Genetic variation &
drug plasma levels

Escitalopram, liver enzymes, and treatment response

Cytochrome P450 (CYP) drug‐metabolizing enzymes regulate drug metabolism and may contribute to interindividual differences in antidepressant response. Here, we investigated the effects of genetic variability in CYP2C19 and CYP2D6 on response, tolerability, and serum concentrations in 178 individuals treated with escitalopram (ESC) from weeks 0-8 (Phase I), who at week 8, either continued on ESC if they were responders or were augmented with ARI if they were non-responders for another eight weeks (Phase II).

Results show that CYP2C19 non-NMs demonstrated 2.00% (95% CI: -3.62 to -0.37) lower symptom improvement during Phase II relative to NMs in ESC-Only, which was not observed in ESC+ARI participants. We provided evidence that this may be due to the altered pharmacokinetics of ESC with ARI co-administration, both of which compete for CYP2D6. In ESC-Only, CYP2C19 and CYP2D6 non-NMs demonstrated higher ESC concentrations at Weeks 10 and 16 compared to NMs, while ESC+ARI showed an association with only CYP2C19, but not with CYP2D6 metaboliser groups.

Instead, there was an association between CYP2D6 metaboliser groups and DHA/ARI ratio in ESC+ARI. This may be because, the competition for CYP2D6 by both ESC and ARI shifts the metabolism of ESC to be more dependent on CYP2C19, and the metabolism of ARI to be more dependent on CYP2D6 in the latter treatment arm. Our findings indicate that medication selection and dosing based on CYP2C19 genotyping could be useful to improve safety and outcome in patients on ESC monotherapy or with ARI augmentation.