Mikito Ueda

The impact of CYP2D6 genotypes on the plasma concentration of paroxetine in Japanese psychiatric patients.

The authors investigated the impact of the CYP2D6 genotypes on the plasma concentration of paroxetine (PAX) in 55 Japanese psychiatric patients. They were administered 10 to 40 mg/day (24+/-10.0 mg/day) of PAX and maintained at the same daily dose for at least two weeks to obtain the steady-state concentrations. The plasma levels of PAX were 15.8+/-15.0, 47.4+/-32.0, 101.2+/-59.9 and 177.5+/-123.6 ng/ml at the daily dose of 10, 20, 30 and 40 mg, respectively, which suggested dose dependent kinetics of PAX. The allele frequencies of the CYP2D65, CYP2D610 and CYP2D641 were 1.8%, 41.8% and 1.8%, respectively. Significantly higher PAX concentrations were observed in the patients having one functional allele compared with those with two functional alleles (150.9+/-20.6 vs. 243.6+/-25.2 ng/ml mg(-1) kg(-1), p<0.05, Newman-Keuls multiple comparison test) or no functional (243.6+/-25.2 vs. 76.7+/-6.1 ng/ml mg(-1) kg(-1), p<0.05, Newman-Keuls multiple comparison test) in the subjects with 30 mg/day of paroxetine. The same trend of findings as in the subjects treated with 30 mg/day were observed in the subjects with 40 mg/day of PAX. The present results suggest that having one non-functional allele is the marker for high plasma concentration of PAX when relatively high daily dose of PAX is administered.

Genetic and pharmacokinetic factors affecting the initial pharmacotherapeutic effect of paroxetine in Japanese patients with panic disorder

ObjectiveThe objective of this study was to evaluate genetic and pharmacokinetic factors affecting the initial pharmacotherapeutic effect of paroxetine (PAX) in Japanese patients with panic disorder (PD).MethodPlasma concentration of PAX was determined by high performance liquid chromatography. Serotonin transporter gene-linked polymorphic region (5-HTTLPR) variants were determined by polymerase chain reaction techniques. PD severity was assessed using the Panic and Agoraphobia Scale (PAS).ResultsMultiple regression analysis revealed that the plasma concentration of PAX, 5-HTTLPR genotype, and comorbid physical illness were significant factors affecting the initial pharmacotherapeutic effect of PAX in PD and indicated that these factors accounted for 52.4% (R2 = 0.524) of the variability in the percent reduction in PAS score. The final model was described by the following equation (P = 0.001): percent reduction in PAS score (%) = 68.5 − 1.2 × [plasma concentration of PAX (ng/ml)] − 33.0 × (L/S = 1, S/S = 0) − 21.8 × (with comorbid physical illness = 1, without comorbid physical illness = 0).ConclusionThe high plasma concentration of PAX, the L/S genotype of 5-HTTLPR, and comorbid physical illness might be associated with a poor response to the initial phase of pharmacotherapy of PD with PAX.

High plasma concentrations of paroxetine impede clinical response in patients with panic disorder.

Selective serotonin reuptake inhibitors are thought to interact with serotonergic neurons and be effective for treatment of panic disorder. In the present study, the authors investigated an association between plasma concentrations of paroxetine in patients with panic disorder and clinical response to initial treatment with paroxetine. Subjects were 21 unrelated Japanese patients who fulfilled DSM-IV-TR criteria for a diagnosis of panic disorder (6 males, 15 females, mean age 35.9 ± 11.3 years). Subjects were administered 10 mg/day of paroxetine for 2 weeks as initial treatment. Improvement of the symptoms of the disorder was assessed with the Panic and Agoraphobia Scale (PAS). In the range of plasma levels >20 ng/mL, none of the subjects showed the reduction ratio in PAS score >0.2. The subjects whose plasma concentrations of paroxetine were less than 20 ng/mL had a significantly higher mean reduction ratio in PAS score than the subjects whose plasma concentrations of paroxetine were >20 ng/mL. Multiple regression analysis showed that the plasma concentration of paroxetine was the only significant factor and accounted for 28.0% of the variability in the reduction ratio of PAS score of the subjects. The final model of correlation was: reduction ratio in PAS score = 0.423 − 0.009 × (plasma concentrations of paroxetine) (R = 0.529, P = 0.014, coefficient of determination (R2) = 0.280). Assuming that the reduction ratio in PAS score was 0.2 in the equation above, plasma concentration of paroxetine is calculated to be about 25 ng/mL, which is suggested to be the upper end of the therapeutic window for the initial phase of the treatment with paroxetine for panic disorder.

Factors affecting discontinuation of initial treatment with paroxetine in panic disorder and major depressive disorder

Objective The aims of the present study were to analyze the association between discontinuation of paroxetine (PAX) and the genetic variants of the polymorphism in the serotonin transporter gene-linked polymorphic region (5-HTTLPR) in Japanese patients with panic disorder (PD) and major depressive disorder (MDD). Methods The 5-HTTLPR genotype was determined by polymerase chain reaction method. PAX plasma concentration was measured by high-performance liquid chromatography to confirm adherence. Results When comparing between the PD and MDD patients with the chi-square test and Fisher’s exact test, the PD patients had a significant and higher discontinuation rate due to non-adherence than did the MDD patients (13.5% [7/52] versus 0% [0/88], respectively; P<0.001). MDD patients had a significant and higher discontinuation rate due to untraceability than PD patients (12.5% [11/88] versus 1.9% [1/52]; P=0.032). Multilogistic regression revealed a tendency for the long/short and short/short genotypes to affect discontinuation due to adverse effects in PD patients (25.0% versus 6.3%, respectively; P=0.054). Conclusion The results indicate that the 5-HTTLPR genotype might contribute to the discontinuation of initial PAX treatment due to adverse effects in PD patients.

Genetic Polymorphism of 1019C/G (rs6295) Promoter of Serotonin 1A Receptor and Catechol-O-Methyltransferase in Panic Disorder.

Objective Family and twin studies have suggested genetic liability for panic disorder (PD) and therefore we sought to determine the role of noradrenergic and serotonergic candidate genes for susceptibility for PD in a Japanese population. Methods In this age- and gender-matched case-control study involving 119 PD patients and 119 healthy controls, we examined the genotype distributions and allele frequencies of the serotonin transporter gene linked polymorphic region (5-HTTLPR), −1019C/G (rs6295) promoter polymorphism of the serotonin receptor 1A (5-HT1A), and catechol-O-methyltransferase (COMT) gene polymorphism (rs4680) and their association with PD. Results No significant differences were evident in the allele frequencies or genotype distributions of the COMT (rs4680), 5-HTTLPR polymorphisms or the −1019C/G (rs6295) promoter polymorphism of 5-HT1A between PD patients and controls. Although there were no significant associations of these polymorphisms with in subgroups of PD patients differentiated by gender or in subgroup comorbid with agoraphobia (AP), significant difference was observed in genotype distributions of the −1019C/G (rs6295) promoter polymorphism of 5-HT1A between PD patients without AP and controls (p=0.047). Conclusion In this association study, the 1019C/G (rs6295) promoter polymorphism of the 5-HT1A receptor G/G genotype was associated with PD without AP in a Japanese population.

Factors Affecting Steady-state Plasma Concentrations of Enantiomeric Mirtazapine and its Desmethylated Metabolites in Japanese Psychiatric Patients

INTRODUCTION This study evaluated the effects of the CYP2D6*10 genotype on steady-state plasma concentrations of enantiomeric mirtazapine (MIR) and N-desmethylmirtazapine (DMIR) in Japanese patients. METHODS Subjects were 77 Japanese patients treated with racemic MIR. Steady-state plasma concentrations of MIR and DMIR enantiomers were measured using stereoselective liquid chromatography. Polymerase chain reaction was used to determine the CYP2D6 genotypes. RESULTS After correcting for dose and body weight, smokers (n=15) had significantly lower S-(+)-MIR than nonsmokers (n=55) (15.1±17.8 vs. 23.9±17.8 ng/mL/mg/kg, Kruskal-Wallis test, p=0.034). One-way analysis of variance revealed that CYP2D6*10 homozygotes had significantly higher corrected plasma concentrations of S-(+)-MIR than the no-variant allele group (p=0.034). Multiple regression analysis revealed a significant positive correlation between the number of CYP2D6*10 alleles and corrected plasma concentrations of S-(+)-MIR. These results yielded the following final model: corrected plasma concentration of S-(+)-MIR=15.9+7.30×(number of CYP2D6*10 alleles) (R=0.279, p=0.023, coefficient of determination (R(2))=0.078). CONCLUSION Homozygous CYP2D6*10 alleles and smoking have a significant impact on the metabolism of S-(+)-MIR in Japanese patients.

Influence of the cytochrome P450 2D6 *10/*10 genotype on the pharmacokinetics of paroxetine in Japanese patients with major depressive disorder: a population pharmacokinetic analysis.

Objective Although the reduced function of the cytochrome P450 2D6*10 (CYP2D6*10) allele is common among Asian populations, existing evidence does not support paroxetine therapy adjustments for patients who have the CYP2D6*10 allele. In this study, we attempted to evaluate the degree of the impact of different CYP2D6 genotypes on the pharmacokinetic (PK) variability of paroxetine in a Japanese population using a population PK approach. Methods This retrospective study included 179 Japanese patients with major depressive disorder who were being treated with paroxetine. CYP2D6*1, *2, *5, *10, and *41 polymorphisms were observed. A total of 306 steady-state concentrations for paroxetine were collected from the patients. A nonlinear mixed-effects model identified the apparent Michaelis–Menten constant (Km) and the maximum velocity (Vmax) of paroxetine; the covariates included CYP2D6 genotypes, patient age, body weight, sex, and daily paroxetine dose. Results The allele frequencies of CYP2D6*1, *2, *5, *10, and *41 were 39.4, 14.5, 4.5, 41.1, and 0.6%, respectively. There was no poor metabolizer who had two nonfunctional CYP2D6*5 alleles. A one-compartment model showed that the apparent Km value was decreased by 20.6% in patients with the CYP2D6*10/*10 genotype in comparison with the other CYP2D6 genotypes. Female sex also influenced the apparent Km values. No PK parameters were affected by the presence of one CYP2D6*5 allele. Conclusion Unexpectedly, elimination was accelerated in individuals with the CYP2D6*10/*10 genotype. Our results show that the presence of one CYP2D6*5 allele or that of any CYP2D6*10 allele may have no major effect on paroxetine PKs in the steady state.

Early Improvement and Marriage Are Determinants of the 12-Month Treatment Outcome of Paroxetine in Outpatients with Panic Disorder

Objective In this study, we investigated the determinants of remission and discontinuation of paroxetine pharmacotherapy in outpatients with panic disorder (PD). Methods Subjects were 79 outpatients diagnosed with PD who took 10–40 mg/day of paroxetine for 12 months. The candidate therapeutic determinants included the serotonin transporter gene-linked polymorphic region and the −1019C/G promoter polymorphism of the serotonin receptor 1A as genetic factors, educational background and marital status as environmental factors, and early improvement (EI) at 2 weeks as a clinical factor were assessed. The Clinical Global Impression scale was used to assess the therapeutic effects of the pharmacotherapy. Results Cox proportional hazards regression was performed to investigate the significant predictive factors of remission and discontinuation. EI was only a significant predictive factor of remission. EI was a significant predictive factor of remission (hazard ratio [HR], 2.709; 95% confidence interval [CI], 1.177–6.235). Otherwise, EI and marital status were significant predictive factors of the discontinuation. EI (HR, 0.266; 95% CI, 0.115–0.617) and being married (HR, 0.437; 95% CI, 0.204–0.939) were considered to reduce the risk of treatment discontinuation. In married subjects, EI was a significant predictive factor of the discontinuation (HR, 0.160; 95% CI, 0.045–0.565). However, in unmarried subjects, EI was not a significantly predictive factor for the discontinuation. Conclusion EI achievement appears to be a determinant of PD remission in paroxetine treatment. In married PD patients, EI achievement also appears to reduce a risk of discontinuation of paroxetine treatment.

PS213. Pharmacokinetics of mirtazapine and its hydroxylated metabolite in Japanese psychiatric patients treated with mirtazapine

Objectives: Venlafaxine is metabolized by CYP2D6 to O-desmethylvenlafaxine (ODV) and by CYP3A4 to N-desmethylvenlafaxine (NDV). CYP2C19 is also involved in the formation of ODV. The PPIs omeprazole and pantoprazole inhibit CYP2C19 to a different extent. Aim of this study was to investigate the potential effects of both PPIs on serum levels of VEN and ODV. Methods: From a therapeutic drug monitoring (TDM) database, serum concentrations of VEN, ODV and the active moiety (VEN + ODV), were analyzed. Data from 120 patients were available and splitted into three groups: patients without PPI [noPPI], with pantoprazole [PANTO] or with omeprazole [OMEP] (n=40 each). The ratio of (ODV/VEN) was calculated as a marker of the metabolizer status. Results: Median test detected no differences regarding the median daily dosage of VEN between the three groups (p=0.995); the mean daily doses for VEN were 207.6mg/d, SD=79.96 in the control-group, 209.06mg/d, SD=78.24 for the pantoprazole group and 203.43mg/d, SD=91.41 for omeprazole group. Plasma concentrations for VEN + ODVEN in the PANTO group were significantly higher than in the control group (p=0.019 for Mann-Whitney U Test). Plasma concentrations for ODVEN and VEN + ODVEN in the OMEP group were significantly higher than in the control group (p=0.001 and p=0.017 for Mann-Whitney U Test) Conclusion: Both, omeprazole and pantoprazole led to a varying extent in increases of the serum concentrations of the active moiety (sum of VEN+ODV). The increase is driven by significantly higher levels of ODV in the OMEP group. This might be due to distinct CYP2C19 blocking properties of both PPIs, hindering the 2C19 mediated metabolization of VEN to N-desmethylvenlafaxine (NDV). PS213 Pharmacokinetics of mirtazapine and its hydroxylated metabolite in Japanese psychiatric patients treated with mirtazapine Takashi Watanabe1, Kazufumi Akiyama1, Akiko Aoki1, Yuki Hayashi1, Yoshimasa Inoue1, Shin Ishiguro1, Kazuko Kato2, Jason Pierce1, Kazutaka Shimoda1, Masataka Shinozaki1, Shoko Tsuchimine3, Mikito Ueda1, Norio Yasui-Furukori3 1Dokkyo Medical University, Japan, 2Sakura La Mental Clinic, Japan, 3Hirosaki University, Japan Abstract Purpose: This study investigated the pharmacokinetics of mirtazapine (MIR) and its hydroxylated metabolite in Japanese psychiatric patients. Patients and Methods: The subjects were 59 Japanese patients treated with racemic MIR. The steady-state plasma concentrations of MIR and N-desmethylmirtazapine (DMIR), 8-hydroxyMIR (8-OH-MIR) were measured using high performance liquid chromatography. CYP2D6 genotypes were determined by polymerase chain reaction. Three subjects whose plasma levels of MIR and DMIR were below the limit of detection were regarded as non-adherent and excluded. Multiple regression analysis (stepwise method) was performed to analyze the relationship between subject-independent variables (gender, age, smoking status and number of mutated CYP2D6 alleles) and subjectdependent variables such as plasma concentrations of MIR, DMIR, 8-OH-MIR (ng/ml/mg/kg; all corrected for dose and body weight) and 8-OH-MIR/MIR ratio. Results: Multiple regression analysis revealed that smoking (p=0.016) and gender (p=0.041) had a significant impact on plasma concentrations of MIR. The final models were described by the following equations: Plasma concentration of MIR = 86.6 31.9 ×smoking status (smoking=1, non-smoking=0) 23.0 × gender (male=1, female=0) (R= 0.45, p=0.002, coefficient of determination (R2) =0.20). Smoking status was a significant factor correlated to plasma concentration of 8-OH-MIR (p=0.034). The final model was described by the following equation: Plasma concentration of 8-OH-MIR (corrected for dose and body weight) = 2.41 1.59×smoking status (smoking=1, non-smoking=0) (R= 0.29, p=0.034, R2=0.08). There were no significant factors correlated to in 8-OH-MIR/MIR ratio in the multiple regression analysis. Conclusion: Gender and smoking polymorphism might affect pharmacokinetics of racemic MIR in Japanese patients.Purpose: This study investigated the pharmacokinetics of mirtazapine (MIR) and its hydroxylated metabolite in Japanese psychiatric patients. Patients and Methods: The subjects were 59 Japanese patients treated with racemic MIR. The steady-state plasma concentrations of MIR and N-desmethylmirtazapine (DMIR), 8-hydroxyMIR (8-OH-MIR) were measured using high performance liquid chromatography. CYP2D6 genotypes were determined by polymerase chain reaction. Three subjects whose plasma levels of MIR and DMIR were below the limit of detection were regarded as non-adherent and excluded. Multiple regression analysis (stepwise method) was performed to analyze the relationship between subject-independent variables (gender, age, smoking status and number of mutated CYP2D6 alleles) and subjectdependent variables such as plasma concentrations of MIR, DMIR, 8-OH-MIR (ng/ml/mg/kg; all corrected for dose and body weight) and 8-OH-MIR/MIR ratio. Results: Multiple regression analysis revealed that smoking (p=0.016) and gender (p=0.041) had a significant impact on plasma concentrations of MIR. The final models were described by the following equations: Plasma concentration of MIR = 86.6 31.9 ×smoking status (smoking=1, non-smoking=0) 23.0 × gender (male=1, female=0) (R= 0.45, p=0.002, coefficient of determination (R2) =0.20). Smoking status was a significant factor correlated to plasma concentration of 8-OH-MIR (p=0.034). The final model was described by the following equation: Plasma concentration of 8-OH-MIR (corrected for dose and body weight) = 2.41 1.59×smoking status (smoking=1, non-smoking=0) (R= 0.29, p=0.034, R2=0.08). There were no significant factors correlated to in 8-OH-MIR/MIR ratio in the multiple regression analysis. Conclusion: Gender and smoking polymorphism might affect pharmacokinetics of racemic MIR in Japanese patients. PS214 Cerebral and peripheral Tryptophan / kynurenine pathway in the pathophysiology of stress-induced bio-behavioural abnormalities