Monoamine Transporter Gene Polymorphisms and Antidepressant Response in Koreans With Late-Life Depression

Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 10/2006; 296(13):1609-18. DOI: 10.1001/jama.296.13.1609
Source: PubMed


Polymorphisms in the serotonin transporter gene (5-HTT) may influence antidepressant response to selective serotonin reuptake inhibitors (SSRIs). The norepinephrine transporter (NET) is the analogous target for norepinephrine reuptake inhibitors (NRIs).
To determine whether antidepressant responses to SSRIs or NRIs are associated with genetic polymorphisms of the corresponding monoamine transporters.
A 6-week naturalistic treatment study with blinded outcome evaluation of 241 Korean inpatients and outpatients with major depression at an academic psychiatry service. Patients were recruited to the study from March 1998 through February 2003.
Treatment with an SSRI (fluoxetine or sertraline; n = 136) or an NRI (nortriptyline; n = 105) antidepressant. Adherence was assessed by measuring plasma concentration at 4 weeks. Patients were genotyped for s/l polymorphisms in 5-HTT promoter region (5-HTTLPR), 5-HTT intron 2 s/l variation, and NET G1287A variation of exon 9.
An SSRI and NRI response (defined as > or =50% decrease in Hamilton Rating Scale for Depression score at 6 weeks).
NRI response was associated with the NET G1287A polymorphism (odds ratio [OR], 7.54; 95% confidence interval [CI], 2.53-22.49; P<.001). An SSRI response was associated with the 5-HTT intron 2 s/l variation (OR, 20.11; 95% CI, 4.27-94.74; P<.001). The 5-HTTLPR was also associated with an SSRI response (OR, 3.34; 95% CI, 1.41-7.91; P = .006). In contrast to studies in white patients, the favorable allele for SSRI response was S 5-HTTLPR. The S 5-HTTLPR was associated also with NRI response (OR, 3.73; 95% CI, 1.32-10.53; P = .01). The NET polymorphism was not associated with an SSRI response. The NET G1287A GG genotype (56% of the population) was associated with better response to the NRI (83.3% [35/42]) than to SSRI (58.7% [44/75]) (OR, 3.52; 95% CI, 1.39-8.95; P = .006). Some genotype combinations were associated with high rates of antidepressant response and others with low rates of response.
Monoamine transporter gene polymorphisms were associated with response to antidepressants with homologous monoamine transporter targets. Combinations of polymorphisms were informative for response and nonresponse. Confirmation of these preliminary findings would permit refined pharmacogenetic selection of antidepressant treatment.

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Available from: Bernard J Carroll, Sep 30, 2014
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    • "The T allele of the norepinephrine transporter T-182C polymorphism was associated with a better antidepressant response , whereas the A/A genotype of the norepinephrine transporter G1287A polymorphism was associated with a slower onset of therapeutic response to milnacipran (Yoshida et al., 2004). These finding were supported by another study that found the A/A and G/A genotypes of the norepinephrine transporter G1287A polymorphism were associated with poorer responsiveness to nortriptyline, but not fluoxetine (Kim et al., 2006). Mouse studies have confirmed the role of the norepinephrine transporter, as well as other noradrenergic-related genes, in the behavioral responses to antidepressants. "
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    • "These associations are mechanistically plausible given the rs2242446 polymorphism is located in the NET promoter region and appears to alter transcription (Zill et al., 2002). In addition, the synonymous rs5569 polymorphism in exon 6 has been linked to alternative mRNA splicing and reduced NET functioning (Sogawa et al., 2010), and has been associated with preferential response to noradrenergic antidepressants (Kim et al., 2006). "
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    • "GSK3B is regulated by several neurotransmitter systems, including serotonergic (Li et al., 2004), dopaminergic (Gil et al., 2003), cholinergic and glutamatergic systems (De Sarno et al., 2006). No correlation between the norepinephrine transporter T182C/G1287A polymorphisms and SSRI response was observed (Kim et al., 2006; Min et al., 2009). There are also studies showing evidence for the involvement of the glutamate system on sexual dysfunction, a well-known side effect of SSRI treatment. "
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