The Serotonin Transporter Gene Locus in Late-Life Major Depressive Disorder

Seripa, Davide; Paroni, Giulia; Bizzarro, Alessandra; Fontana, Andrea; Paris, Francesco; Cascavilla, Leandro; Copetti, Massimiliano; Masullo, Carlo

doi:10.1016/j.jagp.2012.10.012

Cited by 9 publications

(9 citation statements)

References 53 publications

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“…No differences were also observed when the present genotype frequencies were compared with those reported form the 1000 genomes project (http://www.1000genomes.org). We also analyzed at the solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (SLC6A4) locus the polymorphism C, also known as 5HTT gene linked polymorphic region (5HTTLPR) and cytochrome P450 (CYP) 2D6 as previously described [47,48] to avoid the possibility that these two factors may influence our analysis.…”

Section: Genetic Analysismentioning

confidence: 99%

Klotho Gene and Selective Serotonin Reuptake Inhibitors: Response to Treatment in Late-Life Major Depressive Disorder

et al. 2016

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Klotho protein, encoded by the Klotho gene (KL) at locus 13q12, is an antiaging hormone-like protein playing a pivotal role in cell metabolism homeostasis and associated to longevity and age-related diseases. In particular, altered cell metabolism in central nervous system may influence the behavior of serotoninergic neurons. The role of KL in the response to treatment with selective serotonin reuptake inhibitors (SSRIs) in late-life depressive syndromes and late-life major depressive disorder (MDD) is unclear. We genotyped three single-nucleotide polymorphisms (SNPs) of KL in 329 older patients with diagnosis of late-life MDD, treated with SSRIs and evaluated with the Hamilton Rating Scale for Depression 21-items (HRSD-21) at baseline and after 6 months. A reduction ≥50 and <10 % in HDRS-21 score was considered as response or nonresponse to therapy, respectively, and the values of reduction between 10 and 49 % as poor responders. After 6 months of SSRI treatment, 176 patients responded, 54 patients did not respond and 99 patients showed a poor response. Ordinal logistic models showed a significant association between mutation of SNP rs1207568 and responders and, similarly, for each unitary risk allele increase overlapping results were found. Conversely, a significantly higher frequency of the minor genotype of SNP rs9536314 was found in nonresponders. Considering the pre-post differences of HRSD-21 scores as a continue variable, we confirmed a significant improvement of depressive symptoms after treatment in patients carrying at least one minor allele at rs1207568 and a worse response in patients homozygous for the minor allele at rs9536314. Our results were the first that suggested a possible role of KL in the complex pathway of SSRI response in late-life MDD.

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Section: Genetic Analysismentioning

confidence: 99%

Klotho Gene and Selective Serotonin Reuptake Inhibitors: Response to Treatment in Late-Life Major Depressive Disorder

et al. 2016

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“…Our findings suggested a possible 5-HTTLPR influence on the SSRI response in late-life MDD. A further role, if any, of the SLC6A4 locus, including other SLC6A4 variants previously described as possibly related to SSRI therapy outcome (rs25531, inside 5-HTTLPR, and rs254532 or rs2020933) (Huezo-Diaz The antidepressant clinical response was evaluated after 6-month and was defined as a reduction of at least 50% on the HDRS-21 score at follow-up, as already validated by other studies (Alexopoulos et al, 2008;Seripa et al, 2013). Our study cohort was composed of 234 late-life MDD patients, of whom about two-thirds were female, according to the prevalence of LLD in Caucasians (Alexopoulos et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…After 6 months of treatment the clinical assessment was repeated, focusing on therapy response, compliance and drug-related adverse events. As previously reported (Alexopoulos et al, 2008;Seripa et al, 2013), a responder was defined as a patient whom showed a reduction ⩾ 50% on the HDRS-21 score at follow-up. No time-course of symptoms/ response was made.…”

Section: Ssri Treatment and Responder/non-responder Assessment Criteriamentioning

confidence: 99%

“…The polymorphisms rs4795541, rs140701 and rs3813034, spanning a 39.5 kb block at the SLC6A4 locus 17q11.2 (28,562,715 to 28,524,906 bases from pter on the minus DNA strand) were investigated, as recently described (Seripa et al, 2013). In particular, the single nucleotide polymorphisms (SNPs) rs140701 and rs3813034 were selected from the International HapMap Project (US National Institute of Health) as markers of the 20 kb linkage disequilibrium (LD) block (rs140701) and 3 kb LD block (rs381034), which are observed at the SLC6A4 locus (Supplementary Figure 1).…”

Section: Genetic Analysismentioning

confidence: 99%

“…In a community-based older sample, the rate of clinically significant LLD was 14.7% and one-quarter of these patients had late-life MDD (3.7%) (Blazer et al, 1980). More recent data indicates a prevalence of LLD of 54.14% and a prevalence of late-life MDD of 17.85% (Seripa et al, 2013); however, LLD prevalence will probably increase with the population aging, becoming a major public health concern for the future (Ellison et al, 2012;Katon et al, 2003;World Economic Forum, 2011).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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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.

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The serotonin transporter and the activity regulated cytoskeleton‐associated protein genes in antidepressant response and resistance: 5‐HTTLPR and other variants

Calabrò

Fabbri

Crisafulli

et al. 2018

Human Psychopharmacology

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Objective Previous evidence suggested the involvement of serotonin transporter (SLC6A4) and activity regulated cytoskeleton‐associated protein (ARC) in antidepressant action. This study investigated their role in antidepressant efficacy and treatment‐resistant depression (TRD). Methods Three samples (n total = 648) were investigated to test the association between treatment outcomes (response, remission, symptom improvement, and TRD) and 11 polymorphisms within SLC6A4 and ARC genes. The possible modulating effect of age and gender was considered. Response and remission were also investigated using a fixed‐effects meta‐analysis of the three samples. Results SLC6A4 5‐HTTLPR/rs25531 effects on symptom improvement were modulated by age (better improvement in L/LA carriers in older subjects) and gender (better improvement in L/LA female carriers). SLC6A4 STin2 long alleles were associated with remission and lower risk of TRD. Preliminary evidence of association between ARC rs11167152/rs10110456 and different outcomes was found. Conclusions 5‐HTTLPR/rs25531 effect on antidepressant efficacy was modulated by age, in line with previous literature data. STin2 effect on antidepressant efficacy was in line with previous meta‐analyses. A new possible effect of ARC variants on antidepressant efficacy was observed; however, further studies in larger samples are needed to confirm their role.

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The Serotonin Transporter Gene Locus in Late-Life Major Depressive Disorder

Cited by 9 publications

References 53 publications

Klotho Gene and Selective Serotonin Reuptake Inhibitors: Response to Treatment in Late-Life Major Depressive Disorder

Klotho Gene and Selective Serotonin Reuptake Inhibitors: Response to Treatment in Late-Life Major Depressive Disorder

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

The serotonin transporter and the activity regulated cytoskeleton‐associated protein genes in antidepressant response and resistance: 5‐HTTLPR and other variants

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