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Polymorphism of the Serotonin Transporter

Implications for the Use of Selective Serotonin Reuptake Inhibitors

  • Practical Pharmacogenomics
  • Published:
American Journal of Pharmacogenomics

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are used to treat a number of psychiatric disorders related to mood and anxiety, and variations in the serotonin transporter (5-HTT) gene may be involved in a number of these. A polymorphic site in the promoter region is associated with differences in 5-HTT gene expression. Studies suggest that the short allele of the 5-HTT promoter (5-HTTPR) site can adversely influence the antidepressant response to SSRIs, and is associated with anxiety-related traits, depression, and impulsive disorders such as alcohol abuse. Several studies do not replicate these findings; potential confounding factors include age, gender, and population stratification. Other 5-HTT polymorphisms also exist. For example, individuals with the short allele of a variable number of tandem repeats (VNTR) polymorphism, located in the second intron, may have reduced responsiveness to SSRIs, and the STin2.12 allele at this site has been associated with bipolar disorder. Findings both supporting and inconsistent with these conclusions are reviewed. The clinical effects of the polymorphisms may be associated with effects on platelets, neural 5-HTT levels, and indices of serotonergic function.

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References

  1. Staley JK, Malison RT, Innis RB. Imaging of the serotonergic system: Interactions of neuroanatomical and functional abnormalities of depression. Biol Psychiatry 1998; 44(6): 534–49

    PubMed  CAS  Google Scholar 

  2. Catalano M. The challenges of psychopharmacogenetics. Am J Hum Genet 1999; 65(3): 606–10

    PubMed  CAS  Google Scholar 

  3. Lesch KP, Wolozin BL, Estler HC, et al. Isolation of a cDNA encoding the human brain serotonin transporter. J Neural Transm Gen Sect 1993; 91(1): 67–72

    PubMed  CAS  Google Scholar 

  4. Lesch KP, Bengel D, Heils A, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996 Nov; 274(5292): 1527–31

    PubMed  CAS  Google Scholar 

  5. Heils A, Mossner R, Lesch KP. The human serotonin transporter gene polymorphism — basic research and clinical implication. J Neural Transm Gen Sect 1997; 104(10): 1005–14

    CAS  Google Scholar 

  6. Lesch KP, Balling U, Gross J, et al. Organization of the human serotonin transporter gene. J Neural Transm Gen Sect 1994; 95(2): 157–64

    PubMed  CAS  Google Scholar 

  7. Ogilvie AD, Battersby S, Bubb VJ, et al. Polymorphism in serotonin transporter gene associated with susceptibility to major depression. Lancet 1996 Mar; 347(9003): 731–3

    PubMed  CAS  Google Scholar 

  8. Lesch KP, Gross J, Fanzek E, et al. Primary structure of the serotonin transporter in unipolar depression and bipolar disorder. Biol Psychiatry 1995; 37(4): 215–23

    PubMed  CAS  Google Scholar 

  9. Di Bella D, Catalano M, Balling U, et al. Systematic screening for mutations in the coding region of the (5-HTT) gene using PCR and DGGE. Am J Med Genet 1996; 67(6): 541–5

    PubMed  Google Scholar 

  10. Nakamura M, Ueno S, Sano A, et al. The human serotonin tranporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Mol Psychiatry 2000; 5(1): 32–8

    PubMed  CAS  Google Scholar 

  11. Michaelovsky E, Frisch A, Rockah R, et al. A novel allele in the promoter region of the human serotonin transporter gene. Mol Psychiatry 1999; 4(1): 97–9

    PubMed  CAS  Google Scholar 

  12. Flattern NL, Blakely RD. Modified structure of the human serotonin transporter promoter. Mol Psychiatry 2000; 5(1): 110–5

    Google Scholar 

  13. Battersby S, Ogilvie AD, Blackwood DHR, et al. Presence of multiple functional polyadenylation signals and a single nucleotide polymorphism in the 3′ untranslated region of the human serotonin transporter gene. J Neurochem 1999; 72(4): 1384–8

    PubMed  CAS  Google Scholar 

  14. Lesch KP. Serotonin transporter and psychiatric disorders: listening to the gene. Neuroscientist 1998; 4(1): 25–34

    CAS  Google Scholar 

  15. Fiskerstrand CE, Lovejoy, EA, Quinn JP. An intronic polymorphic domain often associated with susceptibility to affective disorders has allele dependent differential enhancer activity in embryonic stem cells. FEBS Lett 1999; 458(2): 171–4

    PubMed  CAS  Google Scholar 

  16. Coccaro EF, Kavoussi RJ, Sheline YI, et al. Impulsive aggression in personality disorder correlates with tritiated paroxetine binding in the platelet. Arch Gen Psychiatry 1996; 53(6): 531–6

    PubMed  CAS  Google Scholar 

  17. Marazziti D, Dell’Osso L, Presta S, et al. Platelet [H3]paroxetine binding in patients with OCD-related disorders. Psychiatry Res 1999; 89(3): 223–8

    PubMed  CAS  Google Scholar 

  18. Leboyer M, Quintin P, Manivet PD, et al. Decreased serotonin transporter binding in unaffected relatives of manic depressive patients. Biol Psychiatry 1999; 46(12): 1703–6

    PubMed  CAS  Google Scholar 

  19. Marazziti D, Rossi A, Dell’Osso L, et al. Decreased platelet 3H-paroxetine binding in untreated panic disorder patients. Life Sci 1999; 65(25): 2735–41

    PubMed  CAS  Google Scholar 

  20. Nemeroff CB, Knight DL, Franks J, et al. Further studies on platelet serotonin transporter binding in depression. Am J Psychiatry 1994; 151(11): 1623–5

    PubMed  CAS  Google Scholar 

  21. Owens MJ, Nemeroff CB. Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem 1994; 40(2): 288–95

    PubMed  CAS  Google Scholar 

  22. Sallee FR, Hilal R, Dougherty D, et al. Platelet serotonin transporter in depressed children and adolescents: 3H-paroxetine platelet binding before and after sertral-ine. J Am Acad Child Adolesc Psychiatry 1998; 37(7): 777–84

    PubMed  CAS  Google Scholar 

  23. Alvarez JC, Gluck N, Arnulf I, et al. Decreased platelet serotonin transporter sites and increased platelet inositol triphosphate levels in patients with unipolar depression: effects of clomipramine and fluoxetine. Clin Pharmacol Ther 1999; 66(6): 617–24

    PubMed  CAS  Google Scholar 

  24. Figueras G, Perez V, San Martino O, et al. Pretreatment platelet 5-HT concentration predicts the short-term response to paroxetine in major depression. Biol Psychiatry 1999; 46(4): 518–24

    PubMed  CAS  Google Scholar 

  25. Pollock BG, Laghrissi-Thode F, Wagner WR, et al. Effect of paroxetine and nortriptyline on platelet activation in depressed patients with ischemic heart disease. J Clin Psychopharmacol 2000; 20: 137–40

    PubMed  CAS  Google Scholar 

  26. Neuger J, Wistedt B, Sinner B, et al. The effect of citalopram treatment on platelet serotonin function in panic disorders. Int Clin Psychoparmacol 2000; 15(2): 83–9

    CAS  Google Scholar 

  27. Lesch KP, Wolozin BL, Murphy DL, et al. Primary structure of the human platelet serotonin uptake site: identity with the brain serotonin transporter. J Neurochem 1993; 60(6): 2319–22

    PubMed  CAS  Google Scholar 

  28. Greenberg BD, Tolliver TJ, Huang S-J, et al. Genetic variation in the serotonin transporter promoter region affects serotonin uptake in blood platelets. Am J Med Genet 1999; 88(1): 83–7

    PubMed  CAS  Google Scholar 

  29. Nobile M, Begni B, Giorda R, et al. Effects of serotonin transporter genotype on platelet serotonin transporter functionality in depressed children and adolescents. J Am Acad Child Adolesc Psychiatry 1999; 38(11): 1396–402

    PubMed  CAS  Google Scholar 

  30. Malison RT, Price LH, Berman R, et al. Reduced brain serotonin transporter availability in major depression as measured by [123I]-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane and single photon emission computed tomography. Biol Psychiatry 1998; 44(11): 1090–8

    PubMed  CAS  Google Scholar 

  31. Lichtermann D, Hranilovic D, Trixler M, et al. Support for allelic association of a polymorphic site in the promoter region of the serotonin transporter gene with risk for alcohol dependence. Am J Pyschiatry 2000; 157(12): 2045–7

    CAS  Google Scholar 

  32. Kapitany T, Schindl M, Schindler SD, et al. The citalopram challenge test in patients with major depression and in healthy controls. Psychiatr Res 1999; 88(2): 75–8

    CAS  Google Scholar 

  33. Bengel D, Murphy DL, Andrews AM, et al. Altered brain serotonin homeostasis and locomotor insensitivity to 3,4-methylenedioxymethamphetamine (‘Ecstasy’) in serotonin transporter-deficient mice. Mol Pharmacol 1998; 53(4): 649–55

    PubMed  CAS  Google Scholar 

  34. Sora I, Wichems C, Takahashi N, et al. Cocaine reward models: conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice. Proc Natl Acad Sci USA 1998 Jun; 95(13): 7699–77048

    PubMed  CAS  Google Scholar 

  35. Fabre V, Boutrel B, Hanoun N, et al. Homeostatic regulation of serotonergic function by the serotonin transporter as revealed by nonviral gene transfer. J Neurosci 2000; 20(13): 5065–75 and autistic disorder in two ethnically distinct samples. Am J Med Genet 2000; 96 (1): 123–7

    PubMed  CAS  Google Scholar 

  36. Pollier F, Sarre S, Aguerre S, et al. Serotonin reuptake inhibition by citalopram in rat strains differing for their emotionality. Neuropsychopharmacology 2000; 22(1): 64–76

    PubMed  CAS  Google Scholar 

  37. Lopez-Rubalcava C, Lucki I. Strain differences in the behavioral effects of antidepressant drugs in the rat forced swimming test. Neuropsychopharmacology 2000; 22(2): 191–9

    PubMed  CAS  Google Scholar 

  38. Jernej B, Hranilovic D, Cicin-Sain L, et al. Serotonin transporter on rat platelets: levels of mRNA underlie inherited differences in uptake kinetics. Neurochem Int 1998; 33(6): 519–23

    PubMed  CAS  Google Scholar 

  39. Mazzanti CM, Lappalainen J, Long JC, et al. Role of the serotonin transporter promotor polymorphism in anxiety-related traits. Arch Gen Psychiatry 1998; 55(10): 93–940

    Google Scholar 

  40. Ricketts MH, Hamer MR, Sage JI, et al. Association of a serotonin transporter gene promoter polymorphism with harm avoidance behavior in an elderly population. Psychiatr Genet 1998; 8(1): 41–4

    PubMed  CAS  Google Scholar 

  41. Auerbach J, Geller V, Lezer S, et al. Dopamine D4 receptor (D4DR) and serotonin transporter promoter (5-HTTLPR) polymorphisms in the determination of temperament in 2-month-old infants. Mol Psychiatry 1999; 4(4): 369–73

    PubMed  CAS  Google Scholar 

  42. Katsuragi S, Kunugi H, Sano A, et al. Association between serotonin transporter gene polymorphism and anxiety-related traits. Biol Psychiatry 1999; 45(3): 368–70

    PubMed  CAS  Google Scholar 

  43. Menza MA, Palermo B, DiPaola R, et al. Depression and anxiety in parkinson’s disease: possible effect of genetic variation in the serotonin transporter. J Geriatr Psychiatry Neurol 1999; 12(2): 49–52

    PubMed  CAS  Google Scholar 

  44. Murakami F, Shimomura T, Kotani K, et al. Anxiety traits associated with a polymorphism in the serotonin transporter gene regulatory region in the Japanese. J Hum Genet 1999; 44(1): 15–7

    PubMed  CAS  Google Scholar 

  45. Ohara K, Suzuki Y, Ochiai M, et al. A variable-number-tandem-repeat of the serotonin transporter gene and anxiety disorders. Prog Neuropsychopharmacol Biol Psychiatry 1999; 23(1): 55–65

    PubMed  CAS  Google Scholar 

  46. Seretti A, Cusin C, Lattuada E, et al. Serotonin transporter gene (5-HTTLPR) is not associated with depressive symptomatology in mood disorders. Mol Psychiatry 1999; 4(3): 280–3

    PubMed  CAS  Google Scholar 

  47. Greenberg BD, Li Q, Lucas FR, et al. Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample. Am J Med Genet 2000; 96(2): 202–16

    PubMed  CAS  Google Scholar 

  48. Osher Y, Hamer D, Benjamin J. Association and linkage of anxiety-related traits with a functional polymorphism of the serotonin transporter gene regulatory region in Israeli sibling pairs. Mol Psychiatry 2000; 5(2): 216–9

    PubMed  CAS  Google Scholar 

  49. Melke J, Baghaei F, Rosmond R, et al. Influence of the serotonin transporter gene on anxiety traits and on the density of paroxetine binding sites in human platelets. Eighth World Congress on Psychiatric Genetics. Am J Med Genet 2000 Aug; 96(4): 536

    Google Scholar 

  50. Melke J, Landen M, Baghei F, et al. Serotonin transporter gene polymorphisms are associated with anxiety-related personality traits in women. Am J Med Genet 2001; 105(5): 458–63

    PubMed  CAS  Google Scholar 

  51. Ebstein RP, Gritsenko I, Nemanov L, et al. No association between the serotonin transporter gene regulatory region polymorphism and the tridimensional personality questionnaire (TPQ) temperament of harm avoidance. Mol Psychiatry 1997; 2(3): 224–6

    PubMed  CAS  Google Scholar 

  52. Nakamura T, Muramatsu T, Ono Y, et al. Serotonin transporter gene regulatory region polymorphism and anxiety-related traits in the Japanese. Am J Med Genet 1997; 74(5): 544–54549

    PubMed  CAS  Google Scholar 

  53. Gelernter J, Kranzler H, Coccaro EF, et al. Serotonin transporter protein gene polymorphism and personality measures in African American and European American subjects. Am J Psychiatry 1998; 155(10): 1332–8

    PubMed  CAS  Google Scholar 

  54. Jorm AF, Henderson AS, Jacomb PA, et al. An association study of a functional polymorphism of the serotonin transporter gene with personality and psychiatric symptoms. Mol Psychiatry 1998; 3(5): 449–51

    PubMed  CAS  Google Scholar 

  55. Flory JD, Manuck SB, Ferrell RE, et al. Neuroticism is not associated with the serotonin transporter (5-HTTLPR) polymorphism. Mol Psychiatry 1999; 4(1): 93–6

    PubMed  CAS  Google Scholar 

  56. Gordon T, Keel J, Hardin TA, et al. Seasonal mood change and neuroticism: The same construct? Compr Psychiatry 1999; 40(6): 415–7

    PubMed  CAS  Google Scholar 

  57. Kumakiri C, Kodama K, Shimizu E, et al. Study of the association between the serotonin transporter gene regulatory region polymorphism and personality traits in a Japanese population. Neurosci Lett 1999; 263(2–3): 205–2051

    PubMed  CAS  Google Scholar 

  58. Gustavsson JP, Nothen MM, Jonsson EG, et al. No association between serotonin transporter gene polymorphisms and personality traits. Am J Med Genet 1999; 88(4): 430–6

    PubMed  CAS  Google Scholar 

  59. Benjamin J, Osher Y, Kotier M, et al. Association between tridimensional personality questionnaire (TPQ) traits and three functional polymorphisms: dopamine receptor D4 (DRD4), serotonin transporter promoter region (5-HTTLPR) and catechol O-methyltransferase (COMT). Mol Psychiatry 2000; 5(1): 96–100

    PubMed  CAS  Google Scholar 

  60. Herbst JH, Zonderman AB, McCrae RR, et al. Do the dimension of the temperament and character inventory map a simple genetic architecture? Evidence from molecular genetics and factor analysis. Am J Psychiatry 2000; 157(8): 1285–90

    PubMed  CAS  Google Scholar 

  61. Jorm AF, Prior M, Sanson A, et al. Association of a functional polymorphism of the serotonin transporter gene with anxiety-related temperament and behavior problems in children: a longitudinal study from infancy to the mid-teens. Mol Psychiatry 2000; 5(5): 542–54

    PubMed  CAS  Google Scholar 

  62. Ebstein RP, Levine J, Geller V, et al. Dopamine D4 receptor and serotonin transporter promoter in the determination of neonatal temperament. Mol Psychiatry 1998; 3(3): 238–46

    PubMed  CAS  Google Scholar 

  63. Delbruck SJW, Wendel B, Grunewald I, et al. A novel allelic variant of the human serotonin transporter gene regulatory polymorphism. Cytogenet Cell Genet 1997; 79(3–4): 214–20

    PubMed  CAS  Google Scholar 

  64. Gelernter J, Cubells JF, Kidd JR, et al. Population studies of polymorphisms of the serotonin transporter protein gene. Am J Med Genet 1999; 88(1): 61–6

    PubMed  CAS  Google Scholar 

  65. Matsushita S, Muramatsu T, Kimura M, et al. Serotonin transporter gene regulatory region polymorphism and panic disorder. Mol Psychiatry 1997; 2(5): 390–2

    PubMed  CAS  Google Scholar 

  66. Ishiguro H, Arinami T, Yamada K, et al. An association study between a transcriptional polymorphism in the serotonin transporter gene and panic disorder in a Japanese population. Psychiatry Clin Neurosci 1997; 51(5): 333–5

    PubMed  CAS  Google Scholar 

  67. Ohara K, Nagai M, Suzuki Y, et al. Association between anxiety disorders and a functional polymorphism in the serotonin transporter gene. Psychiatry Res 1998; 81(2): 277–2798

    PubMed  CAS  Google Scholar 

  68. Hamilton SP, Heiman GA, Haghighi F, et al. Lack of genetic linkage or association between a functional serotonin transporter polymorphism and panic disorder. Psychiatr Genet 1999; 9(1): 1–6

    PubMed  CAS  Google Scholar 

  69. McDougle CJ, Epperson CN, Price LH, et al. Evidence for linkage disequilibrium between serotonin transporter protein gene (SLC6A4) and obsessive compulsive disorder. Mol Psychiatry 1998; 3(3): 270–3

    PubMed  CAS  Google Scholar 

  70. Collier DA, Stober G, Li T, et al. A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry 1996; 1(6): 453–60

    PubMed  CAS  Google Scholar 

  71. Furlong RA, Ho L, Walsh C, et al. Analysis and meta-analysis of two serotonin transporter gene polymorphisms in bipolar and unipolar affective disorders. Am J Med Genet 1998; 81(1): 58–63

    PubMed  CAS  Google Scholar 

  72. Mossner R, Henneberg A, Schmitt A, et al. Allelic variation of serotonin transporter expression is associated with depression in Parkinson’s disease. Mol Psychiatry 2001 6(3): 350–2

    PubMed  CAS  Google Scholar 

  73. Sher L, Hardin TA, Greenberg BD, et al. Seasonality associated with the serotonin transporter promoter repeat length polymorphism. Am J Psychiatry 1999; 156(11): 1837

    PubMed  CAS  Google Scholar 

  74. Rosenthal NE, Mazzanti CM, Barnett RL, et al. Role of serotonin transporter repeat length polymorphism (5-HTTLPR) in seasonality and seasonal affective disorder. Mol Psychiatry 1998; 3(2): 175–7

    PubMed  CAS  Google Scholar 

  75. Kunugi H, Hattori M, Kato T, et al. Serotonin transporter gene polymorphisms: ethnic difference and possible association with bipolar affective disorder. Mol Pyschiatry 1997; 2(6): 457–62

    CAS  Google Scholar 

  76. Rees M, Norton N, Jones I, et al. Association studies of bipolar disorder at the human serotonin transporter gene (hSERT; 5HTT). Mol Psychiatry 1997; 2(5): 398–402

    PubMed  CAS  Google Scholar 

  77. Bellivier F, Henry C, Szoke A, et al. Serotonin transporter gene polymorphisms in patients with unipolar or bipolar depression. Neurosci Lett 1998; 255(3): 143–6

    PubMed  CAS  Google Scholar 

  78. Hoehe MR, Wendel B, Grunewald I, et al. Serotonin transporter (5-HTT) gene polymorphisms are not associated with susceptibility to mood disorders. Am J Med Genet 1998; 81(1): 1–3

    PubMed  CAS  Google Scholar 

  79. Ohara K, Nagai M, Tsukamoto T, et al. Functional polymorphism in the serotonin transporter promoter at the SLC6A4 locus and mood disorders. Biol Psychiatry 1998; 44(7): 550–4

    PubMed  CAS  Google Scholar 

  80. Serretti A, Macciardi F, Di Bella D, et al. Self-esteem in remitted patients with mood disorders is not associated with the dopamine receptor D4 and the serotonin transporter genes. Psychiatry Res 1998 80(2): 137–44

    PubMed  CAS  Google Scholar 

  81. Pollock BG, Ferrell RE, Mulsant BH, et al. Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology 2000; 23(5): 587–90

    PubMed  CAS  Google Scholar 

  82. Kim DK, Lim S-W, Sohn SE, et al. Serotonin transporter gene polymorphism and antidepressant response. Neuroreport 2000; 11(1): 215–9

    PubMed  CAS  Google Scholar 

  83. Serretti A, Lattuada E, Catalano M, et al. Serotonin tranporter gene not associated with psychotic symptomatology of mood disorders. Psychiatry Res 1999; 86(1): 59–65

    PubMed  CAS  Google Scholar 

  84. Russ MJ, Lachman HM, Kashdan T, et al. Analysis of catechol-O-methyl-transferase and 5-hydroxytryptamine transporter polymorphism in patients at risk for suicide [abstract]. American Psychiatric Association 2000 May: 204

    Google Scholar 

  85. Mann JJ, Huang Y-Y, Underwood MD, et al. A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide. Arch Gen Psychiatry 2000; 57(8): 729–38

    PubMed  CAS  Google Scholar 

  86. Ogilvie AD, Battersby S, Bubb VJ, et al. Polymorphism in serotonin transporter gene associated with susceptibility to major depression. Lancet 1996 Mar; 347(9003): 731–3

    PubMed  CAS  Google Scholar 

  87. Battersby S, Ogilvie AD, Smith CAD, et al. Structure of a variable number tandem repeat of the serotonin transporter gene and association with affective disorder. Psychiatr Genet 1996; 6: 177–81

    PubMed  CAS  Google Scholar 

  88. Kunugi H, Tatsumi M, Sakai T, et al. Serotonin transporter gene polymorphism and affective disorder. Lancet 1996 May; 347(9011): 13477

    Google Scholar 

  89. Stober G, Heils A, Lesch KP. Serotonin transporter gene polymorphism and affective disorder. Lancet 1996 May; 347(9011): 1340–1

    PubMed  CAS  Google Scholar 

  90. Oruc L, Verheyen GR, Furac I, et al. Association analysis of the 5-HT2C receptor and 5-HT transporter genes in bipolar disorder. Am J Med Genet 1997; 74(5): 504–6

    PubMed  CAS  Google Scholar 

  91. Esterling LE, Yoshikawa T, Turner G, et al. Serotonin trasnporter (5-HTT) gene and bipolar affective disorder. Am J Med Genet 1998; 81(1): 37–40

    PubMed  CAS  Google Scholar 

  92. Gutierrez B, Arranz MJ, Collier DA, et al. Serotonin transporter gene and risk for bipolar affective disorder: an association study in a Spanish poulation. Biol Psychiatry 1998; 43(11): 844–7

    Google Scholar 

  93. Kirov G, Rees M, Jones I, et al. Bipolar disorder and the serotonin transporter gene: a family-based association study. Psychol Med 1999; 29(5): 1249–54

    PubMed  CAS  Google Scholar 

  94. Vincent JB, Masellis M, Lawrence J, et al. Genetic association analysis of serotonin system genes in bipolar affective disorder. Am J Psychiatry 1999; 156(1): 136–8

    PubMed  CAS  Google Scholar 

  95. Mundo E, Walker M, Tims H, et al. Lack of linkage disequilibrium between serotonin transporter protein gene (SLC6A4) and bipolar disorder. Am J Med Genet 2000; 96(3): 379–83

    PubMed  CAS  Google Scholar 

  96. Kelsoe JR, Remick RA, Sadovnick AD, et al. Genetic linkage study of bipolar disorder and the serotonin transporter. Am J Med Genet 1996; 67(2): 215–7

    PubMed  CAS  Google Scholar 

  97. Mynett-Johnson L, Kealey C, Claffey E, et al. Multimarkerhaplotypes within the serotonin transporter gene suggest evidence of an association with bipolar disorder. Am J Med Genet 2000; 96(6): 845–9

    PubMed  CAS  Google Scholar 

  98. Bellivier F, Laplanche JL, Leboyer M, et al. Serotonin transporter gene and manic depressive illness: an association study. Biol Psychiatry 1997; 41(6): 750–2

    PubMed  CAS  Google Scholar 

  99. Bocchetta A, Piccardi MP, Palmas MA, et al. Family-based association study between bipolar disorder and DRD2, DRD4, DAT, and SERT in Sardinia. Am J Med Genet 1999; 88(5): 522–6

    PubMed  CAS  Google Scholar 

  100. Saleem Q, Ganesh S, Vijaykumar J, et al. Association analysis of 5HT transporter gene in bipolar disorder in the Indian population. Am J Med Genet 2000; 9(2): 170–2

    Google Scholar 

  101. Lejoyeux M. Use of serotonin (5-hydroxytryptamine) reuptake inhibitors in the treatment of alcoholism. Alcohol 1996 Mar; 31Suppl. 1: 69–75

    CAS  Google Scholar 

  102. Tiihonen J, Ryynanen OP, Dauhanen J, et al. Citalopram in the treatment of alcoholism: a double-blind placebo-controlled study. Pharmacopsychiatry 1996; 29(1); 27–9

    PubMed  CAS  Google Scholar 

  103. Landabaso MA, Iraurgi I, Jimenez-Lerma JM, et al. A randomized trial of adding fluoxetine to a naltrexone treatment programme for heroin addicts. Addiction 1998; 93(5): 739–44

    PubMed  CAS  Google Scholar 

  104. Tan EC, Yeo BKL, Ho BKW, et al. Evidence for an association between heroin dependence and a VNTR polymorphism at the serotonin transporter locus. Mol Psychiatry 1999; 4(3): 215–7

    PubMed  CAS  Google Scholar 

  105. Sander T, Harms H, Lesch KP, et al. Association analysis of a regulatory variation of the serotonin transporter gene with severe alcohol dependence. Alcohol Clin Exp Res 1997; 21(8): 1356–9

    PubMed  CAS  Google Scholar 

  106. Hammoumi S, Payen A, Favre J-D, et al. Does the short variant of the serotonin transporter linked polymorphic region constitute a marker of alcohol dependence? Alcohol 1999; 17(2): 107–12

    PubMed  CAS  Google Scholar 

  107. Hallikainen T, Saito T, Lachman HM, et al. Association between low activity serotonin transporter promoter genotype and early onset alcoholism with habitual impulsive violent behavior. Mol Psychiatry 1999; 4(4): 385–8

    PubMed  CAS  Google Scholar 

  108. Sander T, Harms H, Dufeu P, et al. Serotonin transporter gene variants in alcohol-dependent subjects with dissocial personality disorder. Biol Psychiatry 1998; 43(12): 908–12

    PubMed  CAS  Google Scholar 

  109. Ishiguro H, Saito T, Akazawa S, et al. Association between drinking-related antisocial behavior and a polymorphism in the serotonin transporeter gene in a Japanese population. Alcohol Clin Exp Res 1999; 23(7): 1281–4

    PubMed  CAS  Google Scholar 

  110. Edenberg HJ, Reynolds J, Koller DL, et al. A family-based analysis of whether the functional promoter alleles of the serotonin transporter gene HTT affect the risk for alcohol dependence. Alcohol Clin Exp Res 1998; 22(5): 1080–5

    PubMed  CAS  Google Scholar 

  111. Gorwood P, Batel P, Ades J, et al. Serotonin transporter gene polymorphisms, alcoholism, and suicidal behavior. Biol Psychiatry 2000; 48(4): 259–64

    PubMed  CAS  Google Scholar 

  112. Naranjo CA, Bremner KE, Bazoon M, et al. Using fuzzy logic to predict response to citalopram in alcohol dependence. Clin Pharmacol Ther 1997; 62(2): 209–24

    PubMed  CAS  Google Scholar 

  113. Cornelius JR, Salloum IM, Haskett RF, et al. Fluoxetine versus placebo in depressed alcoholics: a 1-year follow-up study. Addict Behav 2000; 25(2) 307–10

    PubMed  CAS  Google Scholar 

  114. Kabel DI, Petty F. A placebo-controlled, double-blind study of fluoxetine in severe alcohol dependence: adjunctive pharmacotherapy during and after inpatient treatment. Alcohol Clin Exp Res 1996; 20(4): 780–4

    PubMed  CAS  Google Scholar 

  115. Kranzler HR, Burleson JA, Korner P, et al. Placebo-controlled trial of fluoxetine as an adjunct to relapse prevention in alcoholics. Am J Psychiatry 1995; 152(3): 391–7

    PubMed  CAS  Google Scholar 

  116. Gerra G, Fertonani G, Zaimovic A, et al. Hostility in heroin abusers subtypes: fluoxetine and naltrexone treatment. Prog Neuropsychopharmacol Biol Psychiatry 1995; 19(8): 1225–37

    PubMed  CAS  Google Scholar 

  117. Hu S, Brody CL, Fisher C, et al. Interaction between the serotonin transporter gene and neuroticism in cigarette smoking behavior. Mol Psychiatry 2000; 5(2): 181–8

    PubMed  CAS  Google Scholar 

  118. Lerman C, Caporaso NE, Audrain J, et al. Interacting effects of the serotonin transporter gene and neuroticism in smoking practices and nicotine dependence. Mol Psychiatry 2000; 5(2): 189–92

    PubMed  CAS  Google Scholar 

  119. Coccaro EF, Kavoussi RJ. Fluoxetine and impulsive aggressive behavior in personality-disordered subjects. Arch Gen Psychiatry 1997; 54(12): 1081–8

    PubMed  CAS  Google Scholar 

  120. Verkes RJ, Van der Mast RC, Hengeveld MW, et al. Reduction by paroxetine of suicidal behavior in patients with repeated suicide attempts but not major depression. Am J Psychiatry 1998; 155(4): 543–7

    PubMed  CAS  Google Scholar 

  121. Bondy B, Erfurth A, de Jonge S, et al. Possible association of the short allele of the serotonin transporter promoter gene polymorphism (5-HTTLPR) with violent suicide. Mol Psychiatry 2000; 5(2): 193–5

    PubMed  CAS  Google Scholar 

  122. Courtet P, Baud P, Abbar M, et al. Association between violent suicidal behavior and the low activity allele of the serotonin transporter gene. Mol Psychiatry 2001; 6(3): 338–41

    PubMed  CAS  Google Scholar 

  123. Bellivier F, Szoke A, Henry C, et al. Possible association between serotonin transporter gene polymorphism and violent suicidal behavior in mood disorders. Biol Psychiatry 2000; 48(4): 319–21

    PubMed  CAS  Google Scholar 

  124. Geijer T, Frisch A, Persson M-L, et al. Search for association between suicide attempt and serotonergic polymorphisms. Psychiatr Genet 2000; 10(1): 19–26

    PubMed  CAS  Google Scholar 

  125. Fitch D, Lesage A, Seguin M, et al. Suicide and the serotonin transporter gene. Mol Psychiatry 2001; 6(2): 127–8

    PubMed  CAS  Google Scholar 

  126. Zalsman G, Frisch A, Bromberg M, et al. Family-based association study of serotonin transporter promoter in suicidal adolescents: no association with suicidality but possible role in violence traits. Am J Med Genet 2000; 105(3): 239–45

    Google Scholar 

  127. Du L, Faludi G, Palkovits M, et al. Frequency of long allele in serotonin transporter gene is increased in depressed suicide victims. Biol Psychiatry 1999; 46(2): 196–201

    PubMed  CAS  Google Scholar 

  128. Evans J, Battersby S, Ogilvie AD, et al. Association of short alleles of a VNTR of the serotonin transporter gene with anxiety symptoms in patients presenting after deliberate self harm. Neuropharmacology 1997; 36(4–5): 439–43

    PubMed  CAS  Google Scholar 

  129. Kumar AM, Kumar M, Sevush S, et al. Serotonin uptake and its kinetics in platelets of women with Alzheimer’s disease. Psychiatry Res 1995; 59(1–2): 145–50

    PubMed  CAS  Google Scholar 

  130. Nyth AL, Gottfries CG. The clinical efficacy of citalopram in treatment of emotional disturbances in dementia disorders. A Nordic multicentre study. Br J Psychiatry 1990 December; 157: 894–901

    PubMed  CAS  Google Scholar 

  131. Pollock BG, Mulsant, BH, Sweet R, et al. An open pilot study of citalopram for behavioral disturbances of dementia. Plasma levels and real-time observations. Am J Geriatric Psychiatry 1997; 5(1): 70–8

    CAS  Google Scholar 

  132. Li T, Holmes C, Sham PC, et al. Allelic functional variation of serotonin transporter expression is a susceptibility factor for late onset Alzheimer’s disease. Neuroreport 1997; 8(4): 683–6

    PubMed  CAS  Google Scholar 

  133. Oliveira JR, Gallindo RM, Maia LG, et al. The short variant of the polymorphism within the promoter region of the serotonin transporter gene is a risk factor for late onset Alzheimer’s disease. Mol Psychiatry 1998; 3(5): 438–41

    PubMed  CAS  Google Scholar 

  134. Kunugi H, Ueki A, Otsuka M, et al. Alzheimer’s disease and 5-HTTLPR polymorphism of the serotonin transporter gene: no evidence for an association. Am J Med Genet 2000; 96(3): 307–9

    PubMed  CAS  Google Scholar 

  135. Zill P, Padberg F, de Jonge S, et al. Serotonin transporter (5-HTT) gene polymorphism in psychogeriatric patients. Neurosci Lett 2000; 284(1–2): 113–5

    PubMed  CAS  Google Scholar 

  136. Sukonick DL, Pollock BG, Sweet RA, et al. The 5-HTTPR polymorphism and aggressive behavior in Alzheimer’s disease. Arch Neurol 2001. In press

  137. Kant R, Smith-Seemiller L, Zeiler D. Treatment of aggression and irritability after head injury. Brain Inj 1998; 12(8): 661–6

    PubMed  CAS  Google Scholar 

  138. Bonnet-Brilhault F, Laurent, C, Thibaut F, et al. Serotonin transporter gene polymorphism and schizophrenia: An association study. Biol Psychiatry 1997; 42(7): 634–6

    PubMed  CAS  Google Scholar 

  139. Mendes de Oliveira JR, Otto PA, Vallada H, et al. Analysis of a novel functional polymorphism within the promoter region of the serotonin transporter gene (5-HTT) in Brazilian patients affected by bipolar disorder and schizophrenia. Am J Med Genet 1998; 81(3): 225–7

    PubMed  CAS  Google Scholar 

  140. Rao D, Jonsson EG, Paus S, et al. Schizophrenia and the serotonin transporter gene. Psychiatr Genet 1998; 8(4): 207–12

    PubMed  CAS  Google Scholar 

  141. Stober G, Jatzke S, Heils A, et al. Susceptibility for schizophrenia is not influenced by a functional insertion/deletion variant in the promoter of the serotonin transporter gene. Eur Arch Psychiatry Clin Neurosci 1998; 248(1): 82–6

    PubMed  CAS  Google Scholar 

  142. Serretti A, Catalano M, Smeraldi E. Serotonin transporter gene is not associated with symptomatology of schizophrenia. Schizophr Res 1999; 35(1): 33–9

    PubMed  CAS  Google Scholar 

  143. Hranilovic D, Schwab SG, Jernej B, et al. Serotonin transporter gene and schizophrenia: evidence for association/linkage disequilibrium in families with affected siblings. Mol Psychiatry 2000; 5(1): 91–5

    PubMed  CAS  Google Scholar 

  144. Tsai S-J, Hong C-J, Yu Y W-Y, et al. Association study of a functional serotonin transporter gene polymorphism with schizophrenia, psychopathology and clozapine response. Schizophr Res 2000; 44(3): 177–81

    PubMed  CAS  Google Scholar 

  145. Malhotra AK, Goldman D, Mazzanti C, et al. A functional serotonin transporter (5-HTT) polymorphism is associated with psychosis in neuroleptic-free schizophrenics. Mol Psychiatry 1998; 3(4): 328–32

    PubMed  CAS  Google Scholar 

  146. Kaiser R, Tremblay P-B, Schmider J, et al. Serotonin transporter polymorphisms: no association with response to antipsychotic treatment, but associations with the schizoparanoid and residual subtypes of schizophrenia. Mol Psychiatry 2001; 6(2): 179–85

    PubMed  CAS  Google Scholar 

  147. Chong S-A, Tan E-C, Tan C-H, et al. Tardive dyskinesia is not associated with the serotonin gene polymorphism (5-HTTLPR) in Chinese. Am J Med Genet 2000; 96(6): 712–6

    PubMed  CAS  Google Scholar 

  148. Modai I, Gibel A, Rauchverger B, et al. Paroxetine binding in aggressive schizophrenic patients. Psychiatry Res 2000; 94(1): 77–81

    PubMed  CAS  Google Scholar 

  149. Vartiainen H, Tiihonen J, Putkonen A, et al. Citalopram, a selective serotonin reuptake inhibitor, in the treatment of aggression in schizophrenia. Acta Psychiatr Scand 1996; 91(5): 348–51

    Google Scholar 

  150. Gordon CT, State RC, Nelson JE, et al. A double-blind comparison of clomipramine, desipramine, and placebo in the treatment of autistic disorder. Arch Gen Psychiatry 1993; 50(6): 441–7

    PubMed  CAS  Google Scholar 

  151. McDougle CJ, Naylor ST, Cohen DJ, et al. A double-blind, placebo-controlled study of fluvoxamine in adults with autistic disorder. Arch Gen Psychiatry 1996; 53(11): 1001–8

    PubMed  CAS  Google Scholar 

  152. Fatemi SH, Realmuto GM, Khan L, et al. Fluoxetine in treatment of adolescent patients with autism: a longitudinal open trial. J Autism Dev Disord 1998; 28(4): 303–7

    PubMed  CAS  Google Scholar 

  153. Scahill L, Koenig K. Pharmacotherapy in children and adolescents with pervasive developmental disorders. J Child Adolesc Psychiatr Nursing 1999; 12(1): 41–3

    CAS  Google Scholar 

  154. DeLong GR, Teague LA, McSwain Kamran M. Effects of fluoxetine treatment in young children with idiopathic autism. Dev Med Child Neurol 1998; 40(8): 551–62

    PubMed  CAS  Google Scholar 

  155. Klauck SM, Poustka F, Benner A, et al. Serotonin transporter (5-HTT) gene variants associated with autism. Hum Mol Genet 1997; 6(13): 2233–8

    PubMed  CAS  Google Scholar 

  156. Yirmiya N, Pilowsky T, Nemanov L, et al. Evidence for an association with the serotonin transporter promoter region polymorphism and autism. Am J Med Genet 2001; 105(4): 381–6

    PubMed  CAS  Google Scholar 

  157. Cook Jr, EH, Courchesne R, Lord C, et al. Evidence of linkage between the serotonin transporter and autistic disorder. Mol Psychiatry 1997; 2(3): 247–50

    PubMed  Google Scholar 

  158. Maestrini E, Lai C, Marlow A, et al. Serotonin transporter (5-HHT) and gamma-aminobutyric acid receptor subunit beta3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families. Am J Med Genet 1999; 88(5): 492–6

    PubMed  CAS  Google Scholar 

  159. Persico AM, Militerai R, Bravaccio C, et al. Lack of association between serotonin transporter gene promoter variants and autistic disorder in two ethnically distinct samples. Am J Med Genet 2000; 96(1): 123–7

    PubMed  CAS  Google Scholar 

  160. Tordjman S, Gutknecht L, Carlier M, et al. Role of the serotonin transporter gene in the behavioral expression of autism. Mol Psychiatry 2001; 6(4): 434–9

    PubMed  CAS  Google Scholar 

  161. Manor I, Eisenberg J, Tyano S, et al. Family-based association study of the serotonin transporter promoter region polymorphism (5-HTTLPR) in attention deficit hyperactivity disorder. Am J Med Genet 2001; 105(1): 91–5

    PubMed  CAS  Google Scholar 

  162. Seeger G, Schloss P, Schmidt MH. Functional polymorphism within the promoter of the serotonin transporter gene is associated with severe hyperkinetic disorders. Mol Psychiatry 2001; 6(2): 235–8

    PubMed  CAS  Google Scholar 

  163. Smeraldi E, Zanardi R, Benedetti F, et al. Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol Psychiatry 1998; 3(6): 508–11

    PubMed  CAS  Google Scholar 

  164. Zanardi R, Benedetti F, Serretti A, et al. Genetic influence on response to serotonergic antidepressants. Eighth World Congress on Psychiatric Genetics. Am J Med Genet 2000 Aug; 96(4): 538

    Google Scholar 

  165. Zanardi R, Benedetti F, Di Bella D, et al. Efficacy of paroxetine in depression is influenced by a functional polymorphism within the promoter of the serotonin transporter gene. J Clin Psychopharmacol 2000; 20(1): 105–6

    PubMed  CAS  Google Scholar 

  166. Arias, B, Gasto C, Catalan R, et al. Variation in the serotonin transporter gene and clinical response to citalopram in major depression. Eighth World Congress on Psychiatric Genetics. Am J Med Genet 2000 Aug; 96(4): 536

    Google Scholar 

  167. Rausch JL, Fei Y, Li J, et al. SERT genotype influence in fluoxetine antidepressant response: a study of initial conditions. Biol Psychiatry 2000; 47 Suppl.: 92S–3S

    Google Scholar 

  168. Benedetti F, Serretti A, Colombo C, et al. Influence of a functional polymorphism within the promoter of the serotonin transporter gene on the effects of total sleep deprivation in bipolar depression. Am J Psychiatry 1999; 156(9): 1450–2

    PubMed  CAS  Google Scholar 

  169. Benedetti F, Colombo C, Barbini B, et al. Genetic differences in antidepressant response to sleep deprivation. Eighth World Congress on Psychiatric Genetics. Am J Med Genet 2000 Aug; 96(4): 537

    Google Scholar 

  170. New AS, Woo-Ming A, Mitropoulou V, et al. Serotonin and the prediction of response time to fluoxetine in patients with mild depression. Psychiatry Res 1999; 88(1): 89–93

    PubMed  CAS  Google Scholar 

  171. Cleare AJ, Muray RM, O’Keane, V. Assessment of serotonergic function in major depression using d-fenfluramine: relation to clinical variables and antidepressant response. Biol Psychiatry 1998; 44(7): 555–61

    PubMed  CAS  Google Scholar 

  172. Whale R, Quested DJ, Harrison PJ, et al. Serotonin transporter (5-HTT) promoter genotype may influence the prolactin response to clomipramine. Psychophar-macology Berl 2000; 150(1): 120–2

    CAS  Google Scholar 

  173. Reist C, Mazzanti C, Vu R, et al. Serotonin transporter promoter polymorphism is associated with attenuated prolactin response to fenfluramine. Am J Med Genet 2001; 105(4): 363–8

    PubMed  CAS  Google Scholar 

  174. Billet EA, Richter MA, King N, et al. Obsessive compulsive disorder, response to serotonin reuptake inhibitors and the serotonin transporter gene. Mol Psychiatry 1997; 2(5): 403–6

    Google Scholar 

  175. Di Bella D, Ergegovesi S, Cavallini MC, et al. Obsessive-compulsive disorder, treatment response and the 5HTT gene. Eighth World Congress on Psychiatric Genetics. Am J Med Genet 2000 Aug; 96(4): 536

    Google Scholar 

  176. McBride PA, Tierney H, DeMeo H, et al. Effects of age and gender on CNS serotonergic responsivity in normal adults. Biol Psychiatry 1990; 27: 1143–55

    PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by the National Institute of Mental Health (MH01509, MH59666, MH52247, and MH30915)

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Authors and Affiliations

  1. Department of Psychiatry, Western Psychiatric Institute and Clinics, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA

    Francis E. Lotrich &  Bruce G. Pollock

  2. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Robert E. Ferrell

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  1. Francis E. Lotrich
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  2. Bruce G. Pollock
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  3. Robert E. Ferrell
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Correspondence to Bruce G. Pollock.

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Lotrich, F.E., Pollock, B.G. & Ferrell, R.E. Polymorphism of the Serotonin Transporter. Am J Pharmacogenomics 1, 153–164 (2001). https://doi.org/10.2165/00129785-200101030-00001

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