1997 Fiscal Year Final Research Report Summary
Molecular pharmacogenetic investigation of pharmacotherapeutic strategy for treatment-resistant depression.
| Project/Area Number |
07671064
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Psychiatric science
|
|---|
| Research Institution | Shiga University of Medical Science |
|---|
Principal Investigator |
SOMEYA Toshiyuki Shiga University of Medical Science, Health Administration Center, Lecturer, 保健管理センター, 講師 (50187902)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
SHIMODA Kazutaka Shiga University of Medical Science, Department of Psychiatry, Instructor, 医学部, 助手 (30196555)
|
|---|
| Project Period (FY) |
1995 – 1997
|
| Keywords | Treatment-resistant depression. / Tricyclic antidepressant. / Metabolism. / Genotyping |
|---|
| Research Abstract |
In this project, we tried to search the biological background of resistant depression by collecting and analyzing the data of plasma levels of tricyclic antidepressants and their metabolites and the genetic data of enzyme (s) which is responsible for metabolism of tricyclic antidepressants. We measured the plasma concentrations of clomipramine and its metabolites, and the metabolic ratios for desmethylation, hydroxylation, and glucuronidation that were calculated from steady-state drug concentrations varied substantially with 36-, 14, and 28-fold interindividual variations, respectively. Plasma levels of clomipramine and its desmethylated, hydroxylated and glucuronidated metabolites were determined in fifty-seven patients who were suffered from DSM-III-R major depressive episode and treated with various daily dose of clomipramine. Discriminant analysis of drug concentrations and clinical response revealed that clinical outcome of approximately 79% of the subjects could be correctly predicted. Nortriptyline is one of the prevalent tricyclic antidepressants that is widely used for treatment of depression. The impact of CYP2D6Ch that is frequently found in Asian, on the metabolism of nortriptyline was investigated. The subjects with homozygote of CYP2D6Ch (Ch/Ch) show approximately 80% higher plasma concentrations of nortriptyline compared with the subjects with homozygote of wild type (Wt/Wt). In Ch/Ch group, nortriptyline/trans-10-hydroxynortriptyline, which is representative of the hydroxylation ratio of nortriptyline, is approximately 240% higher than that of Wt/Wt group. These results suggest that homozygote of CYP2D6Ch decrease the hydroxylation clearance of nortriptyline.
|
