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The common mechanism of drugs in this class is antagonism of the serotonin transporter. Within the serotonin transporter gene <jats:italic><jats:styled-content style=\"fixed-case\">SLC<\/jats:styled-content>6A4<\/jats:italic>, two polymorphic sites termed 5\u2010<jats:styled-content style=\"fixed-case\">HTTLPR<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">ST<\/jats:styled-content>in2 are proposed to have functional consequences and thus have been attractive candidates for pharmacogenetic studies of <jats:styled-content style=\"fixed-case\">SSRI<\/jats:styled-content> efficacy and tolerability. This review summarizes approximately 15 years of study of these polymorphisms as they relate to <jats:styled-content style=\"fixed-case\">SSRI<\/jats:styled-content> tolerability phenotypes. Four online databases (PubMed, Cochrane <jats:styled-content style=\"fixed-case\">CENTRAL<\/jats:styled-content>, Psyc<jats:styled-content style=\"fixed-case\">INFO<\/jats:styled-content>, and Pharm<jats:styled-content style=\"fixed-case\">GKB<\/jats:styled-content>) were searched for articles on polymorphisms of <jats:italic><jats:styled-content style=\"fixed-case\">SLC<\/jats:styled-content>6A4<\/jats:italic> including 5\u2010<jats:styled-content style=\"fixed-case\">HTTLPR<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">ST<\/jats:styled-content>in2 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\u2010<jats:styled-content style=\"fixed-case\">HTTLPR<\/jats:styled-content> S allele is generally associated with greater adverse drug reaction burden during <jats:styled-content style=\"fixed-case\">SSRI<\/jats:styled-content> therapy. The most convincing evidence is in studies of antidepressant\u2010induced mania and gastrointestinal adverse events. Studies of <jats:styled-content style=\"fixed-case\">ST<\/jats:styled-content>in2 are sparse and have conflicting findings. In conclusion, the S allele of 5\u2010<jats:styled-content style=\"fixed-case\">HTTLPR<\/jats:styled-content> 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 <jats:styled-content style=\"fixed-case\">SSRI<\/jats:styled-content>s.<\/jats:p>","DOI":"10.1002\/phar.1978","type":"journal-article","created":{"date-parts":[[2017,6,27]],"date-time":"2017-06-27T08:48:55Z","timestamp":1498553335000},"page":"1089-1104","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["Serotonin Transporter Gene Polymorphisms and Selective Serotonin Reuptake Inhibitor Tolerability: Review of Pharmacogenetic Evidence"],"prefix":"10.1002","volume":"37","author":[{"given":"Jing","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Pharmacy and Therapeutics University of Pittsburgh School of Pharmacy Pittsburgh 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