Hanako Furukori

The -141C Ins/Del polymorphism in the dopamine D2 receptor gene promoter region is associated with anxiolytic and antidepressive effects during treatment with dopamine antagonists in schizophrenic patients

Previous studies have demonstrated a lower density of dopamine D2 receptor (DRD2) in subjects without Del alleles of the -141C Ins/Del polymorphism in DRD2 gene promoter region than in those with one or two Del alleles. The present study aimed to examine whether the -141C Ins/Del DRD2 promoter polymorphism is related to therapeutic response to selective DRD2 antagonists in the treatment of schizophrenia. Subjects consisted of 49 acutely exacerbated schizophrenic inpatients treated with bromperidol (30 cases, mean dose +/- SD: 11.4 +/- 4.8 mg/day) or nemonapride (19 cases, 18 mg/day). Clinical symptoms were evaluated by the Brief Psychiatric Rating Scale (BPRS) before and 3 weeks after the treatment. The -141C Ins/Del DRD2 genotypes, the Ins and Del alleles, were determined by a polymerase chain reaction method. Thirty-five patients were homozygous for the Ins allele and 14 were heterozygous for the Del and Ins alleles. The patients without Del allele showed a higher percentage of improvement in anxiety-depression symptoms than those with Del allele (58.5 +/- 44.5% versus 24.1 +/- 48.2%) after 3 weeks of treatment while percentage improvement in total BPRS or other subgrouped symptoms (positive, negative, excitement and cognitive symptoms) was similar between the two genotype groups. The present results suggest that the -141C Ins/Del DRD2 polymorphism is associated with anxiolytic and antidepressive effects of neuroleptic treatment in schizophrenic patients.

Effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of alprazolam

Abstract To assess the effect of itraconazole, a potent inhibitor of cytochrome P450 (CYP) 3A4, on the single oral dose pharmacokinetics and pharmacodynamics of alprazolam, the study was conducted in a double-blind randomized crossover manner with two phases of treatment with itraconazole-placebo or placebo-itraconazole. Ten healthy male subjects receiving itraconazole 200 mg/day or matched placebo orally for 6 days took an oral 0.8 mg dose of alprazolam on day 4 of each treatment phase. Plasma concentration of alprazolam was measured up to 48 h after alprazolam dosing, together with the assessment of psychomotor function by the Digit Symbol Substitution Test, Visual Analog Scale and Udvalg for kliniske undersøgelser side effect rating scale. Itraconazole significantly (P < 0.01) increased the area under the concentration-time curves from 0 h to infinity (252 ± 47 versus 671 ± 205 ng h/ml), decreased the apparent oral clearance (0.89 ± 0.21 versus 0.35 ± 0.10 ml/min per kg) and prolonged the elimination half-life (15.7 ± 4.1 versus 40.3 ± 13.5 h) of alprazolam. The test performed during itraconazole treatment showed significantly depressed psychomotor function. It is suggested that itraconazole, a potent CYP3A4 inhibitor, increases plasma concentration of alprazolam via its inhibitory effects on alprazolam metabolism. Thus, this study supports previous studies suggesting that CYP3A4 is the major enzyme catalyzing the metabolism of alprazolam. Enhanced side effects of alprazolam by itraconazole coadministration were probably reflected by these pharmacokinetic changes.

Dose-Dependent Effects of Adjunctive Treatment With Aripiprazole on Hyperprolactinemia Induced by Risperidone in Female Patients With Schizophrenia

Hyperprolactinemia is a frequent consequence of treatment with risperidone. Recent studies have suggested that aripiprazole, a partial dopamine agonist, reduces the prolactin response to antipsychotics. Thus, we examined the dose effects of adjunctive treatment with aripiprazole on the plasma concentration of prolactin in patients who had elevated prolactin levels because of risperidone treatment. Aripiprazole was concomitantly administrated to 16 female patients with schizophrenia receiving 2 to 15 mg/d of risperidone. Dosages of aripiprazole were gradually increased from 3 to 12 mg/d with 2- to 4-week intervals. Sample collections for prolactin were conducted before aripiprazole administration (baseline) and 2 to 4 weeks after the dose escalation of aripiprazole and just before next dose escalation. The samples were taken just before the morning dose. The plasma concentration of prolactin during aripiprazole administration (3, 6, 9, or 12 mg/d) was significantly lower than that at baseline. The mean (±SD) percent reductions at 3, 6, 9, and 12 mg/d were 35% ± 14%, 54% ± 17%, 57% ± 19%, and 63% ± 17%, respectively. However, neither the plasma concentration of prolactin nor the reduction ratio differed among the dosages of 6, 9, and 12 mg/d of aripiprazole. Three out of 8 patients with amenorrhea improved after 12 mg/d of aripiprazole. The present study suggests that adjunctive treatment with aripiprazole reduces the prolactin concentration that had been increased because of risperidone treatment. The effect occurs even when a low dosage (3 mg/d) of aripiprazole was used and achieves a plateau at dosages beyond 6 mg/d.

Effect of Carbamazepine on the Single Oral Dose Pharmacokinetics of Alprazolam

The effect of carbamazepine, an inducer of cytochrome P450 (CYP) 3A4, on the single oral dose pharmacokinetics of alprazolam was examined in a double-blind, randomized crossover study with two phases. Seven healthy male subjects took carbamazepine 300 mg/day or matched placebo orally for 10 days, and on the 8th day they took a single oral 0.8 mg dose of alprazolam. Blood samples were taken and psychomotor function was assessed by the Digit Symbol Substitution Test, Visual Analog Scale, and UKU Side Effect Rating Scale up to 48 h after alprazolam dosing. Carbamazepine significantly (p < .01 to .001) decreased the plasma alprazolam concentrations during the elimination phase. Carbamazepine significantly (p < .001) increased the apparent oral clearance (0.90 ± 0.21 vs. 2.13 ± 0.54 ml/min/kg) and shortened the elimination half-life (17.1 ± 4.9 vs. 7.7 ± 1.7 h), with no significant effect on the peak plasma concentration (11.7 ± 1.5 vs. 13.0 ± 3.5 ng/ml). The majority of psychomotor function parameters during the carbamazepine treatment were not significantly different from those during the placebo treatment, probably because of the sedative effect of carbamazepine itself. The present study suggests that carbamazepine decreases plasma concentration of alprazolam by inducing its metabolism. It also supports the previous studies, suggesting that alprazolam is metabolized predominantly by CYP3A4.

Prevalence of metabolic syndrome among patients with schizophrenia in Japan

AIMS In an Asian population, the criteria for metabolic syndrome (MetS) are different from those for Western populations. The aim of this study was to assess the MetS prevalence among patients with schizophrenia or schizoaffective disorder in Japan. METHODS We recruited patients (n=1186), aged 54.8±14.8 (mean±SD) years old with the DSM-IV diagnosis of schizophrenia or schizoaffective disorder who were admitted to seven psychiatric hospitals using a cross-sectional design. MetS prevalence was assessed by three different definitions, including the adapted National Cholesterol Education Program Adult Treatment Panel (ATP III-A). Comparative analysis was performed with schizophrenic subjects and 886 participants from the Iwaki Health Promotion Project 2008 as representative of general population. RESULTS The overall MetS prevalence based on the ATP III-A definition was 27.5%, with 29.8% in male and 25.3% in female patients. In a logistic regression model with age and body mass index as covariates, being schizophrenic was a significant independent factor (odds ratio=2.00 for males, 2.13 for females) in the development of MetS under the ATP III-A definition. The difference of MetS prevalence between patients and the general population was observed for those under 60 years of age. CONCLUSIONS Patients with schizophrenia or schizoaffective disorder in Japan had high prevalence of MetS compared to the general population, and was most apparent for those under 60 years of age. The MetS in schizophrenic patients should be carefully monitored to minimize the risks.

Determination of risperidone and 9-hydroxyrisperidone in human plasma by high-performance liquid chromatography: application to therapeutic drug monitoring in Japanese patients with schizophrenia

A high-performance liquid chromatographic method has been developed for the simultaneous determination of risperidone and its major active metabolite 9-hydroxyrisperidone in plasma. Risperidone and 9-hydroxyrisperidone in plasma were extracted using a CN bonded-solid phase cartridge, followed by, C4 reversed-phase HPLC separation. Risperidone, 9-hydroxyrisperidone and trazodone as an internal standard were detected by ultraviolet absorbance at 280 nm. It was possible to determine risperidone in the concentration range of 1.0-100.0 ng/ml(-1) and 9-hydroxyrisperidone at a range of 2.0-200.0 ng/ml(-1). The detection limits of risperidone and 9-hydroxyrisperidone were 0.5 and 1.0 ng/ml(-1), respectively. The mean recoveries of risperidone and 9-hydroxyrisperidone added to plasma were less than 92.0 and 92.6%, with a coefficient of variation of less than 10.6 and 10.5%, respectively. This method has been used for the simultaneous determination of steady-state plasma concentration (Css) of risperidone and 9-hydroxyrisperidone in schizophrenic patients treated with 3-, 6-, and 12-mg risperidone oral doses per day.

Dose-dependent interaction of paroxetine with risperidone in schizophrenic patients.

Abstract: Augmentation with paroxetine (10-40 mg/d) for antipsychotic treatment may improve the negative symptoms in schizophrenic patients but involves a risk of drug-drug interaction. We studied the effects of paroxetine on plasma concentrations of risperidone and 9-hydroxyrisperidone and their clinical symptoms in risperidone-treated patients. Twelve schizophrenic inpatients with prevailingly negative symptoms receiving risperidone 4 mg/d were, in addition, treated with incremental doses of paroxetine for 12 weeks (10, 20, and 40 mg/d for 4 weeks each). Plasma concentrations of risperidone and 9-hydroxyrisperidone were quantified with liquid chromatography-mass spectrometry mass-mass spectrometry together with clinical assessments before and after each phase of the 3 paroxetine doses. Risperidone concentrations during coadministration of paroxetine 10, 20, and 40 mg/d were 3.8-fold (95% confidence interval, 3.2-5.8, P < 0.01), 7.1-fold (95% confidence interval, 5.3-16.5, P < 0.01), and 9.7-fold (95% confidence interval, 7.8-22.5, P < 0.01) higher than that before paroxetine coadministration, respectively. Active moiety (risperidone plus 9-hydroxyrisperidone) concentration was not increased during the paroxetine 10 mg/d (1.3-fold, not significant) or 20 mg/d (1.6-fold, not significant), but were significantly increased by 1.8-fold (95% confidence interval, 1.4-2.7, P < 0.05) during the paroxetine 40 mg/d. Significant improvement in negative symptoms was observed from 10 to 40 mg/d of paroxetine, whereas scores in extrapyramidal side effects during 20 and 40 mg/d of paroxetine were significantly higher than baseline score. This study indicates that paroxetine increases plasma risperidone concentration and active moiety concentration in a dose-dependent manner. Low-dose coadministration of paroxetine with risperidone may be safe and effective in the treatment of schizophrenic patients with negative symptoms.

The effects of Ginkgo biloba extracts on the pharmacokinetics and pharmacodynamics of donepezil.

The effects of ginkgo supplementation on the steady‐state plasma concentration of donepezil and the activity of cholinesterase in red blood cells and cognitive function were examined. Fourteen inpatients with Alzheimers disease received donepezil 5 mg/day, supplemented with extracts of Ginkgo biloba 90 mg/day for 30 days. Blood samples were collected before and during ginkgo supplementation and 30 days after its discontinuation, together with an assessment of cognitive function. Plasma drug concentration was measured using high‐performance liquid chromatography (HPLC), and cholinesterase in red blood cells was measured using Ellman methods. Cognitive function was evaluated using the Mini‐Mental Scale Examination (MMSE). Plasma concentration of donepezil during ginkgo supplementation (mean ± SD [95% confidence interval]; 24.4 ± 12.6 ng/mL [17.1–31.7 ng/mL]) was not significantly different from that before ginkgo supplementation (22.7 ± 10.3 ng/mL [16.8–28.7 ng/mL]) or that 4 weeks after its discontinuation (25.0 ± 12.9 ng/mL [17.6–32.4 ng/mL]). There was no significant difference between cholinesterase in red blood cells before ginkgo supplementation (1.75 ± 0.21 U [1.63–1.87 U]), during ginkgo supplementation (1.91 ± 0.27 U [1.76–2.07 U]), and 4 weeks after its discontinuation (1.83 ± 0.29 U [1.66–2.00 U]). Ginkgo supplementation did not alter MMSE scores throughout the study. The present study shows that ginkgo supplementation does not have major impact on the pharmacokinetics and pharmacodynamics of donepezil.

Effects of itraconazole on the steady-state plasma concentrations of haloperidol and its reduced metabolite in schizophrenic patients: in vivo evidence of the involvement of CYP3A4 for haloperidol metabolism.

The effects of itraconazole, a potent inhibitor of cytochrome P450 (CYP) 3A4, on the steady-state plasma concentrations of haloperidol and reduced haloperidol were examined in schizophrenic patients. Thirteen schizophrenic patients treated with haloperidol 12 or 24 mg/day received 200 mg/day of itraconazole for 7 days. Plasma concentrations of haloperidol and reduced haloperidol were measured by high-performance liquid chromatography together with clinical assessment by the Brief Psychiatric Rating Scale (BPRS) and the Udvalg for Kliniske Undersogelser side effect rating scale just before and during itraconazole treatment and 1 week after its discontinuation. Plasma concentrations of haloperidol and reduced haloperidol during the itraconazole treatment (16.9 +/- 11.2 and 6.1 +/- 6.6 ng/mL, respectively) were significantly (p < 0.01) higher than those observed before itraconazole treatment (13.0 +/- 7.9 and 4.9 +/- 5.1 ng/mL) or 1 week after its discontinuation (13.5 +/- 8.2 and 4.9 +/- 5.0 ng/mL). No change was found in clinical symptoms assessed by BPRS, whereas neurologic side effects were significantly (p < 0.05) increased during itraconazole coadministration. The elevated plasma concentrations of haloperidol and reduced haloperidol during itraconazole coadministration were likely due to the inhibitory effects of itraconazole on the metabolism of haloperidol and reduced haloperidol. Thus, this study may provide in vivo evidence of involvement of CYP3A4 in the metabolism of haloperidol and possibly in that of reduced haloperidol. Deterioration of neurologic side effects during itraconazole treatment may result from the increased plasma concentrations of haloperidol and reduced haloperidol during itraconazole treatment.

Body mass index and quality of life among outpatients with schizophrenia in Japan.

BackgroundObesity is becoming more prevalent and thus growing as a public health concern in patients with schizophrenia. This investigation evaluated the relationship between body weight and the self-reported quality of life (QOL) of Japanese patients with schizophrenia.MethodsWe recruited outpatients (n=225) aged 42.5 ± 12.8 (mean ± SD) years with a DSM-IV diagnosis of schizophrenia who were admitted to psychiatric hospitals. This study used a cross-sectional design. The assessments included an interview to obtain sociodemographic data, the second version of the Short Form Health Survey (SF-36v2), the 10-item version of the Drug Attitude Inventory (DAI-10), the Clinical Global Impression-Severity (CGI-S) and height and weight measurements. SF-36v2 subscores were examined for differences based on the following body mass index (BMI) categories: healthy weight (BMI < 24.9), overweight (BMI 25–29.9) and obese (BMI > 30). A multiple regression analysis was employed to assess the relationship between these BMI categories and QOL outcomes.ResultsThe overall prevalence of obesity in our sample was 16.4%. A multiple regression model revealed that age, gender, DAI-10 scores, CGI-S scores, social functioning, role emotional functioning, mental health, and Mental Composite Summary (MCS) score were significantly and positively associated with overweight status. Physical functioning, general health, role emotional functioning, mental health, and a physical composite summary (PCS) score were significantly and negatively associated with obesity.ConclusionsThe burden of obesity is both a physical and a mental problem. An obesity intervention program for patients with schizophrenia may improve health-related QOL in patients with schizophrenia.