Evidence-Based Reviews

Are psychostimulants useful in pervasive developmental disorders?

Current Psychiatry. 2004 July;3(7):55-65

References

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A subsequent case report¹¹ found dex-troamphetamine effective when 2 patients ages 9 and 12 with PDD were treated with 10 and 5 mg/d, respectively. Hyperactivity, inattention, and impulsivity improved in both patients, and core PDD features did not worsen.

Levoamphetamine. In an 8-week, double-blind, crossover comparison with levodopa,¹² levoamphetamine, 3.5 to 42 mg/d (mean, 13.4), worsened symptoms in 12 children ages 3 to 12 who had schizophrenia with autistic features. stereotypy emerged or increased in 9 of the 11 patients (82%) available for follow-up, and levoamphetamine was poorly tolerated.

Methylphenidate. In an early report, methylphenidate decreased hyperactivity and impulsivity in 9 of 15 children (60%) ages 2 to 13 with infantile autism.¹³ Dosages of 5 to 10 mg/d or 0.3 to 1 mg/kg/d were given for 2 to 60 weeks (mean, 26). Adverse effects included irritability, insomnia, and anorexia.

Table

Selected reports of stimulant use in pervasive developmental disorders

Medication	Type of report	Dosage (mg/d); duration	Outcome	Adverse effects
Dextroamphetamine	Placebo-controlled¹⁰ (N=16) Case report¹¹ (N=2)	Mean 4.8; N/A Mean 7.5; N/A	Clinical worsening Improved hyperactivity,inattention,impulsivity	Hyperactivity, irritability, decreased appetite, worsened stereotypy N/A
Levoamphetamine	Double-blind¹² (N=12)	Mean 13.4	Clinical worsening	Stereotypy emerged or worsened
Methylphenidate	Retrospective¹³(N=15) Open-label¹⁴ (N=9) Case report¹⁵ (N=1) Double-blind, placebo-controlled, crossover¹⁶ (N=10) Double-blind, placebo-controlled, crossover¹⁷(N=13)	5 to 10; 26 weeks 10 to 50; 2 weeks 20; 4 weeks 20 mg/d for 2 weeks, 40 mg/d for 2 weeks 0.3 mg/kg and 0.6 mg/kg	Improved hyperactivity, impulsivity Improved hyperactivity Improved hyperactivity, concentration Modest benefit over placebo Improved hyperactivity, inattention	Irritability, insomnia, anorexia Initial mild insomnia Dysphoria, angry outbursts Statistically similar to placebo Social withdrawal, irritability
Methylphenidate, levoamphetamine, dextroamphetamine, or pemoline	Retrospective¹⁸ (N=195)	Various dosages, durations	Patients with, Asperger’s disorder were significantly more likely to respond	Agitation, dysphoria, irritability
N/A: not available

A subsequent open-label study and a case report also indicated that methylphenidate improved hyperactivity in patients with autistic disorder:

In the 2-week, open-label study,¹⁴ 9 patients ages 4 to 16 received methylphenidate, 10 to 50 mg/d. Two patients also received haloperidol, 4 and 5 mg/d. Hyperactivity improved significantly, as measured by the Conners Teacher Questionnaire.
In the case report,¹⁵ one child, age 6, was. treated with methylphenidate, 10 mg bid, for 31 days. The drug significantly alleviated hyperactivity and improved concentration. Adverse effects included dysphoria and outbursts of anger.

Box

Atomoxetine: A nonstimulant option for hyperactivity in PDD?

Atomoxetine—a nonstimulant, selective norepinephrine reuptake inhibitor—has been approved to treat hyperactivity and inattention in ADHD, but no evidence has been published on its use in PDDs. A study of desipramine¹⁹ —also a norepinephrine reuptake inhibitor—may offer some insight into the possible efficacy and tolerability of atomoxetine in PDDs.

Desipramine (mean, 127 mg/d) was compared with the serotonin reuptake inhibitor clomipramine (mean, 153 mg/d) in a 10-week, double-blind, crossover study of 24 autistic patients ages 6 to 23. The agents were equally effective and superior to placebo in decreasing hyperactivity, although desipramine was associated with increased aggression and irritability.

Despite these results with desipramine, research is needed to understand atomoxetine’s potential role in treating hyperactivity and inattention in youths with PDDs.

Controlled trials. These early reports were followed by two double-blind, placebo-controlled, crossover studies of methylphenidate in children with autistic disorder.

In the first trial,¹⁶ methylphenidate, 10 or 20 mg/d, improved irritability and hyperactivity in 10 children ages 7 to 11 but was only modestly more beneficial than placebo. Side-effect incidence—including decreased appetite, irritability, and insomnia—was similar during active and placebo treatments. Two patients required adjunctive haloperidol for prevailing behavioral problems.
In the second trial,¹⁷ 8 of 13 children (62%) ages 5 to 11 responded to methylphenidate, 0.3 and 0.6 mg/kg per dose. Hyperactivity and inattention improved significantly, as measured by a minimum 50% decrease in Conners Hyperactivity Index score. Ratings of stereotypy and inappropriate speech also decreased, but no changes were seen in the Child Autism Rating Scale. Adverse effects, which were more common with the 0.6 mg/kg dose, included social withdrawal and irritability.

Retrospective trial. Our group recently completed a retrospective study of 195 youth (mean age, 7.3 years; range, 2 to 19 years) with PDDs treated with a stimulant medication.¹⁸ As a whole, stimulants appeared ineffective.

Analysis of response by PDD subtype found that individuals with Asperger’s disorder—in contrast to those with autistic disorder or PDD not otherwise specified—were significantly more likely to respond to a stimulant medication. Gender, intelligence quotient (IQ), type of stimulant, and dosage did not significantly affect response. Adverse effects—including agitation, dysphoria, and irritability—occurred in 57.5% of the trials.

Atomoxetine. This nonstimulant medication has been approved for treating ADHD. However, research is needed to understand its use in patients with PDDs (Box)¹⁹

Summary. These mixed findings—combined with anecdotal reports from physicians describing the onset or exacerbation of hyperactivity, irritability, and aggression—indicate that much more evidence is needed regarding psychostimulant use in patients with PDDs.