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

Abstract

The serotonin transporter gene promoter polymorphism (5-HTTLPR) has been repeatedly associated with antidepressant response in mood disorder patients, but findings are not consistent across studies. A meta-analysis was performed on 15 studies including data of 1435 subjects. We tested three phenotypes: remission rate, response rate and response rate within 4 weeks using the cochrane review manager. We observed a significant association of the s/s variant of 5-HTTLPR with remission rate (P < 0.0001) and both s/s and s/l variants with response rate (P = 0.0002). Response rate within 4 weeks was associated in both models (P = 0.003-P < 0.00001). This effect is quite robust to ethnic differences although a significant heterogeneity is present in Asian samples.

Interaction between serotonin transporter gene variants and life events predicts response to antidepressants in the GENDEP project

“…A comprehensive meta-analysis, including over 1400 participants revealed a modest association of the short variant of the 5-HTTLPR with poor response and remission to antidepressants. 15 These findings were subsequently replicated by two large pharmacogenetic studies: Genome-based Therapeutic Drugs for Depression (GEN-DEP) 16 and STAR*D, the latter after considering the ethnicity of the study population. 17 Results from the GENDEP study also suggested that the association is drug specific.…”

“…There is evidence to suggest that 5-HTTLPR genotypes operate in either a recessive or additive genetic model in both the moderation of the effects of stress and response to antidepressants. 15,20 Therefore, interactions based on both genotypic models were tested.…”

The lack of genotype–phenotype relationship between platelet serotonin concentration and serotonin transporter gene promoter polymorphism in healthy subjects

“…There are several alleles within 5-HTTLPR, but the most frequent are short (S) and long (L) allele, composed of either 14-or 16-repeat units. The 5-HTTLPR short allele suppresses transcriptional activity of the promoter [14], and it is associated with a poor treatment response to SSRI [32].…”

“…Platelet 5-HT concentration has been found to be altered in different neuro-psychiatric disorders, personality traits and behaviors [13,22,26,27], and it is significantly decreased after treatment with various SSRI [2,22]. It has been proposed that peripheral 5-HT platelet content can mirror the state of the central 5-HT system [3], and that baseline platelet 5-HT concentration might be used as a predictor of the antidepressant treatment response [5,21,22], while long allele of the 5-HTTLPR is related to a good response to antidepressants [32]. The reports on the association between 5-HTTLPR and platelet 5-HT concentration are inconsistent, showing either positive, negative or no association between 5-HTTLPR genotypes and increased, unaltered or decreased platelet 5-HT concentration [8,9,13,33].…”

Pharmacogenetics Studies in STAR*D: Strengths, Limitations, and Results

“…This variant, the insertion of a 43 base pair segment in the promoter region (L-allele) together with the A-allele of the SNP rs25531 in the same region seem to affect gene expression in important ways (43), and thus differential expression of the SSRIs’ target became a good hypothesis to explain SSRI efficacy. A meta-analysis of 15 published studies that included 1,520 patients concluded that there was evidence in favor of a significant association of the long (L) allele with better response to SSRIs (44). This result may reflect publication bias because negative studies tend not to get published.…”