Pharmacokinetic correlates of venlafaxine: associated adverse reactions

  • Georgios SchoretsanitisEmail author
  • Ekkehard Haen
  • Christoph Hiemke
  • Katharina Endres
  • Florian Ridders
  • Tanja Veselinovic
  • Gerhard Gründer
  • Michael Paulzen
Original Paper


To address the potential correlation between plasma concentrations of venlafaxine (VEN), its active metabolite O-desmethylvenlafaxine (ODVEN) and the active moiety, AM, (ODVEN + VEN) and adverse drug reactions (ADR) in a large naturalistic sample of in- and outpatients. We compared plasma concentrations of VEN, ODVEN and AM and dose-adjusted (C/D) levels as well the ODVEN/VEN ratios between patients complaining ADRs, following the Udvalg for Kliniske Undersogelser side effect rating scales (UKU) (n = 114) and patients without ADRs (control group, n = 688) out of a naturalistic database. We also investigated potential pharmacokinetic correlates of the four UKU categories by comparing patients complaining ADRs with those who did not. Based on previous literature we applied different ODVEN/VEN ratio values as cut-offs to split our sample into two groups at a time and compare frequencies of ADRs between the groups. No differences for demographic and pharmacokinetic variables including plasma and C/D concentrations as well as ODVEN/VEN ratios were observed between study groups. Neither the comparisons between females and males nor between elderly and non-elderly patients revealed significant differences (p > 0.05 in all cases). No differences were also reported exploring the patients complaining ADRs from the 4 UKU categories separately. After applying various ODVEN/VEN cut-offs, groups did not display differences in frequencies of ADRs (p > 0.05 in all cases). Our findings do not demonstrate a direct link between venlafaxine metabolism measures and ADRs. Therefore, additional dimensions are needed to be considered in future trials aiming to disentangle the involved aspects of ADRs in patients receiving venlafaxine.


Antidepressants Drug metabolism Psychopharmacology Adverse drug reactions Pharmacokinetics 



The authors wish to express their gratitude to the number of people who contributed with excellent professional technical as well as pharmacological competence to build up the KONBEST data base with 50,049 clinical pharmacological comments as of February 2nd, 2016 (ranked among the professional groups in historical order): A. Köstlbacher created the KONBEST software in his Ph.D. thesis based on an idea of E. Haen, C. Greiner, and D. Melchner along the work flow in the clinical pharmacological laboratory at the Department of Psychiatry and Psychotherapy of the University of Regensburg. A. Köstlbacher and his colleague A. Haas continuously maintain the KONBEST software and its data-mining platform (Haas & Köstlbacher GbR, Regensburg/Germany). The lab technicians performed the quantitative analysis: D. Melchner, T. Jahner, S. Beck, A. Dörfelt, U. Holzinger, and F. Pfaff-Haimerl. The clinical pharmacological comments to drug concentrations were composed by licensed pharmacists and medical doctors: Licensed pharmacists: C. Greiner, W. Bader, R. Köber, A. Hader, R. Brandl, M. Onuoha, N. Ben Omar, K. Schmid, (A) Köppl, M. Silva, (B) Fay, S. Unholzer, (C) Rothammer, S. Böhr, (D) Braun, M. Schwarz; M. Dobmeier, M. Wittmann, M. Vogel, M. Böhme, K. Wenzel-Seifert, B. Plattner, P. Holter, R. Böhm, R. Knorr. Authors are also grateful to Dr. A. Sakalli Kani, Department of Psychiatry, Sivas, Turkey for her valuable feedback and Dr. G. Ozbey, Department of Pharmacology, Akdeniz University Medical Faculty, Antalya, Turkey for providing orientation in how to interpret data from her study. Finally, the first author has based his dissertation in terms of British Association for Psychopharmacology (BAP) Certificate Part II on this work supervised by Professor P. M. Haddad, Department of Psychiatry, Hamad Medical Corporation, Doha, Qatar, to whom authors are particularly grateful for his feedback.

Author contributions

Participated in research design: GS, EH, CH, KE, FR, TV, GG, MP. Performed data analysis: GS, MP. Wrote or contributed to the writing of the manuscript: GS, EH, CH, KE, FR, TV, GG, MP.

Compliance with ethical standards

Conflict of interest

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Georgios Schoretsanitis received a grant from the bequest “in memory of Maria Zaoussi”, State Scholarships Foundation, Greece for clinical research in Psychiatry for the academic year 2015–2016. Ekkehard Haen received speaker’s or consultancy fees from the following pharmaceutical companies: Servier, Novartis, and Janssen-Cilag. He is the managing director of AGATE, a non-profit working group to improve drug safety and efficacy in the treatment of psychiatric diseases. He reports no conflict of interest with this publication. Christoph Hiemke has received speaker’s or consultancy fees from the following pharmaceutical companies: Astra Zeneca, Janssen-Cilag, Pfizer, Lilly and Servier. He is managing director of the psiac GmbH which provides an internet-based drug–drug interaction program for psychopharmacotherapy. He reports no conflict of interest with this publication. Gerhard Gründer has served as a consultant for Allergan (Dublin, Ireland), Boehringer Ingelheim (Ingelheim, Germany), Eli Lilly (Indianapolis, Ind, USA), Janssen-Cilag (Neuss, Germany), Lundbeck (Copenhagen, Denmark), Ono Pharmaceuticals (Osaka, Japan), Otsuka (Chiyoda, Japan), Recordati (Milan, Italy), Roche (Basel, Switzerland), Servier (Paris, France), and Takeda (Osaka, Japan). He has served on the speakers’ bureau of Eli Lilly, Janssen Cilag, Neuraxpharm (Langenfeld, Germany), Lundbeck, Otsuka, Recordati, Roche, Servier, and Trommsdorf (Aachen, Germany). He has received grant support from Boehringer Ingelheim and Roche. He is co-founder of Mind and Brain Institute GmbH (Zornheim, Germany) and Brainfoods GmbH (Zornheim, Germany). He reports no conflict of interest with this publication. All other authors declare no conflicts of interest as well.

Ethical standards

This research work was conducted in accordance with the Code of Ethics of the World Medical Association and the local regulatory authority of RWTH Aachen University hospital. No sources of funding were provided for this project. No potential conflicts of interest are reported.


  1. 1.
    Fogelman SM, Schmider J, Venkatakrishnan K, von Moltke LL, Harmatz JS, Shader RI, Greenblatt DJ (1999) O- and n-demethylation of venlafaxine in vitro by human liver microsomes and by microsomes from cdna-transfected cells: effect of metabolic inhibitors and SSRI antidepressants. Neuropsychopharmacology 20:480–490CrossRefGoogle Scholar
  2. 2.
    Klamerus KJ, Maloney K, Rudolph RL, Sisenwine SF, Jusko WJ, Chiang ST (1992) Introduction of a composite parameter to the pharmacokinetics of venlafaxine and its active o-desmethyl metabolite. J Clin Pharmacol 32:716–724CrossRefGoogle Scholar
  3. 3.
    Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K, Eckermann G, Egberts K, Gerlach M, Greiner C, Grunder G, Haen E, Havemann-Reinecke U, Hefner G, Helmer R, Janssen G, Jaquenoud E, Laux G, Messer T, Mossner R, Muller MJ, Paulzen M, Pfuhlmann B, Riederer P, Saria A, Schoppek B, Schoretsanitis G, Schwarz M, Gracia MS, Stegmann B, Steimer W, Stingl JC, Uhr M, Ulrich S, Unterecker S, Waschgler R, Zernig G, Zurek G, Baumann P (2018) Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry 51:9–62CrossRefGoogle Scholar
  4. 4.
    Abadie D, Rousseau V, Logerot S, Cottin J, Montastruc JL, Montastruc F (2015) Serotonin syndrome: analysis of cases registered in the french pharmacovigilance database. J Clin Psychopharmacol 35:382–388Google Scholar
  5. 5.
    Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG, Turner EH, Higgins JPT, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A, Ioannidis JPA, Geddes JR (2018) Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 391(10128):1357–1366CrossRefGoogle Scholar
  6. 6.
    Horst WD, Preskorn SH (1998) Mechanisms of action and clinical characteristics of three atypical antidepressants: venlafaxine, nefazodone, bupropion. J Affect Disord 51:237–254CrossRefGoogle Scholar
  7. 7.
    Launiainen T, Rasanen I, Vuori E, Ojanpera I (2011) Fatal venlafaxine poisonings are associated with a high prevalence of drug interactions. Int J Leg Med 125:349–358CrossRefGoogle Scholar
  8. 8.
    Sicras-Mainar A, Guijarro P, Armada B, Blanca-Tamayo M, Navarro-Artieda R (2014) Influence of the cyp2d6 isoenzyme in patients treated with venlafaxine for major depressive disorder: clinical and economic consequences. PLoS One 9:e90453CrossRefGoogle Scholar
  9. 9.
    Batista M, Dugernier T, Simon M, Haufroid V, Capron A, Fonseca S, Bonbled F, Hantson P (2013) The spectrum of acute heart failure after venlafaxine overdose. Clin Toxicol 51:92–95CrossRefGoogle Scholar
  10. 10.
    Castanares-Zapatero D, Gillard N, Capron A, Haufroid V, Hantson P (2016) Reversible cardiac dysfunction after venlafaxine overdose and possible influence of genotype and metabolism. Forensic Sci Int 266:e48–e51CrossRefGoogle Scholar
  11. 11.
    Geber C, Ostad Haji E, Schlicht K, Hiemke C, Tadic A (2013) Severe tremor after cotrimoxazole-induced elevation of venlafaxine serum concentrations in a patient with major depressive disorder. Ther Drug Monit 35:279–282CrossRefGoogle Scholar
  12. 12.
    Jornil J, Nielsen TS, Rosendal I, Ahlner J, Zackrisson AL, Boel LW, Brock B (2013) A poor metabolizer of both cyp2c19 and cyp2d6 identified by mechanistic pharmacokinetic simulation in a fatal drug poisoning case involving venlafaxine. Forensic Sci Int 226:e26–e31CrossRefGoogle Scholar
  13. 13.
    Megarbane B, Bloch V, Deye N, Baud FJ (2007) Pharmacokinetic/pharmacodynamic modelling of cardiac toxicity in venlafaxine overdose. Intensive Care Med 33:195–196CrossRefGoogle Scholar
  14. 14.
    Jiang F, Kim HD, Na HS, Lee SY, Seo DW, Choi JY, Ha JH, Shin HJ, Kim YH, Chung MW (2015) The influences of cyp2d6 genotypes and drug interactions on the pharmacokinetics of venlafaxine: exploring predictive biomarkers for treatment outcomes. Psychopharmacology 232:1899–1909CrossRefGoogle Scholar
  15. 15.
    Unterecker S, Pfuhlmann B, Kopf J, Kittel-Schneider S, Reif A, Deckert J (2015) Increase of heart rate and QTC by amitriptyline, but not by venlafaxine, is correlated to serum concentration. J Clin Psychopharmacol 35:460–463Google Scholar
  16. 16.
    Hefner G, Hahn M, Hohner M, Roll SC, Klimke A, Hiemke C (2019) QTC time correlates with amitriptyline and venlafaxine serum levels in elderly psychiatric inpatients. Pharmacopsychiatry 52:38–43CrossRefGoogle Scholar
  17. 17.
    Shams ME, Arneth B, Hiemke C, Dragicevic A, Muller MJ, Kaiser R, Lackner K, Hartter S (2006) Cyp2d6 polymorphism and clinical effect of the antidepressant venlafaxine. J Clin Pharm Ther 31:493–502CrossRefGoogle Scholar
  18. 18.
    Ozbey G, Celikel FC, Cumurcu BE, Kan D, Yucel B, Hasbek E, Percin F, Guzey IC, Uluoglu C (2017) Influence of abcb1 polymorphisms and serum concentrations on venlafaxine response in patients with major depressive disorder. Nord J Psychiatry 71:230–237CrossRefGoogle Scholar
  19. 19.
    Neuner T, Hubner-Liebermann B, Haen E, Hausner H, Felber W, Wittmann M, Agate (2011) Completed suicides in 47 psychiatric hospitals in Germany—results from the agate-study. Pharmacopsychiatry 44:324–330CrossRefGoogle Scholar
  20. 20.
    Fischer-Barnicol D, Lanquillon S, Haen E, Zofel P, Koch HJ, Dose M, Klein HE, Working Group ‘Drugs in P (2008) Typical and atypical antipsychotics—the misleading dichotomy. Results from the working group ‘drugs in psychiatry’ (agate). Neuropsychobiology 57:80–87CrossRefGoogle Scholar
  21. 21.
    US Food & Drug Administration (2014) Drug development and drug interactions: table of substrates, inhibitors and inducers. Accessed 30 Jan 2019
  22. 22.
    Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K (1987) The uku side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand Suppl 334:1–100CrossRefGoogle Scholar
  23. 23.
    Paul L, Musshoff F, Aebi B, Auwärter V, Krämer T, Peters F, Skopp G, Aderjan R, Herbold M, Schmitt G (2009) Richtlinie der gtfch zur qualitätssicherung bei forensisch-toxikologischen untersuchungen. Toxichem Krimtech 76:142–176Google Scholar
  24. 24.
    US Food & Drug Administration (2001) Guidance for industry on biomedical method validation. Accessed 30 Jan 2019
  25. 25.
    Preskorn SH, Kane CP, Lobello K, Nichols AI, Fayyad R, Buckley G, Focht K, Guico-Pabia CJ (2013) Cytochrome p450 2d6 phenoconversion is common in patients being treated for depression: implications for personalized medicine. J Clin Psychiatry 74:614–621CrossRefGoogle Scholar
  26. 26.
    Schoretsanitis G, Haen E, Hiemke C, Fay B, Unholzer S, Correll CU, Grunder G, Paulzen M (2018) Sex and body weight are major determinants of venlafaxine pharmacokinetics. Int Clin Psychopharmacol 33(6):322–329CrossRefGoogle Scholar
  27. 27.
    Reis M, Lundmark J, Bjork H, Bengtsson F (2002) Therapeutic drug monitoring of racemic venlafaxine and its main metabolites in an everyday clinical setting. Ther Drug Monit 24:545–553CrossRefGoogle Scholar
  28. 28.
    Garcia S, Schuh M, Cheema A, Atwal H, Atwal PS (2017) Palpitations and asthenia associated with venlafaxine in a cyp2d6 poor metabolizer and cyp2c19 intermediate metabolizer. Case Rep Genet 2017:6236714Google Scholar
  29. 29.
    Wijnen PA, Limantoro I, Drent M, Bekers O, Kuijpers PM, Koek GH (2009) Depressive effect of an antidepressant: therapeutic failure of venlafaxine in a case lacking cyp2d6 activity. Ann Clin Biochem 46:527–530CrossRefGoogle Scholar
  30. 30.
    Reis M, Aamo T, Spigset O, Ahlner J (2009) Serum concentrations of antidepressant drugs in a naturalistic setting: compilation based on a large therapeutic drug monitoring database. Ther Drug Monit 31:42–56CrossRefGoogle Scholar
  31. 31.
    Karlsson L, Hiemke C, Carlsson B, Josefsson M, Ahlner J, Bengtsson F, Schmitt U, Kugelberg FC (2011) Effects on enantiomeric drug disposition and open-field behavior after chronic treatment with venlafaxine in the p-glycoprotein knockout mice model. Psychopharmacology 215:367–377CrossRefGoogle Scholar
  32. 32.
    Karlsson L, Zackrisson AL, Josefsson M, Carlsson B, Green H, Kugelberg FC (2015) Influence of cyp2d6 and cyp2c19 genotypes on venlafaxine metabolic ratios and stereoselective metabolism in forensic autopsy cases. Pharmacogenom J 15:165–171CrossRefGoogle Scholar
  33. 33.
    Chua EW, Foulds J, Miller AL, Kennedy MA (2013) Novel cyp2d6 and cyp2c19 variants identified in a patient with adverse reactions towards venlafaxine monotherapy and dual therapy with nortriptyline and fluoxetine. Pharmacogenet Genom 23:494–497CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PsychiatryThe Zucker Hillside Hospital, Northwell HealthGlen OaksUSA
  2. 2.Clinical Pharmacology, Department of Psychiatry and PsychotherapyUniversity of RegensburgRegensburgGermany
  3. 3.Department of Pharmacology and ToxicologyUniversity of RegensburgRegensburgGermany
  4. 4.Department of Psychiatry and Psychotherapy, Institute of Clinical Chemistry and Laboratory MedicineUniversity Medical Center of MainzMainzGermany
  5. 5.Department of Psychiatry, Psychotherapy and PsychosomaticsRWTH Aachen UniversityAachenGermany
  6. 6.JARA: Translational Brain MedicineAachenGermany
  7. 7.Department of Molecular Neuroimaging, Central Institute of Mental Health, Medical Faculty MannheimUniversity of HeidelbergMannheimGermany
  8. 8.Alexianer Hospital AachenAachenGermany

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