It has been suggested that the serotonin or 5-hydroxytriptamine (5-HT) transporter (5-HTT) and its gene-linked polymorphic region (5-HTTLPR) are selective serotonin reuptake inhibitor (SSRI) response modulators in late-life depression (LLD), and particularly in late-life major depressive disorder (MDD). Previous studies differed in design and results. Our study aimed to investigate the solute carrier family 6 (neurotransmitter transporter and serotonin) member 4 (SLC6A4) gene locus, encoding 5-HTT and SSRI treatment response in late-life MDD. For a prospective cohort study, we enrolled 234 patients with late-life MDD to be treated with escitalopram, sertraline, paroxetine or citalopram for 6 months. The SLC6A4 polymorphisms rs4795541 (5-HTTLPR), rs140701 and rs3813034 genotypes spanning the SLC6A4 locus were investigated in blinded fashion. No placebo group was included. We assessed responder or non-responder phenotypes according to a reduction in the 21-item version of the Hamilton Depression Rating Scale (HDRS-21) score of ⩾ 50%. At follow-up, 30% of the late-life MDD patients were non-responders to SSRI treatment. No time-course of symptoms and responses was made. A poor response was associated with a higher baseline HDRS-21 score. We observed a significant over-representation of the rs4795541-S allele in the responder patients (0.436 versus 0.321; p = 0.023). The single S-allele dose-additive effect had OR = 1.74 (95% CI 1.12–2.69) in the additive regression model. Our findings suggested a possible influence of 5-HTTLPR on the SSRI response in patients with late-life MDD, which is potentially useful in identifying the subgroups of LLD patients whom need a different pharmacological approach.
AlexopoulosGS (2005) Depression in the elderly. Lancet365: 1961–1970.
3.
AlexopoulosGSCanusoCMGharabawiGM. (2008) Placebo-controlled study of relapse prevention with risperidone augmentation in older patients with resistant depression. Am J Geriatr Psychiatry16: 21–30.
4.
AlexopoulosGSMurphyCFGunning-DixonFM. (2009) Serotonin transporter polymorphisms, microstructural white matter abnormalities and remission of geriatric depression. J Affect Disord119: 132–141.
5.
American Psychiatric Association (2000) Diagnostic and Statistical Manual of Mental Disorders. Washington, DC: American Psychiatric Publishing.
6.
AndersonIM (2000) Selective serotonin reuptake inhibitors versus tricyclic antidepressants: A meta-analysis of efficacy and tolerability. J Affect Disord58: 19–36.
7.
BarretJCFryBMallerJ. (2005) Haploview: Analysis and visualization of LD and haplotype maps. Bioinformatics21: 263–265.
8.
BlazerDG (2003) Depression in late life: Review and commentary. J Gerontol A Biol Sci Med Sci58: 249–265.
9.
BlazerDWilliamsCD (1980) Epidemiology of dysphoria and depression in an elderly population. Am J Psychiatry137: 439–444.
10.
BüchtemannDLuppaMBramesfeldA. (2012) Incidence of late-life depression: A systematic review. J Affect Disord142: 172–179.
11.
CotoERegueroJRAlvarezV. (2003) 5-Hytroxytrptamine 5-HT2A receptor and 5-hydroxytryptamine transporter polymorphisms in acute myocardial infarction. Clin Sci104: 241–245.
12.
CrawfordAALewisGLewisSJ. (2013) Systematic review and meta-analysis of serotonin transporter genotype and discontinuation from antidepressant treatment. Eur Neuropsychopharmacol23: 1143–1150.
13.
DurhamLKWebbSMMilosPM. (2004) The serotonin transporter polymorphism, 5-HTTLPR, is associated with a faster response time to sertraline in an elderly population with major depressive disorder. Psychopharmacol174: 525–529.
14.
El-HageWLemanSCamusV. (2013) Mechanisms of antidepressant resistance. Front Pharmacol4: 146.
15.
EllisonJMKyomenHHHarperDG (2012) Depression in later life: An overview with treatment recommendations. Psychiatr Clin North Am35: 203–229.
16.
European Medicines Agency. Guidelines for good clinical practice. Available at: www.ema.europa.eu (accessed 16 March 2015).
GelernterJ (2014) SLC6A4 polymorphism, population genetics and psychiatric traits. Hum Genet133: 459–461.
19.
GelernterJFreimerM (1994) PstI RFLP at the SERT locus. Hum Mol Genet3: 383.
20.
GENDEP Investigators, MARS Investigators and STAR*D Investigators (2013) Common genetic variation and antidepressant efficacy in major depressive disorder: A meta-analysis of three genome-wide pharmacogenetic studies. Am J Psychiatry170: 207–217.
21.
GerdesLUKlausenICSihmI. (1992) Apolipoprotein E polymorphism in a Danish population compared to findings in 45 other study populations around the world. Genet Epidemiol9: 155–167.
22.
GerretsenPPollockBG (2008) Pharmacogenetics and the serotonin transporter in late-life depression. Expert Opin Drug Metab Toxicol4: 1465–1478.
23.
GreenbergBDTolliverTJHuangSJ. (1999) Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets. Am J Med Genet88: 83–87.
24.
Huezo-DiazPUherRSmithR. (2009) Moderation of antidepressant response by the serotonin transporter gene. Br J Psychiatry195: 30–38.
25.
HUGO Gene Nomenclature Committee. Available at: www.genenames.org (accessed 16 March 2015).
26.
JenningsKAShewardWJHarmarAJ. (2008) Evidence that genetic variation in 5-HT transporter expression is linked to changes in 5-HT2A receptor function. Neuropharmacology54: 776–783.
27.
KatonWJLinERussoJ. (2003) Increased medical costs of a population-based sample of depressed elderly patients. Arch Gen Psychiatry60: 897–903.
28.
KeersR (2011) Interaction between serotonin transporter gene variants and life events predicts response to antidepressants in the GENDEP project. Pharmacogenom J11: 138–145.
29.
KimDKTolliverTJHuangSJ. (2005) Altered serotonin synthesis, turnover and dynamic regulation in multiple brain regions of mice lacking the serotonin transporter. Neuropharmacology49: 798–810.
30.
KimHLimSWKimS. (2006) Monoamine transporter gene polymorphisms and antidepressant response in Koreans with late-life depression. J Am Med Ass296: 1609–1618.
31.
KraftJBPetersEJSlagerSL. (2007) Analysis of association between the serotonin transporter and antidepressant response in a large clinical sample. Biol Psychiatry61: 734–742.
32.
KraftJBSlagerSLMcGrathPJ. (2005) Sequence analysis of the serotonin transporter and associations with antidepressant response. Biol Psychiatry58: 374–381.
33.
KroezeYZhouHHombergJR (2012) The genetics of selective serotonin reuptake inhibitors. Pharmacol Ther136: 375–400.
34.
LebowitzBDPearsonJLSchneiderLS. (1997) Diagnosis and treatment of depression in late life. Consensus statement update. J Am Med Ass278: 1186–1190.
35.
LeschKPBengelDHeilsA. (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science274: 1527–1531.
36.
LotrichFE (2011) Gene-environment interactions in geriatric depression. Psychiatr Clin North Am34: 357–376.
37.
LotrichFEPollockBGKirshnerM. (2008) Serotonin transporter genotype interacts with paroxetine plasma levels to influence depression treatment response in geriatric patients. J Psychiatry Neurosci33: 123–130.
38.
LuppaMSikorskiCLuckT. (2012) Age- and gender-specific prevalence of depression in latest-life: Systematic review and meta-analysis. J Affect Disord136: 212–221.
39.
MillerSADykesDDPoleskyHF (1993) A simple salting-out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res16: 1215.
40.
MulsantBHPollockBGNebesR. (2001) A twelve-week, double-blind, randomized comparison of nortriptyline and paroxetine in older depressed inpatients and outpatients. Am J Geriatr Psychiatry9: 406–414.
41.
MurdochJDSpeedWCPakstisAJ. (2013) Worldwide population variation and haplotype analysis at the serotonin transporter gene SLC6A4 and implications for association studies. Biol Psychiatry74: 879–889.
42.
MurphyGMJrHollanderSBRodriguesHE. (2004) Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression. Arch Gen Psychiatry61: 1163–1169.
43.
MurthyNVSelvarajSCowenPJ. (2010) Serotonin transporter polymorphisms (SLC6A4 insertion/deletion and rs25531) do not affect the availability of 5-HTT to [11C] DASB binding in the living human brain. Neuroimage52: 50–54.
44.
NaismithSLNorrieLMMowszowskiL. (2012) The neurobiology of depression in later-life: Clinical, neuropsychological, neuroimaging and pathophysiological features. Prog Neurobiol98: 99–143.
45.
NelsonJCDelucchiKLSchneiderLS (2013) Moderators of outcome in late-life depression: A patient-level meta-analysis. Am J Psychiatry170: 651–659.
46.
PanzaFFrisardiVCapursoC. (2010) Late-life depression, mild cognitive impairment and dementia: Possible continuum?Am J Geriatr Psychiatry18: 98–116.
47.
PollockBGFerrellREMulsantBH. (2000) Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology23: 587–590.
48.
PorcelliSDragoAFabbriC. (2011) Pharmacogenetics of antidepressant response. J Psychiatry Neurosci36: 87–113.
49.
PorcelliSFabbriCSerrettiA (2012) Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy. Eur Neuropsychopharmacol22: 239–258.
50.
R Development Core Team (2012) R: A Language and Environment for Statistical Computing. Vienna: R Foundation for Statistical Computing.
51.
ReynoldsCFIIIDewMAPollockBG. (2006) Maintenance treatment of major depression in old age. N Engl J Med354: 1130–1138.
52.
RichardEReitzCHonigLH. (2013) Late-life depression,mild cognitive impairment and dementia. JAMA Neurol70:374–382.
53.
Rojas-FernandezCHMillerLJSadowskiCA (2010) Considerations in the treatment of geriatric depression.Overview of pharmacotherapeutic and psychotherapeutic treatment interventions. Res Gerontol Nurs3: 176–186.
54.
SaghafiRBrownCButtersMA. (2007) Predicting 6-week treatment response to escitalopram pharmacotherapy in late-life major depressive disorder. Int J Geriatr Psychiatry22: 1141–1146.
55.
SeripaDPanzaFD’OnofrioG. (2013) The serotonin transporter gene locus in late-life major depressive disorder. Am J Geriatr Psychiatry21: 67–77.
56.
SerrettiAKatoMDe RonchiD. (2007) Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients. Mol Psychiatry12: 247–257.
57.
SheikhJIYesavageJA (1986) Geriatric Depression Scale (GDS). Recent evidence and development of a shorter version. In: BrinkTL (ed) Clinical Gerontology: A Guide to Assessment and Intervention. New York: The Haworth Press, pp. 165–173.
58.
ShelineYIDisabatoBMHranilovichJ. (2012) Treatment course with antidepressant therapy in late-life depression. Am J Psychiatry169: 1185–1193.
59.
SinghYSAltieriSCGilmanTL. (2012) Differential serotonin transport is linked to the rh5-HTTLPR in peripheral blood cells. Transl Psychiatry2: e77.
60.
SternY (2012) Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol11: 1006–1012.
61.
STROBE Statement: Strengthening the reporting of observational studies in epidemiology. Available at: www.strobe-statement.org (accessed 16 March 2015).
62.
TaylorMJSenSBhagwagarZ (2010) Antidepressant response and the serotonin transporter gene-linked polymorphic region. Biol Psychiatry68: 536–543.
US National Institute of Health. International HapMap Project. Available at: http://hapmap.ncbi.nlm.nih.gov (accessed 16 March 2015).
65.
US National Institute of Health. National Center for Biotechnology Information. Available at: www.ncbi.nlm.nih.gov (accessed 16 March 2015).
66.
World Economic Forum (2011) The global economic burden of noncommunicable diseases. Report for the World Economic Forum and Harvard School of Public Health, September2011. Available at: www.weforum.org(accessed 16 March 2015).
67.
World Medical Association. Declaration of Helsinki. Available at: www.wma.net (accessed 16March 2015).
68.
WrayNRJamesMRGordonSD. (2009) Accurate, large-scale genotyping of 5HTTLPR and flanking single nucleotide polymorphisms in an association study of depression, anxiety and personality measures. Biol Psychiatry66: 468–476.
69.
WuMAndreescuCButtersMA. (2011) Default-mode network connectivity and white matter burden in late-life depression. Psychiatry Res194: 39–46.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
