Genetic influence on response to serotonergic antidepressants

The mechanism of action of selective serotonin reuptake inhibitors (SSRIs) involves the block of the neuronal serotonin transporter (5-HTT). A functional polymorphism in the transcriptional control region upstream of the 5-HTT coding sequence has been recently reported. The long and short variants of this 5-HTT gene-linked polymorphic region (5-HTTLPR) have different transcriptional efficiencies, with the basal transcription of the long variant being more than twice that of the short form. Previous studies showed that the differences in 5-HTT mRNA synthesis resulted in different 5-HTT expression and 5-HT cellular uptake; that 5-HTT binding and 5-HTT mRNA levels varied significantly by 5-HTTLPR genotype; and that 5-HTTLPR influenced whole blood 5-HT content. Since 5-HTT is the primary target of action for SSRIs, we hypothesized that allelic variation of 5-HTT gene expression could influence the individual response to these drugs. In a sample of 166 inpatients, we observed that the efficacy of fluvoxamine in the treatment of delusional depression and the efficacy of paroxetine in the treatment of non-delusional depression was influenced by 5-HTTLPR polymorphism. Homozygotes for the long variant and heterozygotes showed better clinical responses than homozygotes for the short variant.