Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects: Meta-analysis of data from genome-wide association studies

Chiara Fabbri; Katherine E. Tansey; Roy H. Perlis; Joanna Hauser; Neven Henigsberg; Wolfgang Maier; Ole Mors; Anna Placentino; Marcella Rietschel; Daniel Souery; Gerome Breen; Charles Curtis; Sang-Hyuk Lee; Stephen Newhouse; Hamel Patel; Michael O'Donovan; Glyn Lewis; Gregory Jenkins; Richard M. Weinshilboum; Anne Farmer; Katherine J. Aitchison; Ian Craig; Peter McGuffin; Koen Schruers; Joanna M. Biernacka; Rudolf Uher; Cathryn M. Lewis

doi:10.1016/j.euroneuro.2018.05.009

Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects: Meta-analysis of data from genome-wide association studies

Chiara Fabbri, Katherine E. Tansey, Roy H. Perlis, Joanna Hauser, Neven Henigsberg, Wolfgang Maier, Ole Mors, Anna Placentino, Marcella Rietschel, Daniel Souery, Gerome Breen, Charles Curtis, Sang-Hyuk Lee, Stephen Newhouse, Hamel Patel, Michael O'Donovan, Glyn Lewis, Gregory Jenkins, Richard M. Weinshilboum, Anne FarmerKatherine J. Aitchison, Ian Craig, Peter McGuffin, Koen Schruers, Joanna M. Biernacka, Rudolf Uher, Cathryn M. Lewis

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Abstract

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%).

Original language	English
Journal	European Neuropsychopharmacology
Early online date	28 Jun 2018
DOIs	https://doi.org/10.1016/j.euroneuro.2018.05.009
Publication status	E-pub ahead of print - 28 Jun 2018

Keywords

CYP2C19
Gene
Antidepressant
Response
Side effects
Major depression

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10.1016/j.euroneuro.2018.05.009

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Fabbri, C., Tansey, K. E., Perlis, R. H., Hauser, J., Henigsberg, N., Maier, W., Mors, O., Placentino, A., Rietschel, M., Souery, D., Breen, G., Curtis, C., Lee, S.-H., Newhouse, S., Patel, H., O'Donovan, M., Lewis, G., Jenkins, G., Weinshilboum, R. M., ... Lewis, C. M. (2018). Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects: Meta-analysis of data from genome-wide association studies. European Neuropsychopharmacology. Advance online publication. https://doi.org/10.1016/j.euroneuro.2018.05.009

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title = "Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects: Meta-analysis of data from genome-wide association studies",

abstract = "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%).",

keywords = "CYP2C19, Gene, Antidepressant, Response, Side effects, Major depression",

author = "Chiara Fabbri and Tansey, {Katherine E.} and Perlis, {Roy H.} and Joanna Hauser and Neven Henigsberg and Wolfgang Maier and Ole Mors and Anna Placentino and Marcella Rietschel and Daniel Souery and Gerome Breen and Charles Curtis and Sang-Hyuk Lee and Stephen Newhouse and Hamel Patel and Michael O'Donovan and Glyn Lewis and Gregory Jenkins and Weinshilboum, {Richard M.} and Anne Farmer and Aitchison, {Katherine J.} and Ian Craig and Peter McGuffin and Koen Schruers and Biernacka, {Joanna M.} and Rudolf Uher and Lewis, {Cathryn M.}",

year = "2018",

month = jun,

day = "28",

doi = "10.1016/j.euroneuro.2018.05.009",

language = "English",

journal = "European Neuropsychopharmacology",

issn = "0924-977X",

publisher = "Elsevier",

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Fabbri, C, Tansey, KE, Perlis, RH, Hauser, J, Henigsberg, N, Maier, W, Mors, O, Placentino, A, Rietschel, M, Souery, D, Breen, G , Curtis, C , Lee, S-H , Newhouse, S , Patel, H, O'Donovan, M, Lewis, G, Jenkins, G, Weinshilboum, RM, Farmer, A, Aitchison, KJ, Craig, I , McGuffin, P, Schruers, K, Biernacka, JM, Uher, R & Lewis, CM 2018, 'Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects: Meta-analysis of data from genome-wide association studies', European Neuropsychopharmacology. https://doi.org/10.1016/j.euroneuro.2018.05.009

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.

PY - 2018/6/28

Y1 - 2018/6/28

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 - CYP2C19

KW - Gene

KW - Antidepressant

KW - Response

KW - Side effects

KW - Major depression

UR - http://www.scopus.com/inward/record.url?scp=85049099531&partnerID=8YFLogxK

U2 - 10.1016/j.euroneuro.2018.05.009

DO - 10.1016/j.euroneuro.2018.05.009

M3 - Article

SN - 0924-977X

JO - European Neuropsychopharmacology

JF - European Neuropsychopharmacology

ER -

Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects: Meta-analysis of data from genome-wide association studies

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Keywords

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