Abstract
Cytochrome P450 CYP2D6 represents an extensively characterized polymorphic drug-metabolizing enzyme. The CYP2D6-gene is highly polymorphic and more than 70 different alleles are known currently. The activity of the enzyme markedly varies among individuals from poor to intermediate and extensive up to ultrarapid metabolism on the basis of the polymorphism of the CYP2D6 gene. Association studies provide growing evidence for the clinical importance of the CYP2D6 polymorphism investigating whether the CYP2D6 genotype distribution differs from that of the normal population either in patients with marked adverse effects or in nonresponders during treatment with CYP2D6 substrates. However, these scientifically important studies present less information for dose adjustments necessary to individualize pharmacotherapy in a given clinical case. With respect to psychopharmacological drug metabolism several antidepressants were characterized as being CYP2D6 substrates. Thus, this review summarizes dose recommendations of current antidepressants.
Similar content being viewed by others
References
Alexanderson B, Bertilsson L, Borga O, Sjoqvist F (1971) Studies on the metabolism and pharamcokinetics of nortriptyline and desmethylimipramine in man. Chem Biol Interact 3:235–236
Amsterdam JD, Fawcett J, Quitkin FM, Reimherr FW, Rosenbaum JF, Michelson D, Hornig-Rohan M, Beasley CM (1997) Fluoxetine and norfluoxetine plasma concentrations in major depression: a multicenter study. Am J Psychiatry 154:963–969
Balant-Gorgia AE, Schulz P, Dayer P, Balant L, Kubli A, Gertsch C, Garrone G (1982) Role of oxidation polymorphism on blood and urine concentrations of amitriptyline and its metabolites in man. Arch Psychiatr Nervenkr 232:215–222
Barbhaiya RH, Buch AB, Greene DS (1996) Single and multiple dose pharmacokinetics of nefazodone in subjects classified as extensive and poor metabolizers of dextromethorphan. Br J Clin Pharmacol 42:573–581
Baumann P, Jonzier-Perey M, Koeb L, Kupfer A, Tinguely D, Schopf J (1986) Amitriptyline pharmacokinetics and clinical response: II. Metabolic polymorphism assessed by hydroxylation of debrisoquine and mephenytoin. Int Clin Psychopharmacol 1:102–112
Bertilsson L, Aberg-Wistedt A, Gustafsson LL, Nordin C (1985) Extremely rapid hydroxylation of debrisoquine: a case report with implication for treatment with nortriptyline and other tricyclic antidepressants. Ther Drug Monit 7:478–480
Bertilsson L, Dahl ML, Sjoqvist F, Aberg-Wistedt A, Humble M, Johansson I, Lundqvist E, Ingelman-Sundberg M (1993) Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine. Lancet 341:63
Bertilsson L, Mellstrom B, Sjoqvist F (1979) Pronounced inhibition of noradrenaline uptake by 10-hydroxymetabolites of nortriptyline. Life Sci 25:1285–1292
Bertschy G, Vandel S, Francois T, Bonin B, Bouquet S, Baumann P, Volmat R, Sechter D, Bizouard P (1992) Metabolic interaction between tricyclic antidepressant and fluvoxamine and fluoxetine, a pharmacogenetic approach. Clin Neuropharmacol 15 Suppl 1 Pt A:78A-79A
Bertschy G, Vandel S, Vandel B, Allers G, Volmat R (1991) Fluvoxamine-tricyclic antidepressant interaction. An accidental finding. Eur J Clin Pharmacol 40:119–120
Bolaji OO, Coutts RT, Baker GB (1993) Metabolism of trimipramine in vitro by human CYP2D6 isozyme. Res Commun Chem Pathol Pharmacol 82:111–120
Breyer-Pfaff U, Kroeker M, Winkler T, Kriemler P (1985) Isolation and identification of hydroxylated maprotiline metabolites. Xenobiotica 15:57–66
Breyer-Pfaff U, Pfandl B, Nill K, Nusser E, Monney C, Jonzier-Perey M, Baettig D, Baumann P (1992) Enantioselective amitriptyline metabolism in patients phenotyped for two cytochrome P450 isozymes. Clin Pharmacol Ther 52:350–358
Brosen K, Skjelbo E (1991) Fluoxetine and norfluoxetine are potent inhibitors of P450IID6—the source of the sparteine/debrisoquine oxidation polymorphism. Br J Clin Pharmacol 32:136–137
Carrillo JA, Dahl ML, Svensson JO, Alm C, Rodriguez I, Bertilsson L (1996) Disposition of fluvoxamine in humans is determined by the polymorphic CYP2D6 and also by the CYP1A2 activity. Clin Pharmacol Ther 60:183–190
Dahl ML, Bertilsson L, Nordin C (1996) Steady-state plasma levels of nortriptyline and its 10-hydroxy metabolite: relationship to the CYP2D6 genotype. Psychopharmacology (Berl) 123:315–319
Dahl ML, Johansson I, Palmertz MP, Ingelman-Sundberg M, Sjoqvist F (1992) Analysis of the CYP2D6 gene in relation to debrisoquin and desipramine hydroxylation in a Swedish population. Clin Pharmacol Ther 51:12–17
Dahl ML, Tybring G, Elwin CE, Alm C, Andreasson K, Gyllenpalm M, Bertilsson L (1994) Stereoselective disposition of mianserin is related to debrisoquin hydroxylation polymorphism. Clin Pharmacol Ther 56:176–183
Dahl ML, Voortman G, Alm C, Elwin CE, Delbressine L, Vos R, Bogaards JJP, Bertilsson L (1997) In vitro and in vivo studies on the disposition of mirtazapine in humans. Clin Drug Invest 13:37–46
Dalen P, Dahl ML, Ruiz ML, Nordin J, Bertilsson L (1998) 10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes. Clin Pharmacol Ther 63:444–452
Danish University Antidepressant Group (DUAG) (1999) Clomipramine dose-effect study in patients with depression: clinical end points and pharmacokinetics. Clin Pharmacol Ther 66:152–165
Dessain EC, Schatzberg AF, Woods BT, Cole JO (1986) Maprotiline treatment in depression. A perspective on seizures. Arch Gen Psychiatry 43:86–90
Eap CB, Bender S, Gastpar M, Fischer W, Haarmann C, Powell K, Jonzier-Perey M, Cochard N, Baumann P (2000) Steady state plasma levels of the enantiomers of trimipramine and of its metabolites in CYP2D6-, CYP. Ther Drug Monit 22:209–214
Eap CB, Koeb L, Holsboer-Trachsler E, Baumann P (1992) Plasma levels of trimipramine and metabolites in four patients: determination of the enantiomer concentrations of the hydroxy metabolites. Ther Drug Monit 14:380–385
Eap CB, Laurian S, Souche A, Koeb L, Reymond P, Buclin T, Baumann P (1992) Influence of quinidine on the pharmacokinetics of trimipramine and on its effect on the waking EEG of healthy volunteers. A pilot study on two subjects. Neuropsychobiology 25:214–220
Eap CB, Lima CA, Macciardi F, Woggon B, Powell K, Baumann P (1998) Steady state concentrations of the enantiomers of mianserin and desmethylmianserin in poor and in homozygous and heterozygous extensive metabolizers of debrisoquine. Ther Drug Monit 20:7–13
Firkusny L, Gleiter CH (1994) Maprotiline metabolism appears to co-segregate with the genetically-determined CYP2D6 polymorphic hydroxylation of debrisoquine. Br J Clin Pharmacol 37:383–388
Fjordside L, Jeppesen U, Eap CB, Powell K, Baumann P, Brosen K (1999) The stereoselective metabolism of fluoxetine in poor and extensive metabolizers of sparteine. Pharmacogenetics 9:55–60
Fukuda T, Yamamoto I, Nishida Y, Zhou Q, Ohno M, Takada K, Azuma J (1999) Effect of the CYP2D6*10 genotype on venlafaxine pharmacokinetics in healthy adult volunteers. Br J Clin Pharmacol 47:450–453
Fuller RW, Snoddy HD, Krushinski JH, Robertson DW (1992) Comparison of norfluoxetine enantiomers as serotonin uptake inhibitors in vivo. Neuropharmacology 31:997–1000
Haddock RE, Johnson AM, Langley PF, Nelson DR, Pope JA, Thomas DR, Woods FR (1989) Metabolic pathway of paroxetine in animals and man and the comparative pharmacological properties of its metabolites. Acta Psychiatr Scand Suppl 350:24–26
Hamelin BA, Turgeon J, Vallee F, Belanger PM, Paquet F, LeBel M (1996) The disposition of fluoxetine but not sertraline is altered in poor metabolizers of debrisoquin. Clin Pharmacol Ther 60:512–521
Haritos VS, Ghabrial H, Ahokas JT, Ching MS (2000) Role of cytochrome P450 2D6 (CYP2D6) in the stereospecific metabolism of E- and Z-doxepin. Pharmacogenetics 10:591–603
Hartter S, Wetzel H, Hammes E, Hiemke C (1993) Inhibition of antidepressant demethylation and hydroxylation by fluvoxamine in depressed patients. Psychopharmacology (Berl) 110:302–308
Hyttel J, Bogeso KP, Perregaard J, Sanchez C (1992) The pharmacological effect of citalopram residues in the (S)-(+)-enantiomer. J Neural Transm Gen Sect 88:157–160
Ishida M, Otani K, Kaneko S, Ohkubo T, Osanai T, Yasui N, Mihara K, Higuchi H, Sugawara K (1995) Effects of various factors on steady state plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine. Int Clin Psychopharmacol 10:143–146
Jauch R, Griesser E, Oesterhelt G, Arnold W, Meister W, Ziegler WH, Guentert TW (1990) Biotransformation of moclobemide in humans. Acta Psychiatr Scand Suppl 360:87–90
Jauch R, Kopitar Z, Prox A, Zimmer A (1976) [Pharmacokinetics and metabolism of trazodone in man (author’s transl)]. Arzneimittelforschung 26:2084–2089
Ketter TA, Flockhart DA, Post RM, Denicoff K, Pazzaglia PJ, Marangell LB, George MS, Callahan AM (1995) The emerging role of cytochrome P450 3A in psychopharmacology. J Clin Psychopharmacol 15:387–398
Ketter TA, Jenkins JB, Schroeder DH, Pazzaglia PJ, Marangell LB, George MS, Callahan AM, Hinton ML, Chao J, Post RM (1995) Carbamazepine but not valproate induces bupropion metabolism. J Clin Psychopharmacol 15:327–333
Kirchheiner J, Brosen K, Dahl ML, Gram LF, Kasper S, Roots I, Sjoqvist F, Spina E, Brockmoller J (2001) CYP2D6 and CYP2C19 genotype-based dose recommendations for antidepressants: a first step towards subpopulation-specific dosages. Acta Psychiatr Scand 104:173–192
Kobayashi K, Ishizuka T, Shimada N, Yoshimura Y, Kamijima K, Chiba K (1999) Sertraline N-demethylation is catalysed by multiple isoforms of human cytochrome P-450 in vitro. Drug Metab Dispos 27:763–766
Kuss HJ, Jungkunz G (1986) Nonlinear pharmacokinetics of chlorimipramine after infusion and oral administration in patients. Prog Neuropsychopharmacol Biol Psychiatry 10:739–748
Lessard E, Yessine MA, Hamelin BA, O’Hara G, LeBlanc J, Turgeon J (1999) Influence of CYP2D6 activity on the disposition and cardiovascular toxicity of the antidepressant agent venlafaxine in humans. Pharmacogenetics 9:435–443
Liu J, Stewart JT (1997) Quantitation of trimipramine enantiomers in human serum by enantioselective high-performance liquid chromatography and mixed-mode disc solid-phase extraction. J Chromatogr B Biomed Sci Appl 700:175–182
Madsen H, Hansen TS, Brosen K (1996) Imipramine metabolism in relation to the sparteine oxidation polymorphism – a family study. Pharmacogenetics 6:513–519
Mellstrom B, Bertilsson L, Lou YC, Sawe J, Sjoqvist F (1983) Amitriptyline metabolism: relationship to polymorphic debrisoquine hydroxylation. Clin Pharmacol Ther 34:516–520
Mellstrom B, Sawe J, Bertilsson L, Sjoqvist F (1986) Amitriptyline metabolism: association with debrisoquin hydroxylation in nonsmokers. Clin Pharmacol Ther 39:369–371
Meyer JW, Woggon B, Kupfer A (1988) Importance of oxidative polymorphism on clinical efficacy and side-effects of imipramine – a retrospective study. Pharmacopsychiatry 21:365–366
Meyer UA, Amrein R, Balant LP, Bertilsson L, Eichelbaum M, Guentert TW, Henauer S, Jackson P, Laux G, Mikkelsen H, Peck C, Pollock BG, Priest R, Sjoqvist F, Delini-Stula A (1996) Antidepressants and drug-metabolizing enzymes–expert group report. Acta Psychiatr Scand 93:71–79
Mihara K, Otani K, Suzuki A, Yasui N, Nakano H, Meng X, Ohkubo T, Nagasaki T, Kaneko S, Tsuchida S, Sugawara K, Gonzalez FJ (1997) Relationship between the CYP2D6 genotype and the steady-state plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine. Psychopharmacology (Berl) 133:95–98
Mihara K, Otani K, Tybring G, Dahl ML, Bertilsson L, Kaneko S (1997) The CYP2D6 genotype and plasma concentrations of mianserin enantiomers in relation to therapeutic response to mianserin in depressed Japanese patients. J Clin Psychopharmacol 17:467–471
Muth EA, Moyer JAHJT, Andree TH, Husbands GEM (1991) Biochemical, neurophysiological, and behavioral effects of Wy-45,233 and other identified metabolites of the antidepressant venlafaxine. l. Drug Dev Res 23:191–199
Nielsen KK, Brosen K, Gram LF (1992) Steady-state plasma levels of clomipramine and its metabolites: impact of the sparteine/debrisoquine oxidation polymorphism. Danish University Antidepressant Group. Eur J Clin Pharmacol 43:405–411
Nielsen KK, Brosen K, Hansen MG, Gram LF (1994) Single-dose kinetics of clomipramine: relationship to the sparteine and S-mephenytoin oxidation polymorphisms. Clin Pharmacol Ther 55:518–527
Nordin C, Siwers B, Benitez J, Bertilsson L (1985) Plasma concentrations of nortriptyline and its 10-hydroxy metabolite in depressed patients – relationship to the debrisoquine hydroxylation metabolic ratio. Br J Clin Pharmacol 19:832–835
Olesen OV, Linnet K (1999) Studies on the stereoselective metabolism of citalopram by human liver microsomes and cDNA-expressed cytochrome P450 enzymes. Pharmacology 59:298–309
Otani K, Yasui N, Kaneko S, Ishida M, Ohkubo T, Osanai T, Sugawara K, Fukushima Y (1995) Trazodone treatment increases plasma prolactin concentrations in depressed patients. Int Clin Psychopharmacol 10:115–117
Otton SV, Ball SE, Cheung SW, Inaba T, Rudolph RL, Sellers EM (1996) Venlafaxine oxidation in vitro is catalysed by CYP2D6. Br J Clin Pharmacol 41:149–156
Pollock BG, Sweet RA, Kirshner M, Reynolds CF, III (1996) Bupropion plasma levels and CYP2D6 phenotype. Ther Drug Monit 18:581–585
Rau T, Heide R, Bergmann K, Wuttke H, Werner U, Feifel N, Eschenhagen T (2002) Effect of the CYP2D6 genotype on metoprolol metabolism persists during long-term treatment. Pharmacogenetics 12:465–472
Rau T, Wohlleben G, Wuttke H, Thuerauf N, Lunkenheimer J, Lanczik M, Eschenhagen T (2004) CYP2D6 genotype: impact on adverse effects and nonresponse during treatment with antidepressants-a pilot study. Clin Pharmacol Ther 75:386–393
Rocchetti M, Pellizzoni C, Poggesi L (1995) Genetic polymorphism and reboxetine metabolism. Therapie 50:80
Rudorfer MV, Golden RN, Potter WZ (1984) Second-generation antidepressants. Psychiatr Clin North Am 7:519–534
Sanchez C, Hyttel J (1999) Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding. Cell Mol Neurobiol 19:467–489
Sindrup SH, Brosen K, Gram LF, Hallas J, Skjelbo E, Allen A, Allen GD, Cooper SM, Mellows G, Tasker TC (1992) The relationship between paroxetine and the sparteine oxidation polymorphism. Clin Pharmacol Ther 51:278–287
Sindrup SH, Brosen K, Hansen MG, Aaes-Jorgensen T, Overo KF, Gram LF (1993) Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms. Ther Drug Monit 15:11–17
Sjoqvist F, Bertilsson L, Asberg M (1980) Monitoring tricyclic antidepressants. Ther Drug Monit 2:85–93
Spigset O, Granberg K, Hagg S, Norstrom A, Dahlqvist R (1997) Relationship between fluvoxamine pharmacokinetics and CYP2D6/CYP2C19 phenotype polymorphisms. Eur J Clin Pharmacol 52:129–133
Spigset O, Granberg K, Hagg S, Soderstrom E, Dahlqvist R (1998) Non-linear fluvoxamine disposition. Br J Clin Pharmacol 45:257–263
Spina E, Gitto C, Avenoso A, Campo GM, Caputi AP, Perucca E (1997) Relationship between plasma desipramine levels, CYP2D6 phenotype and clinical response to desipramine: a prospective study. Eur J Clin Pharmacol 51:395–398
Sprouse J, Clarke T, Reynolds L, Heym J, Rollema H (1996) Comparison of the effects of sertraline and its metabolite desmethylsertraline on blockade of central 5-HT reuptake in vivo. Neuropsychopharmacology 14:225–231
Stimmel GL, Dopheide JA, Stahl SM (1997) Mirtazapine: an antidepressant with noradrenergic and specific serotonergic effects. Pharmacotherapy 17:10–21
Suckow RF, Cooper TB (1984) Determination of trimipramine and metabolites in plasma by liquid chromatography with electrochemical detection. J Pharm Sci 73:1745–1748
Tasker TC, Kaye CM, Zussman BD, Link CG (1989) Paroxetine plasma levels: lack of correlation with efficacy or adverse events. Acta Psychiatr Scand Suppl 350:152–155
Traskman L, Asberg M, Bertilsson L, Cronholm B, Mellstrom B, Neckers LM, Sjoqvist F, Thoren P, Tybring G (1979) Plasma levels of chlorimipramine and its demethyl metabolite during treatment of depression. Clin Pharmacol Ther 26:600–610
Vormfelde SV, Bitsch A, Meineke I, Gundert-Remy UM, Gleiter CH (1997) Non-response to maprotiline caused by ultra-rapid metabolism that is different from CYP2D6? Eur J Clin Pharmacol 52:387–390
Wienkers LC, Allievi C, Hauer MJ, Wynalda MA (1999) Cytochrome P-450-mediated metabolism of the individual enantiomers of the antidepressant agent reboxetine in human liver microsomes. Drug Metab Dispos 27:1334–1340
Wong DT, Bymaster FP, Reid LR, Mayle DA, Krushinski JH, Robertson DW (1993) Norfluoxetine enantiomers as inhibitors of serotonin uptake in rat brain. Neuropsychopharmacology 8:337–344
Yasui N, Otani K, Kaneko S, Ohkubo T, Osanai T, Ishida M, Mihara K, Kondo T, Sugawara K, Fukushima Y (1995) Inhibition of trazodone metabolism by thioridazine in humans. Ther Drug Monit 17:333–335
Yue QY, Zhong ZH, Tybring G, Dalen P, Dahl ML, Bertilsson L, Sjoqvist F (1998) Pharmacokinetics of nortriptyline and its 10-hydroxy metabolite in Chinese subjects of different CYP2D6 genotypes. Clin Pharmacol Ther 64:384–390
Zanger UM, Fischer J, Raimundo S, Stuven T, Evert BO, Schwab M, Eichelbaum M (2001) Comprehensive analysis of the genetic factors determining expression and function of hepatic CYP2D6. Pharmacogenetics 11:573–585
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Thuerauf, N., Lunkenheimer, J. The impact of the CYP2D6-polymorphism on dose recommendations for current antidepressants. Eur Arch Psychiatry Clin Neurosci 256, 287–293 (2006). https://doi.org/10.1007/s00406-006-0663-5
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00406-006-0663-5