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

Abstract

Background: 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).

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: 5-HTTLPR; Antidepressants; Major depressive disorder; Rs25531; SSRIs.