Moderators, mediators, and other predictors of risperidone response in children with autistic disorder and irritability

Abstract

Objective/background: The National Institute of Mental Health (NIMH) Research Units on Pediatric Psychopharmacology (RUPP) Autism Network found an effect size of d = 1.2 in favor of risperidone on the main outcome measure in an 8-week double-blind, placebo-controlled trial for irritability in autistic disorder. This paper explores moderators and mediators of this effect.

Method: Intention-to-treat (ITT) analyses were conducted with suspected moderators and mediators entered into the regression equations. MacArthur Foundation Network subgroup guidelines were followed in the evaluation of the results.

Results: Only baseline severity moderated treatment response: Higher severity showed greater improvement for risperidone but not for placebo. Weight gain mediated treatment response negatively: those who gained more weight improved less with risperidone and more with placebo. Compliance correlated with outcome for risperidone but not placebo. Higher dose correlated with worse outcome for placebo, but not risperidone. Of nonspecific predictors, parent education, family income, and low baseline prolactin positively predicted outcome; anxiety, bipolar symptoms, oppositional-defiant symptoms, stereotypy, and hyperactivity negatively predicted outcome. Risperidone moderated the effect of change in 5'-nucleotidase, a marker of zinc status, for which decrease was associated with improvement only with risperidone, not with placebo.

Conclusion: The benefit-risk ratio of risperidone is better with greater symptom severity. Risperidone can be individually titrated to optimal dosage for excellent response in the majority of children. Weight gain is not necessary for risperidone benefit and may even detract from it. Socioeconomic advantage, low prolactin, and absence of co-morbid problems nonspecifically predict better outcome. Mineral interactions with risperidone deserve further study.

FIG. 1.

Baseline ABC Irritability subscale score as a moderator of response to risperidone. ABC = Abberrant Behavior Checklist, PBO = placebo, RIS = risperidone, BL = baseline. Lines represent mean ABC Irritability Subscale score at each week by treatment and moderator subgroups.

FIG. 2.

Weight gain (percent of baseline kg) as mediator of response to risperidone. ABC = Aberrant Behavior Checklist. Lines represent regression of outcome on weight gain. Main effect is expected effect when weight gain is unaffected by treatment, and is drawn at the mean placebo weight gain. Observed effect is the difference between average placebo and risperidone response on the outcome measure. The two horizontal dotted ghost lines at about 4 and 15 represent mean improvement of respective treatment groups.

FIG. 3.

Relationship between optimal perceived dose (mg/day) and outcome. Horizontal dotted ghost lines at 4 and 15 represent mean improvement of respective treatment groups. Bolded lines represent the regression of ABC Irritability subscale score on the perceived dose of risperidone.

FIG. 4.

Relationship between percent compliance and outcome. Horizontal dotted ghost lines at 4 and 15 represent mean improvement of respective treatment groups. Bolded lines represent the regression of ABC Irritability subscale score on the percent of compliance with the treatment prescription.