Risperidone is the most commonly prescribed antipsychotic medication in the US. It is an atypical (second generation) antipsychotic used in the treatment of schizophrenia, bipolar disorder, severe dementia, and irritability associated with autism.
Risperidone is metabolized to the active metabolite 9-hydroxyrisperidone by the enzyme CYP2D6 and to a lesser extent by CYP3A4. Individuals who carry two inactive copies of the CYP2D6 gene are termed “poor metabolizers” and may have a decreased capacity to metabolize risperidone. These individuals may be at a higher risk of adverse effects because of increased exposure to plasma risperidone, compared to normal metabolizers, who carry two active copies of CYP2D6. Individuals who are CYP2D6 ultrarapid metabolizers (who carry more than two functional copies of CYP2D6) may have a decreased response to therapy, resulting from lower steady-state risperidone concentrations.
The FDA-approved drug label states that analysis of clinical studies involving a modest number of poor metabolizers (n=70) does not suggest that poor and extensive (normal) metabolizers have different rates of adverse effects (1). In addition, the Dutch Pharmacogenetics Working Group (DPWG) recently changed its dosing recommendations to “no action is needed” for CYP2D6 poor metabolizers taking risperidone (2).