Genes Influence Response to Antidepressants

SEOUL, South. Korea, Oct. 3 -- The key to selecting the right antidepressant for initial treatment of late-life depression may lie in a patient's genes, according to researchers here.

The presence of certain polymorphisms in the serotonin transporter and norepinephrine transporter genes may determine whether the patients is likely to benefit more from a selective serotonin reuptake inhibitor (SSRI), norepinephrine reuptake inhibitor (NRI), or other class of antidepressants, they found.

"Initial drug treatments fail in 30% to 40% of patients with major depression,". Doh Kwan Kim, M.D., Ph.D., of Sungkyunkwan University School of Medicine, and colleagues, wrote in the Oct. 4 issue of Journal of the American Medical Association. "Pharmacogenetic prediction of response is one possibility for improving the efficiency of antidepressant treatment."

There is evidence that both drug choice and ethnic variations may influence the effects of genetics on patient responses to antidepressants, the authors noted.

"In white populations, depressed patients with the long allele 5-HTTLPR genotypes (sl and ll) generally show a greater response to SSRIs than those with a short allele genotype (ss)," they wrote. "However, studies in Japanese and Korean populations report an association in the opposite direction. The effect of this polymorphism on treatment outcome may also depend on the mechanism of antidepressant action."

To determine whether patient responses to SSRIs or NRIs are associated with genetic polymorphisms of the corresponding monoamine transporters, the authors studied 241 adult inpatients and outpatients who were being treated for major depression at the psychiatric service of the Samsung Medical Center here.

Patients were assigned to e either the NRI Aventyl (nortriptyline), or to the SSRIs Prozac (fluoxetine) or Zoloft (sertraline). Although Aventyl is technically classified as a tricyclic antidepressant, part of its mechanism of action is norepinephrine reuptake inhibition.

The decision to assign a patient to an SSRI rather than NRI was left to the discretion of the clinician, on the basis of known adverse effects of Aventyl in at-risk individuals. Patients were assigned to an SSRI if they were frail or had a history of osteoporosis, falls, or known cardiovascular disease, including a history of hypotension.

The mean patient age was 55.8 (range 22 to 76), and the mean age at depression onset was 51 years. A total of 105 patients received Aventyl, 51 were given Prozac, and 85 received Zoloft. The investigators monitored patient compliance with the assigned therapy by measuring plasma concentrations of the prescribed drugs at four weeks.

They also genotyped patients for s/l polymorphisms in the 5-HTT promoter region, 5-HTT intron 2 s/l variation, and the norepinephrine transport (NET) G1287A variation of exon 9.

The main study outcome was response to SSRIs and the NRI, defined as a 50% or greater decrease in Hamilton Rating Scale for Depression score at six weeks.

They found that patients who responded to Aventyl were nearly eight times more likely to carry the NET G1287A polymorphism (odds ratio, 7.54, 95% confidence interval, 2.53-22.49, P<0.001). An even stronger association was seen between an SSRI response and the presence of the 5-HTT intron 2 s/l variation (odds ratio 20.11, 95% CI, 4.27- 94.74, P<0.001).

A less robust, but still significant association between a polymorphism and an SSRI response was seen with s/l variants in the 5-HTT promoter region (odds ratio, 3.34, 95% CI, 1.41-7.91, P=0.006).

They found that in this population of unrelated patients of Korean origin, the favorable allele for SSRI response was S 5-HTTLPR, which contrasts with findings of the influence of polymorphisms on antidepressant responses in white patients, the authors noted.

They also found that the S 5-HTTLPR was associated also with a response to Aventyl (odds ratio, 3.73, 95% CI, 1.32-10.53; P=0.01).

The NET polymorphism was not associated with an SSRI response in their study. They also determined that the NET G1287A GG genotype, which occurs in 56% of the population in Korea, was associated with better response to Aventyl than to either Prozac or Zoloft. (83.3% to 58.7%, odds ratio 3.52, 95% CI, 1.39-8.95; P=0.006).

The presence of some of the genotype combinations was predictive of a high rate of antidepressant responses, while other combinations were predictive of low response rates, the authors noted.

Several limitations were pointed out by the authors. "Our patients were mostly elderly (77% age more than 50), and most (60%) had late-onset illnesses with few previous depressive episodes." In addition, the absence of a placebo-treated group prevented determination of the rate of nonspecific or non-drug attributable response,

"The results of this study need to be confirmed in other populations, using selective NRIs other than nortriptyline," they wrote. "Additional studies in younger populations with depression are also needed. Confirmation of these preliminary findings would permit refined pharmacogenetic selection of antidepressant treatment."