Risperidone-Associated Diabetes Mellitus in Children
Elizabeth A. Koller, MDJames T. Cross, MS
Bruce Schneider, MD
Division of Metabolic and Endocrine Drug Products; Center for Drug Evaluation and Review; Food and Drug Administration; Rockville, MD 20857, USA
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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The limitations of spontaneous adverse-event reports include incomplete reporting, lack of control groups, confounding by concomitant medications or diagnoses, inability to assess causality, and detection or reporting biases. Also, MedWatch cannot estimate incidence for this type of event, because the degree of underreporting is not known. The fact that there were no diabetes adverse events reported in the prospective 1-year study by Turgay et al1 argues against a causal association. However, MedWatch can provide signals of infrequent adverse events that may not be apparent in small samples selected for clinical trials. The benefits of atypical antipsychotic drugs for the treatment of specific behavioral problems in children are increasingly evident.1,6 However, because these drugs are not yet indicated for such use in children, awareness of potential adverse effects may help avoid unnecessary harm. Atypical antipsychotic drugs will likely be prescribed to millions of children over the coming decades. To date, the 77-patient open study by Turgay et al1 represents one of the longest published studies of an atypical antipsychotic in children. Until additional prospective studies are conducted, clinicians should be vigilant and monitor their patients appropriately.*
REFERENCES
- Turgay A, Binder C, Snyder R, Fisman S. Long-term safety and efficacy of risperidone for the treatment of disruptive behavior disorders in children with subaverage IQs. Pediatrics.2002; 110(3) . Available at: www.pediatrics.org/cgi/content/full/110/3/e34
- Croarkin PE, Jacobs KM, Bain BK. Diabetic ketoacidosis associated with risperidone treatment?
Psychosomatics.2000; 41
:369
–370
[Free Full Text] - Mallya A, Chawla P, Boyer SK, DeRosear L. Resolution of hyperglycemia on risperidone discontinuation. J Clin Psychiatry.2002; 63 :453 –454[Web of Science][Medline]
- Ardizzone TD, Bradley RJ, Freeman AM 3rd, Dwyer DS. Inhibition of glucose transport in PC12 cells by the atypical antipsychotic drugs risperidone and clozapine, and structural analogs of clozapine. Brain Res.2001; 923 :82 –90[CrossRef][Web of Science][Medline]
- Koller E, Mazalowski S, Doraiswamy PM. Atypical antipsychotics and hyperglycemia in adolescents.
JAMA.2001; 286
:2547
–2548
[Free Full Text] - McCracken JT, McGough J, Shah B, et al. Risperidone in children with autism and serious behavioral problems.
N Engl J Med.2002; 347
:314
–321
[Abstract/Free Full Text]
Atilla Turgay, MD
University of Toronto and; the Scarborough Hospital; Toronto, Ontario, Canada
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
- Turgay A, Binder C, Snyder R, Fisman S. Long-term safety and efficacy of risperidone for the treatment of disruptive behavior disorders in children with subaverage IQs. Pediatrics.2002; 110(3) . Available at: www.pediatrics.org/cgi/content/full/110/3/e34
- Findling RL, Aman M, De Smedt G, Derivan A. Long-term safety and efficacy of risperidone in children with significant conduct problems and borderline IQ or mental retardation. Postered at Association of Emergency Room Physicians, 2002
- Fegert J, Findling RL, De Smedt G. Interim results from a multicenter study of the long-term safety and efficacy of risperidone in children and adolescents with severe disruptive behaviors and subaverage IQ. Postered at Society for Biological Psychiatry; 2002
- Jin H, Meyer JM, Jeste DV. Phenomenology of and risk factors for new-onset diabetes mellitus and diabetic ketoacidosis associated with atypical antipsychotics: An analysis of 45 published cases. Ann Clin Psychiatry.2002; 14 :59 –64[CrossRef][Medline]
- Ardizzone TD, Bradley RJ, Freeman AM 3rd, Dwyer DS. Inhibition of glucose transport in PC12 cells by the atypical antipsychotic drugs risperidone and clozapine, and structural analogs of clozapine. Brain Res.2001; 923 :82 –90
PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics
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