Genetic Variations in the Serotonergic System Mediate a Combined, Weakened Response to SSRI Treatment: A Proposed Model1,2

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-HTT(L/L)−1A(C/C)) reporting the most favorable response to SSRI treatment, and individuals homozygous for the S allele and the G allele (5-HTT(S/S)–1A(G/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 5-HTR1A genes.