Risperidone response

This section contains excerpted¹information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

2016 Statement from the US Food and Drug Administration (FDA): Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone.

CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to genetic polymorphism (about 6%–8% of Caucasians, and a very low percentage of Asians, have little or no activity and are "poor metabolizers") and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive² CYP 2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers.

Please review the complete therapeutic recommendations that are located here: (1).

2017 Summary of recommendations from the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP):

CYP2D6 Poor metabolizers:

No action is needed for this gene-drug interaction.

The genetic variation can result in both an increase in side effects and a stronger decrease in schizophrenia symptoms. In addition to this, the genetic variation may lead to a decrease in the required maintenance dose. However, as the effect on the dose is smaller than that of the normal biological variation, action is not useful.

CYP2D6 intermediate metabolizers:

No action is needed for this gene-drug interaction.

There is little evidence to support an increase in side effects caused by the genetic variation. The genetic variation may lead to a decrease in the required maintenance dose. However, as the effect on the dose is smaller than that of the normal biological variation, action is not useful.

CYP2D6 ultrarapid metabolizers:

No action is needed for this gene-drug interaction.

Genetic variation may lead to an increase in the required maintenance dose. However, as the effect is smaller than that of the normal biological variation, action is not useful.

Please review the complete therapeutic recommendations that are located here: (2).

¹ The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labeled all formulations containing the generic drug.

² The FDA statement uses the term “extensive metabolizer.” CPIC recently introduced standardized nomenclature for pharmacogenetic terms, which included replacing the term “extensive metabolizer” with the term “normal metabolizer.” More details can be found in the 2016 paper, “Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC)” 16. Caudle, K.E., H.M. Dunnenberger, R.R. Freimuth, J.F. Peterson, et al., Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC). Genet Med, 2016.