TY - JOUR
T1 - Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects
T2 - Meta-analysis of data from genome-wide association studies
AU - Fabbri, Chiara
AU - Tansey, Katherine E
AU - Perlis, Roy H
AU - Hauser, Joanna
AU - Henigsberg, Neven
AU - Maier, Wolfgang
AU - Mors, Ole
AU - Placentino, Anna
AU - Rietschel, Marcella
AU - Souery, Daniel
AU - Breen, Gerome
AU - Curtis, Charles
AU - Lee, Sang-Hyuk
AU - Newhouse, Stephen
AU - Patel, Hamel
AU - O'Donovan, Michael
AU - Lewis, Glyn
AU - Jenkins, Gregory
AU - Weinshilboum, Richard M
AU - Farmer, Anne
AU - Aitchison, Katherine J
AU - Craig, Ian
AU - McGuffin, Peter
AU - Schruers, Koen
AU - Biernacka, Joanna M
AU - Uher, Rudolf
AU - Lewis, Cathryn M
N1 - Copyright © 2018 Elsevier B.V. and ECNP. All rights reserved.
PY - 2018/8
Y1 - 2018/8
N2 - Cytochrome (CYP) P450 enzymes have a primary role in antidepressant metabolism and variants in these polymorphic genes are targets for pharmacogenetic investigation. This is the first meta-analysis to investigate how CYP2C19 polymorphisms predict citalopram/escitalopram efficacy and side effects. CYP2C19 metabolic phenotypes comprise poor metabolizers (PM), intermediate and intermediate+ metabolizers (IM; IM+), extensive and extensive+ metabolizers (EM [wild type]; EM+) and ultra-rapid metabolizers (UM) defined by the two most common CYP2C19 functional polymorphisms (rs4244285 and rs12248560) in Caucasians. These polymorphisms were genotyped or imputed from genome-wide data in four samples treated with citalopram or escitalopram (GENDEP, STAR*D, GenPod, PGRN-AMPS). Treatment efficacy was assessed by standardized percentage symptom improvement and by remission. Side effect data were available at weeks 2-4, 6 and 9 in three samples. A fixed-effects meta-analysis was performed using EM as the reference group. Analysis of 2558 patients for efficacy and 2037 patients for side effects showed that PMs had higher symptom improvement (SMD = 0.43, CI = 0.19-0.66) and higher remission rates (OR = 1.55, CI = 1.23-1.96) compared to EMs. At weeks 2-4, PMs showed higher risk of gastro-intestinal (OR = 1.26, CI = 1.08-1.47), neurological (OR = 1.28, CI = 1.07-1.53) and sexual side effects (OR = 1.52, CI = 1.23-1.87; week 6 values were similar). No difference was seen at week 9 or in total side effect burden. PMs did not have higher risk of dropout at week 4 compared to EMs. Antidepressant dose was not different among CYP2C19 groups. CYP2C19 polymorphisms may provide helpful information for guiding citalopram/escitalopram treatment, despite PMs being relatively rare among Caucasians (∼2%).
AB - Cytochrome (CYP) P450 enzymes have a primary role in antidepressant metabolism and variants in these polymorphic genes are targets for pharmacogenetic investigation. This is the first meta-analysis to investigate how CYP2C19 polymorphisms predict citalopram/escitalopram efficacy and side effects. CYP2C19 metabolic phenotypes comprise poor metabolizers (PM), intermediate and intermediate+ metabolizers (IM; IM+), extensive and extensive+ metabolizers (EM [wild type]; EM+) and ultra-rapid metabolizers (UM) defined by the two most common CYP2C19 functional polymorphisms (rs4244285 and rs12248560) in Caucasians. These polymorphisms were genotyped or imputed from genome-wide data in four samples treated with citalopram or escitalopram (GENDEP, STAR*D, GenPod, PGRN-AMPS). Treatment efficacy was assessed by standardized percentage symptom improvement and by remission. Side effect data were available at weeks 2-4, 6 and 9 in three samples. A fixed-effects meta-analysis was performed using EM as the reference group. Analysis of 2558 patients for efficacy and 2037 patients for side effects showed that PMs had higher symptom improvement (SMD = 0.43, CI = 0.19-0.66) and higher remission rates (OR = 1.55, CI = 1.23-1.96) compared to EMs. At weeks 2-4, PMs showed higher risk of gastro-intestinal (OR = 1.26, CI = 1.08-1.47), neurological (OR = 1.28, CI = 1.07-1.53) and sexual side effects (OR = 1.52, CI = 1.23-1.87; week 6 values were similar). No difference was seen at week 9 or in total side effect burden. PMs did not have higher risk of dropout at week 4 compared to EMs. Antidepressant dose was not different among CYP2C19 groups. CYP2C19 polymorphisms may provide helpful information for guiding citalopram/escitalopram treatment, despite PMs being relatively rare among Caucasians (∼2%).
U2 - 10.1016/j.euroneuro.2018.05.009
DO - 10.1016/j.euroneuro.2018.05.009
M3 - Journal article
C2 - 30135031
SN - 0924-977X
VL - 28
SP - 945
EP - 954
JO - European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
JF - European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
IS - 8
ER -