CYP2D6 Metabolizer Phenotype Is Associated with Early Antidepressant Discontinuation in the UK Biobank

Background/Objectives: Antidepressant treatment response is highly variable, and CYP2D6 metabolizer phenotype has been proposed as a contributor to this variability. It was examined whether CYP2D6 metabolizer phenotype is associated with real-world antidepressant treatment outcomes in a large population-based cohort. Methods: Using genetic and longitudinal primary care prescription data from the UK Biobank, we evaluated associations between CYP2D6 metabolizer phenotype and prescription-based proxies of treatment outcomes, including discontinuation, switching, and side effects. Analyses were stratified by antidepressant and adjusted for demographic covariates. Results: Among 26,957 individuals of European ancestry prescribed CYP2D6-metabolized antidepressants, reduced metabolic capacity was significantly associated with early discontinuation of paroxetine (N = 5718), venlafaxine (N = 2327), and mirtazapine (N = 3340). For paroxetine, poor metabolizers had higher odds of discontinuation compared with normal metabolizers and, among discontinuers, were more likely to stop immediately rather than later. Similar early discontinuation signals were observed for venlafaxine, with intermediate metabolizers showing increased risk. Mirtazapine also demonstrated increased odds of early discontinuation among poor metabolizers. No significant association was observed for fluoxetine. Associations with switching were limited, and no significant associations were detected for side effects. Conclusions: CYP2D6 variation appears to primarily influence early antidepressant discontinuation within the first 30 days of treatment, particularly for paroxetine, venlafaxine, and mirtazapine, rather than treatment switching or side effects. These findings provide observational support relevant to drug-specific gene interactions and suggest a role for CYP2D6-guided prescribing in clinical practice, notably in the first 30 days of antidepressant treatment.