Short communicationSerotonin transporter promoter region polymorphisms do not influence treatment response to escitalopram in patients with major depression
Introduction
It is difficult in clinical practice to predict which patients will respond well to any particular pharmacological treatment despite such predictions having the potential to help clinicians avoid lengthy ineffective medication trials and to reduce patients' exposure to drug side effects (Malhotra et al., 2007). The serotonin transporter (5-HTT) gene has become a main target for pharmacogenetic studies in affective disorders due to its being the target of therapeutic effects of many antidepressants. Several studies have implicated a polymorphism in the promoter region of the 5-HTT gene, 5-HTTLPR, in therapeutic outcomes to treatment with selective serotonin re-uptake inhibitors (SSRIs). In particularly there was reported that the more highly expressed variant, the long allele (L), of this polymorphism was associated with better clinical response in Caucasian subjects, although the opposite finding has been observed in Asian populations (for review Serretti et al., 2008). These findings were not replicated in the largest sample of depressive patients, those from the Sequenced Treatment Alternatives to Relieve Depression (STAR⁎D) trial, where no association between response to citalopram and 5-HTTLPR was found (Kraft et al., 2007). Recently, Serretti et al. (2007) performed a meta-analysis of 5-HTTLPR effect on the antidepressant treatment based on 15 available studies including data of 1435 subjects. The results of this meta-analysis confirmed the significant, and independent from ethnic differences, association of the L variant of 5-HTTLPR with a better response to SSRIs whereas the subjects with SS genotype had difficulties to reach remission. Additionally, the meta-analysis of 5-HTTLPR on the SSRIs-induced side effects in 2323 patients showed significantly reduced risk of adverse effects for the L allele (Kato and Serretti, 2008). Taken together these mentioned studies indicated 5-HTTLPR polymorphism as possible predictor for both treatment response and intolerance to SSRIs.
More recently, two subtypes of the L allele have been described, whereas L variant with an adenosine at SNP rs25531 (La) has been reported to have higher activity than the long variant with a guanine at rs25531 (Lg) (Hu et al., 2006). Earlier, rs25531 SNP has been associated with treatment outcomes to SSRI fluoxetine (Kraft et al., 2005, Peters et al., 2004). However, no evidence of association between genotype at the rs25531 SNP and remission to SSRI citalopram was found in depressive patients derived from STAR⁎D trial (Mrazek et al., 2008). Nevertheless, the side effect burden analyzing in STAR⁎D sample showed that subjects carrying the low-expression S or Lg alleles were more likely to experience citalopram adverse effects (Hu et al., 2007).
Escitalopram, the S-enantiomer of citalopram, is a SSRI that binds to both the primary site on the 5-HTT as well as to an allosteric site that greatly augments the efficacy of the inhibition of serotonin reuptake (Sanchez et al., 2004). It has been shown to be significantly superior yet with improved tolerability compared with conventional SSRIs (Kennedy et al., 2006). Moreover higher 5-HTT occupancy in midbrain was found after multiple dose administration of 10 mg/day escitalopram compared with 20 mg/day citalopram despite similar plasma concentrations of the S-enantiomer (Klein et al., 2007). These results can also be explained by an attenuating effect of R-citalopram on the occupancy of S-citalopram at the 5-HTT. Considering this unique action mechanism of escitalopram we aimed in current study to investigate the possible impact of 5-HTT promoter region polymorphisms on its treatment response and side effects in patients with major depression who were participated in our recent clinical trial (Maron et al., in press).
Section snippets
Subjects
The study sample consisted of 135 outpatients with Major Depressive Disorder, MDD (mean age 31.1 ± 11.6 years, 68% females) recruited at the Psychiatry Clinic of the Tartu University Hospital in Tartu, Estonia. The diagnosis according to DSM-IV criteria was verified using Mini International Neuropsychiatric Interview (M.I.N.I. 5.0.0) and substantiated by psychiatric history and medical records. At least moderate severity of depression was required for inclusion as indicated by a Montgomery–Asberg
Results
At the end of week 12 of treatment with escitalopram, 82 patients (60.7%) were defined as responders and 79 of them (in total 58.5%) achieved remission according to mentioned criteria for response and remission. Forty four patients (32.6%) showed insufficient or partial response to treatment and 9 patients (6.7%) discontinued escitalopram treatment due to lack of efficacy or side effects. Taken together the daily dose of escitalopram was increased and kept at 20 mg in 85 patients. As almost all
Discussion
To the best of our knowledge this is the first study report exploring the predictive effect of 5-HTT promoter region polymorphisms on the treatment outcomes to escitalopram in patients with major depression. Overall, we failed to demonstrate any significant associations between 5-HTTLPR variations and treatment response to escitalopram. Several previous studies have shown that treatment response to SSRIs is influenced by long alleles of 5-HTTLPR and is associated with rs25531 SNP (Serretti et
Role of the funding source
The investigation was supported by Estonian Science Foundation grants 7034 (EM) and 6465 (AM); by target grants SF0182582s03, SF0180142s08 (AM) and SF0180125s08 (VV) from the Ministry of Education of Estonia and by Estonian Biocentre project EU23619 (AM) from Enterprise Estonia.
Contributors
Eduard Maron, David J. Nutt and Andres Metspalu designed this study, and were involved in data analyses and interpretation and manuscript preparation. Authors Triin Eller and Veiko Vasar were involved in clinical data and sample collection. Authors Anu Tammiste and Kristi Kallassalu were involved in data analyses, interpretation and manuscript preparation. All authors contributed to and have approved the final manuscript.
Conflict of interest
The authors declare no conflict of interest related to this work.
Acknowledgements
Authors thank study nurses Birgit Aumeste, Merle Taevik and Ketlin Veeväli for their assistance.
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2018, Journal of Affective DisordersCitation Excerpt :Serotonin: Given the imbalance of monoamine levels associated with MDD, the serotonin (5HT) transporter and receptors have unsurprisingly been studied in numerous trials as potential predictors of MDD risk and treatment outcome. Regarding the 5HT transporter, while no significant associations were initially identified with STAR*D participants (Kraft et al., 2007), follow-up analyses have shown differential treatment outcomes associated with the serotonin transporter linked polymorphic region (5-HTTLPR) of the SLC6A4 gene, notably across races in response to treatment with SSRIs (Mrazek et al., 2009), although other groups have not been able to replicate these data and several other studies failed to find any association of 5-HTTLPR (Maron et al., 2009; Perlis et al., 2010; Serretti et al., 2013). Discovery and validation of SNPs in the serotonin receptors have been equally as complex.
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2014, Pharmacology Biochemistry and BehaviorCitation Excerpt :The discovery of this haplotype is potentially very important because carriers of the A allele of this SNP within the L allele of the 5-HTTLPR variant yielded high mRNA levels, whereas carriers of the G allele within the L allele of the 5-HTTLPR variant exhibited transcription rates similar to carriers of the S allele (Hu et al., 2006). In the presence of the G allele, the L allele has been associated with non-response to antidepressant treatment (Kraft et al., 2005) although more recent studies have reported a lack of association (Gudayol-Ferre et al., 2010; Maron et al., 2009). In addition, the low expressing alleles (the S allele and the G*L alleles) are associated with adverse effects of antidepressant drugs (Hu et al., 2007).
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Joint first authors.