Malone et al conducted a 6-week, open-label comparison of olanzapine, mean 7.9 mg/d, versus haloperidol, mean 1.4 mg/d, in 12 children with autistic disorder.5 Five of six subjects who received olanzapine responded, compared with three of six who received haloperidol, as determined by a CGI classification of “much improved” or “very much improved.” Anger/uncooperativeness and hyperactivity were reduced significantly only in the olanzapine group. Weight gain and sedation were the most common adverse effects with both medications. Weight gain was greater with olanzapine (mean 9 lbs) than with haloperidol (mean 3.2 lbs).
Quetiapine. Only one report addresses quetiapine in children and adolescents with autism.6 Two of six patients completed this 16-week, open-label trial of quetiapine, 100 to 350 mg/d (1.6 to 5.2 mg/kg/d). The group showed no statistically significant improvement in behavioral symptoms. Two patients achieved CGI ratings of “much improved” or “very much improved.” One subject dropped out after a possible seizure during treatment, and three others withdrew because of sedation or lack of response.
Ziprasidone. McDougle et al conducted a naturalistic, open-label study of ziprasidone, 20 to 120 mg/d (mean 59.2 mg/d), in 12 subjects ages 8 to 20. Nine were diagnosed with autism and three with a pervasive developmental disorder not otherwise specified (NOS). Six subjects responded across 14 weeks of treatment, as determined by ratings of “much improved” or “very much improved” on the CGI.7
Transient sedation was the most common adverse effect. Mean weight change was −5.83 lbs (range −35 to +6 lbs). Despite ziprasidone’s reported risk of causing abnormal cardiac rhythms, no cardiovascular adverse effects were reported.
Clozapine. Three case reports but no controlled studies have addressed clozapine in autistic disorder:
- Zuddas et al used clozapine, 100 to 200 mg/d for 3 months, to treat three children ages 8 to 12.8 Previous trials of haloperidol were ineffective, but the patients’ aggression, hyperactivity, negativism, and language and communication skills improved with clozapine, as measured by the Children’s Psychiatric Rating Scale (CPRS) and the Self-Injurious Behavior Questionnaire.
- Chen et al used clozapine, 275 mg/d, to treat a 17-year-old male inpatient.9 Aggression was significantly reduced across 15 days, as determined by a 21-question modified version of the CPRS. Side effects included mild constipation and excessive salivation.
- Clozapine, 300 mg/d for 2 months, reduced aggression in an adult patient and was associated with progressive and marked improvement of aggression and social interaction, as measured by the CGI and the Visual Analog Scale (VAS). No agranulocytosis or extrapyramidal symptoms were observed across 5 years of therapy.10
Clozapine’s adverse effect profile probably explains why the literature contains so little data regarding its use in patients with autism. This drug’s propensity to lower the seizure threshold discourages its use in a population predisposed to seizures. Autistic patients also have a low tolerance for frequent venipuncture and limited ability to communicate agranulocytosis symptoms.
Antidepressants
Clomipramine—a tricyclic antidepressant with anti-obsessional properties—has shown some positive effects in treating autistic behaviors. Even so, this compound is prescribed infrequently to patients with autism because of low tolerability. In one recent double-blind, placebo-controlled, crossover study, 36 autistic patients ages 10 to 36 received:
- clomipramine, 100 to 150 mg/d (mean 128 mg/d)
- haloperidol, 1 to 1.5 mg/d (mean 1.3 mg/d)
or placebo for 7 weeks. Among patients who completed the trial, clomipramine and haloperidol were similarly effective in reducing overall autistic symptoms, irritability, and stereotypy. However, only 37.5% of those receiving clomipramine completed the study because of adverse effects, behavioral problems, and general lack of efficacy.11
Table
CONTROLLED EVIDENCE* FOR BEHAVIOR-BASED DRUG THERAPY OF AUTISM
| Medication | Behaviors improved | Significant adverse effects | Comments |
|---|---|---|---|
| Risperidone 2 | Aggression, irritability | Mild transient sedation | Conducted in adults |
| Risperidone 3 | Aggression, irritability | Weight gain, increased appetite, sedation, tremor, hypersalivation | Largest controlled study to date in children with autism |
| Clomipramine 11 | Irritability, stereotypy | Tachycardia, tremors, diaphoresis, insomnia, nausea | Conducted in children and adults |
| Fluvoxamine 12 | Aggression, repetitive phenomena | Nausea, sedation | No published controlled pediatric data; unpublished pediatric data unfavorable |
| Clonidine 24 | Hyperactivity, irritability, stereotypies, oppositional behavior, aggression, self-injury | Hypotension, sedation, decreased activity | Small number of subjects |
| Clonidine 25 | Impulsivity, self-stimulation, hyperarousal | Sedation and fatigue | Small number of subjects |
| Methylphenidate 28 | Hyperactivity, irritability | Social withdrawal and irritability | Adverse effects more common at 0.6 mg/kg/dose |
| • Double-blind, placebo-controlled studies | |||
Fluvoxamine. Only one double-blind, placebo-controlled study has examined the use of an SSRI in autistic disorder.12 In this 12-week trial, 30 adults with autism received fluvoxamine, mean 276.7 mg/d, or placebo. Eight of 15 subjects in the fluvoxamine group were categorized as “much improved” or “very much improved” on the CGI.
Fluvoxamine was much more effective than placebo in reducing repetitive thoughts and behavior, aggression, and maladaptive behavior. Adverse effects included minimal sedation and nausea.
Unpublished data of McDougle et al suggest that autistic children and adolescents respond less favorably than adults to fluvoxamine. In a 12-week, double-blind, placebocontrolled trial in patients ages 5 to 18, only 1 of 18 subjects responded to fluvoxamine at a mean dosage of 106.9 mg/d. Agitation, increased aggression, hyperactivity, and increased repetitive behavior were reported.