What is SLC6A4?
The serotonin transporter, encoded by the SLC6A4 gene, plays a critical role in the mechanism of action of many antidepressant medications. The serotonin transporter is responsible for serotonin reuptake into the presynaptic neuron. Many antidepressants have some serotonin reuptake blocking activity, but it is thought to be the major mechanism of action of the selective serotonin reuptake inhibitors (SSRIs).
Several polymorphisms have been identified in this gene. The best studied is an insertion/deletion in the promoter region of the gene, called the 5-HTTLPR. Individuals who carry the deletion (called the “short” or “S” allele) have lower transcription rates than those who carry the insertion (called the “long” or “L” allele), resulting in lower transporter density.
Another variant, rs25531, is a single A>G substitution near the promoter region of SLC6A4. An initial study found that this allele stratified the long form of the gene into two groups: high transcriptional activity (LA) and transcriptional activity comparable to the short allele (LG).1 However, subsequent attempts to replicate this finding have failed.2,3 Nevertheless, many clinical trials have genotyped the rs25531 SNP in conjunction with the long/short polymorphism to measure their impact on SSRI efficacy and adverse events.
Is there a connection between SLC6A4 genotype and antidepressant efficacy?
Multiple meta-analyses have reviewed the impact of the 5-HTTLPR on antidepressant efficacy. Most recently, Karlovic et al. reviewed results from 35 studies and 3 meta-analyses (total n = 8,424) from 1998 to January 2012.4 The results were divided by medication class and ethnicity. Among Caucasians taking SSRIs, 14 of 17 studies found that carriers of the S allele showed a poorer response to SSRIs. In contrast, analyses for patients of any ancestry taking non-SSRI antidepressants showed mixed results, suggesting a weaker effect within non-Caucasian populations. These meta-analysis results mirror that of Porcelli et al., who performed an analysis on 33 studies (total n = 5,479) from 1998 to November 2010.5 When analyzing 16 studies of Caucasians on SSRIs, individuals with the S/S genotype were significantly less likely to respond to SSRI treatment than individuals with the L/L genotype (odds ratio (OR) = 1.71, p = 0.003). These findings have been replicated in several other meta-analyses.6–8
The rs25531 SNP has been evaluated in eleven publications (total n = 4,645) to determine if it adds additional specificity to SLC6A4 genotyping for SSRI response beyond solely testing for the 5-HTTLPR (i.e. LA vs. LG + S).9–19 Only 4 studies (total n = 666) showed that the rs25531 SNP (in combination with the 5-HTTLPR) was better able to predict SSRI response than testing for the 5-HTTLPR alone9,11,18,19, while 7 studies (total n = 3979) 10,12–17, including two independent analyses of STAR*D data10,15, showed no additional impact.
Is there a connection between SLC6A4 genotype and antidepressant-induced adverse events?
In 2010, Kato et al. performed a meta-analysis of 8 studies (total n = 2,642) on the 5-HTTLPR and SSRI-induced side effects.20 They found that subjects carrying the S allele had an increased risk of side effects (OR = 1.55, p = 0.0001).
The impact of the rs25531 SNP on antidepressant-induced side effects is less well studied. In the STAR*D sample (n = 1,655), Hu et al. found a significant effect of SLC6A4 when using the undifferentiated L/S allele, as well as when differentiating the L allele by the rs25531 SNP (i.e. LA vs. LG + S).21 Smaller studies examining the impact of the rs25531 allele have produced mixed results.19,22,23
What is the clinical significance of SLC6A4 genotyping?
As one of the most studied polymorphisms in psychiatry, the SLC6A4 5-HTTLPR has demonstrated the ability to predict efficacy and adverse events with SSRI treatment in multiple meta-analyses, particularly for patients of Caucasian ancestry. The effect size of the polymorphism (OR = 1.71 and 1.55 for efficacy and adverse events, respectively) exceeds the standard set for cost-effectiveness by Perlis et al. (OR = 1.5) in a simulation of data from the STAR*D study24, and has demonstrated cost-effectiveness in two independent cost-effectiveness modeling scenarios25,26.
However, the rs25531 SNP has not demonstrated an impact on antidepressant efficacy, and there is not yet enough data to fully determine its impact on antidepressant-induced adverse events. More data is needed before the rs25531 SNP can be recommended for use in treatment selection.
What treatment options exist for individuals with genetic variation in SLC6A4?
Individuals with genetic variation in SLC6A4 may benefit from non-selective antidepressant pharmacotherapy, such as mirtazapine, bupropion, SNRIs, or tricyclic antidepressants.
A number of studies have focused on mirtazapine, owing to its unique mechanism of action with little affinity for the serotonin transporter. Murphy et al found that individuals carrying an S allele showed reduced response and increased side effects to paroxetine, but no impact on response and reduced side effects to mirtazapine relative to L/L individuals27, while Kang et al found that individuals with the S/S genotype actually responded better to mirtazapine than L-allele carriers28. Two other studies found no impact of SLC6A4 genotype on mirtazapine response.19,29 Similarly, individuals with the S/S genotype showed a favorable response to nortriptyline in one study30, and no difference between genotypes in a second study31.
The impact of SLC6A4 on venlafaxine response has produced mixed results. One study found an impact of SLC6A4 genotype on escitalopram, but not venlafaxine32, a second study found poorer response among individuals with the S/S genotype33, and a third study found poorer response among individuals with the LA/LA genotype34. Other non-selective antidepressants are less well-studied, but preliminary data suggest little impact of SLC6A4 response. For example, milnacipran, a norepinephrine reuptake inhibitor, was unaffected by SLC6A4 variation in one study of 96 Japanese patients35, and duloxetine was unaffected in one study of 250 patients36.
Because investigations of the medications above showed no impact of SLC6A4 genotype on efficacy (and in some cases, improved efficacy among S/S individuals), these medications are potentially preferential over SSRIs among patients with SLC6A4 variation. However, these medications may be influenced by variation in other pharmacokinetic or pharmacodynamic genes. Combinatorial pharmacogenomic testing through GeneSight analyzes variation at 8 genetic loci (including SLC6A4) and has demonstrated clinical utility in multiple published clinical trials.37–40
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