TY - JOUR
T1 - Genetic differences in cytochrome P450 enzymes and antidepressant treatment response
AU - Hodgson, Karen
AU - Tansey, Katherine
AU - Dernovšek, Mojca Zvezdana
AU - Hauser, Joanna
AU - Henigsberg, Neven
AU - Maier, Wolfgang
AU - Mors, Ole
AU - Placentino, Anna
AU - Rietschel, Marcella
AU - Souery, Daniel
AU - Smith, Rebecca
AU - Craig, Ian W.
AU - Farmer, Anne E.
AU - Aitchison, Katherine J.
AU - Belsy, Sarah
AU - Davis, Oliver S P
AU - Uher, Rudolf
AU - McGuffin, Peter
PY - 2014/2/1
Y1 - 2014/2/1
N2 - Aims: Antidepressant response varies between patients, possibly due to differences in the rate cytochrome P450 enzymes metabolise antidepressants into inactive compounds. Drug metabolism rates are influenced by common variants in the genes encoding these enzymes. However, it remains unclear whether treatment outcomes can be predicted by either CYP450 genotype or antidepressant serum concentration. Methods: In GENDEP (a pharmacogenetic study of depressed individuals treated with either escitalopram or nortriptyline), serum concentrations of antidepressants and their primary metabolite were measured after eight weeks treatment and variants in CYP2D6 and CYP2C19 were genotyped. Results: Amongst patients taking escitalopram (n=223), the genotype CYP2C19 was significantly associated with escitalopram serum concentrations and desmethylescitalopram:escitalopram ratio. For those taking nortriptyline (n=161), the CYP2D6 genotype was significantly associated with nortriptyline and 10-hydroxynortriptyline serum concentrations and 10-hydroxynortriptyline: nortriptyline ratio. CYP450 genotypes conferring greater enzyme activity were linked to lower drug serum concentrations and higher metabolite:drug ratios. Nonetheless, no significant association was found between either CYP450 genotype or antidepressant serum concentration and treatment response. Conclusions: While there is a significant relationship between the CYP450 genotype and serum concentrations of escitalopram and nortriptyline, the genotypes are not predictive of differences in treatment response for either drug. Furthermore, differences in antidepressant serum concentrations are not associated with variability in treatment response.
AB - Aims: Antidepressant response varies between patients, possibly due to differences in the rate cytochrome P450 enzymes metabolise antidepressants into inactive compounds. Drug metabolism rates are influenced by common variants in the genes encoding these enzymes. However, it remains unclear whether treatment outcomes can be predicted by either CYP450 genotype or antidepressant serum concentration. Methods: In GENDEP (a pharmacogenetic study of depressed individuals treated with either escitalopram or nortriptyline), serum concentrations of antidepressants and their primary metabolite were measured after eight weeks treatment and variants in CYP2D6 and CYP2C19 were genotyped. Results: Amongst patients taking escitalopram (n=223), the genotype CYP2C19 was significantly associated with escitalopram serum concentrations and desmethylescitalopram:escitalopram ratio. For those taking nortriptyline (n=161), the CYP2D6 genotype was significantly associated with nortriptyline and 10-hydroxynortriptyline serum concentrations and 10-hydroxynortriptyline: nortriptyline ratio. CYP450 genotypes conferring greater enzyme activity were linked to lower drug serum concentrations and higher metabolite:drug ratios. Nonetheless, no significant association was found between either CYP450 genotype or antidepressant serum concentration and treatment response. Conclusions: While there is a significant relationship between the CYP450 genotype and serum concentrations of escitalopram and nortriptyline, the genotypes are not predictive of differences in treatment response for either drug. Furthermore, differences in antidepressant serum concentrations are not associated with variability in treatment response.
KW - Antidepressant
KW - cytochrome P450 enzymes
KW - depression
KW - drug metabolism
KW - pharmacogenetics
UR - http://www.scopus.com/inward/record.url?scp=84892908817&partnerID=8YFLogxK
U2 - 10.1177/0269881113512041
DO - 10.1177/0269881113512041
M3 - Article (Academic Journal)
C2 - 24257813
AN - SCOPUS:84892908817
VL - 28
SP - 133
EP - 141
JO - Journal of Psychopharmacology
JF - Journal of Psychopharmacology
SN - 0269-8811
IS - 2
ER -