Shin Ono

Dysregulation of adipocytokines related to second-generation antipsychotics in normal fasting glucose patients with schizophrenia.

Objective The underlying mechanism for second-generation antipsychotic (SGA)-related glucose-lipid metabolic dysfunction is not fully understood. Recent studies have suggested a possible impact of SGAs on endocrine regulation, especially on adipocytokines. We examined the effect of each SGA on various adipocytokines in normal fasting glucose (NFG) subjects. Method The study population comprised 113 Japanese inpatients with schizophrenia who were treated with olanzapine, risperidone, or quetiapine, and 123 healthy control (CONT) volunteers. All of the subjects were diagnosed with NFG. Plasma concentration of adiponectin, leptin, tumor necrosis factor &agr;, total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were compared between the SGA and CONT groups. Results Second-generation antipsychotic subjects had significantly higher leptin levels in comparison to the CONT subjects. The plasma concentration of adiponectin, total cholesterol, and high-density lipoprotein cholesterol in the SGA subjects were significantly lower than those in the CONT subjects. There were no significant differences in tumor necrosis factor &agr;, triglyceride, and low-density lipoprotein cholesterol levels between the 2 groups. In a stepwise multiple regression analysis, olanzapine was found to be a factor that contributed to decreased adiponectin levels, and the CONT subjects were detected to be a factor associated with lower leptin levels. Conclusions The present study indicates the possibility that the administration of SGAs may affect adipocytokines in the NFG stage, excluding the impaired fasting glucose group, which is in the transition stage into diabetes mellitus.

QT prolongation of the antipsychotic risperidone is predominantly related to its 9-hydroxy metabolite paliperidone.

A dose‐dependent increase in risk of sudden cardiac death for the antipsychotic drug risperidone was reported. However, few reports have so far addressed QT prolongation associated with the use of risperidone or its major active metabolite, which is also used as a separate antipsychotic drug, paliperidone.

Increased risk of antipsychotic-related QT prolongation during nighttime: a 24-hour holter electrocardiogram recording study.

Abstract Most antipsychotic agents can cause QT prolongation, which causes torsades de pointes. The QT interval in healthy subjects is longer during nighttime than during daytime. The QT interval of patients treated with antipsychotics may be prolonged during nighttime, and the effects of antipsychotics on the QT interval may differ between antipsychotics. This study investigated the circadian dynamics of the QT interval in patients treated with antipsychotics and healthy controls, using a 24-hour Holter electrocardiogram in a clinical setting. Sixty-six patients with a diagnosis of schizophrenia that were treated with risperidone or olanzapine and 40 healthy volunteers were enrolled. The QT intervals were corrected using the Fridericia formula (QTcF = QT / RR1/3). Mean ± SD nighttime QTcFs were 411.6 ± 29.0, 395.9 ± 21.2, and 387.8 ± 19.0 milliseconds (ms) in the risperidone, olanzapine, and control groups, respectively. The mean daytime QTcFs were 397.7 ± 23.4, 392.4 ± 18.9, and 382.6 ± 17.3 ms, respectively. The mean nighttime QTcF of the risperidone group was significantly longer than that of the olanzapine and control groups, although there was no significant difference in the mean daytime QTcF between the risperidone and olanzapine groups. The current study used 24-hour Holter electrocardiograms to reveal significantly longer QT intervals in the risperidone group especially during nighttime. In clinical practices, evaluations of the QT interval have been conducted over short periods in the daytime, but it is believed that such methods may not be able to fully elucidate the effects of antipsychotics on the QT interval.

CYP2D6 genotype and smoking influence fluvoxamine steady-state concentration in Japanese psychiatric patients: lessons for genotype–phenotype association study design in translational pharmacogenetics

The CYP2D6 enzyme is a capacity-limited high-affinity drug elimination pathway that metabolizes numerous psychiatric medicines. The capacity-limited nature of this enzyme suggests that drug dose may serve as an important factor that influence genotype–phenotype associations. However, dose dependency of CYP2D6 genotype contributions to drug elimination, and its interaction with environmental factors (e.g., smoking) did not receive adequate attention in translational study designs. Fluvoxamine is a selective serotonin reuptake inhibitor antidepressant. Fluvoxamine concentration is one of the factors previously linked to clinical remission in moderate to severe depression. We investigated the joint effect of smoking (an inducer of CYP1A2) and CYP2D6 genotype on interindividual variability in fluvoxamine steady-state concentration. Fluvoxamine concentration was measured in 87 patients treated with 50, 100, 150 or 200 mg/d. While CYP2D6 genotype significantly influenced fluvoxamine concentration in all four dose groups (p < 0.05), the percentage variance explained (R 2) by CYP2D6 decreased as the dose of fluvoxamine increased. Smoking status (nonsmokers vs. smoking 20 or more cigarettes/d) significantly affected fluvoxamine concentration in the 50 mg/d group only (p = 0.005). Together, CYP2D6 genotype and smoking status explained 23% of the variance in fluvoxamine concentration but only at the low 50 mg/d dose group. These findings contribute to evidence-based and personalized choice of fluvoxamine dose using smoking status and CYP2D6 genetic variation. Additionally, these data lend evidence for drug dose as an important variable in translational pharmacogenetic study design and pharmaceutical phenotype associations with capacity-limited drug metabolism pathways such as CYP2D6.

Dose-dependent effect of the CYP2D6 genotype on the steady-state fluvoxamine concentration.

Several studies have reported that the cytochrome P450 (CYP) 2D6 plays an important role in the fluvoxamine metabolism. However, some other studies have reported that the CYP2D6 genotype has no major impact on the fluvoxamine concentration. This study investigated the dose-dependent effect of CYP2D6-variant alleles on the steady-state fluvoxamine concentration. There were 23 patients whose plasma concentrations of fluvoxamine were measured at 4 doses (50, 100, 150, and 200 mg/d). The differences in the plasma fluvoxamine concentration were analyzed between 2 genotype groups divided by the number of CYP2D6-variant alleles (with 0 and 1 or 2 variant alleles). The results demonstrated the nonlinear kinetics of fluvoxamine metabolism, and the degree of nonlinear kinetics decreased as the dose was increased. Significant differences in fluvoxamine concentration were observed between the subjects with 0 variant alleles and the subjects with 1 or 2 variant alleles (P = 0.044) when they were treated by 50 mg of fluvoxamine. There were no significant differences in the plasma concentration of fluvoxamine at 100, 150, and 200 mg/d. The present study suggests that the effect of the CYP2D6 genotype on fluvoxamine metabolism is greater at lower doses of fluvoxamine.

Dose-dependent effects of olanzapine on QT intervals and plasma prolactin levels in Japanese patients with stable schizophrenia

There have been few reports regarding olanzapine (OLZ)‐related QT prolongation and hyperprolactinemia. This study evaluated the dose‐dependent effect of OLZ on QT interval and plasma prolactin (PRL) level in a single sample of patients with schizophrenia.

Effect of the cytochrome P450 2D6*10 allele on risperidone metabolism in Japanese psychiatric patients

The sum of the serum levels of risperidone (RIS) and 9‐hydroxyrisperidone (9‐OH‐RIS), which is the active moiety serum level, could be important for estimating the clinical effects of RIS. However, there have been no consistent results reported about the relationship between cytochrome P450 (CYP) 2D6*10 allele and plasma 9‐OH‐RIS or active moiety levels. We investigated the effect of the number of CYP2D6*10 alleles on steady‐state plasma RIS, 9‐OH‐RIS, and active moiety levels in Japanese patients.

Impact of the abcb1 Gene Polymorphism on Plasma 9-hydroxyrisperidone and Active Moiety Levels in Japanese Patients With Schizophrenia

Abstract9-Hydroxyrisperidone (9-OH-RIS) is an active metabolite of the antipsychotic drug risperidone (RIS). The total active moiety level, in other words the sum of the RIS and 9-OH-RIS serum levels, may be important for estimating the clinical effects of RIS treatment. However, there have been no consistent results reported regarding the relationship between cytochrome P450 (CYP) 2D6 or adenosine triphosphate–binding cassette subfamily B member 1 (ABCB1) variant alleles and 9-OH-RIS or total active moiety plasma levels. Seventy-four Japanese patients treated with RIS were examined in the present study. Steady-state plasma RIS and 9-OH-RIS were measured. The CYP2D6*5, CYP2D6*10, ABCB1 3435C>T, and ABCB1 2677G>T/A genotypes were detected. Multiple regression analysis showed that the dose-corrected plasma RIS levels were significantly correlated with the number of CYP2D6 variant alleles and ABCB1 3435C>T genotypes, whereas the 9-OH-RIS and total active moiety levels were significantly correlated with the ABCB1 3435C>T genotypes and with age. On the other hand, the ABCB1 2677G>T/A genotypes did not affect plasma RIS, 9-OH-RIS, or total active moiety levels. The ABCB1 3435C>T genetic polymorphism may predict plasma 9-OH-RIS and total active moiety levels.

Improvement of tardive dyskinesia and dystonia associated with aripiprazole following a switch to quetiapine: case report and review of the literature

What is known and Objective:  Aripiprazole has a low risk of extrapyramidal symptoms. Switching to aripiprazole has been reported to improve tardive dyskinesia caused by other medications. The authors report a case and review previous reports of dystonia and dyskinesia associated with aripiprazole.

Diagnostic classification and demographic features in 283 patients with somatoform disorder

Abstract  A total of 283 patients with somatoform disorder (SFD) seen in a psychiatry clinic were surveyed and their diagnostic subtypes, demographic features, and comorbidities, analyzed. The results indicate that: (i) SFD comprises 5.8% of first‐visit outpatients; (ii) undifferentiated SFD (USFD) and SFD not otherwise specified (SFD‐NOS) account for the majority of patients; (iii) there are 1.7‐fold more women than men; (iv) age of onset is lower in patients with somatization disorder or body dysmorphic disorder and higher in patients with hypochondriasis or pain disorder; (v) the mean number of years of education was 11.2 years; and (vi) comorbid illness were seen in 24.8% of patients, and included mood disorder, anxiety disorder, and personality disorder, as well as borderline intellectual functioning and mental retardation. The data indicate that the majority of patients with SFD are given a diagnosis of residual category, such as USFD or SFD‐NOS, and that the age of onset varies depending on the diagnostic subtype. SFD was more frequently seen in women, associated with comorbidities.