TY - JOUR T1 - Genetic variations in the serotonergic system mediate a combined, weakened response to SSRI treatment: a proposed model JF - eneuro JO - eneuro DO - 10.1523/ENEURO.0032-14.2015 SP - ENEURO.0032-14.2015 AU - Adam Pettitt Y1 - 2015/05/25 UR - http://www.eneuro.org/content/early/2015/05/24/ENEURO.0032-14.2015.abstract N2 - Individuals with the short (S) allele in the promoter region of the serotonin transporter gene (5-HTTLPR) show a less favorable response to selective serotonin reuptake inhibitor (SSRI) treatment than individuals with the long (L) allele. Similarly, individuals with the C(-1019)G allele for the mutation found in the promoter region of the serotonin 1A receptor gene (5-HTR1A) have shown blunted responses to SSRI treatment when compared with individuals lacking this polymorphism. While these findings have been replicated across multiple studies, only two studies to date have reported data for a gene-gene interaction associated with response to SSRI treatment. Both of these studies reported a combined effect for these genotypes, with individuals homozygous for the L allele and the C allele (5-HTTL/L – 1AC/C) reporting the most favorable response to SSRI treatment and individuals homozygous for the S allele and the G allele (5-HTTS/S – 1AG/G) reporting the least favorable response to SSRI treatment. Additionally, no neural mechanisms have been proposed to explain why this gene-gene interaction has been observed. To that end, this article provides a review of the relevant literature associated with these polymorphisms and proposes a feasible model that describes a genotype-dependent modulation of postsynaptic serotonin signaling associated with the 5-HTT and 5HTR1A gene. Significance Statement: Approximately forty percent of individuals that seek pharmacological treatment for depression do not initially respond to selective serotonin reuptake inhibitor (SSRI) antidepressants. Past research has attempted to determine if specific mutations in genes associated with the serotonergic system can help to predict response to antidepressant treatment; however, results have been inconclusive. Additionally, very little research has examined how multiple mutations can cause a combined, reduced response to SSRI antidepressant treatment. This article provides a review of the relevant literature, offers a model for why individuals with multiple mutations in the serotonergic system show a blunted response to SSRIs, and provides a basis for further research regarding genotype-dependent response to antidepressant treatment. ER -