Influence of the serotonin transporter gene-linked polymorphic region on the antidepressant response to fluvoxamine in Japanese depressed patients

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Abstract

The presence of the long (l) variant of the serotonin (5-hydroxytryptamine: 5-HT) transporter gene-linked polymorphic region (5-HTTLPR) is reported to be associated with a more favorable and faster antidepressant effect of selective serotonin reuptake inhibitors in Caucasians. The frequency of the l allele is lower in Japanese than in Caucasians; therefore, the antidepressant effect of fluvoxamine can be not as good in Japanese as in Caucasians. The authors investigated whether 5-HTTLPR was associated with the antidepressant response to fluvoxamine in 66 Japanese patients with major depressive disorder in a protocolized-dosing 6-week study. The short (s) allele frequency was significantly higher in the responsive individuals than in the nonresponsive ones (P=.010). The present study suggests that fluvoxamine is not less effective in depressive patients carrying the s allele than in the ones carrying the l allele and it is not less effective in Japanese than in Caucasians.

Introduction

There is considerable evidence supporting the hypothesis that alterations in the serotonergic neuronal function are involved in the pathophysiology of depression (Owens and Nemeroff, 1994). Serotonin (5-hydroxytryptamine: 5-HT) transporter (5-HTT) plays a critical role in the termination of 5-HT neurotransmission by sodium-dependent uptake into the presynaptic neuron (Rudnick and Clark, 1993). Heils et al. (1996) reported the long (l) and short (s) (44 bp insertion/deletion) variants of the 5-HTT gene-linked polymorphic region (5-HTTLPR). Several investigators have suggested that they are associated with the susceptibility of affective disorders Collier et al., 1996, Furlong et al., 1998, but conflicting results have also been reported Ewald et al., 1998, Ohara et al., 1998. The polymorphism of the 5-HTT gene seems to be associated not only with the susceptibility of affective disorders but also with the treatment response to selective serotonin reuptake inhibitors (SSRIs), because they are thought to exert their effects through binding to 5-HTT and inhibiting 5-HT reuptake.

Zanardi et al. (2000) reported that patients with major depressive disorder who are homozygous for the s variant of the 5-HTTLPR had a significantly poorer response to treatment using paroxetine than others. The frequencies of the s and l alleles are approximately 79% and 21% among Japanese, while 42% and 58% among Caucasians, respectively (Kunugi et al., 1997). If the allelic variation of 5-HTTLPR can be a predictor of an antidepressant response, the antidepressant effect of SSRIs can be not as good in Japanese as in Caucasians. To clarify this issue, the authors first investigated whether the allelic variation of 5-HTTLPR was associated with the antidepressant response to fluvoxamine in Japanese depressed patients. The authors selected fluvoxamine because it has a higher selectivity than fluoxetine and paroxetine for blocking the reuptake of 5-HT (Richelson, 1996).

Section snippets

Subjects and treatment

Sixty-six patients meeting the DSM-IV (American Psychiatric Association, 1994) diagnosis of major depressive disorder, whose score of Montgomery and Åsberg (1979) Depression Rating Scale (MADRS) was more than 20 points, were included in this study. They had no severe medical diseases and other Axis I or Axis II disorders. The patients had to be between 20 and 69 years old and free from psychotropic drugs at least 14 days before their entry into the present study. All patients provided informed

Patient characteristics

Among 66 patients, four patients could not end the 6-week study because of gastrointestinal symptoms such as nausea and vomiting. Five patients had no complaints and stopped visiting our hospital. Fifty-seven patients ended the 6-week study. Three of the patients in the 6-week study were excluded from the present study because at least one of their duplicate plasma samples showed 0 ng/ml of the fluvoxamine level and their compliance was considered to be extremely poor. Subjects who completed

Discussion

The present study showed that fluvoxamine could be more effective in depressive patients carrying the s allele than in ones carrying the l allele. Kim et al. (2000) reported that s/s patients with major depressive disorder showed better response than other groups in Korean patients. Their results were similar to ours in part, but their study had methodological problems. They used two SSRIs (fluoxetine and paroxetine), and their doses were not protocolized. They did not examine the plasma levels

Conclusions

The present study suggests that fluvoxamine is not less effective in depressive patients carrying the s allele than in ones carrying the l allele and it is not less effective in Japanese than in Caucasians. It is difficult to explain the mechanism underlying this racial difference of the antidepressant response. Further studies should be needed to clarify whether the 5-HTTLPR can be a predictor of the antidepressant effect of SSRIs.

Acknowledgements

This study was supported in part by a grant from the Japan Research Foundation for Clinical Pharmacology.

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