Evidence-Based Reviews

Are psychostimulants useful in pervasive developmental disorders?

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

Kimberly A. Stigler, MD

David J. Posey, MD

Christopher J. McDougle, MD

Evidence is mixed; nonstimulants may be more effective for managing hyperactivity and inattention

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References

1. Greenhill LL, Pliszka S, Dulcan MK, et al. Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults. J Am Acad Child Adolesc Psychiatry 2002;41(2 suppl):26S-49S.

2. Posey DJ, McDougle CJ. The pharmacotherapy of target symptoms associated with autistic disorder and other pervasive developmental disorders. Harv Rev Psychiatry 2000;8(2):45-63.

3. Jaselskis CA, Cook EH Jr, Fletcher KE, Leventhal BL. Clonidine treatment of hyperactive and impulsive children with autistic disorder. J Clin Psychopharmacol 1992;12(5):322-7.

4. Fankhauser MP, Karumanchi VC, German ML, et al. A double-blind, placebo-controlled study of the efficacy of transdermal clonidine in autism. J Clin Psychiatry 1992;53(3):77-82.

5. Posey DJ, Decker J, Sasher TM, et al. A retrospective analysis of guanfacine in the treatment of autism. J Child Adolesc.

6. Malone RP, Cater J, Sheikh RM, et al. Olanzapine versus haloperidol in children with autistic disorder: an open pilot study. J Am Acad Child Adolesc Psychiatry 2001;40(8):887-94.

7. McCracken JT, McGough J, Shah B, et al. Risperidone in children with autism and serious behavioral problems. N Engl J Med 2002;347(5):314-21.

8. Campbell M. Pharmacotherapy in early infantile autism. Biol Psychiatry 1975;10(4):399-423.

9. Aman MG. Stimulant drug effects in developmental disorders and hyperactivity—toward a resolution of disparate findings. J Autism Dev Disord 1982;12(4):385-98.

10. Campbell M, Fish B, David R, et al. Response to triiodothyronine and dextroamphetamine: a study of preschool schizophrenic children. J Autism Child Schizophr 1972;2(4):343-58.

11. Geller B, Guttmacher LB, Bleeg M. Coexistence of childhood onset pervasive developmental disorder and attention deficit disorder with hyperactivity. Am J Psychiatry 1981;138(3):388-9.

12. Campbell M, Small AM, Collins PJ, et al. Levodopa and levoamphetamine: a crossover study in young schizophrenic children. Curr Ther Res Clin Exp 1976;19(1):70-86.

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Psychostimulants benefit many patients with attention-deficit/hyperactivity disorder (ADHD)¹ and thus might seem a logical choice to manage hyperactivity and inattention in youths with a pervasive developmental disorder (PDD). Some PDD patients do respond to psychostimulant therapy, but others worsen—and side effects are common.

Youths with PDDs often exhibit maladaptive behaviors—aggression, self-injury, irritability, hyperactivity, inattention—with repetitive activity patterns and fundamentally impaired social interaction and communication.² To help you treat youths with PDD, we draw on the evidence, clinical experience, and our research to suggest psychostimulants’ role in a multimodal approach.

Targeting hyperactivity and inattentions

Step 1. Our approach begins with behavioral therapy (Figure), which includes identifying situations that trigger maladaptive behavior and environments that yield optimum behavior. The therapist assesses the child’s baseline attention and works with him or her to gradually increase it, using reinforcement and visual token boards.

Algorithm Suggested approach to hyperactivity and/or inattention in patients with PDDs

To set limits and expectations, the therapist introduces structure such as designating work and break areas and using visual schedules and timers to indicate activity duration. Minimizing distractions and understanding the child’s sensory needs may increase motivation and attention. Initially, the therapist allows numerous breaks and then may slowly decrease them as the child progresses. Tailoring work and play materials to the child’s interests can also help increase attention.

Step 2. Many patients will not respond to behavior therapy alone and will require added drug therapy. Based on evidence, we suggest starting with an alpha-2 adrenergic agonist. Guanfacine may be considered the drug of choice because of clonidine’s higher risk of adverse effects, such as hypotension and sedation. Obtain a baseline ECG with either agent, as clonidine has been associated with rare cardiovascular events.

Clonidine. Two small studies showed that clonidine may be of some benefit to patients with PDDs:

Results were mixed in a 6-week, double-blind, placebo-controlled, crossover study of clonidine (4 to 10 μg/kg/d) in 8 autistic children ages 5 to 13.³ Teacher and parent rating instruments reflected significantly improved hyperactivity, irritability, and oppositional behavior. Clinician ratings, however, showed no significant difference between clonidine and placebo. Adverse effects with clonidine included hypotension, sedation, and decreased activity.
In a 4-week, double-blind, placebo-con-trolled, crossover study of transdermal clonidine (0.16 to 0.48 mg/kg/d; mean: 3.6 μg/kg/d), clinician ratings showed significantly decreased hyperactivity, impulsivity, and anxiety in 9 autistic males ages 5 to 33. Sedation and fatigue were common adverse effects.

Guanfacine. In a recent retrospective review,⁵ we examined outcomes of 80 PDD patients ages 3 to 18 who received guanfacine (0.25 to 9 mg/d; mean: 2.6). Hyperactivity, inattention, and tics decreased in 19 patients (24%) treated for a mean 10 months.

Step 3. If clonidine or guanfacine fails to reduce hyperactivity and inattention, discontinue it and consider a psychostimulant trial.

Because psychostimulants’ efficacy in PDDs remains inconclusive, we suggest beginning with a low dosage and carefully monitoring the patient for worsening target symptoms and activation, such as emerging aggression or irritability.

Step 4. If hyperactivity and inattention remain prominent and treatment-refractory, we suggest that you discontinue the stimulant and consider an atypical antipsychotic trial. With the atypicals, monitor patients closely for adverse effects, including weight gain, extrapyramidal symptoms, and tardive dyskinesia. Fasting serum glucose and lipid profiles and liver function tests are recommended at least every 6 months and more often in individuals at risk for diabetes or hepatic disease.

Two studies provide evidence of atypicals’ efficacy in PDDs:

In a 6-week open-label comparison,⁶ olanzapine significantly reduced hyperactivity and anger or uncooperativeness in 12 children with autistic disorder, but haloperidol did not. Average weight gain was 9 lbs in patients receiving olanzapine vs 3.2 lbs in those receiving haloperidol.
An 8-week, double-blind study⁷ compared risperidone (0.5 to 3.5 mg/d; mean: 1.8) with placebo in 101 children and adolescents with autistic disorder. Response rates were 69% in the risperidone group and 12% in the control group. Risperidone reduced hyperactivity, aggression, agitation, and repetitive behavior. Adverse drug effects included weight gain (2.7 kg vs. 0.8 kg with placebo), increased appetite, and sedation.

Psychostimulant use in PDDs

Evidence is conflicting on psychostimulant use in patients with PDDs (Table). Early reviews suggested that stimulants were ineffective in PDDs and associated with adverse effects.^8,9 Some preliminary studies supported that view, but recent reports have been mixed.

Dextroamphetamine. Campbell et al¹⁰ published a placebo-controlled study comparing triiodothyronine and dextroamphetamine (mean dosage, 4.8 mg/d; range 1.25 to 10 mg/d) in 16 children ages 3 to 6 (mean, 4.3 years) with diagnoses of autism, schizophrenia, and organic brain syndrome. All diagnostic groups worsened clinically with dextroamphetamine, and adverse effects—hyperactivity, worsened stereotypy, irritability, and decreased appetite—were common.