Elsevier

Biological Psychiatry

Volume 61, Issue 6, 15 March 2007, Pages 734-742
Biological Psychiatry

Original article
Analysis of Association Between the Serotonin Transporter and Antidepressant Response in a Large Clinical Sample

https://doi.org/10.1016/j.biopsych.2006.07.017Get rights and content

Background

SLC6A4 encodes the serotonin transporter, the protein primarily responsible for the termination of serotonin neurotransmission. Because many antidepressants inhibit the transporter, it has been the focus of intense pharmacogenetic analysis. We sought to replicate our previous findings that SLC6A4 is associated with response to a selective serotonin reuptake inhibitor (SSRI) in a large case–control study.

Methods

Genotypes at the SLC6A4 locus were obtained for 1,914 subjects in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and then tested for association to treatment response of the SSRI citalopram.

Results

Nine tagging single nucleotide polymorphisms and two variants previously associated with antidepressant response, including a promoter repeat polymorphism, were genotyped. Single marker and haplotypic analyses failed to detect association with antidepressant response in the largest clinical sample studied to date.

Conclusions

The lack of association between response to an SSRI and variation at the SLC6A4 locus in this large sample, carefully characterized for response to citalopram, strongly suggests that SSRI response in major depression is not determined by DNA variation at this locus. These findings do not replicate findings of a number of studies with considerably smaller sample sizes. Other genetic determinants of SSRI response in depression should be sought.

Section snippets

Sample

Of the 4,041 subjects, DNA was obtained from 1,953 subjects as part of the National Institute of Mental Health (NIMH) Human Genetics Initiative. The design of STAR*D was to enroll adults experiencing a major depressive episode who exhibited neither an inadequate response nor intolerance to an adequate trial of any of the STAR*D protocol treatments during the current episode. The overall aim of STAR*D (principal investigator, A. John Rush, NIMH Contract N01-MH-90003) was to determine

Results

Of the 1,953 subjects who consented to give DNA, data for 1,914 subjects are described in this report. The 39 samples that were unavailable for genotyping did not differ from the remaining samples in demographic or clinical variables. Using our responder versus nonresponder phenotype (R/NR), 1,660 of the 1,914 samples could be categorized, with 991 responders and 669 nonresponders, for a response rate of 59.7%. We excluded 254 because they did not reach the 6-week treatment threshold. The

Discussion

We failed to detect association between any of the SNPs within the SLC6A4 and antidepressant response phenotype. Our failure to detect association in a large sample is strong evidence against a role for variation in this gene as a factor in response to SSRIs. In our primary phenotype, categorical response versus nonresponse, our results differed with regard to a number of other studies in which associations were found between response and SLC6A4. There may be a number of reasons for this

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