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


METHODS
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.


CONCLUSIONS
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.
Arnold
L Eugene
LE
Department of Psychiatry, Ohio State University, Columbus, Ohio, USA.
Farmer
Cristan
C
Kraemer
Helena Chmura
HC
Davies
Mark
M
Witwer
Andrea
A
Chuang
Shirley
S
DiSilvestro
Robert
R
McDougle
Christopher J
CJ
McCracken
James
J
Vitiello
Benedetto
B
Aman
Michael G
MG
Scahill
Lawrence
L
Posey
David J
DJ
Swiezy
Naomi B
NB
D000293:Adolescent; D001321:Autistic Disorder / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D054316:Biomarkers, Pharmacological / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D018849:Controlled Clinical Trials as Topic; D018492:Dopamine Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007508:Irritable Mood / Q000187:drug effects*; D008297:Male; D055118:Medication Adherence; D018967:Risperidone / Q000494:pharmacology / Q000627:therapeutic use*
D054316:Biomarkers, Pharmacological; D018492:Dopamine Antagonists; D018967:Risperidone