Influence of CYP2D6 Genotypes and Phenotypes on the Plasma Levels and Clinical Response to Aripiprazole

The antipsychotic aripiprazole is mainly metabolized by the cytochrome P450 (CYP) 2D6. The main objective of this study was to evaluate the influence of CYP2D6 phenotypes on aripiprazole plasma levels and treatment duration.

466 patients treated with aripiprazole for up to 12 months and with at least one aripiprazole plasma level in steady-state condition were selected. CYP2D6 genotypes and phenoconversion to poor metabolizer status due to strong CYP2D6 inhibition were considered. Aripiprazole plasma level-to-dose ratios and treatment duration up to discontinuation, defined as switching to another psychotropic drug and/or stopping the follow-up, were analyzed using robust linear models and Cox regression, respectively. Akaike variable selection was applied.

CYP2D6 poor metabolizers (genetically determined n = 19 and phenoconverted, n = 52) showed higher aripiprazole concentration-to-dose (P < .001) and aripiprazole plus dehydroaripiprazole concentration-to-dose (P < .001) ratios when compared to normal metabolizers (n = 255). CYP2D6 extreme metabolizers (ie, poor and ultrarapid metabolizers) had higher risk of treatment discontinuation versus intermediate and normal metabolizers after 3, 6, and 12 months of treatment (HR: 2.08, 1.75, 1.59, respectively; P = .013, P = .019, and P = .047, respectively). For a pharmacogenetic-guided treatment, the number of patients needed to genotype to prevent 1 patient from aripiprazole discontinuation was 15.

CYP2D6 poor metabolism was associated with increased aripiprazole and aripiprazole plus dehydroaripiprazole concentrations-to-dose. CYP2D6 extreme phenotypes were associated with increased risk of treatment discontinuation over 1 year of treatment. This finding supports the applicability of pre-emptive CYP2D6 genotyping, which is expected to decrease aripiprazole adverse events and inefficacy that would probably lead to treatment discontinuation.