Antidepressant treatment and altered CYP2D6 activity: are pharmacokinetic variations clinically relevant?

摘要

BACKGROUND: Many currently used antidepressants are substrates of the cytochrome P450 (CYP) 2D6 enzyme. In patients who experience variations in the activity of this enzyme (e.g., CYP2D6 poor and ultrarapid metabolizers [PMs and UMs]), whether caused by genetic polymorphisms or concomitant administration of a CYP2D6 inhibitor (i.e., phenoconversion), the pharmacokinetics, and hence the effects, of CYP2D6 substrate antidepressants can be altered. METHODS: This literature review describes the clinical and empirical evidence indicating that alterations in CYP2D6 activity can negatively affect treatment outcomes in patients receiving antidepressant pharmacotherapies that are CYP2D6 substrates. RESULTS: Based on results from a small, prospective trial, a population analysis, and a pooled analysis, CYP2D6 PMs treated with agents dependent on CYP2D6 metabolism to form an active metabolite can experience a decline in antidepressant effect. Based on a population analysis and two case studies, CYP2D6 UMs treated with antidepressants that are CYP2D6 substrates and administered in a pharmacologically active form do not experience an antidepressant effect due to the agent being too rapidly eliminated from the body. Conversely, based on prospective trials, population analyses, and case studies, phenotypic and phenoconverted CYP2D6 PMs can experience an increase in concentration-dependent adverse events due to the agent being eliminated too slowly from the body. CONCLUSIONS: Despite these examples, few large-scale, prospective trials exploring the effect of altered CYP2D6 metabolism on antidepressant outcomes have been conducted. Future clinical trials of CYP2D6-dependent antidepressants should be designed to allow for stratification of treatment outcomes by CYP2D6 metabolizer status.