Risperidone

Risperidone (Risperdal®), a psychotropic atypical antipsychotic agent, is thought to act via dopamine D₂ and serotonin (5-HT [5-hydroxytryptamine])_2A receptor antagonism. The clinical efficacy of oral risperidone in the treatment of bipolar mania and schizophrenia in adult patients is well established. In the US, risperidone is also approved for the treatment of irritability associated with autistic disorder in children and adolescents aged 5–16 years, for the treatment of schizophrenia in adolescents aged 13–17 years and, as monotherapy, for the short-term treatment of acute manic and mixed episodes associated with bipolar I disorder in children and adolescents aged 10–17 years.

Oral risperidone treatment was better than placebo treatment in reducing irritability and other behavioral symptoms associated with autistic disorder in children and adolescents in two well designed short-term trials, with these benefits maintained in those receiving risperidone for up to 6 months. The drug had a clinically manageable tolerability profile, with most adverse events being of mild to moderate intensity. There are some aspects of treatment, such as weight gain, somnolence, and hyperglycemia, that require monitoring, and the long-term safety of risperidone in children and adolescents with autistic disorder remains to be fully determined. With these issues in mind, risperidone offers a valuable emerging option for the treatment of irritability associated with autistic disorder in children and adolescents.

Although the mechanism of action of risperidone, a benzisoxazole derivative, is unknown, its pharmacodynamic effects are thought to be mediated via dopamine D₂ and serotonin 5-HT_2A receptor antagonism. Risperidone and its active metabolite 9-hydroxyrisperidone have high in vitro binding affinity for these receptors, which results in significant inhibition of both serotonin and dopamine, with the pharmacologic effects of risperidone attributed to the combined effects of risperidone plus 9-hydroxyrisperidone. The neurotransmitter binding profile of risperidone may provide the putative mechanisms for its antipsychotic effects and generally lower incidence of adverse effects relative to older antipsychotic agents.

Dosage adjustments are required in patients with moderate to severe renal impairment due to reduced clearance, and in patients with hepatic impairment due to an increase in the free fraction of the drug. Coadministration of CYP2D6 and/or CYP3A inhibitors (e.g. clozapine and fluoxetine) may interfere with the conversion of risperidone to 9-hydroxyrisperidone, whereas coadministration of inducers (e.g. carbamazepine and rifampin [rifampicin]) may decrease the combined plasma concentrations of the drug and its metabolite.

In two 8-week, randomized, double-blind trials (n = 101 and 55) in autistic children and adolescents (aged 5–17 years), patients receiving oral risperidone (mean modal dosage of 1.37–1.96 mg/day) had significantly greater improvements from baseline in irritability scores than those receiving placebo (primary endpoint). In modified intent-to-treat analyses, parent-rated mean Aberrant Behavior Checklist-Irritability Subscale (ABC-IS) scores were reduced by 56.9% and 65.0% from baseline in the risperidone groups versus a decrease of 14.1% and 34.7%, respectively, in the placebo groups. There were also significantly greater improvements from baseline for some of the other ABC subscale mean scores (Stereotypic behavior, lethargy/social withdrawal, and/or hyperactivity/noncompliance subscales) in risperidone groups than in placebo groups and a significantly higher proportion of patients in risperidone groups achieved a positive response. Other secondary endpoints also favored risperidone treatment in one or both of these short-term trials, including those for repetitive behavior and measures of relatedness and impaired communication (assessed using the parent-rated modified Ritvo-Freeman Real Life Rating Scale [RFRLRS], the validated clinician-rated Children’s Yale-Brown Obsessive Compulsive Scale [CYBOCS], and the clinician-rated Maladaptive Behavior Domain of Vineland Adaptive Behavior Scales [MBD-VABS]), scores for the conduct problem, hyperactive, and overly sensitive subscales of the parent-rated Nisonger Child Behavior Rating Form, and the score for hyperactivity on the visual analog scale for the most troublesome symptoms.

The benefits of up to 6 months’ risperidone treatment (mean modal dosage of risperidone was 1.96 mg/day), in terms of mean ABC-IS scores (no clinically relevant change) and clinician-rated Clinical Global Impression-Improvement scores (coprimary endpoints), were maintained in an open-label extension and double-blind, placebo-controlled, discontinuation trial (n = 63). Efficacy was also maintained in the longer term, according to secondary endpoints, including changes from baseline in most other mean ABC subscales, and in RFRLRS, CYBOCS, and MBD-VABS scores. In addition, patients receiving risperidone showed significant improvements in adaptive behavior for areas of communication, daily living skills, and socialization. Of note, significantly fewer patients in the risperidone-treatment group than in the placebo-treatment group relapsed during the placebo-controlled discontinuation phase; as a consequence, the discontinuation phase was stopped early.

Risperidone had a clinically manageable tolerability profile in children and adolescents with autistic disorder receiving up to 6 months’ treatment in short- and longer-term clinical trials. Most treatment-emergent adverse events were of mild to moderate intensity, with most resolving spontaneously or being effectively managed with dosage adjustments. In short-term trials, very few patients discontinued treatment due to an adverse event. In a pooled descriptive analysis of short-term clinical trials, the most common treatment-emergent adverse events (i.e. those occurring in >10% of patients receiving risperidone [n = 76] and at a rate that was at least twice that in the placebo group [n = 80]) were somnolence, increased appetite, fatigue, upper respiratory tract infection, increased saliva, constipation, dry mouth, tremor, and dystonia. The most common of these was somnolence, which was generally transient in nature.

There was a higher incidence of adverse events associated with extrapyramidal symptoms in the risperidone group than in the placebo group in a pooled analysis of short-term trials evaluating risperidone treatment. In clinical trials, tardive dyskinesia occurred in 2 of 1885 children and adolescents with autistic disorder or other psychiatric disorders receiving risperidone, with these cases resolving upon discontinuation of treatment. Risperidone treatment was associated with weight gain in short- and longer-term trials, with these increases being in excess of developmentally expected norms. There was no correlation between serum leptin levels and weight gain in 63 children and adolescents with autistic disorder receiving risperidone for up to 6 months. In double-blind trials, 49% of children and adolescents receiving risperidone had elevated serum prolactin levels compared with 2% of patients in the placebo group. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. In addition, when long-standing hyperlactinemia is associated with hypogonadism, patients of both genders may experience a decrease in bone density. In a retrospective analysis of pooled data from five clinical trials in 572 evaluable children (aged 5–15 years) with disruptive behavior disorders, there were no statistically or clinically relevant effects on growth, or the onset or progression of puberty with risperidone treatment for up to 1 year.