. Aripiprazole was well tolerated. No acute EPS or changes in heart rate or blood pressure were recorded. Of the 5 subjects, 2 experienced mild transient somnolence. There was a reduction in average weight, but this may have been secondary to discontinuing a prior atypical antipsychotic drug that had caused significant weight gain.
Our group recently reported preliminary results from an ongoing open-label prospective study of aripiprazole in youth with Asperger’s disorder and PDD NOS (85). All subjects initially received 1.25 mg/d aripiprazole with flexible dosing during the first 6 weeks (to optimize response and tolerability) up to a maximum of 15 mg/d. The dose was maintained at the optimal dose for the next 8 weeks of treatment. Outcome measures included the CGI-I and ABC. During this 14-week trial, 13 children and adolescents (mean age, 8.9 years) received aripiprazole (dose range, 2.5–15 mg; mean dose, 7.5 mg/d). Of the 13 subjects, 12 (92.3%) responded to treatment based on a CGI-I global score of “much” or “very much” improved and at least a 25% improvement on the ABC Irritability subscale. Aripiprazole was well tolerated. The mean weight gain was 1.2 kg.