Effects of CYP2C19 and CYP2D6 gene variants on escitalopram and aripiprazole treatment outcome and serum levels: results from the CAN-BIND 1 study

Abstract

Cytochrome P450 drug-metabolizing enzymes may contribute to interindividual differences in antidepressant outcomes. We investigated the effects of CYP2C19 and CYP2D6 gene variants on response, tolerability, and serum concentrations. Patients (N = 178) were treated with escitalopram (ESC) from weeks 0–8 (Phase I), and at week 8, either continued ESC if they were responders or were augmented with aripiprazole (ARI) if they were non-responders (<50% reduction in Montgomery–Åsberg Depression Rating Scale from baseline) for weeks 8–16 (Phase II). Our results showed that amongst patients on ESC-Only, CYP2C19 intermediate and poor metabolizers (IM + PMs), with reduced or null enzyme function, trended towards significantly lower symptom improvement during Phase II compared to normal metabolizers (NMs), which was not observed in ESC + ARI. We further showed that CYP2D6 NMs and IM + PMs had a higher likelihood of reporting a treatment-related central nervous system side effect in ESC-Only and ESC + ARI, respectively. The differences in the findings between ESC-Only and ESC + ARI may be due to the altered pharmacokinetics of ESC by ARI coadministration in ESC + ARI. We provided evidence for this postulation when we showed that in ESC-Only, CYP2C19 and CYP2D6 IM + PMs demonstrated significantly higher ESC concentrations at Weeks 10 and 16 compared to NMs. In contrast, ESC + ARI showed an association with CYP2C19 but not with CYP2D6 metabolizer group. Instead, ESC + ARI showed an association between CYP2D6 metabolizer group and ARI metabolite-to-drug ratio suggesting potential competition between ESC and ARI for CYP2D6. Our findings suggest that dosing based on CYP2C19 and CYP2D6 genotyping could improve safety and outcome in patients on ESC monotherapy.

ABCB1 Gene Variants and Antidepressant Treatment Outcomes: A Systematic Review and Meta‐Analysis Including Results from the CAN‐BIND‐1 Study

“…A detailed description of the CAN-BIND-1 protocol, study design, inclusion, and exclusion criteria are available elsewhere. [24][25][26] Briefly, the sample consisted of 211 participants (18-61 years old) recruited at 6 clinical centers across Canada. Participants were diagnosed with MDD in a current major depressive episode according to the Diagnostic and Statistical Manual for Mental Disorders IV (DSM-IV-TR; American Psychiatric Association, 2000) using the Mini International Neuropsychiatric Interview (MINI).…”

“…Descriptive statistics for demographic and clinical characteristics by each genotype of the six ABCB1 SNPs were generated using the chi-squared test for categorical variables and the Kruskal-Wallis's rank sum test for continuous variables. Given the different treatments in phase II and different metabolizing enzymes of the administered drugs (i.e., ESC mainly metabolized by CYP2C19, and ARI mainly metabolized by CYP2D6 26 ), treatment arms were analyzed…”

“…Descriptive statistics for demographic and clinical characteristics by each genotype of the six ABCB1 SNPs were generated using the chi‐squared test for categorical variables and the Kruskal‐Wallis's rank sum test for continuous variables. Given the different treatments in phase II and different metabolizing enzymes of the administered drugs (i.e., ESC mainly metabolized by CYP2C19, and ARI mainly metabolized by CYP2D6 26 ), treatment arms were analyzed separately for phase II (ESC‐only arm and ESC + ARI arm). The false discovery rate approach 28 was used to control for multiple comparisons in the analysis of each subsample (i.e., total sample for phase I, and by treatment arms for phase II) with a significance threshold of q < 0.05.…”

“…The CAN‐BIND‐1 is a multicenter discovery study designed to identify predictors of treatment response in MDD participants (http://clinicaltrials.gov identifier: NCT01655706). A detailed description of the CAN‐BIND‐1 protocol, study design, inclusion, and exclusion criteria are available elsewhere 24–26 . Briefly, the sample consisted of 211 participants (18–61 years old) recruited at 6 clinical centers across Canada.…”

Utilizing pharmacogenetics when treating first episode psychosis

“…Nevertheless, studies of real-world utility of pharmaco genetic testing indicate that certain subgroups, such as the most severely ill 10 or those who are nonadherent to treatment, 11 may have substantially greater odds of improvement when prescribing follows pharmacogenetics-based recommend ations. Regarding antipsychotics, prescribing guidelines have been developed only for CYP2D6 2 and CYP3A4, 12 and the evidence for testing other variants 13 has not yet been deemed sufficient to make more general recommendations.…”