CYP2C19 polymorphisms and outcomes of Escitalopram treatment in Brazilians with major depression

Abstract

Escitalopram (ESC), a selective serotonin reuptake inhibitor indicated for the treatment of depression and anxiety disorders, is primarily metabolized by cytochrome P450 (CYP) 2C19, which is a highly polymorphic enzyme known to cause inter-individual differences in pharmacokinetics. We hypothesized that CYP2C19 polymorphisms are associated with major depressive disorder (MDD) remission in patients treated with ESC in the long term. Thirty-one patients with MDD receiving chronic treatment with ESC monotherapy or combination therapy with other antidepressants (mirtazapine and bupropion), in naturalistic conditions, were included in the study. For comparison of genotype and phenotype frequencies, a group of 126 healthy subjects was also included. The CYP2C19∗2, CYP2C19∗3, and CYP2C19∗17 polymorphisms were analyzed by RFLP-PCR genotyping. The CYP2C19 genotypes and phenotypes were similar in patient and healthy subject groups. Four phenotypes were found in the healthy subject group: ultra-rapid (UM; 28%), extensive (EM; 52%), intermediate (IM; 17%), and poor metabolizers (PM; 3%). The patient group showed the UM (22.5%), EM (55%), and IM (22.5%) phenotypes. The UM patients had significantly higher ESC doses than both EM and IM patients (20.7 ± 4.5, 15.7 ± 3.8, and 14.0 ± 3.3 mg/day, respectively; p = 0.0041). Furthermore, all patients using ESC in combination with mirtazapine or bupropion antidepressants (ESC plus mirtazapine or bupropion) were UM metabolizers, suggesting that the ∗17 ultra-rapid allele seems to be the factor responsible for lower response to ESC, even at higher doses. The CYP2C19 UM phenotype is associated with higher ESC doses and antidepressant combinations for symptom remission in MDD patients.