Effect of Serum Leptin on Weight Gain Induced by Olanzapine in Female Patients with Schizophrenia.

BACKGROUND: Olanzapine (OLZ) treatment is associated with a high risk of weight gain, and may cause abnormalities in glycolipid metabolism. Therefore, the underlying mechanism of OLZ-related weight gain is needed to clarify but not yet been adequately determined. In recent years, adipocytokines such as leptin, adiponectin, and tumor necrosis factor (TNF)-α, which play important roles in energy homeostasis, have been suggested as biomarkers of weight gain. Here, we determined if baseline plasma concentrations of leptin, adiponectin, and TNF-α predict weight gain following OLZ treatment. METHODS: We recruited 31 schizophrenia outpatients (12 men and 19 women, 28.8 ± 10.2 years old) that were unmedicated or on another antipsychotic monotherapy medication. Baseline body mass index (BMI) and plasma levels of leptin, adiponectin, and TNF-α were obtained. All patients started or were switched to OLZ monotherapy for a maximum of 1 year. BMI was also obtained at the endpoint. RESULTS: Mean BMI change following OLZ treatment was 2.1 ± 2.7 kg/m2. BMI change from baseline to endpoint negatively-correlated with baseline leptin levels in female patients (r = -0.514, P = 0.024), but not male patients. Baseline adiponectin or TNF-α levels were not correlated with BMI change. CONCLUSION: Baseline plasma leptin can have an effect on subsequent weight gain following OLZ treatment in female patients with schizophrenia.

GIPR Gene Polymorphism and Weight Gain in Patients With Schizophrenia Treated With Olanzapine.

Association between gastric inhibitory polypeptide receptor polymorphism, rs10423928, and body mass index in olanzapine-treated schizophrenia was examined. Body mass index change for the A/T+A/A genotypes was significantly higher than that for the T/T genotype. rs10423928 may predict weight gain in schizophrenia.

Impact of the ABCB1 gene polymorphism on plasma 9-hydroxyrisperidone and active moiety levels in Japanese patients with schizophrenia.

9-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.

The lipid profiles in Japanese patients with schizophrenia treated with antipsychotic agents.

OBJECTIVE: Antipsychotic-treated schizophrenia patients are susceptible to dyslipidemia. However, the results of previous studies of North American and UK populations including various races have been contradictory with regard to which lipid measure was the most affected in patients with schizophrenia taking antipsychotic agents. The aim of this study was to investigate the effect of schizophrenia patients receiving antipsychotic agents on each lipid measure in a Japanese population. METHODS: The samples included 136 control individuals and 157 patients with schizophrenia treated with antipsychotic agents. Age, gender distribution and body mass index (BMI) of the controls were matched with the patients. RESULTS: The high-density lipoprotein cholesterol (HDL-cholesterol) levels were significantly lower in patients than in the control subjects (P<.001). However, there were no significant differences in either the low-density lipoprotein cholesterol (LDL-cholesterol) or triglyceride levels between the patient and control groups. We performed a multiple linear regression analysis, and schizophrenia receiving antipsychotics was an independent predictor of decreased HDL-cholesterol. An increased BMI, male gender and cigarette smoking were also major predictors of a decreased HDL-cholesterol level (r(2)=0.42, P<.001). CONCLUSION: At least in Japanese with schizophrenia receiving antipsychotic agents, the HDL-cholesterol levels should be closely monitored in all patients, even those who are not obese or do not smoke, to decrease their risk of cardiovascular disease.

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 α, 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 α, 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.

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 (R²) 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 effects of the 3435 C>T genotype of ABCB1 gene on the steady-state plasma concentration of fluvoxamine in psychiatric patients.

UNLABELLED: This study investigated effects of the 3435 C>T genotype of the adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1, MDR1) gene on the steady-state plasma concentration of fluvoxamine (FLV). METHODS: Sixty-two psychiatric patients were treated with different doses (50, 100, 150, and 200 mg/d) of FLV. Blood samples were collected after at least 2 weeks of treatment with the same daily dose to obtain steady-state concentrations of FLV, and 3435 C>T genotype was determined by polymerase chain reaction. RESULTS: FLV concentration-to-dose ratio was significantly different among 3435 C>T genotype groups at the 200 mg/d dose (P = 0.019). A post-hoc analysis revealed that FLV concentration-to-dose ratio was significantly higher in the TT genotype group as compared with the CC genotype group at the 200 mg/d dose (median value of concentration-to-dose ratio (ng/mL)/(mg/d), 0.861 vs 0.434, P = 0.026). FLV concentration-to-dose ratio was significantly higher in the CT + TT genotype group than the CC genotype group at the 200 mg/d dose (median value of concentration-to-dose ratio (ng/mL)/(mg/d), 0.618 vs 0.434, P = 0.031). At 50, 100, and 150 mg/d dose, FLV concentration-to-dose ratios were not significantly different among 3435 C>T genotype groups. At 50, 100, and 150 mg/d dose, no significant differences were found in FLV concentration-to-dose ratios between the CT + TT genotype group and CC genotype group. CONCLUSIONS: This study suggests that pharmacokinetics of FLV depend on ABCB1 gene polymorphism only at the 200 mg/d dose.

Plasma concentrations of cytokines and neurohumoral factors in a case of fulminant myocarditis successfully treated with intravenous immunoglobulin and percutaneous cardiopulmonary support.

A 53-year-old Japanese man with fulminant myocarditis was referred. Percutaneous cardiopulmonary support (PCPS) was introduced immediately and intravenous immunoglobulin (IVIG) therapy followed for 2 days. Cardiac function showed signs of recovery on the 4th hospital day and the patient was weaned from PCPS on the 7th hospital day. Creatine kinase-MB peaked at 12 h after admission and was 176 ng/ml. Endomyocardial biopsy showed active myocarditis. A marked increase of the neutralizing antibody titer suggested coxsackievirus B3 infection. Plasma concentrations of cytokines and neurohumoral factors were analyzed. Proinflammatory cytokines, such as interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF-alpha), and anti-inflammatory cytokines, such as IL-1 receptor antagonist, soluble TNF receptor-1 and IL-10, were elevated on admission and all had decreased on the 7th hospital day. Brain natriuretic peptide and noradrenaline were already elevated upon admission (1,940 pg/ml and 4.6 ng/ml, respectively) and decreased thereafter. Although IVIG therapy under PCPS is a common treatment for fulminant myocarditis, the immunological response in vivo remains unclear. This case demonstrated suppression of serum cytokines after IVIG and PCPS treatment. Immunological parameters in those who have been treated with IVIG and PCPS and survived without complications are of great value for evaluation of the therapy. Further analysis with more cases in a multicenter study is necessary.