Short communication
Serotonin transporter promoter region polymorphisms do not influence treatment response to escitalopram in patients with major depression

https://doi.org/10.1016/j.euroneuro.2009.01.010Get rights and content

Abstract

Several studies and meta-analyses have implicated a polymorphism in the promoter region of the serotonin transporter (5-HTT) gene, 5-HTTLPR in treatment outcomes of selective serotonin re-uptake inhibitors in patients with major depression. In this study we investigated the impact of 5-HTTLPR and a functional SNP rs25531 on the treatment outcomes to escitalopram in depressive patients. The study sample consisted of 135 outpatients with major depressive disorder (mean age 31.1 ± 11.6 years, 68% females) treated with escitalopram 10–20 mg/day for 12 weeks. There were no significant associations between 5-HTT promoter region polymorphisms and response rate or mean change of depressive symptoms during escitalopram treatment. However we showed that patients carrying S allele of 5-HTTLPR may have increased risk for some side effects, including headache, induced by escitalopram medication.

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.

References (23)

  • MalhotraA.K. et al.

    Genomics and the future of pharmacotherapy in psychiatry

    Int. Rev. Psychiatry

    (2007)
  • Cited by (62)

    • Pharmacogenetic association of bi- and triallelic polymorphisms of SLC6A4 with antidepressant response in major depressive disorder

      2020, Journal of Affective Disorders
      Citation Excerpt :

      Besides, one article reported findings from 3 trials with different design and populations and was then considered as 3 independent studies in our analysis (Calabro et al., 2018). Finally, 49 studies were included in present study, of which 46 were for 5-HTTLPR biallelic polymorphism (Arias et al., 2003; Basu et al., 2015; Bousman et al., 2014; Bozina et al., 2008; Calabro et al., 2018; Chang et al., 2014; Dogan et al., 2008; Durham et al., 2004; Gressier et al., 2009; Hong et al., 2006; Hu et al., 2007; Huezo-Diaz et al., 2009; Illi et al., 2011; Joyce et al., 2003; Kang et al., 2007; Kato et al., 2005; Kim et al., 2000; Kim et al., 2006; Kirchheiner et al., 2007; Lee et al., 2010; Manoharan et al., 2016; Maron et al., 2009; Min et al., 2009; Mrazek et al., 2009; Ng et al., 2016; Ng et al., 2006; Poland et al., 2013; Pollock et al., 2000; Rausch et al., 2002; Reimherr et al., 2010; Ruhe et al., 2009; Sahraian et al., 2013; Serretti et al., 2004; Smeraldi et al., 1998; Tatham et al., 2017; Tomita et al., 2014; Umene-Nakano et al., 2010; Wilkie et al., 2009; Yoshida et al., 2002; Yoshida et al., 2004; Yoshimura et al., 2009; Yu et al., 2002; Zanardi et al., 2000; Zanardi et al., 2001) and 10 for 5-HTTLPR/rs25531 triallelic polymorphism (Calabro et al., 2018; Camarena et al., 2019; Dreimuller et al., 2012; Hu et al., 2007; Kato et al., 2013; Manoharan et al., 2016; Maron et al., 2009; Ruhe et al., 2009). The basic characteristics of eligible studies for biallelic and triallelic polymorphism were listed in Table 1 and 2, respectively.

    • Treatment resistant depression

      2020, Ketamine for Treatment-Resistant Depression: Neurobiology and Applications
    • Peripheral biomarkers of major depression and antidepressant treatment response: Current knowledge and future outlooks

      2018, Journal of Affective Disorders
      Citation 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.

    • Drugs, genes and the blues: Pharmacogenetics of the antidepressant response from mouse to man

      2014, Pharmacology Biochemistry and Behavior
      Citation 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).

    View all citing articles on Scopus
    1

    Joint first authors.

    View full text