Prolactin release in children treated with risperidone: impact and role of CYP2D6 metabolism

OBJECTIVE: Little is known about the role of CYP2D6 polymorphism in risperidone-induced prolactin release in children. METHOD: Twenty-five children (aged 5-15 years) with pervasive developmental disorders were genotyped for CYP2D6 polymorphisms. Serum prolactin, risperidone, and 9-hydroxyrisperidone were assessed at baseline and after 8 weeks of risperidone treatment (mean dosage, 0.06 +/- 0.03 mg/kg/d). After 24 weeks of treatment, prolactin was measured in a subsample of 15 children. Adverse effects were evaluated using a clinician-rated survey. RESULTS: Mean +/- SD prolactin levels increased from 7.8 +/- 8.0 ng/mL at baseline to 33.2 +/- 12.8 ng/mL at week 8 (P < 0.001), with a slight decrease to 28.8 +/- 13.6 ng/mL at week 24. At week 8, serum prolactin level was positively correlated with dose per kilogram (r = 0.648, P < 0.001), number of functional CYP2D6 genes (J = 2.117, P = 0.034), and serum 9-hydroxyrisperidone concentration (r = 0.664, P = 0.001) and was negatively correlated with the risperidone/9-hydroxyrisperidone ratio (r = -0.571, P = 0.004) but not with risperidone concentration (r = -0.243, P = 0.264) nor age (r = 0.072, P = 0.733). Prolactin elevation was not associated with adverse effects. CONCLUSIONS: Low-to-intermediate doses of risperidone induced a 4-fold prolactin increase in children without a clear development of tolerance up to 6 months. CYP2D6 ultrarapid metabolism may be a risk factor for more pronounced prolactin elevation.