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To the Editor.—
The elegant trial by Turgay et al1 highlights the emerging promise of risperidone to treat behavioral disturbances in children. Although the study found that risperidone was useful and safe in children for up to 48 weeks, weight gain was reported to have occurred in 36% of subjects. Because of the lack of a control group, the authors speculate that about half of the 8.5 kg gained was due to normal growth rather than an adverse drug effect.1 These findings are of interest, because significant weight gain may lead to hyperlipidemia or diabetes. Although there were no cases of treatment-emergent diabetes reported in the study by Turgay et al,1 risperidone-associated diabetes has been reported previously in adults2,3 and a mechanism proposed.4 To our knowledge, there are no published reports of risperidone-associated diabetes in children.
We queried the Food and Drug Administration’s MedWatch Drug Surveillance System (January 1993 through February 2002) to identify adverse events of risperidone-associated diabetes in subjects 
18. Among >100 risperidone-associated diabetic adverse-event reports, we identified 12 in children (Table 1). Of the new-onset cases, diabetes occurred in 7 individuals within 6 months of risperidone initiation. Two subjects had ketoacidosis, and 2 had possible neuroleptic malignant syndrome. There was only limited information on discontinuation effects. Hyperglycemia normalized after risperidone discontinuation in 3 including 1 on a diabetic diet. Diagnoses listed for risperidone use were psychosis, schizophrenia, developmental disorder, Tourette’s syndrome, conduct disorder, autism, aggression, and anxiety disorder. These findings are similar to those we have reported previously for clozapine and olanzapine.5
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REFERENCES
Carin Binder, MBA
Department of Clinical Affairs; Janssen, Inc; Toronto, Ontario, Canada
In Reply.—
We thank the authors for their comments. The open-label trial in 77 children described by Turgay et al1 did not show any occurrence of hyperglycemia or diabetes mellitus. The children in the trial were on risperidone monotherapy or on risperidone with psychostimulants. Neither group received psychotropics other than sleep aids if needed. Fasting blood glucose was not obtained during the trial. There are two other long-term open-label trials2,3 with risperidone in this patient population. The 3 trials included a total of 688 children; only 1 case of ketonuria (severity indicated as mild) was reported in a 5-year-old boy. No action was taken, and the event resolved spontaneously during the trial. The fact that there were no adverse events related to diabetes reported in prospective studies covering 688 children for up to 1 year strengthens the lack of a causal relationship between risperidone and diabetes.
As the authors point out in their letter, MedWatch can provide signals of infrequent adverse events despite the many limitations as listed by the authors. The MedWatch database does not report type of diabetes, and it is not known whether the pediatric cases referred to were type 1 or 2 diabetes. Type 1 diabetes is an autoimmune disease and far less likely to be drug-related as well as the more common type of diabetes in children.
The emergence of diabetes mellitus in patients treated with antipsychotics involves a poorly understood and complicated mechanism that may be independent of weight gain.4 The hypothesis of glucose inhibition in cell lines5 referenced by Koller et al bears further scrutiny. Peripheral GLUT-4 transporters in muscle are insulin-regulated, whereas central nervous system GLUT-1 and -3 transporters are not. Having similar actions in both tissues by atypical antipsychotics is improbable. Animal models of homozygous GLUT-4 knockout mice do not develop diabetes but have evidence of insulin resistance. Therefore, the L6 cells would likely need to have some a priori genetic abnormality to explain the peripheral manifestations of diabetes.
In conclusion, however, we agree with Koller et al that clinicians should be vigilant with children when on any antipsychotic and institute dietary management and exercise regimens as we recommended in our original article.
FOOTNOTES
* For guidance from the Food and Drug Administration about drug labeling for atypical antipsychotics, see www.lilly.com/pdf/2003_9_17_fda_letter.pdf. 
REFERENCES
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