Download PDF
Pharmacopsychiatry 2012; 45(06): 229-235
DOI: 10.1055/s-0031-1301366
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

The Effect of Age, Sex, Smoking and Co-Medication on Serum Levels of Venlafaxine and O-Desmethylvenlafaxine under Naturalistic Conditions

S. Unterecker
1   Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany
,
C. Hiemke
2   Department of Psychiatry and Psychotherapy, University of Mainz, Mainz, Germany
,
C. Greiner
3   Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany
,
E. Haen
3   Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany
,
B. Jabs
4   Department of Psychiatry and Psychotherapy, University of Dresden, Dresden, Germany
,
J. Deckert
1   Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany
,
B. Pfuhlmann
1   Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany
› Author Affiliations
Further Information

Publication History

received 16 September 2011
revised 21 December 2011

accepted 11 January 2012

Publication Date:
16 March 2012 (online)

Also available at
    Permissions and Reprints

Abstract

Introduction:

Venlafaxine (VEN) is a modern antidepressant which exerts both serotonin and norepinephrine reuptake inhibition. In this study we examined the influence of age, sex, smoking, and co-medication on serum levels of VEN and its metabolite O-desmethylvenlafaxine (ODVEN) in patients treated with VEN under naturalistic conditions.

Methods:

We retrospectively evaluated 478 TDM analyses of VEN requested in the Pychiatric University Hospitals of Mainz, Regensburg, and Würzburg. The determination of serum levels was performed by virtually identical chromatographic methods in the TDM laboratories of the participating hospitals.

Results:

Serum levels varied widely on each dose level. Women had about 30% higher dose-corrected serum levels of VEN and ODVEN than men (p<0.01), and patients older than 60 years showed about 46% higher levels of both compounds than younger ones (p<0.01). In smokers, mean serum levels of ODVEN were 21% lower than in non-smokers. Combining these variables a considerable increase of the differences between the subgroups was found indicating an additive effect. ANOVA over the 8 different groups was significant for ODVEN (p<0.01) and sum (p<0.01), but not for VEN (n.s.). Co-medication with other psychotropic drugs was associated with a decreasing ODVEN/VEN ratio indicating a reduced metabolism in patients receiving polypharmacy.

Discussion:

These findings show that TDM is useful to identify factors affecting the pharmacokinetic properties of VEN. It is concluded that sex, age and smoking should be considered for optimal dosing of patients with VEN.

Key words

pharmacokinetics - venlafaxine - depression treatment
 

  • References

  • 1 Harvey AT, Rudolph RL, Preskorn SH. Evidence of the dual mechanisms of action of venlafaxine. Arch Gen Psychiatry 2000; 57: 503-509
    CrossrefPubMedGoogle Scholar
  • 2 Holliday SM, Benfield P. Venlafaxine: a review of its pharmacology and therapeutic potential in depression. Drugs 1995; 49: 280-294
    CrossrefPubMedGoogle Scholar
  • 3 Horst WD, Preskorn SH. Mechanisms of action and clinical characteristics of three atypical antidepressants: venlafaxine, nefazodone, bupropion. J Affect Disord 1998; 51: 237-254
    CrossrefPubMedGoogle Scholar
  • 4 Muth EA, Moyer JA, Haskins JT et al. Biochemical, neurophysiological, and behavioral effects of Wy-45,233 and other identified metabolites of the antidepressant venlafaxine. Drug Dev Res 1991; 23: 191-199
    CrossrefPubMedGoogle Scholar
  • 5 Gutierrez MA, Stimmel GL, Aiso JY. Venlafaxine: a 2003 update. Clin Ther 2003; 25: 2138-2154
    CrossrefPubMedGoogle Scholar
  • 6 Lecrubier Y, Bourin M, Moon C. Efficacy of venlafaxine in depressive illness in general practice. Acta Psychiatr Scand 1997; 95: 485-493
    CrossrefPubMedGoogle Scholar
  • 7 Linden M, Ludewig K, Munz T et al. Dosage finding and outcome of venlafaxine treatment in psychiatric outpatients and inpatients: results of a drug utilization observation study. Pharmacopsychiatry 2003; 36: 197-205
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Sauer H, Huppertz-Helmhold S, Dierkes W. Efficacy and safety of venlafaxine ER vs. amitriptyline ER in patients with major depression of moderate severity. Pharmacopsychiat 2003; 36: 169-175
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Nemeroff CB, Entsuah R, Benattia I et al. Comprehensive analysis of remission (COMPARE) with venlafaxine versus SSRIs. Biol Psychiatry 2008; 63: 424-434
    CrossrefPubMedGoogle Scholar
  • 10 Shrivastava RK, Cohn C, Crowder J et al. Long-term safety and clinical acceptability of venlafaxine and imipramine in outpatients with major depression. J Clin Psychopharmacol 1994; 14: 322-329
    PubMedGoogle Scholar
  • 11 Fogelman S, Schmider J, Greenblatt DJ et al. Metabolism of venlafaxine: the role of P450 isoforms. J Clin Pharmacol 1995; 35: 936-941
    PubMedGoogle Scholar
  • 12 Otton SV, Ball SE, Cheung SW et al. Venlafaxine oxidation in vitro is catalysed by CYP2D6. Br J Clin Pharmacol 1996; 41: 149-156
    CrossrefPubMedGoogle Scholar
  • 13 Veefkind AH, Haffmans PM, Hoencamp E. Venlafaxine serum levels and CYP2D6 genotype. Ther Drug Monit 2000; 22: 202-208
    CrossrefPubMedGoogle Scholar
  • 14 Parks V, Patat A, Behrle J et al. Safety, pharmacokinetics (PK) and pharmacodynamics (PD) of ascending single doses of desvenlafaxine (DVS-233 SR) in healthy subjects. Clin Pharmacol Ther 2005; 77: 28
    PubMedGoogle Scholar
  • 15 Perry R, Cassagnol M. Desvenlafaxine: a new serotonin-norepinephrine reuptake inhibitor for the treatment of adults with major depressive disorder. Clin Ther 2009; 31: 1374-1404
    CrossrefPubMedGoogle Scholar
  • 16 Choong E, Dobrinas M, Carrupt PA et al. The permeability P-glycoprotein: a focus on enantioselectivity and brain distribution. Expert Opin Drug Metab Toxicol 2010; 6: 953-965
    CrossrefPubMedGoogle Scholar
  • 17 Karlsson L, Schmitt U, Josefsson M et al. Blood-brain barrier penetration of the enantiomers of venlafaxine and its metabolites in mice lacking P-glycoprotein. Eur Neuropsychopharmacol 2010; 20: 632-640
    CrossrefPubMedGoogle Scholar
  • 18 Hiemke C, Baumann P, Bergemann N et al. AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011. Pharmacopsychiatry 2011; 44: 195-235
    Google Scholar
  • 19 Hiemke C. Clinical utility of drug measurements and pharmacokinetics – therapeutic drug monitoring in psychiatry. Eur J Clin Pharmacol 2008; 64: 159-166
    CrossrefPubMedGoogle Scholar
  • 20 Shams MEE, Arneth B, Hiemke C et al. CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine. J Clin Pharm Ther 2006; 31: 493-502
    CrossrefPubMedGoogle Scholar
  • 21 Van der Weide J, van Baalen-Benedek EH, Kootstra-Ros JE. Metabolic ratios of psychotropics as indication of cytochrome P450 2D6/2C19 genotype. Ther Drug Monit 2005; 27: 478-483
    CrossrefPubMedGoogle Scholar
  • 22 Reis M, Lundmark J, Björk H et al. Therapeutic drug monitoring of racemic venlafaxine and its main metabolites in an everyday clinical setting. Ther Drug Monit 2002; 24: 545-553
    CrossrefPubMedGoogle Scholar
  • 23 Reis M, Aamo T, Spigset O et al. Serum concentrations of antidepressant drugs in a naturalistic setting: compilation based on a large therapeutic drug monitoring database. Ther Drug Monit 2009; 31: 42-56
    CrossrefPubMedGoogle Scholar
  • 24 Klamerus KJ, Parker VD, Rudolph RL et al. Effects of age and gender on venlafaxine and O-desmethylvenlafaxine pharmacokinetics. Pharmacotherapy 1996; 16: 915-923
    PubMedGoogle Scholar
  • 25 Alexanderson B, Evans DA, Sjoqvist F. Steady-state plasma levels of nortriptyline in twins: influence of genetic factors and drug therapy. Br Med J 1969; 4: 764-768
    CrossrefPubMedGoogle Scholar
  • 26 Bertilsson L, Mellström B, Sjökvist F et al. Slow hydroxylation of nortriptyline and concomitant poor debrisoquine hydroxylation: clinical implications. Lancet 1981; 339: 560-561
    PubMedGoogle Scholar
  • 27 Brosen K, Gram LF. Clinical significance of the sparteine/debrisoquine oxidation polymorphism. Eur J Clin Pharmacol 1989; 36: 537-547
    CrossrefPubMedGoogle Scholar
  • 28 Preskorn S, Patroneva A, Silman H et al. Comparison of the pharmacokinetics of venlafaxine extended release and desvenlafaxine in extensive and poor cytochrome P450 2D6 metabolizers. J Clin Psychopharmacol 2009; 29: 39-43
    CrossrefPubMedGoogle Scholar
  • 29 Dong SX, Ping ZZ, Xiao WZ et al. Effect of active and passive cigarette smoking on CYP1A2-mediated phenacetin disposition in Chinese subjects. Ther Drug Monit 1998; 20: 371-375
    CrossrefPubMedGoogle Scholar
  • 30 Berg MJ. Drugs and smoking. J Gend Specif Med 1999; 2: 27-30
    PubMedGoogle Scholar
  • 31 Bies RR, Bigos KL, Pollock BG. Gender differences in the pharmacokinetics and pharmacodynamics of antidepressants. J Gend Specif Med 2003; 6: 12-20
    PubMedGoogle Scholar
  • 32 Mangoni AA, Jackson SH. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. Br J Clin Pharmacol 2004; 57: 6-14
    PubMedGoogle Scholar
  • 33 Meibohm B, Beierle I, Derendorf H. How important are gender differences in pharmacokinetics?. Clin Pharmacokinet 2002; 41: 329-342
    CrossrefPubMedGoogle Scholar
  • 34 Richelson E. Pharmacokinetic drug interactions of new antidepressants: a review of the effects on the metabolism of other drugs. Mayo Clin Proc 1997; 72: 835-847
    CrossrefPubMedGoogle Scholar
  • 35 Ereshefsky L. Drug-drug interactions involving antidepressants: focus on venlafaxine. J Clin Psychopharmacol 1996; 16: 37S-50S
    CrossrefPubMedGoogle Scholar
  • 36 Goldberg RJ. Antidepressant use in the elderly. Current status of nefazodone, venlafaxine and moclobemide. Drugs Aging 1997; 11: 119-131
    CrossrefPubMedGoogle Scholar
  • 37 Grözinger M, Dragicevic A, Hiemke C et al. Melperone is an inhibitor of the CYP2D6 catalyzed O-demethylation of venlafaxine. Pharmacopsychiatry 2003; 36: 3-6
    Article in Thieme ConnectPubMedGoogle Scholar