Association Between a Functional Serotonin Transporter Promoter Polymorphism and Citalopram Treatment in Adult Outpatients With Major Depression

CONTEXT: The HTTLPR, a functional polymorphism of the serotonin transporter gene solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (SLC6A4), promoter, affects transcription and may be involved in antidepressant drug treatment outcome, although response rates with antidepressants can be lower in patients who experience adverse effects. OBJECTIVE: To test the hypothesis that HTTLPR is associated with treatment outcome to citalopram. DESIGN: A clinical effectiveness trial, Sequenced Treatment Alternatives to Relieve Depression, collected DNA samples from outpatients with nonpsychotic major depressive disorder who received citalopram in the first treatment step. The triallelic HTTLPR locus was genotyped in 1775 samples to discriminate between long (L) and short (S) alleles, followed by the A > G substitution. The low-expression S and L(G) alleles were grouped together compared with the high-expression L(A) allele. SETTING: Eighteen primary care and 23 psychiatric care sites across the United States. PARTICIPANTS: Ages 18 to 75 years, meeting criteria for single or recurrent nonpsychotic major depression. MAIN OUTCOME MEASURES: Categorical response, remission, tolerance, and adverse effect burden. RESULTS: Expression-based grouping produced a significant finding of association between the L(A) allele and adverse effect burden in the entire sample (P = .004 genotype frequency; P < .001 allele frequency). To control for bias from population stratification, a white American subsample was analyzed. A lesser adverse effect burden was associated with L(A)L(A) genotype frequency (P = .03) or L(A) allele frequency (P = .007). These findings in white patients did not hold when the L allele was undifferentiated. No association was observed between treatment outcome phenotypes and HTTLPR. Development of diarrhea and the presence of the low-expression S or L(G) alleles were the strongest risk factors associated with adverse effect burden. CONCLUSIONS: The HTTLPR polymorphism is associated with citalopram adverse effects. Because the L(A) allele confers increased SLC6A4 transcription, increased serotonin transporter levels in brain and other tissues may lead to fewer adverse effects for antidepressant medications that target the transporter.