Antidepressants and drug‐metabolizing enzymes — expert group report

Abstract

Antidepressant drugs are extensively metabolized. Consequently, the biotransformation pattern of antidepressants has an important influence on their clinical properties, i.e., pharmacokinetics, toxicity, drug-drug interactions, side-effect profile and last but not least therapeutic efficacy. It was against this background that a multidisciplinary group of experts discussed the clinical relevance of the rapidly increasing body of knowledge of antidepressant-metabolizing enzymes. The variability of the response of a given individual to an antidepressant is determined genetically and by the environment. Genetic polymorphism of drug-metabolizing enzymes and inhibition by other substrates may affect the enzymatic biotransformation of antidepressants. In vitro assay techniques allow an estimation of the potential variability in clinical response to antidepressants and a reasonable prediction of the drug-drug interaction patterns. The results of in vitro tests should therefore be considered early in the development of an antidepressant as a background for designing clinical studies (treatment schedules and dosing). Physicians should have an understanding of the relevance of genetic polymorphism for clinical practice. Education is needed in order to fill the existing gaps in knowledge about antidepressant-enzyme interactions and their application in daily treatment practice. The information on potential drug interactions determined by genetic polymorphism and based on studies with enzymes should be increasingly contained in drug compendia.

Polymorphism of CYP2D6, CYP2C19, CYP2C9 and CYP2C8 in the Faroese population

“…Poor metabolizer pheno-and genotype may result in very high plasma drug concentration and lead to side effects [38]. Hence, the high frequency of CYP2D6 poor metabolizers among Faroese presumably result in a respectively larger part of the population suffering from adverse effects when taking CYP2D6 substrates, especially TCA's than seen in other populations.…”

Toward a better understanding of depression: New mechanistic considerations of antidepressant action provide a basis for development of delay-free drugs

“…It has long been known that all clinically proven antidepressants, including the MAOIs, interfere with the liver enzyme cytochrome P 450 2D6 (CYP2D6) [Meyer et al, 1996]. A recent clinical study indicates that the CYP2D6 gene could be important for the development of depression.…”

Service innovations

“…Patients who are poor metabolisers might be expected to be more likely to suffer adverse drug events, whereas patients who are extensive metabolisers are theoretically less likely to achieve therapeutic plasma drug levels. These observations resulted in an expert group recommending routine CYP2D6 screening in psychiatric patients (Meyer et al, 1996). More recently, Wolf et al (2000) have echoed this view.…”