Serotonin Transporter Gene Polymorphisms and Selective Serotonin Reuptake Inhibitor Tolerability: Review of Pharmacogenetic Evidence

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are first-line pharmacotherapy for mood and anxiety disorders. The common mechanism of drugs in this class is antagonism of the serotonin transporter. Within the serotonin transporter gene SLC6A4, two polymorphic sites termed 5-HTTLPR and STin2 are proposed to have functional consequences and thus have been attractive candidates for pharmacogenetic studies of SSRI efficacy and tolerability. This review summarizes approximately 15 years of study of these polymorphisms as they relate to SSRI tolerability phenotypes. Four online databases (PubMed, Cochrane CENTRAL, PsycINFO, and PharmGKB) were searched for articles on polymorphisms of SLC6A4 including 5-HTTLPR and STin2 by using a systematic approach. Specific and general psychopharmacology terms, along with adverse effect and tolerability concepts, added to the search strategy. The Human Gene Mutation Database was checked for additional references. Forty studies met the inclusion criteria. While null and occasionally opposite associations are reported, the low expression 5-HTTLPR S allele is generally associated with greater adverse drug reaction burden during SSRI therapy. The most convincing evidence is in studies of antidepressant-induced mania and gastrointestinal adverse events. Studies of STin2 are sparse and have conflicting findings. In conclusion, the S allele of 5-HTTLPR may be predictive of increased adverse event burden, and this effect appears specific to certain classes of adverse events. Limitations and challenges in interpreting this body of evidence include assay errors, dissimilar grouping of genotypes, the role of ethnicity in associations, and study methodological differences. The clinical utility of serotonin transporter genotypes is not yet delineated but will ultimately depend on genotypic effects on both tolerability and efficacy of SSRIs.

CYP2D6 metabolizer status and HTTLPR variant of SLC6A4 associated with antidepressant-induced mania in bipolar disorder

“…Considering the recommendation of Zhu et al [33] we investigated whether the HTTLPR findings would remain significant when controlling for CYP2D6 metabolizer status. The sample used for this study was the same as the one used to first implicate the HTTLPR polymorphism in AIM.…”

“…In this study we will investigate whether metabolizer status of the 5 hepatic genes outlined plays a role in the risk of developing AIM. As suggested by Zhu et al [33], we would also like to expand on the findings of the HTTLPR polymorphism of SLC6A4 and determine whether this finding remains significant after controlling for CYP2D6 metabolizer status. In addition, we would like to examine whether these two genes have an additive effect contributing to AIM.…”

5-HTTLPR and MTHFR 677C>T polymorphisms and response to yoga-based lifestyle intervention in major depressive disorder: A randomized active-controlled trial

“…[ 35 75 ] Several studies have reported poor response with SS/SL genotype. [ 35 36 37 38 76 77 ] A meta-analysis by Porcelli et al . [ 37 ] show that L allele/LL genotype of 5-HTTLPR may be a predictor of better antidepressant response (odds ratio [OR] = 1.58) and remission (OR = 1.53) in the SSRI group.…”

“…[ 34 35 ] Patients with S allele exhibit lower remission rates, increased side effects, and intolerance to drug therapy. [ 35 36 37 38 ] Serotonin can modify neuroplasticity both during development[ 39 ] and adult life, and alterations in serotonin homeostasis can modify the fine wiring of brain connections and cause behavior changes. 5-HTTLPR genotypes may affect neuroplasticity.…”

Genetische Grundlagen der Posttraumatischen Belastungsstörung (PTBS)

“…[88,91]). Pharmakogenetische Studien konnten bei Angststörungen aufzeigen, dass genetische Varianten über ihre Wirkung auf die Pharmakokinetik und -dynamik sowohl das Ansprechen auf eine anxiolytische Therapie mit Antidepressiva als auch die Nebenwirkungen beeinflussen können (siehe Übersichtsartikel [92][93][94][95]). Auch bei PTBS gibt es erste Hinweise darauf, dass sich genetische Unterschiede auf den Behandlungserfolg auswirken können.…”