Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Response to fluoxetine and serotonin 1A receptor (C-1019G) polymorphism in Taiwan Chinese major depressive disorder

Abstract

Serotonin systems appear to play a key role in the pathogenesis of major depression and the therapeutic mechanisms of antidepressants. The firing rate of dorsal raphe serotonergic neurons is controlled by somatodendritic 5-hydroxytryptamine 1A (HTR1A) autoreceptors, and desensitization of these receptors is implicated in the antidepressant mechanism of selective serotonin reuptake inhibitors. We tested whether a functional polymorphism (C-1019G) in the promoter region of the HTR1A gene and serotonin-related genetic variants are related to fluoxetine antidepressant effect. We genotyped the HTR1A C-1019G polymorphism as well as polymorphisms in the serotonin transporter gene-linked polymorphic region (SERTPR), variable-number tandem-repeat polymorphisms in intron 2 (STin2) of the serotonin transporter gene, serotonin 2A receptor (T102C), tryptophan hydroxylase (A218C), and G-protein beta3 subunit (C825T) in 224 Chinese patients from southern Taiwan with major depression, who accepted 4-week fluoxetine treatment and therapeutic evaluation. Our results demonstrated that the HTR1A −1019C/C carriers (P=0.009) and SERTPR l/l carriers (P<0.001) showed a better response to fluoxetine, while other polymorphisms were not associated with fluoxetine therapeutic response. The major limitation of this study is the lack of a placebo control. Future prospective study with placebo control may help to predict and individualize antidepressant treatment.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Neumeister A, Young T, Stastny J . Implications of genetic research on the role of the serotonin in depression: emphasis on the serotonin type 1A receptor and the serotonin transporter. Psychopharmacology 2004; 174: 512–524.

    Article  CAS  Google Scholar 

  2. Fava M . Management of nonresponse and intolerance: switching strategies. J Clin Psychiatry 2000; 61 (Suppl 2): 10–12.

    PubMed  Google Scholar 

  3. Serretti A, Zanardi R, Rossini D, Cusin C, Lilli R, Smeraldi E . Influence of tryptophan hydroxylase and serotonin transporter genes on fluvoxamine antidepressant activity. Mol Psychiatry 2001; 6: 586–592.

    Article  CAS  Google Scholar 

  4. Lerer B, Macciardi F . Pharmacogenetics of antidepressant and mood-stabilizing drugs: a review of candidate-gene studies and future research directions. Int J Neuropsychopharmacol 2002; 5: 255–275.

    Article  CAS  Google Scholar 

  5. Kirchheiner J, Bertilsson L, Bruus H, Wolff A, Roots I, Bauer M . Individualized medicine – implementation of pharmacogenetic diagnostics in antidepressant drug treatment of major depressive disorders. Pharmacopsychiatry 2003; 36 (Suppl 3): S235–S243.

    CAS  PubMed  Google Scholar 

  6. Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D et al. Allelic variation of human serotonin transporter gene expression. J Neurochem 1996; 66: 2621–2624.

    Article  CAS  Google Scholar 

  7. Nakamura M, Ueno S, Sano A, Tanabe H . The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Mol Psychiatry 2000; 5: 32–38.

    Article  CAS  Google Scholar 

  8. Smeraldi E, Zanardi R, Benedetti F, Di Bella D, Perez J, Catalano M . Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol Psychiatry 1998; 3: 508–511.

    Article  CAS  Google Scholar 

  9. Tsai SJ, Hong CJ . Pharmacogenetics of selective serotonin reuptake inhibitor response in major depression. Curr Pharmacogenom 2003; 1: 1–7.

    Article  CAS  Google Scholar 

  10. Smits KM, Smits LJ, Schouten JS, Stelma FF, Nelemans P, Prins MH . Influence of SERTPR and STin2 in the serotonin transporter gene on the effect of selective serotonin reuptake inhibitors in depression: a systematic review. Mol Psychiatry 2004; 9: 433–441.

    Article  CAS  Google Scholar 

  11. Kim DK, Lim SW, Lee S, Sohn SE, Kim S, Hahn CG et al. Serotonin transporter gene polymorphism and antidepressant response. Neuroreport 2000; 11: 215–219.

    Article  CAS  Google Scholar 

  12. Yoshid K, Ito K, Sato K, Takahashi H, Kamata M, Higuchi H et al. Influence of the serotonin transporter gene-linked polymorphic region on the antidepressant response to fluvoxamine in Japanese depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 383–386.

    Article  Google Scholar 

  13. Minov C, Baghai TC, Schule C, Zwanzger P, Schwarz MJ, Zill P et al. Serotonin-2A-receptor and -transporter polymorphisms: lack of association in patients with major depression. Neurosci Lett 2001; 303: 119–122.

    Article  CAS  Google Scholar 

  14. Walther DJ, Peter JU, Bashammakh S, Hortnagl H, Voits M, Fink H et al. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 2003; 299: 76.

    Article  CAS  Google Scholar 

  15. Serretti A, Zanardi R, Rossini D, Cusin C, Lilli R, Smeraldi E . Influence of tryptophan hydroxylase and serotonin transporter genes on fluvoxamine antidepressant activity. Mol Psychiatry 2001; 6: 586–592.

    Article  CAS  Google Scholar 

  16. Zill P, Baghai TC, Zwanzger P, Schule C, Minov C, Riedel M et al. Evidence for an association between a G-protein beta3-gene variant with depression and response to antidepressant treatment. Neuroreport 2000; 11: 1893–1897.

    Article  CAS  Google Scholar 

  17. Joyce PR, Mulder RT, Luty SE, McKenzie JM, Miller AL, Rogers GR et al. Age-dependent antidepressant pharmacogenomics: polymorphisms of the serotonin transporter and G protein beta3 subunit as predictors of response to fluoxetine and nortriptyline. Int J Neuropsychopharmacol 2003; 6: 339–346.

    Article  CAS  Google Scholar 

  18. Newman ME, Lerer B, Shapira B . 5-HT-1A receptor-mediated effects of antidepressants. Prog Neuropsychopharmacol Biol Psychiatry 1993; 17: 1–19.

    Article  CAS  Google Scholar 

  19. Stahl SM . Mechanism of action of serotonin selective reuptake inhibitors. Serotonin receptors and pathways mediate therapeutic effects and side effects. J Affect Disord 1998; 51: 215–235.

    Article  CAS  Google Scholar 

  20. Suzuki Y, Sawamura K, Someya T . The effects of a 5-hydroxytryptamine 1A receptor gene polymorphism on the clinical response to fluvoxamine in depressed patients. Pharmacogenomics J 2004; 4: 283–286.

    Article  CAS  Google Scholar 

  21. Kobilka BK, Frielle T, Collins S, Yang-Feng T, Kobilka TS, Francke U et al. An intronless gene encoding a potential member of the family of receptors coupled to guanine nucleotide regulatory proteins. Nature 1987; 329: 75–79.

    Article  CAS  Google Scholar 

  22. Rothe C, Gutknecht L, Freitag C, Tauber R, Mossner R, Franke P et al. Association of a functional −1019C&gt;G 5-HT1A receptor gene polymorphism with panic disorder with agoraphobia. Int J Neuropsychopharmacol 2004; 7: 189–192.

    Article  CAS  Google Scholar 

  23. Lemonde S, Turecki G, Bakish D, Du L, Hrdina PD, Bown CD et al. Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosci 2003; 23: 8788–8799.

    Article  CAS  Google Scholar 

  24. Strobel A, Gutknecht L, Rothe C, Reif A, Mossner R, Zeng Y et al. Allelic variation in 5-HT 1A receptor expression is associated with anxiety- and depression-related personality traits. J Neural Transm 2003; 110: 1445–1453.

    Article  CAS  Google Scholar 

  25. Serretti A, Artioli P, Lorenzi C, Pirovano A, Tubazio V, Zanardi R . The C(−1019)G polymorphism of the 5-HT1A gene promoter and antidepressant response in mood disorders: preliminary findings. Int J Neuropsychopharmacol 2004; 7: 453–460.

    Article  CAS  Google Scholar 

  26. Hamilton M . Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967; 6: 278–296.

    Article  CAS  Google Scholar 

  27. Yu YW, Tsai SJ, Chen TJ, Lin CH, Hong CJ . Association study of the serotonin transporter promoter polymorphism and symptomatology and antidepressant response in major depressive disorders. Mol Psychiatry 2002; 7: 1115–1119.

    Article  CAS  Google Scholar 

  28. Tsai SJ, Hong CJ, Cheng CY . Serotonin transporter genetic polymorphisms and harm avoidance in the Chinese. Psychiatr Genet 2002; 12: 165–168.

    Article  Google Scholar 

  29. Hong CJ, Tsai SJ, Wang YC . Association between tryptophan hydroxylase gene polymorphism (A218C) and schizophrenic disorders. Schizophr Res 2001; 49: 59–63.

    Article  CAS  Google Scholar 

  30. Lin CH, Tsai SJ, Yu YW, Song HL, Tu PC, Sim CB et al. No evidence for association of serotonin-2A receptor variant (102T/C) with schizophrenia or clozapine response in a Chinese population. Neuroreport 1999; 10: 57–60.

    Article  CAS  Google Scholar 

  31. Lin CN, Tsai SJ, Hong CJ . Association analysis of a functional G protein beta3 subunit gene polymorphism (C825T) in mood disorders. Neuropsychobiology 2001; 44: 118–121.

    Article  CAS  Google Scholar 

  32. Nurnberg HG, Thompson PM, Hensley PL . Antidepressant medication change in a clinical treatment setting: a comparison of the effectiveness of selective serotonin reuptake inhibitors. J Clin Psychiatry 1999; 60: 574–579.

    Article  CAS  Google Scholar 

  33. Hong CJ, Hu WH, Chen CC, Hsiao CC, Tsai SJ, Ruwe FJ . A double-blind, randomized, group-comparative study of the tolerability and efficacy of 6 weeks' treatment with mirtazapine or fluoxetine in depressed Chinese patients. J Clin Psychiatry 2003; 64: 921–926.

    Article  CAS  Google Scholar 

  34. Blier P, Ward NM . Is there a role for 5-HT1A agonists in the treatment of depression? Biol Psychiatry 2003; 53: 193–203.

    Article  CAS  Google Scholar 

  35. Parker G . Differential effectiveness of newer and older antidepressants appears mediated by an age effect on the phenotypic expression of depression. Acta Psychiatr Scand 2002; 106: 168–170.

    Article  CAS  Google Scholar 

  36. Morishita S, Arita S . Differential effects of fluvoxamine, paroxetine and milnacipran for depression, especially with regard to age. Hum Psychopharmacol 2004; 19: 405–408.

    Article  CAS  Google Scholar 

  37. Cidis Meltzer C, Drevets WC, Price JC, Mathis CA, Lopresti B, Greer PJ et al. Gender-specific aging effects on the serotonin 1A receptor. Brain Res 2001; 895: 9–17.

    Article  CAS  Google Scholar 

  38. Parsey RV, Oquendo MA, Simpson NR, Ogden RT, Van Heertum R, Arango V et al. Effects of sex, age, and aggressive traits in man on brain serotonin 5-HT1A receptor binding potential measured by PET using [C-11]WAY-100635. Brain Res 2002; 954: 173–182.

    Article  CAS  Google Scholar 

  39. Gobbi G, Murphy DL, Lesch K, Blier P . Modifications of the serotonergic system in mice lacking serotonin transporters: an in vivo electrophysiological study. J Pharmacol Exp Ther 2001; 296: 987–995.

    CAS  PubMed  Google Scholar 

  40. Rausch JL, Johnson ME, Fei YJ, Li JQ, Shendarkar N, Hobby HM et al. Initial conditions of serotonin transporter kinetics and genotype: influence on SSRI treatment trial outcome. Biol Psychiatry 2002; 51: 723–732.

    Article  CAS  Google Scholar 

  41. Murphy Jr GM, Kremer C, Rodrigues HE, Schatzberg AF . Pharmacogenetics of antidepressant medication intolerance. Am J Psychiatry 2003; 160: 1830–1835.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by Grant 92-2314-B-075-087 from the National Science Council, Taiwan, and, Grant VGH92-161 from the Taipei Veterans General Hospital.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to S-J Tsai.

Additional information

Duality of Interest

None declared.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hong, CJ., Chen, TJ., Yu, YY. et al. Response to fluoxetine and serotonin 1A receptor (C-1019G) polymorphism in Taiwan Chinese major depressive disorder. Pharmacogenomics J 6, 27–33 (2006). https://doi.org/10.1038/sj.tpj.6500340

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500340

Keywords

This article is cited by

Search

Quick links