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Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients

Abstract

The serotonin transporter gene promoter polymorphism (5-HTTLPR) has been repeatedly associated with antidepressant response in mood disorder patients, but findings are not consistent across studies. A meta-analysis was performed on 15 studies including data of 1435 subjects. We tested three phenotypes: remission rate, response rate and response rate within 4 weeks using the cochrane review manager. We observed a significant association of the s/s variant of 5-HTTLPR with remission rate (P<0.0001) and both s/s and s/l variants with response rate (P=0.0002). Response rate within 4 weeks was associated in both models (P=0.003–P<0.00001). This effect is quite robust to ethnic differences although a significant heterogeneity is present in Asian samples.

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References

  1. Greenberg PE, Stiglin LE, Finkelstein SN, Berndt ER . The economic burden of depression in 1990. J Clin Psychiatry 1993; 54: 405–418.

    CAS  PubMed  Google Scholar 

  2. Sartorius N . The economic and social burden of depression. J Clin Psychiatry 2001; 62(Suppl 15): 8–11.

    PubMed  Google Scholar 

  3. Wittchen H-U, Jacobi F . Size and burden of mental disorders in Europe – a critical review and appraisal of 27 studies. Eur Neuropsychopharmacol 2005; 15: 357–376.

    Article  CAS  PubMed  Google Scholar 

  4. Ustun TB . The worldwide burden of depression in the 21st century. In: Weismann MM (ed). Treatment of Depression: Bridging the 21st Century. American Psichiatric Press: Washington, DC, 2001, pp 35–45.

    Google Scholar 

  5. Fava M, Davidson KG . Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am 1996; 19: 179–200.

    Article  CAS  PubMed  Google Scholar 

  6. Fava M . Diagnosis and definition of treatment-resistant depression. Biol Psychiatry 2003; 53: 649–659.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Serretti A, Calati R, Mandelli L, De Ronchi D . Serotonin transporter gene variants and behaviour: a comprehensive review. Current Drug Targets, in press.

  9. Smeraldi E, Zanardi R, Benedetti F, Dibella 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  PubMed  Google Scholar 

  10. Serretti A, Artioli P, Quartesan R . Pharmacogenetics in the treatment of depression: pharmacodynamic studies. Pharmacogenet Genom 2005; 15: 61–67.

    Article  CAS  Google Scholar 

  11. 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  PubMed  Google Scholar 

  12. Munafo MR, Flint J . Meta-analysis of genetic association studies. Trends Genet 2004; 20: 439–444.

    Article  CAS  PubMed  Google Scholar 

  13. Cho HJ, Meira-Lima I, Cordeiro Q, Michelon L, Sham P, Vallada H et al. Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis. Mol Psychiatry 2005; 12: 12.

    Google Scholar 

  14. Lasky-Su JA, Faraone SV, Glatt SJ, Tsuang MT . Meta-analysis of the association between two polymorphisms in the serotonin transporter gene and affective disorders. Am J Med Genet B Neuropsychiatr Genet 2005; 133: 110–115.

    Article  Google Scholar 

  15. Arias B, Catalan R, Gasto C, Gutierrez B, Fananas L . 5-HTTLPR polymorphism of the serotonin transporter gene predicts non-remission in major depression patients treated with citalopram in a 12-weeks follow up study. J Clin Psychopharmacol 2003; 23: 563–567.

    Article  CAS  PubMed  Google Scholar 

  16. Hong CJ, Chen TJ, Yu YW, Tsai SJ . Response to fluoxetine and serotonin 1A receptor (C-1019G) polymorphism in Taiwan Chinese major depressive disorder. Pharmacogenom J 2006; 6: 27–33.

    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  PubMed  Google Scholar 

  18. Kato M, Fukuda T, Wakeno M, Fukuda K, Okugawa G, Ikenaga Y et al. Effects of the serotonin type 2A, 3A and 3B receptor and the serotonin transporter genes on paroxetine and fluvoxamine efficacy and adverse drug reactions in depressed Japanese patients. Neuropsychobiol 2006; 53: 186–195.

    Article  CAS  Google Scholar 

  19. 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  PubMed  Google Scholar 

  20. Kirchheiner J, Nickchen K, Sasse J, Bauer M, Roots I, Brockmoller J . A 40-basepair VNTR polymorphism in the dopamine transporter (DAT1) gene and the rapid response to antidepressant treatment. Pharmacogenom J 2006.

  21. Serretti A, Artioli P . The pharmacogenomics of selective serotonin reuptake inhibitors. Pharmacogenom J 2004; 4: 233–244.

    Article  CAS  Google Scholar 

  22. Yoshida 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  CAS  PubMed  Google Scholar 

  23. 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  PubMed  Google Scholar 

  24. Zanardi R, Benedetti F, Di Bella D, Catalano M, Smeraldi E . Efficacy of paroxetine in depression is influenced by a functional polymorphism within the promoter of the serotonin transporter gene. J Clin Psychopharmacol 2000; 20: 105–107.

    Article  CAS  PubMed  Google Scholar 

  25. Zanardi R, Serretti A, Rossini D, Franchini L, Cusin C, Lattuada E et al. Factors affecting fluvoxamine antidepressant activity: influence of pindolol and 5-HTTLPR in delusional and nondelusional depression. Biol Psychiatry 2001; 50: 323–330.

    Article  CAS  PubMed  Google Scholar 

  26. Quitkin FM, Rabkin JG, Ross D, Stewart JW . Identification of true drug response to antidepressants. Use of pattern analysis. Arch Gen Psychiatry 1984; 41: 782–786.

    Article  CAS  PubMed  Google Scholar 

  27. Durham LK, Webb SM, Milos PM, Clary CM, Seymour AB . The serotonin transporter polymorphism, 5HTTLPR, is associated with a faster response time to sertraline in an elderly population with major depressive disorder. Psychopharmacology (Berlin) 2004; 174: 525–529.

    Article  CAS  Google Scholar 

  28. Kraft JB, Slager SL, McGrath PJ, Hamilton SP . Sequence analysis of the serotonin transporter and associations with antidepressant response. Biol Psychiatry 2005; 58: 374–381.

    Article  CAS  PubMed  Google Scholar 

  29. Lee MS, Lee HY, Lee HJ, Ryu SH . Serotonin transporter promoter gene polymorphism and long-term outcome of antidepressant treatment. Psychiatr Genet 2004; 14: 111–115.

    Article  PubMed  Google Scholar 

  30. 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  PubMed  Google Scholar 

  31. Murphy Jr GM, Hollander SB, Rodrigues HE, Kremer C, Schatzberg AF . Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression. Arch Gen Psychiatry 2004; 61: 1163–1169.

    Article  CAS  PubMed  Google Scholar 

  32. Pollock BG, Ferrell RE, Mulsant BH, Mazumdar S, Miller M, Sweet RA et al. Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology 2000; 23: 587–590.

    Article  CAS  PubMed  Google Scholar 

  33. 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  PubMed  Google Scholar 

  34. Lesch KP . Variation of serotonergic gene expression: neurodevelopment and the complexity of response to psychopharmacologic drugs. Eur Neuropsychopharmacol 2001; 11: 457–474.

    Article  CAS  PubMed  Google Scholar 

  35. Hranilovic D, Stefulj J, Schwab S, Borrmann-Hassenbach M, Albus M, Jernej B et al. Serotonin transporter promoter and intron 2 polymorphisms: relationship between allelic variants and gene expression. Biol Psychiatry 2004; 55: 1090–1094.

    Article  CAS  PubMed  Google Scholar 

  36. Greenberg BD, Tolliver TJ, Huang SJ, Li Q, Bengel D, Murphy DL . Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets. Am J Med Genet 1999; 88: 83–87.

    Article  CAS  PubMed  Google Scholar 

  37. Javors MA, Seneviratne C, Roache JD, Ait-Daoud N, Bergeson SE, Walss-Bass MC et al. Platelet serotonin uptake and paroxetine binding among allelic genotypes of the serotonin transporter in alcoholics. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 7–13.

    Article  CAS  PubMed  Google Scholar 

  38. Teshima KM, Przeworski M . Directional positive selection on an allele of arbitrary dominance. Genetics 2006; 172: 713–718.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Williams NM, O'Donovan MC, Owen MJ . Is the dysbindin gene (DTNBP1) a susceptibility gene for schizophrenia? Schizophr Bull 2005; 31: 800–805.

    Article  PubMed  Google Scholar 

  40. Allison DB . Transmission-disequilibrium tests for quantitative traits. Am J Hum Genet 1997; 60: 676–690.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Peters EJ, Slager SL, McGrath PJ, Knowles JA, Hamilton SP . Investigation of serotonin-related genes in antidepressant response. Mol Psychiatry 2004; 9: 879–889.

    Article  CAS  PubMed  Google Scholar 

  42. Hu XZ, Lipsky RH, Zhu G, Akhtar LA, Taubman J, Greenberg BD et al. Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet 2006; 78: 815–826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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  PubMed  Google Scholar 

  44. Smeraldi E, Serretti A, Artioli P, Lorenzi C, Catalano M . Serotonin transporter gene-linked polymorphic region: possible pharmacogenetic implications of rare variants. Psychiatr Genet 2006; 16: 153–158.

    Article  PubMed  Google Scholar 

  45. Kunugi H, Hattori M, Kato T, Tatsumi M, Sakai T, Sasaki T et al. Serotonin transporter gene polymorphisms: ethnic difference and possible association with bipolar affective disorder. Mol Psychiatry 1997; 2: 457–462.

    Article  CAS  PubMed  Google Scholar 

  46. Kato M, Ikenaga Y, Wakeno M, Okugawa G, Nobuhara K, Fukuda T et al. Controlled clinical comparison of paroxetine and fluvoxamine considering the serotonin transporter promoter polymorphism. Int Clin Psychopharmacol 2005; 20: 151–156.

    Article  PubMed  Google Scholar 

  47. Kirchheiner J, Nickchen K, Bauer M, Wong ML, Licinio J, Roots I et al. Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry 2004; 9: 442–473.

    Article  CAS  PubMed  Google Scholar 

  48. Kendler KS . ‘A gene for …’: the nature of gene action in psychiatric disorders. Am J Psychiatry 2005; 162: 1243–1252.

    Article  PubMed  Google Scholar 

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Serretti, A., Kato, M., De Ronchi, D. et al. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients. Mol Psychiatry 12, 247–257 (2007). https://doi.org/10.1038/sj.mp.4001926

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