Antidepressant Response and the Serotonin Transporter Gene-Linked Polymorphic Region

doi:10.1016/j.biopsych.2010.04.034

Biological Psychiatry

Volume 68, Issue 6, 15 September 2010, Pages 536-543

https://doi.org/10.1016/j.biopsych.2010.04.034 Get rights and content

Background

The serotonin transporter gene-linked polymorphic region (5-HTTLPR) has been proposed as a predictor of antidepressant response. Insertion or deletion of a 44-base pair-long region gives rise to short “S” and long “L” forms of the promoter region, the “S” form being associated with reduced serotonin transporter expression.

Methods

A systematic review and meta-analysis was performed to clarify the effect of 5-HTTLPR on antidepressant response and remission rates. Data were obtained from 28 studies with 5408 participants. Three genotype comparisons were tested—SS versus (SL or LL), (SS or SL) versus LL, and SS versus LL.

Results

There was no statistically significant effect on antidepressant response. Compared with L carriers, there was an apparent effect of the SS genotype on remission rate (relative risk: .88; 95% confidence interval: .79–.98; p = .02). However, after trim and fill correction for missing data, the effect disappeared (relative risk: .92; 95% confidence interval: .81–1.05; p = .23), indicating that the initial significant effect was likely the result of publication bias. No significant effect on remission rate was seen for SS versus LL and SS/SL versus LL. Substantial unexplained heterogeneity of effect sizes was observed between studies, pointing to additional interacting factors contributing to an association in some cases.

Conclusions

The 5-HTTLPR biallelic short/long polymorphism by itself does not seem to usefully predict antidepressant response.

Section snippets

Methods and Materials

Trials in which patients with MDD received antidepressant medication and outcomes were reported by 5-HTTLPR polymorphism status were sought. Electronic databases were searched (EMBASE, MEDLINE, PsycINFO) from 1996 to July 2009, Week 1, with search terms (5-HT OR 5-HT OR 5HTT OR SERT OR transporter OR LPR OR serotonin OR SLC6A4) AND (VNTR OR variant OR polymorphism OR allele OR “tandem repeat$”) AND (antidepressant OR SSRI or SRI or “reuptake inhibitor” OR paroxetine OR citalopram OR fluoxetine

Results

A total of 28 trials provided suitable data for inclusion in this meta-analysis (Table 1). The studies varied in size; the largest individual study was STAR* D, although most of other studies included over 100 participants. Studies were performed in a wide range of geographic locations; however, participant diagnoses were made to standard internationally accepted criteria in all cases (in most cases DSM-IV was used). Some studies included a minority of participants with bipolar depression (

Discussion

We report the largest meta-analysis of the effect of 5-HTTLPR polymorphisms on response or remission to antidepressant medication in patients with MDD. Our results find no significant effect of the biallelic polymorphism on response to SSRI medication. Although we see a weak effect of the polymorphism on remission, a number of factors like publication bias or lack of reporting of the remission outcome seem to explain this finding. Therefore, there is little evidence to suggest continued

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Citation Excerpt :
As the evidence accumulated, the association between clinical response and ADs in Caucasians seems to be confirmed. Several previous meta-analyses (Porcelli et al., 2012; Serretti et al., 2007; Taylor et al., 2010), as well as the present analysis with the largest sample size, yield more favorable clinical outcomes for L allele and LL genotype for Caucasian that carriers have higher response and remission rates when treated with SSRIs. However, the clinical impact of a single locus seems to be modest, since 5-HTTLPR was estimated to explain only 3.2% of variance in antidepressants response (Porcelli et al., 2012).
Antidepressants (ADs) are the main clinical therapy for depression, but approximately half of users do not get adequate response. The biallelic (5-HTTLPR) and triallelic (5-HTTLPR/rs25531) polymorphisms in SLC6A4 have been frequently investigated, but their associations with ADs response are in controversy. Here, we performed a meta-analysis to assess their modulation effect to ADs response in major depressive disorder (MDD).
We performed literature search in PubMed, Web of Science and EMBASE before June 2019. Pooled analysis of genetic associations with response and remission, meta-regression and sensitivity analysis were performed, and publication bias was assessed.
Literature search yielded 49 eligible studies with 46 and 10 studies for biallelic and triallelic polymorphism, respectively. L allele of 5-HTTLPR was associated with both of response and remission rates. In the Caucasians using SSRIs only, carriers of LL/LS or LL genotype were more likely to be responders compared to SS carriers (LL/LS vs. SS: OR=1.55, 95%CI 1.20-2.00, p=0.001; LL vs. SS: OR=1.97, 95%CI 1.45-2.67, p<0.001). Similar associations were also found with remission rate. However, no effects on response or remission were found in the Asians or mixed/other antidepressant subgroups. Additionally, the 5-HTTLPR/rs25531 triallelic polymorphism may not associate with ADs response. Meta-regression showed that percent of female in participants, year of publication and treatment duration modulated the association in Caucasians.
5-HTTLPR, instead of 5-HTTLPR/rs25531 triallelic polymorphism, may exert as a marker for the prediction of response to SSRIs in Caucasians with MDD.
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Archival ReportAntidepressant Response and the Serotonin Transporter Gene-Linked Polymorphic Region

Background

Methods

Results

Conclusions

Section snippets

Methods and Materials

Results

Discussion

Biol Psychiatry

Neuropharmacology

J Clin Epidemiol

Neuropsychopharmacology

Biol Psychiatry

Biol Psychiatry

Prog Neuropsychopharmacol Biol Psychiatry

Biol Psychiatry

Prog Neuropsychopharmacol Biol Psychiatry

Am J Hum Genet

Prog Neuropsychopharmacol Biol Psychiatry

Eur Neuropsychopharmacol

Biol Psychiatry

Am J Hum Genet

Eur Neuropsychopharmacol

Early onset of selective serotonin reuptake inhibitor antidepressant action: Systematic review and meta-analysis

Arch Gen Psychiatry

Medication augmentation after the failure of SSRIs for depression

N Engl J Med

How can we realize the promise of personalized antidepressant medicines?

Nat Rev Neurosci

Allelic variation of human serotonin transporter gene expression

J Neurochem

Serotonin transporter: Gene, genetic disorders, and pharmacogenetics

Mol Interv

Meta-analyses of genetic studies on major depressive disorder

Mol Psychiatry

Five-HTTLPR genotype and anxiety-related personality traits: A meta-analysis and new data

Am J Med Genet B Neuropsychiatr Genet

Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: A meta-analysis

JAMA

Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine

Mol Psychiatry

Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients

Mol Psychiatry

Association between a functional serotonin transporter promoter polymorphism and citalopram treatment in adult outpatients with major depression

Arch Gen Psychiatry

R: A Language and Environment for Statistical Computing

Meta: Meta-Analysis

Measuring inconsistency in meta-analyses

BMJ

A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints

Stat Med

Archival Report
Antidepressant Response and the Serotonin Transporter Gene-Linked Polymorphic Region