Takehiko Tezuka

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

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.

Monoamine oxidase: A gene polymorphism, tryptophan hydroxylase gene polymorphism and antidepressant response to fluvoxamine in Japanese patients with major depressive disorder

Monoamine oxidase A (MAOA) and tryptophan hydroxylase (TPH) are the staple enzymes in the metabolism of serotonin (5-HT). The genetic polymorphisms of these two enzymes might individually alter the production, release, reuptake or degradation of 5-HT during the treatment of selective serotonin reuptake inhibitors (SSRIs), leading to the individual differences in the antidepressant effects of SSRIs. The authors investigated whether a functional polymorphism in the MAOA gene promoter (MAOA-VNTR) and a TPH gene polymorphism in intron 7 (TPH-A218C) were associated with the antidepressant response to fluvoxamine in 66 Japanese patients with major depressive disorder during a 6-week study with a specific dosage plan. Fifty-four patients completed the study. The present study fails to demonstrate that the genetic polymorphisms of MAOA-VNTR and TPH-A218C affect the antidepressant effect of fluvoxamine in Japanese patients with major depressive disorder.

A variable number of tandem repeats in the serotonin transporter gene does not affect the antidepressant response to fluvoxamine

A variable number of tandem repeats (VNTR) in the second intron of the serotonin transporter gene (STin2) has been studied in association with the susceptibility to affective disorders. Recently, it was reported that selective serotonin reuptake inhibitors were more effective in patients with major depressive disorder having the homozygous allele pair (12-copy/12-copy) of VNTR in the STin2 than in ones having other allele combinations. As the study had methodological problems, further studies are needed to confirm the above finding. Therefore, the authors investigated whether the allelic variation of VNTR in the STin2 was associated with the antidepressant response to fluvoxamine in 66 patients with major depressive disorder. Fluvoxamine was prescribed up to 200 mg/day in the dosing protocol for 6 weeks. The present study showed no significant association between the polymorphism of VNTR in the STin2 and the treatment response to fluvoxamine.

Association between -1438G/A Promoter Polymorphism in the 5-HT 2A Receptor Gene and Fluvoxamine Response in Japanese Patients with Major Depressive Disorder

Genetic polymorphism of the serotonin 5-HT2A receptor seems to be associated with therapeutic response to selective serotonin reuptake inhibitors (SSRIs). The present study investigated whether a novel –1438G/A polymorphism in the promoter region of the 5-HT2A receptor gene is associated with therapeutic response to fluvoxamine (an SSRI) in 66 Japanese patients with major depressive disorder. Fluvoxamine (50 to 200 mg) was administered twice daily for 6 weeks. Fifty-four patients completed this study. The genotype distribution and the allele frequencies showed no significant difference between responders and non-responders. The time-course of the Montgomery-Åsberg Depression Rating Scale scores showed no significant difference among –1438G/G, –1438G/A, and –1438A/A genotype groups. The results demonstrated that the –1438G/A promoter polymorphism in the 5-HT2A receptor gene was unlikely to have a major role in therapeutic response to fluvoxamine in Japanese patients with major depressive disorder.

No association between the serotonergic polymorphisms and incidence of nausea induced by fluvoxamine treatment.

We investigated the association between serotonergic polymorphisms and incidence of nausea, which is the most frequent side-effect of selective serotonin reuptake inhibiters (SSRIs), in 66 patients treated with fluvoxamine in a protocolized-dosing method. We focused on three polymorphisms of serotonin (5-HT) neuronal systems such as 5-HT transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR), a variable number of tandem repeat (VNTR) polymorphism in the second intron of the 5-HTT gene (STin2) and tryptophan hydroxylase (TPH) gene polymorphism in intron 7 (TPH-A218C), which have been reported to possess positive association with treatment response to SSRIs. In addition to this, the relationship between development of nausea and treatment response was also analyzed. Results suggested that these three polymorphisms did not affect the development of fluvoxamine-induced nausea, and that incidence of nausea was not a phenomenon that predicts the treatment response to fluvoxamine.

Application of a recombinant Fab fragment from a phage display library for sensitive detection of a target antigen by an inhibition ELISA system

We have found that the recombinant Fab (rFab) produced by phage display system was detectable for a target antigen more sensitive than the parental monoclonal antibody (MoAb). The Fab phage display library was constructed from hybridoma cells producing APU-6 MoAb specific for a modified nucleoside, pseudouridine that have been studied as a urinary marker for malignancy. Fab-displayed phage clones were screened by a direct ELISA, and the single positive clone was finally obtained. Although the reaction pattern of rFab against pseudouridine and uridine was almost identical to that of MoAb, detection sensitivity of rFab was approximately 30 times higher than that of MoAb. Since the sensitivity of rFab was almost identical to that of Fab fragment prepared by papain digestion of MoAb, the increased sensitivity is considered to be the nature of Fab fragment. The sensitivity of established assay system was sufficient for quantitative determination of serum pseudouridine levels in healthy individuals and cancer patients. This procedure may be applicable for improvement of detection sensitivity of a MoAb-based inhibition ELISA system for drugs or low molecular weight compounds.

Monoamine oxidase-A gene polymorphism and antidepressant response to fluvoxamine in Japanese patients with major depressive disorder

The subjects were 30 patients with depression treated with clomipramine. Clinical assessment was carried out with the Hamilton Depression Scale. Fourteen questions were asked in order to rate side effects. Side effects were rated with the score from 0 to 3 (0=not at all, 1=a little bit, 2= apparent but tolerable, 3= intolerable) according to the severity. Steady-state concentrations of clomipramine and its metabolites were determined by high-performance liquid chromatography. For genotyping of CYP2D6 and CYP2C19, polymerase chain reaction methods were used. The subjects were divided into groups by the number of CYP2D6 or CYP2C19 mutated alleles.

Practical Analysis on the Trial Drugs under the Previous GCP.

The practical management regarding trial drugs according to the previous GCP system was analyzed between 1992 and 1996 to provide important information regarding the developmental status of new drugs or preparations under a newly revised revised system in our hospital. These findings helped to clarify the present status regarding the management of trial drugs especially regarding each specific drug.