Role of the serotonin transporter gene locus in the response to SSRI treatment of major depressive disorder in late life

Abstract

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.

Serotonin Transporter Gene Polymorphisms and Selective Serotonin Reuptake Inhibitor Tolerability: Review of Pharmacogenetic Evidence

“…In 214 depressed white patients treated with various SSRIs, 5‐HTTLPR genotype was not significantly associated with overall ADR incidence or any specific ADR domain, although S allele carriers had numerically higher incidence in most domains . A study of 234 late‐life depression patients treated with SSRIs found no association between 5‐HTTLPR genotype and dropout due to ADRs . The largest study that failed to show an association between 5‐HTTLPR and ADRs or dropout rate was performed using a subset of depressed European ancestry patients treated with escitalopram in the Genome Based Therapeutic Drugs for Depression (GENDEP) project (n=450) .…”

“…12 On the contrary, seven studies of white populations have found no association between 5-HTTLPR and tolerability. [13][14][15][16][17][18][19] One of the earliest publications examining broad SSRI tolerability by SLC6A4 genotypes demonstrated no difference in mean number of ADRs by 5-HTTLPR genotype in 36 depressed white patients treated with fluoxetine, although there were compelling associations between genotype and neuropsychiatric side effects that are covered elsewhere in this review. 13 In 74 pediatric patients treated with citalopram, there was no association between 5-HTTLPR genotype and risk of individual ADRs with the exception of agitation.…”

“…17 A study of 234 late-life depression patients treated with SSRIs found no association between 5-HTTLPR genotype and dropout due to ADRs. 18 The largest study that failed to show an association between 5-HTTLPR and ADRs or dropout rate was performed using a subset of depressed European ancestry patients treated with escitalopram in the Genome Based Therapeutic Drugs for Depression (GENDEP) project (n=450). 19 In addition to these null results, we identified one study that noted a positive association between general tolerability measures and 5-HTTLPR in the opposite direction of other positive studies: the 5-HTTLPR L allele was associated with a higher ADR index in citalopram-treated patients with depression secondary to traumatic brain injury.…”

Hydroxytryptamine transporter gene-linked polymorphic region (5HTTLPR) is associated with delusions in Alzheimer’s disease

“…Genomic DNA was purified from fresh/frozen blood samples following salting-out method [41]. Analysis of the 5-HTTLPR and apolipoprotein E (APOE) polymorphisms were made in blinded fashion previously described [42, 43].…”

Genetic influence alters the brain synchronism in perception and timing

“…The results of genotyping in the 5-HTTLPR region in this retrospective study indicate that carriers of the short alleles, same in heterozygosity, exhibit better performance in financial activities and a lower percentage of economic losses compared to homozygotes for the long allele. The relationship of SLC6A4 5-HTTLPR polymorphism with variable serotonin expression has been associated with neuropsychiatric conditions [ 11 ], social anxiety disorder [ 31 ], aggressiveness [ 32 ], depression [ 33 ] and impulsivity [ 34 ], diseases that contribute to the deficit in the time perception. However, genetic studies associated with cognitive parameters are not only linked to SLC6A4 5-HTTLPR [ 35 ], but the studies by Burt and Mikolajewski [ 36 ] show that that subjects make less harmful decisions, besides an adjuvant action of variations in the 5HTR2A gene on cognitive aspects.…”