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.
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