An investigation of MEDLINE and other database resources was carried out to summarize the research conducted between 1970 and 2003 in the role of CYP2D6 genetics on SSRI dose exposure.[2] Area-under-the-concentration curve (AUC) values of 5 SSRIs in poor metabolizers, intermediate metabolizers, and extensive metabolizers as a measure of bioavailability were collected. Dose adjustments were then calculated to compensate for variability in CYP2D6 metabolizer status in white patients. On the basis of metabolizer phenotype, the following dose adjustments were extrapolated for extensive vs poor metabolizers: 33%-129% for fluvoxamine, 66%-114% for paroxetine, 56%-119% for fluoxetine (including the AUC of its active metabolite), 98%-101% for citalopram, and 99-100% for sertraline. A dose adjustment of 130% for paroxetine was extrapolated for ultrarapid metabolizers.However, the study authors concluded that dose adjustments that are based on CYP2D6 could not be recommended for SSRIs for various reasons. They noted the limited data from multiple dosing, which more accurately reflects the clinical situation; the unknown effect of saturation kinetics of some SSRIs (eg, paroxetine and fluvoxamine); and the long-term effect of inhibition of CYP2D6 by some SSRIs (eg, fluoxetine, fluvoxamine, and paroxetine) when given in chronic treatment regimens. Thus, basic human pharmacokinetic data do not strongly support routine clinical use of CYP2D6 testing.Another study scanning 1200 Web-based articles between 1966 and 2006 for treatment of major depression found no consistent association between CYP2D6 genotype and SSRI metabolism, efficacy, or risk for side effects.[3]Although 2 studies showed greater nonresponse to SSRIs among ultrarapid metabolizers relative to the general population, the data were inconsistent across other studies. The study authors concluded that there is no established association between plasma drug concentration and SSRI drug response at standard doses.Finally, a study of SSRI drug response and tolerability in 1953 patients enrolled in the Sequenced Treatment of Alternatives to Relieve Depression (STAR*D) study also showed no significant association between CYP2D6 variants and citalopram response, remission, or tolerability when comparing extensive metabolizers with poor metabolizers. However, the study design included numerous concomitant medications with unknown confounding effects.[4]The complexity derived from interaction between multiple CYP enzymes was highlighted in a study of the impact of extensive and poor metabolizer status for CYP2D6 and CYP2C19 on the SSRI citalopram. Researchers showed that the AUC for citalopram correlated with the combined CYP2D6/CYP2C19 metabolizer status.[5] For example, individuals with CYP2D6 extensive metabolizer/CYP2C19 poor metabolizer status showed significantly higher citalopram AUC compared with extensive/extensive metabolizer or poor/extensive metabolizer carriers. Because citalopram metabolism is preferentially catalyzed by CYP2C19 over CYP2D6, consideration of more than 1 genetic variant may be necessary to guide medication dosing decisions.
Pharmacogenomics of SSRIs: Clinical Implications
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