Skip to main content
Log in

The pharmacogenetics of the selective serotonin reuptake inhibitors

  • Review
  • Published:
The clinical investigator Aims and scope Submit manuscript

Summary

Citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline are selective serotonin reuptake inhibitors (SSRIs), which are thought to act as antidepressants through their ability to inhibit presynaptic serotonin reuptake in the brain. The elimination of the SSRIs proceeds predominantly via oxidation catalyzed by cytochrome P450 in the liver. Paroxetine and fluoxetine are potent inhibitors of cytochrome P4502D6 and hence may cause serious interactions with drugs metabolized by this isozyme, notably tricyclic antidepressants, some neuroleptics, and some antiarrhythmics. Citalopram, fluvoxamine and sertraline do not share this property. Fluvoxamine is the only SSRI that is a potent inhibitor of cytochrome P4501A2 and hence causes serious pharmacokinetic interactions with amitriptyline, clomipramine, imipramine, theophylline, and presumably caffeine and other drugs which are metabolized by the isozyme. Citalopram and fluoxetine are administered as racemates, but practically nothing is known about the stereoselective metabolism of the two drugs. Citalopram is partially metabolized via the mephenytoin oxidation polymorphism, and paroxetine is partially metabolized via the sparteine/debrisoquine oxidation polymorphism. The pharmacogenetic differences in the oxidation of the SSRIs themselves are probably of no clinical relevance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Abbreviations

CYP:

cytochrome P450

EM:

extensive metabolizer

PM:

poor metabolizer

SSRI:

selective serotonin reuptake inhibitor

References

  1. Bergstrom RF, Peyton AL, Lemberger L (1992) Quantification and mechanism of the fluoxetine tricyclic antidepressant interaction. Clin Pharmacol Ther 51:239–248

    Google Scholar 

  2. Bertschy G, Vandel S, Vandel B, Allers G, Volmat R (1991) Fluvoxamine-tricyclic antidepressant interaction. Eur J Clin Pharmacol 40:119–120

    Google Scholar 

  3. Bloomer JC, Woods FR, Haddock RE, Lennard MS, Tucker GT (1992) The role of cytochrome P4502D6 in the metabolism of paroxetine by human liver microsomes. Br J Clin Pharmacol 33:521–523

    Google Scholar 

  4. Brøsen K, Gram LF (1989) Clinical significance of the sparteine/debrisoquine oxidation polymorphism. Eur J Clin Pharmacol 36:537–547

    Google Scholar 

  5. Brøsen K, Skjelbo E (1992) Fluoxetine and norfluoxetine are potent inhibitors of P450IID6 — the source of the sparteine/debrisoquine oxidation polymorphism. Br J Clin Pharmacol 32:136–137

    Google Scholar 

  6. Brøsen K, Gram LF, Kragh-Sørensen (1991) Extremely slow metabolism of amitriptyline but normal metabolism of imipramine and desipramine in an extensive metabolizer of sparteine, debrisoquine and mephenytoin. Ther Drug Monit 13:177–182

    Google Scholar 

  7. Brosen K, Hansen JG, Nielsen KK, Sindrup SH, Gram LF (1993) Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine. Eur J Clin Pharmacol 44:349–355

    Google Scholar 

  8. Brosen K, Sindrup SH, Skjelbo E, Nielsen KK, Gram LF (1993) Role of genetic polymorphism in psychopharmacology — an update. In: Gram LF, Balant LP, Meltzer HY, Dahl SG (eds) Clinical pharmacology in psychiatry: strategies in drug development. Psychopharmacology series. Springer, Berlin Heidelberg New York, pp 199–211

    Google Scholar 

  9. Brosen K, Skjelbo E, Rasmussen BB, Poulsen HE, Loft S (1993) Fluvoxamine is a potent inhibitor of cytochrome P4501A2. Biochem Pharmacol 45:1211–1214

    Google Scholar 

  10. Crewe HK, Lennard MS, Tucker GT, Woods FR, Haddock RE (1992) The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes. Br J Clin Pharmacol 34:262–265

    CAS  PubMed  Google Scholar 

  11. Diot P, Jonville AP, Gerard F, Bonelle M, Autret E, Breteau M, Lemarie E, Lavadier M (1991) Possible interaction entre theophylline et fluvoxamine. Therapie 46:170–171

    Google Scholar 

  12. Fuller RW, Snoddy HD, Krushinski JH, Robertson DW (1992) Comparison of norfluoxetine enantiomers as serotonin uptake inhibitors in vivo. Neuropharmacology 31:997–1000

    Google Scholar 

  13. Gram LF, Hansen MGJ, Sindrup SH, Brøsen K, Poulsen JH, Aaes-Jørgensen T, Overø KF (1993) Citalopram: interaction studies with levomepromazine, imipramine, and lithium. Ther Drug Monit 15:18–24

    Google Scholar 

  14. Heim M, Meyer UA (1990) Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification. Lancet 336:529–532

    Google Scholar 

  15. Hyttel J, Bogeso KP, Perregaard J, Sánchez C(1992) The pharmacological effect of citalopram resides in the (S)-(+)-enantiomer. J Neural Transm 88:157–160

    Google Scholar 

  16. Lemoine A, Gautier JC, Azoulay D, Kiffel L, Guengerich FP, Beaune P, Maurel P, Leroux JP (1993) The major pathway of imipramine metabolism is catalyzed by cytochromes P-450 1A2 and P-450 3A4 in human liver. Mol Pharmacol 43:827–832

    Google Scholar 

  17. Nebert WD, Nelson DR, Coon MJ, Estabrook RW, Feyereisen R, Fujii-Kuriyama Y, Gonzalez FJ, Guengerich FP, Gunsalus IC, Johnson EF, Loper JC, Sato R, Waterman MR, Waxman DJ (1991) The P450 superfamily: update on new sequences, gene mapping, and recommended nomenclature. DNA Cell Biol 10:1–14

    Google Scholar 

  18. Otton SV, Dafang W, Joffe RT, Cheung SW, Sellers EM (1993). Inhibition by fluoxetine of cytochrome P4502D6 activity. Clin Pharmacol Ther 53:401–409

    Google Scholar 

  19. Preskorn SH, Aldeman J, Messig M, Harris S, Ching M (1992) Desipramine levels after sertraline or fluoxetine. Presented at the American Psychiatric Association Meeting, May 1992, USA

  20. Sindrup SH, Gram LF, Brosen K, Eshoj O, Mogensen EF (1990) The selective serotonin inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain 42:135–144

    Google Scholar 

  21. Sindrup SH, Brosen K, Gram LF (1992) Pharmacokinetics of the selective serotonin reuptake inhibitor paroxetine: non-linearity and relation to the sparteine oxidation polymorphism. Clin Pharmacol Ther 51:288–295

    Google Scholar 

  22. Sindrup SH, Brosen K, Gram L, Hallas J, Skjelbo E, Allen A, Allen GD, Cooper SM, Mellows G, Tasker TCG, Zussmann BD (1992) The relationship between paroxetine and the sparteine oxidation polymorphism. Clin Pharmacol Ther 51:278–287

    Google Scholar 

  23. Sindrup SH, Brosen K, Hansen MGJ, Aaes-Mogensen T, Overø KF, Gram LF (1993) Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms. Ther Drug Monit 15:11–17

    CAS  PubMed  Google Scholar 

  24. Skjelbo E, Brosen K, Hallas J, Gram LF (1991) The mephenytoin oxidation polymorphism is partially responsible for the N-demethylation of imipramine. Clin Pharmacol Ther 49:18–23

    Google Scholar 

  25. Skjelbo E, Brosen K (1992) Inhibitors of imipramine metabolism by human liver microsomes. Br J Clin Pharmacol 34:256–261

    CAS  PubMed  Google Scholar 

  26. Sperber AD (1991) Toxic interaction between fluvoxamine and sustained release theophylline in an 11-year-old boy. Drug Safety 6:460–462

    Google Scholar 

  27. Spina E, Campo GM, Avenoso A, Pollicino MA, Caputi AP (1992) Interaction between fluvoxamine and imipramine/desipramine in four patients. Ther Drug Monit 14:194–196

    Google Scholar 

  28. Spina E, Pollicino AM, Avenoso A, Campo GM, Perucca E, Caputi AP (1993) Effect of fluvoxamine on the pharmacokinetics of imipramine and desipramine in healthy subjects. Ther Drug Monit 15:243:246

    Google Scholar 

  29. Thomson AH, McGovern EM, Bennie P, Caldwell G, Smith M (1992) Interaction between fluvoxamine and theophylline. Pharm J, vol 137

  30. Torok-Both GA, Baker GB, Coutts RT, McKenna KF, Aspeslet LJ (1992) Simultaneous determination of fluoxetine and norfluoxetine enantiomers in biological samples by gas chromatography with electron-capture detection. J Chromatogr 579:99–106

    Article  CAS  PubMed  Google Scholar 

  31. van Harten J (1993) Clinical pharmacokinetics of selective serotonin Reuptake inhibitors. Clin Pharmacokinet 24:203–220

    PubMed  Google Scholar 

  32. Vandel S, Bertschy G, Bonin B, Nezelof S, Francois TH, Vandel B, Sechter D, Bizouard P (1992) Tricyclic antidepressant plasma levels after fluoxetine addition. Neuropsychobiology 25:202–207

    Google Scholar 

  33. Vaughan DA (1988) Interaction of fluoxetine with tricyclic antidepressants. Am J Psychiatry 145:1478

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brøsen, K. The pharmacogenetics of the selective serotonin reuptake inhibitors. Clin Investig 71, 1002–1009 (1993). https://doi.org/10.1007/BF00180032

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00180032

Key words

Navigation