Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy

Abstract

In the last decade the serotonin transporter gene promoter polymorphism (5-HTTLPR) was likely the most studied genetic variant as predictor of antidepressant response. Nevertheless results are not consistent across studies and previous meta-analysis, since various factors seem to modulate its effect on antidepressant response.

With the aim of clarifying this issue, we systematically reviewed literature, selecting 33 studies for an exploratory analysis without any a priori hypothesis. Then we analyzed separately 19 studies performed on Caucasians and 11 on Asians. We tested two phenotypes – remission and response rates – and three genotype comparisons – ll versus ls/ss, ss versus ll/ls and ll versus ss – using the Cochrane review manager. Evaluations were performed separately for SSRIs and mixed/other drugs. Possible clinical modulators were investigated.

In the exploratory analysis, we found an association between l allele and l/l genotype and remission. When the analysis was split for ethnic group, in Caucasians we found an association between l allele and both response (OR = 1.58, C.I. 1.16–2.16, p = 0.004), and remission (OR = 1.53, C.I. 1.14–2.04, p = 0.004) in the SSRI group. Only a marginal association between l allele and remission (OR = 1.41, C.I. 1.02–1.95, p = 0.04) survived pooling together mixed antidepressant treatments. In Asians, a small effect of 5-HTTLPR on remission for mixed antidepressants was detected (OR = 2.10, C.I. 1.15–3.84, p = 0.02). Gender, age and age at onset modulated the association in Caucasians. Gender, age and depression severity at baseline modulated the association in Asians.

In conclusion, in Caucasians 5-HTTLPR may be a predictor of antidepressant response and remission, while in Asians it does not appear to play a major role.

Introduction

Nowadays depression has still an enormous economic burden due to both direct and indirect costs, in the order of tens of billions of dollars each year in the US alone (Halfin, 2007, Wang et al., 2003). Several factors are responsible of this economic burden. Among the most relevant ones, there are the still unsatisfactory rates of response and remission (Machado et al., 2006, Papakostas et al., 2006) (47 and 33%, respectively, in the STAR*D cohort) (Trivedi et al., 2006). Furthermore, initial side effects and failure to perceive benefit are common reasons of early discontinuation (Masand, 2003). The detection of factors that could predict response and minimize side effects of treatments therefore remains an essential goal. Clinical factors have been extensively investigated, but results are still controversial and cannot be translated into the clinical practice (Papakostas et al., 2008, Serretti et al., 2009). On the other hand, several lines of evidence suggested that genetic factors contribute for about 50% of the antidepressant response (Angst, 1965, Franchini et al., 1998, Kirchheiner et al., 2004, Maier and Zobel, 2008, Serretti et al., 1998), although so far the inconsistency of results has not allowed clinical applications.

Despite this discouraging scenario, some polymorphisms were repeatedly associated to antidepressant response, particularly a polymorphism within the promoter of the serotonin transporter gene (SLC6A4), i.e. the 5-HTTLPR. It is a 44 bp insertion/deletion involving two units in a sequence of sixteen repeated elements and possibly influences serotonin transporter (SERT) expression, with the long (l) allele associated with a twice basal expression compared to the short (s) allele (Heils et al., 1996). 5-HTTLPR is a priori excellent candidate for genetic studies, since SERT is one of the main targets for antidepressant drugs and the primary target for SSRIs. Furthermore, it has been associated with several psychiatric disorders with affective symptomatology (i.e. bipolar disorder, anxiety disorders, eating disorders, substance abuse) and to pathological behaviors and personality traits related to anxiety, impulsivity and stress (Serretti et al., 2006). Concerning antidepressant pharmacogenetics, increasing evidence suggest that in Caucasian l allele is associated with better response, although negative findings have been reported as well (Table 1). On the other hand, in Asians an association between s allele and better response was initially reported, though several following studies reported no associations while only few studies found an association with l allele or l/l genotype (see Table 1 and our previous meta-analysis (Serretti et al., 2007b)). So far other ethnicities have not been investigated enough to reach any conclusion. These contradictory findings between Caucasian and other populations may be due to several reasons. Firstly, l allele is much less frequent in Asian compared to Western populations. Indeed: 1. the l/l genotype is present in 29–43% of Caucasians, but in 1–13% of East Asians (Goldman et al., 2010); 2. the s allele is present in 42% of Caucasians, but in 79% of Asians (Kunugi et al., 1997); 3. the s/s genotype varied from 21.6 to 28.3% in the studies including mainly Caucasian patients, while in studies on Asian patients these frequencies varied between 55.6 and 60.0% (Smits et al., 2004). Thus, the low frequency of l allele and l/l genotype in Asians weakens the association between them and response found by some authors. Secondly, other genetic variants within the SERT gene or other related gene may represent further stratification factors. Indeed, a second polymorphism identified within the l allele (rs25531A/G) may determinate a reduced expression of the gene (l_G allele), comparable with the expression due to the s allele (Hu et al., 2006). In the light of this finding all the studies performed before the detection of this mutation should be carefully re-examined and future investigations should provide a better covering of the gene (Dong et al., 2009). Finally some recent findings suggested possible interactions between 5-HTTLPR genotype and drug plasma concentration (Lotrich et al., 2008), augmentation strategies (Benedetti et al., 2008, Stamm et al., 2008), life events (Mandelli et al., 2009a) and gender (Walderhaug et al., 2007).

Taken together, these data underline the need for further investigations in order to reach any definitive conclusion. Our previous meta-analysis exploring the association between 5-HTTLPR and antidepressant response, reported positive correlations between l allele and l/l genotype and both response and remission (Serretti et al., 2007b). Despite these results, the increasing amount of data about the topic, especially after the publication of STAR*D results, may be useful to further clarify the role of this relevant polymorphism. These considerations leaded to a new meta-analysis on 5-HTTLPR and antidepressant response. Conversely to our findings, authors did not find any association between 5-HTTLPR and both antidepressant response and remission (Taylor et al., 2010). Nevertheless, they did not perform separate meta-analyses on the basis of the ethnicity that, as stated above, is a well-known confounding factor in pharmacogenetic studies. The confounding role of ethnicity seems even more relevant for 5-HTTLPR, since the very different frequencies of its alleles among different populations (see above) and the increasing evidence of a different effect of 5-HTTLPR in Caucasian and Asian populations (Table 1). As a matter of fact, also Taylor and colleagues observed that ethnicity may be a stratifying factor, thus they included it as moderator in their meta-regression, finding a negative result. Despite this, the limited statistical power of meta-regression approach (Baker et al., 2009) and the previously reported considerations suggest the need of further analysis to clarify this issue. Therefore the aim of the present paper was to perform a meta-analysis on the association between 5-HTTLPR and antidepressant response, firstly considering available studies until November 2010 both on Caucasian and Asian samples to perform an exploratory analysis without any a priori hypothesis. We then tried to dissect the obtained results by separated analysis in Caucasian and Asian populations, in order to reach a relatively definitive conclusion on the role of 5-HTTLPR on the antidepressant response in both the populations in exam. Despite the recent evidence of possible influence exerted by other polymorphisms within SLC6A4promoter, we focus this meta-analysis on the biallelic insertion/deletion polymorphism; indeed, it is the most known and studied so far, while data about the role of the other polymorphisms within the region are still poor and contradictory (Perroud et al., 2010) (see also Discussion). Further, possible modulators of the association were investigated.