Metabolic drug interactions with newer antipsychotics: a comparative review

Newer antipsychotics introduced in clinical practice in recent years include clozapine, risperidone, olanzapine, quetiapine, sertindole, ziprasidone, aripiprazole and amisulpride. These agents are subject to drug-drug interactions with other psychotropic agents or with medications used in the treatment of concomitant physical illnesses. Most pharmacokinetic interactions with newer antipsychotics occur at the metabolic level and usually involve changes in the activity of the major drug-metabolizing enzymes involved in their biotransformation, i.e. the cytochrome P450 (CYP) monooxygenases and/or uridine diphosphate-glucuronosyltransferases (UGT). Clozapine is metabolized primarily by CYP1A2, with additional contribution by other CYP isoforms. Risperidone is metabolized primarily by CYP2D6 and, to a lesser extent, CYP3A4. Olanzapine undergoes both direct conjugation and CYP1A2-mediated oxidation. Quetiapine is metabolized by CYP3A4, while sertindole and aripiprazole are metabolized by CYP2D6 and CYP3A4. Ziprasidone pathways include aldehyde oxidase-mediated reduction and CYP3A4-mediated oxidation. Amisulpride is primarily excreted in the urine and undergoes relatively little metabolism. While novel antipsychotics are unlikely to interfere with the elimination of other drugs, co-administration of inhibitors or inducers of the major enzymes responsible for their metabolism may modify their plasma concentrations, leading to potentially significant effects. Most documented metabolic interactions involve antidepressant and anti-epileptic drugs. Of a particular clinical significance is the interaction between fluvoxamine, a potent CYP1A2 inhibitor, and clozapine. Differences in the interaction potential among the novel antipsychotics currently available may be predicted based on their metabolic pathways. The clinical relevance of these interactions should be interpreted in relation to the relative width of their therapeutic index. Avoidance of unnecessary polypharmacy, knowledge of the interaction profiles of individual agents, and careful individualization of dosage based on close evaluation of clinical response and, possibly, plasma drug concentrations are essential to prevent and minimize potentially adverse drug interactions in patients receiving newer antipsychotics.