Kaplan + Sadock's Synopsis of Psychiatry, 11e

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Chapter 31: Child Psychiatry

efficacious at doses of 0.25 to 0.5 mg/kg for youth with autism spectrum disorder and ADHD symptoms. Efficacy of methyl- phenidate in this population was less effective than in children with ADHD without autism spectrum disorder, and children with autism spectrum disorder developed more frequent side effects, including increased irritability, compared to ADHD children. A study of methylphenidate in the treatment of hyper- activity and inattention in preschoolers with autism spectrum disorder found the stimulant safe and relatively efficacious; half of the preschoolers developed side effects including increased stereotypies, gastrointestinal upset, sleep problems, and emotional lability. Among nonstimulants, one double-blind placebo-controlled study of hyperactivity, impulsivity, and inattention using atomoxetine in children with autism spectrum disorder found that it was significantly more effective than pla- cebo. Side effects included sedation, irritability, constipation, and nausea. Clonidine, an a -agonist has also been studied in children with autism spectrum disorder for the treatment of hyperactivity with mixed results. Guanfacine was also found to be of use in some cases. Repetitive and Stereotypic Behavior.  These core symp­ toms of autism spectrum disorder have been studied using selective serotonin reuptake inhibitor (SSRI) antidepressants, second-generation antipsychotics (SGAs), and mood-stabiliz- ing agents such as valproate. One study with fluoxetine found the medication group only slightly better and not significantly better than the placebo group regarding the target symptoms, and another trial with escitalopram found no difference between groups. Risperidone, however, was found to be effective in tar- geting irritability, and restrictive and repetitive behaviors were improved. One recent study using valproate in a 12-week trial with 55 children with a mean age of 9½ years with autism spec- trum disorder, found that those who were considered responders with respect to irritability were also found to be spending less time engaging in repetitive behaviors. Agents Administered For Behavioral Impairment In Autism Spectrum Disorder Based On Open Trials.  Quetiapine is an antipsychotic with more potent 5-H 2 than D 2 receptor blocking properties. Although only open-label trials have been done with this agent, it is sometimes tried when ris- peridone and olanzapine are not efficacious or well tolerated. It has been used in clinical practice at doses ranging from 50 to 200 mg per day. Adverse effects include drowsiness, tachycar- dia, agitation, and weight gain. Clozapine has a heterocyclic chemical structure that is related to certain conventional antipsychotics, such as loxapine (Loxitane), although clozapine carries a lower risk of extrapy- ramidal symptoms. It is not generally used in the treatment of aggression and self-injurious behavior unless those behaviors coexist with psychotic symptoms. The most serious adverse effect is agranulocytosis, which necessitates monitoring white blood cell count weekly during clozapine use. Its use is gener- ally limited to treatment-resistant psychotic patients. Ziprasidone has receptor-blocking properties at the 5-HT 2A and D 2 receptor sites and carries little risk of extrapyramidal and antihistaminic effects. No guidelines exist for its use in autis- tic children with aggressive and self-injurious behaviors, but it has been used clinically to treat the latter behaviors in children

including aggression, temper tantrums and self-injurious behav- iors, hyperactivity, impulsivity, and inattention.

Irritability.  Two second-generation antipsychotics, risperi- done and aripiprazole, have been approved by the Food and Drug Administration (FDA) in the United States for treatment of irritability in individuals with autism spectrum disorder. Ris- peridone, a high-potency antipsychotic with combined dopa- mine (D 2 ) and serotonin (5-HT 2 ) receptor antagonist properties, has been shown to subdue aggressive or self-injurious behaviors in children with and without autism spectrum disorder. Starting with the National Institutes of Health supported Research Units on Pediatric Psychopharmacology randomized controlled trial of risperidone for treating irritability in autism spectrum disor- der in 2002, there have been seven randomized controlled tri- als, three reanalysis studies, and two add-on studies, which have converged to confirm risperidone as an efficacious pharma- cological treatment for irritability in children and adolescents with autism spectrum disorder in doses ranging from 0.5 mg to 1.5 mg. Some of the preschoolers in this study were also receiving intensive behavioral treatments. Risperidone is con- sidered the first-line of medication treatment for children and adolescents with autism spectrum disorder who exhibit severe irritability. Despite its efficacy, risperidone’s main side effects of weight gain and increased appetite; metabolic side effects such as hyperglycemia, prolactin elevation, and dyslipidemia; along with other common adverse effects such as fatigue, drowsiness, dizziness, and drooling have limited its use in some individu- als. Risperidone should be used with caution in individuals with underlying cardiac abnormalities or hypotension, since risperi- done may contribute to orthostatic hypotension. In further con- tinuation studies of risperidone in the treatment of irritability in autism spectrum disorder, persistent efficacy and tolerability were found over a 6-month period, with a rapid return of symp- toms in good responders when the risperidone was discontin- ued. Other drugs studied in the treatment of irritability in autism spectrum disorder include aripiprazole and olanzapine. Two large studies utilizing aripiprazole in the treatment of tantrums, aggression, and self-injury in children and adoles- cents with autism spectrum disorder found that aripiprazole was both efficacious and safe. Doses ranged from 5 mg to 15 mg per day. Main side effects included sedation, dizziness, insomnia, akathisia, nausea, and vomiting. Although weight gain was not as pronounced as with risperidone, it was still considered a moderate adverse event, with approximately 1.3 to 1.5 kg gained during an 8-week study period. The weight gain was similar at the lower and higher doses. Olanzapine, which specifically blocks 5-HT 2A and D 2 receptors and also blocks muscarinic receptors, has been studied in children and adolescents with autism spectrum disorder for the treatment of irritability with a trend toward a positive response; however, significant weight gain of approximately 3.5 kg occurred. The main side effect was sedation. Hyperactivity, Impulsivity, and Inattention.  Several randomized placebo-controlled trials of methylphenidate have been conducted for the treatment of hyperactivity, impulsivity, and inattention in children and adolescents with autism spec- trum disorder. The Research Units of Pediatric Psychophar- macology found methylphenidate to be at least moderately