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Depression Study Suggests Genotype Improves Response to NRIs While Dulling SSRI Efficacy

A study published this week on the genetics of response to antidepressants suggests that a particular genotype can dull the efficacy of selective serotonin reuptake inhibitors while improving a patient’s response to less-popular norepinephrine reuptake inhibitors, or NRIs.
Published in this week’s Journal of the American Medical Association, the study followed 241 Korean patients being treated for depression and links variants in their norepinephrine transporter and serotonin transporter genes with how they respond to one NRI and two SSRIs.
Apparently ethnicity plays an important role in one of the polymorphisms: According to the study authors, one variant of the serotonin transporter gene produces diametrically opposite responses in East Asians and Caucasians, a finding the same group originally reported in 2000.
The implications of the research are “huge for clinical practice and for the market in antidepressant drugs,” Bernard Carroll, scientific director of the Pacific Behavioral Research Foundation and study author, told Pharmacogenomics Reporter this week.
“If this genotyping is taken up in clinical services then the use of [first-line] SSRI drugs … to treat depression will probably be cut in half, if not more,” said Carroll, who is also former chairman of psychiatry at Duke University and former chairman of the US Food and Drug Administration advisory committee for psychiatric drugs.
The study, led by author Hyeran Kim of Samsung Medical Center in Seoul, South Korea, has “added another dimension” to understanding how norepinephrine transporters affect the efficacy of antidepressant drugs, “and now it makes a lot more sense,” Dennis O’Kane, director of the Nucleotide Polymorphism Laboratory at the Mayo Clinic in Rochester, Minn., told Pharmacogenomics Reporter this week. “The Samsung group has made a great contribution to pharmacogenetics by getting this study carried out.”
The findings could trigger pharmacogenomic testing of transporter genes to guide antidepressant treatment “within two to three years,” assuming the Korean study is replicated, O’Kane said.
The Research
The study included only Korean patients: 105 took the NRI nortriptyline and 136 took one of two SSRIs, either fluoxetine or sertraline. In the NRI group, those carrying the NET gene polymorphism G1287A GG were more likely to respond to the drug, with an odds ratio of 7.54.
Specifically, patients with the GG genotype had an 83-percent response rate to the NRI and a 58-percent response rate to the SSRIs. This genotype is present in about 56 percent of the Korean population and about 45 percent of the white population in the United States. The odds ratio for this group’s response to the NRI compared to the SSRIs was 3.52. 
The NRI patient group carrying the NET G1287A genotype GG “really stands out” because of their differential responses to antidepressants and because of their prevalence, said Carroll.
However, Korean patients carrying a “short” intron variation in the serotonin transporter gene 5-HTT responded more often to the SSRIs fluoxetine or sertraline, with an odds ratio of 20.11. Patients with a short promoter variation of 5-HTT were also more likely to respond to an SSRI, with an odds ratio of 3.34, and they were more likely to respond to an NRI, with an odds ratio of 3.73.
The researchers checked drug levels in the blood at four weeks to eliminate patients who stopped taking the drug, or whose drug metabolism, due to genetics or other factors, was too extensive to keep it at therapeutic levels. The researchers gauged response to the antidepressants at 6 weeks of therapy as a decrease of more than 50 percent in the Hamilton rating scale for depression.
Should genotyping take hold in the clinic, physicians may have to take ethnicity into account. In Caucasians, the Korean study showed that the “L” promoter variation of 5-HTT was associated with SSRI response.
“Just to make matters interesting, it turns out the Chinese are more like Caucasians than Koreans and Japanese” in their responses to SSRIs, said Carroll. “The finding of ethnic variation is real — I think there’s little doubt now about that” since the group replicated its 2000 findings and those of other researchers, he said.
Nortriptyline is a generic tricyclic antidepressant that also acts partly on the serotonin receptor. The drug is marketed by Mansfield, Mass.-based Tyco Healthcare as Pamelor and by India-based Ranbaxy Pharmaceuticals under the name Aventyl. Fluoxetine became a generic in 2001 — it was originally marketed by Lilly as Prozac. Sertraline is marketed by Pfizer as Zoloft and became a generic in June. 
The market research company IMS Health estimates the size of the 2005 antidepressant market as $12.5 billion. Zoloft, the most recent SSRI to lose its patent exclusivity, had sales of $3 billion in 2005.
Carroll estimated the size of the SSRI market alone at about $10 billion.
Is There a Diagnostic In the House?
The Mayo Clinic in July licensed a 5-HTT promoter-region genotyping test from Pathway Diagnostics, but it is not yet used as a regular part of clinical care at the clinic, said Mayo’s O’Kane. “We thought about bringing up the intronic repeat [genotyping] as well,” but there was not enough interest in that procedure within the organization, he said. “This is really the beginning of a very exciting story … this paper adds a lot to it.”

“If this genotyping is taken up in clinical services then the use of [first-line] SSRI drugs … to treat depression will probably be cut in half, if not more.”

The intellectual property issues surrounding 5-HTT genotyping are not completely clear, but Mayo nonetheless decided to license the test from Pathway, which has a patent application pending.
Pathway did not return calls before deadline, and it was not clear whether transporter genotyping is offered by other laboratories. O’Kane said he was not aware of other labs offering such tests.
Roche Molecular Diagnostics, which markets its AmpliChip largely to the psychiatric market — specifically to help clinicians estimate dosages for antidepressants and other drugs — is not currently exploring development of a neurotransmitter transporter genotyping test, a company spokesperson said this week.
Next Steps
Carroll said Pfizer’s NRI reboxetine, which failed clinical trials in the United States, is a candidate for reevaluation in clinical trials using a pharmacogenomically enriched patient population to achieve FDA approval.
“I’m sure that had they looked at it [in clinical trials] in the GG NET subset, they most likely would have found a benefit,” he said.
Pfizer markets reboxetine as Edronax in “more than 60 countries,” according to a company representative. She was not able to say before deadline whether Pfizer would attempt a pharmacogenomics-assisted clinical trial in the near future.
Carroll and colleagues have not discussed their results with any drug makers, but “as soon as [the study] hits the street we’re going to get some requests for consultation from drug companies,” he said. The group has also not spoken to diagnostics companies, he added.

The researchers next plan to follow up their findings with a possible study in Caucasian patients with Duke University, said Carroll. The research should also be verified in younger subjects, he added.

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