Skip to main content
SpringerLink
Log in

Serotonin transporter genotype and function in relation to antidepressant response in Koreans

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Serotonin transporter (5-HTT) gene polymorphisms are linked with antidepressant response to selective serotonin reuptake inhibitor drugs (SSRIs), though the favorable allelic variant differs by ethnic group (Caucasian versus Korean or Japanese). In Caucasian patients, response also is linked to measures of platelet 5-HTT function.

Objectives

Here, we study both 5-HTT gene polymorphisms and 5-HTT function as determinants of antidepressant response to SSRIs in Korean patients.

Methods

We enrolled 99 patients with major depression and 48 control subjects. For statistical power, both samples were enriched with the l/l 5-HTTLPR polymorphism, which is uncommon in Koreans. Patients were treated with fluoxetine or sertraline. Response was assessed at 6 weeks. Subjects were genotyped for s/l polymorphism in the 5-HTT promoter region (5-HTTLPR). Platelet 5-HTT activity was determined as maximal uptake rate (Vmax) and affinity constant (Km).

Results

Response was differentially associated with the s allele of 5-HTTLPR, which also was significantly associated with Vmax. These associations are opposite to those reported in Caucasian populations. Responders had significantly higher Vmax and Km than nonresponders. In Koreans as well as Caucasians, high Vmax is related to antidepressant response to SSRIs, though the 5-HTTLPR polymorphism associations with both response and function differ by ethnicity.

Conclusions

Both ethnicity and function must be considered in evaluating candidate gene biomarkers of response to SSRIs in depression.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • American Psychiatric Association (2000) Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR, 4th edn. American Psychiatric Association, Washington, DC

    Google Scholar 

  • Anderson IM (2000) Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. J Affect Disord 58:19–36

    Article  PubMed  CAS  Google Scholar 

  • Colligan RC, Osborne D, Swenson WM, Offord KP (1984) The MMPI: development of contemporary norms. J Clin Psychol 40:100–107

    Article  PubMed  CAS  Google Scholar 

  • Da Prada M, Cesura AM, Launay JM, Richards JG (1988) Platelets as a model for neurones? Experientia 44:115–126

    Article  PubMed  Google Scholar 

  • Franke L, Schewe HJ, Uebelhack R, Muller-Oerlinghausen B (2003) High platelet-serotonin uptake activity is associated with a rapid response in depressed patients treated with amitriptyline. Neurosci Lett 345:105–108

    Article  PubMed  CAS  Google Scholar 

  • Fredman SJ, Fava M, Kienke AS, White CN, Nierenberg AA, Rosenbaum JF (2000) Partial response, nonresponse, and relapse with selective serotonin reuptake inhibitors in major depression: a survey of current “next-step” practices. J Clin Psychiatry 61:403–408

    Article  PubMed  CAS  Google Scholar 

  • Gelernter J, Kranzler H, Cubells JF (1997) Serotonin transporter protein (SLC6A4) allele and haplotype frequencies and linkage disequilibria in African- and European-American and Japanese populations and in alcohol-dependent subjects. Hum Genet 101:243–246

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Hachisu M, Ichimaru Y (2000) Pharmacological and clinical aspects of fluvoxamine (Depromel), the first selective serotonin reuptake inhibitor approved for clinical use employed in Japan. Nippon Yakurigaku Zasshi 115:271–279

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D, Lesch KP (1996) Allelic variation of human serotonin transporter gene expression. J Neurochem 66:2621–2624

    Article  PubMed  CAS  Google Scholar 

  • Heils A, Mossner R, Lesch KP (1997) The human serotonin transporter gene polymorphism—basic research and clinical implications. J Neural Transm 104:1005–1014

    Article  PubMed  CAS  Google Scholar 

  • Hranilovic D, Stefulj J, Schwab S, Borrmann-Hassenbach M, Albus M, Jernej B, Wildenauer D (2004) Serotonin transporter promoter and intron 2 polymorphisms: relationship between allelic variants and gene expression. Biol Psychiatry 55:1090–1094. doi:10.1016/j.biopsych.2004.01.029

    Article  PubMed  CAS  Google Scholar 

  • Kim DK, Lim SW, Lee S, Sohn SE, Kim S, Hahn CG, Carroll BJ (2000) Serotonin transporter gene polymorphism and antidepressant response. Neuroreport 11:215–219

    Article  PubMed  CAS  Google Scholar 

  • Kim H, Lim SW, Kim S, Kim JW, Chang YH, Carroll BJ, Kim DK (2006) Monoamine transporter gene polymorphisms and antidepressant response in Koreans with late-life depression. JAMA 296:1609–1618. doi:10.1001/jama.296.13.1609

    Article  PubMed  CAS  Google Scholar 

  • Kiyohara C, Yoshimasu K (2009) Molecular epidemiology of major depressive disorder. Environ Health Prev Med 14:71–87. doi:10.1007/s12199-008-0073-6

    Article  PubMed  CAS  Google Scholar 

  • Kugaya A, Sanacora G, Staley JK, Malison RT, Bozkurt A, Khan S, Anand A, Van Dyck CH, Baldwin RM, Seibyl JP, Charney D, Innis RB (2004) Brain serotonin transporter availability predicts treatment response to selective serotonin reuptake inhibitors. Biol Psychiatry 56:497–502. doi:10.1016/j.biopsych.2004.07.001

    Article  PubMed  CAS  Google Scholar 

  • Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531

    Article  PubMed  CAS  Google Scholar 

  • Mellerup E, Bennike B, Bolwig T, Dam H, Hasholt L, Jorgensen MB, Plenge P, Sorensen SA (2001) Platelet serotonin transporters and the transporter gene in control subjects, unipolar patients and bipolar patients. Acta Psychiatr Scand 103:229–233

    Article  PubMed  CAS  Google Scholar 

  • Meltzer HY, Arora RC, Baber R, Tricou BJ (1981) Serotonin uptake in blood platelets of psychiatric patients. Arch Gen Psychiatry 38:1322–1326

    Article  PubMed  CAS  Google Scholar 

  • Nobile M, Begni B, Giorda R, Frigerio A, Marino C, Molteni M, Ferrarese C, Battaglia M (1999) Effects of serotonin transporter promoter genotype on platelet serotonin transporter functionality in depressed children and adolescents. J Am Acad Child Adolesc Psychiatry 38:1396–1402. doi:10.1097/00004583-199911000-00014

    Article  PubMed  CAS  Google Scholar 

  • O’Reilly RL, Bogue L, Singh SM (1994) Pharmacogenetic response to antidepressants in a multicase family with affective disorder. Biol Psychiatry 36:467–471

    Article  PubMed  Google Scholar 

  • Orsulak PJ, Liu PK, Akers LC (2001) Antidepressant drugs. In: Shaw LM (ed) Clinical toxicology laboratory: contemporary practice of poisoning evaluation. AACC Press, Washington, DC, pp 223–236

    Google Scholar 

  • Owens MJ, Nemeroff CB (1994) Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem 40:288–295

    PubMed  CAS  Google Scholar 

  • Peterson NA, Raghupathy E (1973) Developmental transitions in uptake of amino acids by synaptosomal fractions isolated from rat cerebral cortex. J Neurochem 21:97–110

    Article  PubMed  CAS  Google Scholar 

  • Pollock BG, Ferrell RE, Mulsant BH, Mazumdar S, Miller M, Sweet RA, Davis S, Kirshner MA, Houck PR, Stack JA, Reynolds CF, Kupfer DJ (2000) Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology 23:587–590. doi:10.1016/S0893-133X(00)00132-9

    Article  PubMed  CAS  Google Scholar 

  • Porcelli S, Fabbri C, Serretti A (2012) Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy. Eur Neuropsychopharmacol 4:239–258

    Article  Google Scholar 

  • Ramamoorthy S, Giovanetti E, Qian Y, Blakely RD (1998) Phosphorylation and regulation of antidepressant-sensitive serotonin transporters. J Biol Chem 273:2458–2466

    Article  PubMed  CAS  Google Scholar 

  • Rausch JL (2005) Initial conditions of psychotropic drug response: studies of serotonin transporter long promoter region (5-HTTLPR), serotonin transporter efficiency, cytokine and kinase gene expression relevant to depression and antidepressant outcome. Prog Neuropsychopharmacol Biol Psychiatry 29:1046–1061. doi:10.1016/j.pnpbp.2005.03.011

    Article  PubMed  CAS  Google Scholar 

  • Rausch JL, Johnson ME, Fei YJ, Li JQ, Shendarkar N, Hobby HM, Ganapathy V, Leibach FH (2002) Initial conditions of serotonin transporter kinetics and genotype: influence on SSRI treatment trial outcome. Biol Psychiatry 51:723–732

    Article  PubMed  CAS  Google Scholar 

  • Shaw DM, MacSweeney DA, Woolcock N, Bevan-Jones AB (1971) Uptake and release of 14 C-5-hydroxytryptamine by platelets in affective illness. J Neurol Neurosurg Psychiatry 34:224–225

    Article  PubMed  CAS  Google Scholar 

  • Slotkin TA, McCook EC, Ritchie JC, Seidler FJ (1996) Do glucocorticoids contribute to the abnormalities in serotonin transporter expression and function seen in depression? An animal model. Biol Psychiatry 40:576–584

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Taylor MJ, Sen S, Bhagwagar Z (2010) Antidepressant response and the serotonin transporter gene-linked polymorphic region. Biol Psychiatry 68:536–543

    Article  PubMed  CAS  Google Scholar 

  • Tournel G, Houdret N, Hedouin V, Deveau M, Gosset D, Lhermitte M (2001) High-performance liquid chromatographic method to screen and quantitate seven selective serotonin reuptake inhibitors in human serum. J Chromatogr B Biomed Sci Appl 761:147–158

    Article  PubMed  CAS  Google Scholar 

  • Walsh BT, Seidman SN, Sysko R, Gould M (2002) Placebo response in studies of major depression: variable, substantial, and growing. JAMA 287:1840–1847

    Article  PubMed  Google Scholar 

  • Wirz-Justice A, Puhringer W (1978) Seasonal incidence of an altered diurnal rhythm of platelet serotonin in unipolar depression. J Neural Transm 42:45–53

    Article  PubMed  CAS  Google Scholar 

  • Yoshida K, Ito K, Sato K, Takahashi H, Kamata M, Higuchi H, Shimizu T, Itoh K, Inoue K, Tezuka T, Suzuki T, Ohkubo T, Sugawara K, Otani K (2002) Influence of the serotonin transporter gene-linked polymorphic region on the antidepressant response to fluvoxamine in Japanese depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 26:383–386

    Article  PubMed  CAS  Google Scholar 

  • Yu YW, Tsai SJ, Chen TJ, Lin CH, Hong CJ (2002) Association study of the serotonin transporter promoter polymorphism and symptomatology and antidepressant response in major depressive disorders. Mol Psychiatry 7:1115–1119. doi:10.1038/sj.mp.4001141

    Article  PubMed  CAS  Google Scholar 

  • Zivin JA, Waud DR (1982) How to analyze binding, enzyme and uptake data: the simplest case, a single phase. Life Sci 30:1407–1422

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the Korea Science and Engineering Foundation (KOSEF) NRL Program (Grant R0A-2007-000-20129-0), the Korean Health Technology R&D Project from Ministry of Health & Welfare (A110339), Center for Genome Research of Samsung Biomedical Research Institute (GRC-P-10-03), and Samsung Biomedical Research Institute grant (C-A9-205). Dr. Carroll has received royalties from MultiHealth Systems, Toronto (licensee for the Carroll Depression Scales); royalty from Springer Publishing Company (for a published chapter); and honoraria for lectures sponsored by the South Carolina Psychiatric Association and the Brentwood Biomedical Research Institute at The University of California, Los Angeles. The sponsors of this study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Conflict of interest

The authors have declared that no conflict of interest exists.

Disclosure

All of the authors declare that they have no relationship with the organization supporting this research and no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Kangnam-gu, Seoul, 135-710, Korea

    Woojae Myung, Hyeran Kim, Jae Won Chung, Min Young Seo & Doh Kwan Kim

  2. Center for Clinical Research, Samsung Biomedical Research Institute, Seoul, Korea

    Shinn-Won Lim

  3. Biostatistics Team, Samsung Biomedical Research Institute, Seoul, Korea

    Seonwoo Kim

  4. Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    Jong-Won Kim

  5. Pacific Behavioral Research Foundation, Carmel, CA, USA

    Bernard J. Carroll

Authors
  1. Woojae Myung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shinn-Won Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seonwoo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hyeran Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jae Won Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Min Young Seo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jong-Won Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bernard J. Carroll
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Doh Kwan Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Doh Kwan Kim.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Myung, W., Lim, SW., Kim, S. et al. Serotonin transporter genotype and function in relation to antidepressant response in Koreans. Psychopharmacology 225, 283–290 (2013). https://doi.org/10.1007/s00213-012-2813-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-012-2813-y

Keywords

Search

Navigation