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

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)945-954
Number of pages10
JournalEuropean Neuropsychopharmacology
Volume28
Issue number8
DOIs
StatePublished - Aug 1 2018

Fingerprint

Citalopram
Genome-Wide Association Study
Cytochromes
Antidepressive Agents
Meta-Analysis
Cytochrome P-450 Enzyme System
Pharmacogenetics
Cytochrome P-450 CYP2C19
Genome
Phenotype
Genes

Keywords

  • Antidepressant
  • CYP2C19
  • Gene
  • Major depression
  • Response
  • Side effects

ASJC Scopus subject areas

  • Pharmacology
  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Biological Psychiatry
  • Pharmacology (medical)

Cite this

Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects : Meta-analysis of data from genome-wide association studies. / Fabbri, Chiara; Tansey, Katherine E.; Perlis, Roy H.; Hauser, Joanna; Henigsberg, Neven; Maier, Wolfgang; Mors, Ole; Placentino, Anna; Rietschel, Marcella; Souery, Daniel; Breen, Gerome; Curtis, Charles; Lee, Sang Hyuk; Newhouse, Stephen; Patel, Hamel; O'Donovan, Michael; Lewis, Glyn; Jenkins, Gregory; Weinshilboum, Richard M; Farmer, Anne; Aitchison, Katherine J.; Craig, Ian; McGuffin, Peter; Schruers, Koen; Biernacka, Joanna M; Uher, Rudolf; Lewis, Cathryn M.

In: European Neuropsychopharmacology, Vol. 28, No. 8, 01.08.2018, p. 945-954.

Research output: Contribution to journalArticle

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, SH, 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, vol. 28, no. 8, pp. 945-954. https://doi.org/10.1016/j.euroneuro.2018.05.009
Fabbri, Chiara ; Tansey, Katherine E. ; Perlis, Roy H. ; Hauser, Joanna ; Henigsberg, Neven ; Maier, Wolfgang ; Mors, Ole ; Placentino, Anna ; Rietschel, Marcella ; Souery, Daniel ; Breen, Gerome ; Curtis, Charles ; Lee, Sang Hyuk ; Newhouse, Stephen ; Patel, Hamel ; O'Donovan, Michael ; Lewis, Glyn ; Jenkins, Gregory ; Weinshilboum, Richard M ; Farmer, Anne ; Aitchison, Katherine J. ; Craig, Ian ; McGuffin, Peter ; Schruers, Koen ; Biernacka, Joanna M ; Uher, Rudolf ; Lewis, Cathryn M. / Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects : Meta-analysis of data from genome-wide association studies. In: European Neuropsychopharmacology. 2018 ; Vol. 28, No. 8. pp. 945-954.
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AU - Jenkins, Gregory

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AU - Craig, Ian

AU - McGuffin, Peter

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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%).

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KW - Response

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