Genotype influences antidepressant discontinuation in a pre-emptive pharmacogenetic testing population

We performed a retrospective cohort study to evaluate risk of antidepressant discontinuation as a function of CYP2C19 and CYP2D6 phenotype. Patients who participated in an elective genomic screening and had a diagnosis of depression or anxiety with a corresponding antidepressant were analyzed. This resulted in 5 808 patients comprising 8 571 antidepressant orders. Of the total antidepressant orders, 51% of the antidepressants ordered before pharmacogenetic testing were discontinued. A multivariate analysis - accounting for age, medication tenure, allergies, PHQ-9, malaise/fatigue, and medication indication - revealed a significant association between metabolizer status and discontinuation for CYP2C19 increased metabolizers (ultrarapid plus rapid metabolizers) compared to normal metabolizers (n = 4 635) (HR = 1.17 [1.08, 1.27], p < 0.001) for CPIC guideline-recommended medications (i.e., citalopram, escitalopram, sertraline). Stratifying risk by individual drug maintained significant associations for escitalopram (HR = 1.27 [1.1, 1.46], p < 0.05) and sertraline (HR = 1.15 [1.01, 1.31], p < 0.05). While the CYP2D6 decreased metabolizer group (intermediate plus poor metabolizers) did not reach statistical significance for guideline recommended medications (i.e., paroxetine, venlafaxine, vortioxetine), the individual effect for venlafaxine showed an increased risk of discontinuation (HR = 1.23 [1.01, 1.5], p < 0.05). These results suggest phenotypic variations may have variable impact on risk of discontinuation amongst different antidepressant medications, but for escitalopram, sertraline, and venlafaxine, the risk of discontinuation in particular phenotypes should be considered at the time of therapy initiation.