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

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...

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Autores principales: Islam, Farhana, Marshe, Victoria S., Magarbeh, Leen, Frey, Benicio N., Milev, Roumen V., Soares, Claudio N., Parikh, Sagar V., Placenza, Franca, Strother, Stephen C., Hassel, Stefanie, Taylor, Valerie H., Leri, Francesco, Blier, Pierre, Uher, Rudolf, Farzan, Faranak, Lam, Raymond W., Turecki, Gustavo, Foster, Jane A., Rotzinger, Susan, Kennedy, Sidney H., Müller, Daniel J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9448818/
https://www.ncbi.nlm.nih.gov/pubmed/36068210
http://dx.doi.org/10.1038/s41398-022-02124-4
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author Islam, Farhana
Marshe, Victoria S.
Magarbeh, Leen
Frey, Benicio N.
Milev, Roumen V.
Soares, Claudio N.
Parikh, Sagar V.
Placenza, Franca
Strother, Stephen C.
Hassel, Stefanie
Taylor, Valerie H.
Leri, Francesco
Blier, Pierre
Uher, Rudolf
Farzan, Faranak
Lam, Raymond W.
Turecki, Gustavo
Foster, Jane A.
Rotzinger, Susan
Kennedy, Sidney H.
Müller, Daniel J.
author_facet Islam, Farhana
Marshe, Victoria S.
Magarbeh, Leen
Frey, Benicio N.
Milev, Roumen V.
Soares, Claudio N.
Parikh, Sagar V.
Placenza, Franca
Strother, Stephen C.
Hassel, Stefanie
Taylor, Valerie H.
Leri, Francesco
Blier, Pierre
Uher, Rudolf
Farzan, Faranak
Lam, Raymond W.
Turecki, Gustavo
Foster, Jane A.
Rotzinger, Susan
Kennedy, Sidney H.
Müller, Daniel J.
author_sort Islam, Farhana
collection PubMed
description 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.
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spelling pubmed-94488182022-09-08 Effects of CYP2C19 and CYP2D6 gene variants on escitalopram and aripiprazole treatment outcome and serum levels: results from the CAN-BIND 1 study Islam, Farhana Marshe, Victoria S. Magarbeh, Leen Frey, Benicio N. Milev, Roumen V. Soares, Claudio N. Parikh, Sagar V. Placenza, Franca Strother, Stephen C. Hassel, Stefanie Taylor, Valerie H. Leri, Francesco Blier, Pierre Uher, Rudolf Farzan, Faranak Lam, Raymond W. Turecki, Gustavo Foster, Jane A. Rotzinger, Susan Kennedy, Sidney H. Müller, Daniel J. Transl Psychiatry Article 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. Nature Publishing Group UK 2022-09-06 /pmc/articles/PMC9448818/ /pubmed/36068210 http://dx.doi.org/10.1038/s41398-022-02124-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Islam, Farhana
Marshe, Victoria S.
Magarbeh, Leen
Frey, Benicio N.
Milev, Roumen V.
Soares, Claudio N.
Parikh, Sagar V.
Placenza, Franca
Strother, Stephen C.
Hassel, Stefanie
Taylor, Valerie H.
Leri, Francesco
Blier, Pierre
Uher, Rudolf
Farzan, Faranak
Lam, Raymond W.
Turecki, Gustavo
Foster, Jane A.
Rotzinger, Susan
Kennedy, Sidney H.
Müller, Daniel J.
Effects of CYP2C19 and CYP2D6 gene variants on escitalopram and aripiprazole treatment outcome and serum levels: results from the CAN-BIND 1 study
title Effects of CYP2C19 and CYP2D6 gene variants on escitalopram and aripiprazole treatment outcome and serum levels: results from the CAN-BIND 1 study
title_full Effects of CYP2C19 and CYP2D6 gene variants on escitalopram and aripiprazole treatment outcome and serum levels: results from the CAN-BIND 1 study
title_fullStr Effects of CYP2C19 and CYP2D6 gene variants on escitalopram and aripiprazole treatment outcome and serum levels: results from the CAN-BIND 1 study
title_full_unstemmed Effects of CYP2C19 and CYP2D6 gene variants on escitalopram and aripiprazole treatment outcome and serum levels: results from the CAN-BIND 1 study
title_short Effects of CYP2C19 and CYP2D6 gene variants on escitalopram and aripiprazole treatment outcome and serum levels: results from the CAN-BIND 1 study
title_sort effects of cyp2c19 and cyp2d6 gene variants on escitalopram and aripiprazole treatment outcome and serum levels: results from the can-bind 1 study
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9448818/
https://www.ncbi.nlm.nih.gov/pubmed/36068210
http://dx.doi.org/10.1038/s41398-022-02124-4
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