THE CYP2D6 GENOTYPE AND PLASMA-CONCENTRATIONS OF MIANSERIN ENANTIOMERS IN RELATION TO THERAPEUTIC RESPONSE TO MIANSERIN IN DEPRESSED JAPANESE PATIENTS

The relationship between therapeutic response to racemic mianserin and steady-state plasma concentrations of S(+)- and R(-)- mianserin was s tudied in 26 Japanese patients with major depression. The daily dose o f mianserin was 30 mg, and the duration of treatment was 3 weeks. Rega rding S-mianserin, the proportion of responders (final Montgomery-Asbe rg Depression Rating Scale score of 10 or less) was significantly high er in the plasma concentration range of 10 to 23 ng/mL than outside (1 0 of 11 vs. 3 of 15, p = 0.0005). Such a plasma concentration differen ce between responders and nonresponders was not found for R-mianserin. In 15 patients, the relationships between the CYP2D6 genotype, determ ined by allele-specific polymerase chain reaction analysis and Escheri chia coli RI restriction fragment length polymorphism, plasma concentr ations of the enantiomers, and the therapeutic response were studied. Five patients were homozygous for the wild type (wt) allele (wt/wt), n ine were heterozygous for the CYP2DGCh (Ch) allele causing decreased C YP2D6 activity (Ch/wt), and one patient was heterozygous for the Ch al lele and the defect allele CYP2DGD (D) (Ch/D). The Ch/wt group showed significantly higher plasma concentrations of S-mianserin (mean +/- SD : 15 +/- 6 vs. 8 +/- 1 ng/mL, p = 0.007) and proportion of responders (8 of 9 vs. 1 of 5, p = 0.023) than the wt/wt group. The patient with the Ch/D genotype had the highest plasma concentration of S-mianserin (37 ng/ mL) and a poor response. No significant relationship was found between the CYP2D6 genotype and plasma concentration of S-mianserin. The study presented here thus suggests that the CYP2D6 genotype plays a major role in controlling plasma concentration of the S-enantiomer o f mianserin, which contributes to a major extent to the antidepressant effect during mianserin treatment.