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 - Funding Information:
N Henigsberg participated in clinical trials sponsored by pharmaceutical companies including GlaxoSmithKline and Lundbeck. D Souery is serving in national advisory boards or consulting for Janssen, TEVA, Glaxo Smith Kline. His center is receiving unrestricted financial support from Lundbeck and Fondation René de Spoellberghe. W Maier, KJ Aitchison, AE Farmer and P McGuffin have received consultancy fees and honoraria for participating in expert panels from pharmaceutical companies including Lundbeck and GlaxoSmithKline and Roche Diagnostics. Dr Perlis reported serving on scientific advisory boards or consulting for Genomind LLC, Healthrageous, Pfizer, Perfect Health, Proteus Biomedical, PsyBrain Inc, and RID Ventures LLC and reported receiving royalties through Massachusetts General Hospital from Concordant Rater Systems (now Bracket/Medco). N Perroud received honoraria for participating in expert panels from pharmaceutical companies including Lundbeck. G Bondolfi is a member of a national advisory board for Bristol–Myer Squibb and Pfizer and has received research funding from GlaxoSmithKline, Wyeth–Lederle, Bristol–Myers Squibb and Sanofi Aventis. M O'Donovan's department received £2000 in lieu of an honorarium to M O'Donovan from Lilly as a result of his participation in sponsored symposia in 2012. Those symposia were unrelated to the contents of this manuscript. The other authors declare no conflict of interest.
Funding Information:
The NEWMEDS study was funded by the Innovative Medicine Initiative Joint Undertaking (IMI-JU) under grant agreement n° 115008 of which resources are composed of European Union and the European Federation of Pharmaceutical Industries and Associations (EFPIA) in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (FP7/2007–2013). EFPIA members Pfizer, Glaxo Smith Kline, and F. Hoffmann La-Roche have contributed work and samples to the project presented here. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Funding Information:
The PGRN-AMPS dataset used for the analyses described in this manuscript was obtained from dbGaP (study accession phs000670.v1.p1). PGRN-AMPS was supported, in part, by NIH grants RO1 GM28157, U19 GM61388 (The Pharmacogenomics Research Network), U01 HG005137, R01 CA138461, P20 1P20AA017830-01 (The Mayo Clinic Center for Individualized Treatment of Alcohol Dependence), and a PhRMA Foundation Center of Excellence in Clinical Pharmacology Award.
Funding Information:
The GENDEP project was supported by a European Commission Framework 6 grant (contract reference: LSHB-CT-2003-503428). The Medical Research Council, United Kingdom, and GlaxoSmithKline (G0701420) provided support for genotyping.
Funding Information:
We thank the NIMH for providing access to data on the STAR-D sample. We also thank the authors of previous publications in this dataset, and foremost, we thank the patients and their families who agreed to be enrolled in the study. Data and biomaterials were obtained from the limited access datasets distributed from the NIH-supported ‘‘Sequenced Treatment Alternatives to Relieve Depression’’ (STAR*D). The study was supported by NIMH Contract No. N01MH90003 to the University of Texas Southwestern Medical Center. The ClinicalTrials.gov identifier is NCT00021528 .
Funding Information:
Dr Rudolf Uher is supported by the Canada Research Chairs Program.
Funding Information:
The GENDEP project was supported by a European Commission Framework 6 grant (contract reference: LSHB-CT-2003-503428). The Medical Research Council, United Kingdom, and GlaxoSmithKline (G0701420) provided support for genotyping.
Publisher Copyright:
© 2018 Elsevier B.V. and ECNP
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%).
KW - Antidepressant
KW - CYP2C19
KW - Gene
KW - Major depression
KW - Response
KW - Side effects
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U2 - 10.1016/j.euroneuro.2018.05.009
DO - 10.1016/j.euroneuro.2018.05.009
M3 - Article
C2 - 30135031
AN - SCOPUS:85049099531
SN - 0924-977X
VL - 28
SP - 945
EP - 954
JO - European Neuropsychopharmacology
JF - European Neuropsychopharmacology
IS - 8
ER -