Psychopharmacology in Autism Spectrum Disorders

Henry W.M. Kwok


Curr Opin Psychiatry. 2003;16(5) 

In This Article

Antipsychotic Medications

Antipsychotic drugs are among the most commonly used psychopharmacological agents for the treatment of challenging behaviors in ASD. It is widely accepted that the action of conventional drugs such as haloperidol, chlorpromazine and thioridazine involve the ability to block post-synaptic dopamine (D2) receptors in the limbic system and striatum. Early studies have demonstrated haloperidol to be effective in the treatment of agitation, hyperactivity, aggression, stereotypic behaviors, motor and vocal tics, and affective lability, but less effective in correcting impairments of communication and social interaction.[7] However, these conventional drugs may have undesirable side-effects, such as dystonia[8] and tardive dyskinesia,[9] that limit their clinical use and acceptance by parents, especially when they are prescribed on a long-term basis. Review of the recent literature shows that the focus has shifted towards the second-generation antipsychotic medications, which produce a greatly reduced risk of extrapyramidal symptoms. They differ pharmacologically from the conventional drugs principally in their lower affinity for the dopamine (D2) receptors, their greater affinities for the serotonin (5-hydroxytryptamine) and norepinephrine receptors, and their ability to modulate glutamate receptor-mediated functions and behaviors,[10][11*]. A low ratio between the dopamine (D2) and 5-hydroxytryptamine-2a receptor antagonism is believed to be important to the atypical properties of these agents.[12]

Risperidone is a benzisoxazole derivative with strong antidopaminergic and antiserotonergic activities.[13] In the systematic review by Barnard et al.[14*] on the use of atypical antipsychotics in autism, the authors concluded that risperidone might be effective in reducing hyperactivity, aggression and repetitive behaviors, often without inducing severe adverse reactions.

Scahill et al.[15**] conducted a multi-site, randomized, double-blind trial of risperidone in comparison with a placebo for the treatment of autistic disorder accompanied by severe tantrums, aggression or self-injurious behavior in children aged 5-17 years. The majority of the subjects (91%) lived at home with parents and their mental age was at least 18 months. Of the 49 children treated with risperidone for 8 weeks (dose range: 0.5-3.5 mg/day), 57% showed a reduction in the 'irritability' score on the Aberrant Behaviour Checklist, as compared with a 14% decrease in the placebo group (P < 0.001). However, scores on the 'social withdrawal' subscale, which rates social isolation and interest in communicating with others, did not differ significantly between the two groups. Adverse effects, including weight gain, fatigue, drowsiness, dizziness, drooling, tremor and constipation, were more common in the risperidone group, though most were mild and self-limited.

Diler et al.[16*] reported a 6-month, open-label study of risperidone in 16 autistic children aged 3-7.5 years. The mean dose was 1.5 mg/day. Thirteen children demonstrated at least a one-grade improvement on the Clinical Global Impression-Severity of Illness scale, and scores on 11 of the 15 subscales of the Childhood Autism Rating Scale also showed significant improvement. Another open-label study by Casaer et al.[17*] on seven autistic children (mean age 7.6 years) found that total scores on the Aberrant Behaviour Checklist were significantly improved after 4 weeks of treatment with risperidone. The incidence of adverse effects was low and there were no significant abnormalities in laboratory tests, vital signs or electrocardiograms.

Two other studies[18*,19] reported favorable results from the use of risperidone in autistic children with problem behaviors including hyperactivity, irritability and aggressiveness. In the study by Boon-Yasidhi et al.,[18*] the authors reported on five cases of very young children aged 2.1-3.7 years. On the other hand, there is a case report by Raheja et al.[20] on the successful use of risperidone to treat a 30-year-old man with Asperger's syndrome. Reduction of aggressive behavior and improvement in social relations were observed.

Olanzapine, a thienobenzodiazepine derivative, is another atypical antipsychotic medication. It resembles clozapine in chemical structure and pharmacological profile[21] but does not share the risk of inducing blood dyscrasia. Positive effects of olanzapine on children, adolescents and adults with pervasive developmental disorders have been described in a previous pilot study.[22] Kemner et al.[23**] conducted a further open-label study on 23 children (aged 6-16 years) with this disorder in an outpatient setting. They found that there was significant improvement on three subscales of the Aberrant Behaviour Checklist ('irritability', 'hyperactivity' and 'excessive speech'). However, only three children were considered responders in terms of the Clinical Global Impression of Severity/Improvement scores. The most important adverse events reported were weight gain, loss of strength (asthenia) and increased appetite. Extrapyramidal symptoms were not a problem and they disappeared after the dose was lowered.

Although weight gain is one of the major drawbacks of olanzapine, it may be a self-limiting phenomenon[24] and appears to be associated with a low baseline body mass index.[25] Metabolic abnormalities are another area of current concern with regard to olanzapine treatment. Hyperglycemia,[26] new-onset diabetes[27] and elevation of serum triglyceride levels[28] have been reported. However, these findings are not exclusive to olanzapine and have been reported in patients with schizophrenia, who are known to have higher rates of diabetes even without the introduction of antipsychotic agents,[29].[30] It is not known whether these metabolic abnormalities would also occur in patients with ASD treated with olanzapine, but it is probably worthwhile to perform regular laboratory screening in these individuals.

Ziprasidone is a benzothiazolylpiperazine which is chemically unrelated to any antipsychotic drug currently in use.[31] Pharmacologically, it has remarkable 5-hydroxytryptamine-1A agonistic activity[32] and also inhibits serotonin and norepinephrine reuptake.[33] In a preliminary open-label evaluation of the safety and effectiveness of ziprasidone in 12 patients (aged 8-20 years) with autism[34*], six (50%) were considered responders after treatment for at least 6 weeks. The assessment was based on ratings on the Clinical Global Impression scale. The most common side-effect was sedation. A current concern of ziprasidone treatment is its cardiovascular effect, i.e. prolongation of the QTC interval on electrocardiograms. This preliminary study reported no chest pain, tachycardia, palpitation, dizziness or syncope.


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