Analysis of association between the serotonin transporter and antidepressant response in a large clinical sample.
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.
Kraft
Jeffrey B
JB
Department of Psychiatry and Center for Human Genetics, University of California, San Francisco, California 94143-0984, USA.
Peters
Eric J
EJ
Slager
Susan L
SL
Jenkins
Greg D
GD
Reinalda
Megan S
MS
McGrath
Patrick J
PJ
Hamilton
Steven P
SP
D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use; D015283:Citalopram / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*
D018687:Antidepressive Agents, Second-Generation; D015283:Citalopram; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493230:SLC6A4 protein, human