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Moderation of antidepressant response by the serotonin transporter gene

  • Patricia Huezo-Diaz (a1), Rudolf Uher (a1), Rebecca Smith (a1), Marcella Rietschel (a2), Neven Henigsberg (a3), Andrej Marušiˇ (a4), Ole Mors (a5), Wolfgang Maier (a6), Joanna Hauser (a7), Daniel Souery (a8), Anna Placentino (a9), Astrid Zobel (a6), Erik Roj Larsen (a10), Piotr M. Czerski (a7), Bhanu Gupta (a1), Farzana Hoda (a1), Nader Perroud (a1), Anne Farmer (a1), Ian Craig (a1), Katherine J. Aitchison (a1) and Peter McGuffin (a1)...



There have been conflicting reports on whether the length polymorphism in the promoter of the serotonin transporter gene (5-HTTLPR) moderates the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs). We hypothesised that the pharmacogenetic effect of 5-HTTLPR is modulated by gender, age and other variants in the serotonin transporter gene.


To test the hypothesis that the 5-HTTLPR differently influences response to escitalopram (an SSRI) compared with nortriptyline (a noradrenaline reuptake inhibitor).


The 5-HTTLPR and 13 additional markers across the serotonin transporter gene were genotyped in 795 adults with moderate-to-severe depression treated with escitalopram or nortriptyline in the Genome Based Therapeutic Drugs for Depression (GENDEP) project.


The 5-HTTLPR moderated the response to escitalopram, with long-allele carriers improving more than short-allele homozygotes. A significant three-way interaction between 5-HTTLPR, drug and gender indicated that the effect was concentrated in males treated with escitalopram. The single-nucleotide polymorphism rs2020933 also influenced outcome.


The effect of 5-HTTLPR on antidepressant response is SSRI specific conditional on gender and modulated by another polymorphism at the 5' end of the serotonin transporter gene.

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Corresponding author

Rudolf Uher, P080, Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, 16 De Crespigny Park, London SE5 8AF UK. Email:


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These authors contributed equally to the work.

The GENDEP study was funded by a European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428. Lundbeck provided both nortriptyline and escitalopram free of charge for the GENDEP study. GlaxoSmithKline contributed by funding an add-on project in the London centre. The sponsors had no role in the design and conduct of the study, in data collection, analysis, interpretation or writing the report.

Declaration of interest

N.H. participated in clinical trials sponsored by pharmaceutical companies including GlaxoSmithKline and Lundbeck. A.F, P.M. and K.J.A have received consultancy fees and honoraria for participating in expert panels from pharmaceutical companies, including Lundbeck and GlaxoSmithKline.



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1 Thase, ME, Entsuah, AR, Rudolph, RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry 2001; 178: 234–41.
2 Trivedi, MH, Rush, AJ, Wisniewski, SR, Nierenberg, AA, Warden, D, Ritz, L, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163: 2840.
3 Franchini, L, Serretti, A, Gasperini, M, Smeraldi, E. Familial concordance of fluvoxamine response as a tool for differentiating mood disorder pedigrees. J Psychiatr Res 1998; 32: 255–9.
4 Uher, R, McGuffin, P. The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis. Mol Psychiatry 2008; 13: 131–46.
5 Lesch, KP, Balling, U, Gross, J, Strauss, K, Wolozin, BL, Murphy, DL, et al. Organization of the human serotonin transporter gene. J Neural Transm Gen Sect 1994; 95: 157–62.
6 Smeraldi, E, Zanardi, R, Benedetti, F, Di, BD, Perez, J, Catalano, M. Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol Psychiatry 1998; 3: 508–11.
7 Serretti, A, Kato, M, De, RD, Kinoshita, T. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients. Mol Psychiatry 2007; 12: 247–57.
8 Kim, H, Lim, SW, Kim, S, Kim, JW, Chang, YH, Carroll, BJ, et al. Monoamine transporter gene polymorphisms and antidepressant response in Koreans with late-life depression. JAMA 2006; 296: 1609–18.
9 Kraft, JB, Peters, EJ, Slager, SL, Jenkins, GD, Reinalda, MS, McGrath, PJ, et al. Analysis of association between the serotonin transporter and antidepressant response in a large clinical sample. Biol Psychiatry 2007; 61: 734–42.
10 Mrazek, DA, Rush, AJ, Biernacka, JM, O'Kane, DJ, Cunningham, JM, Wieben, ED, et al. SLC6A4 variation and citalopram response. Am J Med Genet B Neuropsychiatr Genet 2009; 150B: 341–51.
11 Gelernter, J, Cubells, JF, Kidd, JR, Pakstis, AJ, Kidd, KK. Population studies of polymorphisms of the serotonin transporter protein gene. Am J Med Genet 1999; 88: 61–6.
12 Hu, X, Oroszi, G, Chun, J, Smith, TL, Goldman, D, Schuckit, MA. An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk. Alcohol Clin Exp Res 2005; 29: 816.
13 Kraft, JB, Slager, SL, McGrath, PJ, Hamilton, SP. Sequence analysis of the serotonin transporter and associations with antidepressant response. Biol Psychiatry 2005; 58: 374–81.
14 Wendland, JR, Martin, BJ, Kruse, MR, Lesch, KP, Murphy, DL. Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531. Mol Psychiatry 2006; 11: 224–6.
15 Braganca, J, Eloranta, JJ, Bamforth, SD, Ibbitt, JC, Hurst, HC, Bhattacharya, S. Physical and functional interactions among AP-2 transcription factors, p300/CREB-binding protein, and CITED2. J Biol Chem 2003; 278: 16021–9.
16 Damberg, M. Transcription factor AP-2 and monoaminergic functions in the central nervous system. J Neural Transm 2005; 112: 1281–96.
17 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: 815–26.
18 Martin, J, Cleak, J, Willis-Owen, SA, Flint, J, Shifman, S. Mapping regulatory variants for the serotonin transporter gene based on allelic expression imbalance. Mol Psychiatry 2007; 12: 421–2.
19 MacKenzie, A, Quinn, J. A serotonin transporter gene intron 2 polymorphic region, correlated with affective disorders, has allele-dependent differential enhancer-like properties in the mouse embryo. Proc Natl Acad Sci USA 1999; 96: 15251–5.
20 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: 339–46.
21 Tauscher, J, Verhoeff, NP, Christensen, BK, Hussey, D, Meyer, JH, Kecojevic, A, et al. Serotonin 5-HT1A receptor binding potential declines with age as measured by [11C]WAY-100635 and PET. Neuropsychopharmacology 2001; 24: 522–30.
22 van Dyck, CH, Malison, RT, Seibyl, JP, Laruelle, M, Klumpp, H, Zoghbi, SS, et al. Age-related decline in central serotonin transporter availability with [(123)I]beta-CIT SPECT. Neurobiol Aging 2000; 21: 497501.
23 Yamamoto, M, Suhara, T, Okubo, Y, Ichimiya, T, Sudo, Y, Inoue, M, et al. Age-related decline of serotonin transporters in living human brain of healthy males. Life Sci 2002; 71: 751–7.
24 Hiroi, R, McDevitt, RA, Neumaier, JF. Estrogen selectively increases tryptophan hydroxylase-2 mRNA expression in distinct subregions of rat midbrain raphe nucleus: association between gene expression and anxiety behavior in the open field. Biol Psychiatry 2006; 60: 288–95.
25 Biegon, A, McEwen, BS. Modulation by estradiol of serotonin receptors in brain. J Neurosci 1982; 2: 199205.
26 Sumner, BE, Fink, G. The density of 5-hydoxytryptamine2A receptors in forebrain is increased at pro-oestrus in intact female rats. Neurosci Lett 1997; 234: 710.
27 Wissink, S, van der, BB, Katzenellenbogen, BS, van der Saag, PT. Synergistic activation of the serotonin-1A receptor by nuclear factor-kappa B and estrogen. Mol Endocrinol 2001; 15: 543–52.
28 Lu, NZ, Eshleman, AJ, Janowsky, A, Bethea, CL. Ovarian steroid regulation of serotonin reuptake transporter (SERT) binding, distribution, and function in female macaques. Mol Psychiatry 2003; 8: 353–60.
29 McQueen, JK, Wilson, H, Fink, G. Estradiol-17 beta increases serotonin transporter (SERT) mRNA levels and the density of SERT-binding sites in female rat brain. Brain Res Mol Brain Res 1997; 45: 1323.
30 Walderhaug, E, Magnusson, A, Neumeister, A, Lappalainen, J, Lunde, H, Refsum, H, et al. Interactive effects of sex and 5-HTTLPR on mood and impulsivity during tryptophan depletion in healthy people. Biol Psychiatry 2007; 62: 593–99.
31 Sjoberg, RL, Nilsson, KW, Nordquist, N, Ohrvik, J, Leppert, J, Lindstrom, L, et al. Development of depression: sex and the interaction between environment and a promoter polymorphism of the serotonin transporter gene. Int J Neuropsychopharmacol 2006; 9: 443–9.
32 Uher, R, Maier, W, Hauser, J, Marušič, A, Schmael, C, Mors, O, et al. Differential efficacy of escitalopram and nortriptyline on dimensional measures of depression. Br J Psychiatry 2009; 194: 252–9.
33 World Health Organization. The ICD–10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. WHO, 1992.
34 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorder (4th edn) (DSM–IV). APA, 1994.
35 Wing, JK, Sartorius, N, Ustin, TB. Diagnosis and Clinical Measurement in Psychiatry. A Reference Manual for SCAN. World Health Organization, 1998.
36 Montgomery, SA, Åsberg, M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134: 382–9.
37 Hamilton, M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 5662.
38 Hamilton, M. Development of a rating scale for primary depressive illness. Br J Clin Psychol 1967; 6: 278–96.
39 Beck, AT, Ward, CH, Mendelson, M, Mock, J, Erbaugh, J. An inventory for measuring depression. Arch Gen Psychiatry 1961; 4: 561–71.
40 Lingjaerde, O, Ahlfors, UG, Bech, P, Dencker, SJ, Elgen, K. The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand Suppl 1987; 334: 1100.
41 Uher, R, Farmer, A, Henigsberg, N, Rietschel, M, Mors, O, Maier, W, et al. Adverse reactions to antidepressants. Br J Psychiatry in press.
42 Uher, R, Farmer, A, Maier, W, Rietschel, M, Hauser, J, Marusic, A, et al. Measuring depression: comparison and integration of three scales in the GENDEP study. Psychol Med 2008; 38: 289300.
43 Freeman, B, Smith, N, Curtis, C, Huckett, L, Mill, J, Craig, IW. DNA from buccal swabs recruited by mail: evaluation of storage effects on long-term stability and suitability for multiplex polymerase chain reaction genotyping. Behav Genet 2003; 33: 6772.
44 De Bakker, PI, Yelensky, R, Pe'er, I, Gabriel, SB, Daly, MJ, Altshuler, D. Efficiency and power in genetic association studies. Nat Genet 2005; 37: 1217–23.
45 Seldin, MF, Shigeta, R, Villoslada, P, Selmi, C, Tuomilehto, J, Silva, G, et al. European population substructure: clustering of northern and southern populations. PLoS Genet 2006; 2: e143.
46 Barrett, JC, Fry, B, Maller, J, Daly, MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–5.
47 Wittke-Thompson, JK, Pluzhnikov, A, Cox, NJ. Rational inferences about departures from Hardy-Weinberg equilibrium. Am J Hum Genet 2005; 76: 967–86.
48 Stephens, M, Donnelly, P. A comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 2003; 73: 1162–9.
49 Stephens, M, Smith, NJ, Donnelly, P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978–89.
50 Cordell, HJ. Estimation and testing of genotype and haplotype effects in case-control studies: comparison of weighted regression and multiple imputation procedures. Genet Epidemiol 2006; 30: 259–75.
51 Falush, D, Stephens, M, Pritchard, JK. Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies. Genetics 2003; 164: 1567–87.
52 Devlin, B, Roeder, K. Genomic control for association studies. Biometrics 1999; 55: 9971004.
53 Purcell, S, Neale, B, Todd-Brown, K, Thomas, L, Ferreira, MA, Bender, D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–75.
54 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: 323–30.
55 Weiss, LA, Abney, M, Cook, EH Jr, Ober, C. Sex-specific genetic architecture of whole blood serotonin levels. Am J Hum Genet 2005; 76: 3341.
56 Morgan, ML, Cook, IA, Rapkin, AJ, Leuchter, AF. Estrogen augmentation of antidepressants in perimenopausal depression: a pilot study. J Clin Psychiatry 2005; 66: 774–80.
57 Soares, CN, Almeida, OP, Joffe, H, Cohen, LS. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry 2001; 58: 529–34.
58 Katz, MM, Koslow, SH, Frazer, A. Onset of antidepressant activity: reexamining the structure of depression and multiple actions of drugs. Depress Anxiety 1996; 4: 257–67.
59 Serretti, A, Mandelli, L, Lorenzi, C, Pirovano, A, Olgiati, P, Colombo, C, et al. Serotonin transporter gene influences the time course of improvement of “core” depressive and somatic anxiety symptoms during treatment with SSRIs for recurrent mood disorders. Psychiatry Res 2007; 149: 185–93.
60 Hu, XZ, Rush, AJ, Charney, D, Wilson, AF, Sorant, AJ, Papanicolaou, GJ, et al. Association between a functional serotonin transporter promoter polymorphism and citalopram treatment in adult outpatients with major depression. Arch Gen Psychiatry 2007; 64: 783–92.
61 Murphy, GM Jr, 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: 1163–9.


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Moderation of antidepressant response by the serotonin transporter gene

  • Patricia Huezo-Diaz (a1), Rudolf Uher (a1), Rebecca Smith (a1), Marcella Rietschel (a2), Neven Henigsberg (a3), Andrej Marušiˇ (a4), Ole Mors (a5), Wolfgang Maier (a6), Joanna Hauser (a7), Daniel Souery (a8), Anna Placentino (a9), Astrid Zobel (a6), Erik Roj Larsen (a10), Piotr M. Czerski (a7), Bhanu Gupta (a1), Farzana Hoda (a1), Nader Perroud (a1), Anne Farmer (a1), Ian Craig (a1), Katherine J. Aitchison (a1) and Peter McGuffin (a1)...
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