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Background: Hyperprolactinemia is a troublesome adverse effect of antipsychotics. Aripiprazole (ARP), which is one of second-generation antipsychotics, has been reported to lower serum prolactin (PRL) levels. However, few studies have compared the effect of ARP on plasma PRL levels between monopharmacy and polypharmacy with antipsychotics., Methods: We conducted a large-scale investigation of the physical risk for inpatients with schizophrenia using a questionnaire covering demographic data, the number, dose and type of antipsychotics, and serum PRL levels., Results: Sufficient data to conduct an assessment of the effect on PRL levels between antipsychotic monopharmacy and polypharmacy were obtained from 316 of the inpatients. Serum PRL levels in ARP combination group were lower than non-ARP combination group, regardless of antipsychotic monopharmacy or polypharmacy., Conclusions: The present study suggests that ARP lowers serum PRL levels regardless of monopharamacy or polypharmacy with antipsychotics.

Clozapine is an antipsychotic agent prescribed to psychotic patients exhibiting tolerance and/or resistance to the conventional antipsychotic medications that mainly drive monoamine antagonism. As the pharmacological fundamentals of its unique antipsychotic profile have been unrevealed, here, we attempted to obtain hints at this question. Here, we found that clozapine directly acts on ErbB kinases to downregulate epidermal growth factor (EGF)/neuregulin signaling. In cultured cell lines and cortical neurons, EGF-triggered ErbB1 phosphorylation was diminished by 30 μM clozapine, but not haloperidol, risperidone, or olanzapine. The neuregulin-1-triggered ErbB4 phosphorylation was attenuated by 10 μM clozapine and 30 μM haloperidol. We assumed that clozapine may directly interact with the ErbB tyrosine kinases and affect their enzyme activity. To test this assumption, we performed in vitro kinase assays using recombinant truncated ErbB kinases. Clozapine (3-30 μM) significantly decreased the enzyme activity of the truncated ErbB1, B2, and B4 kinases. Acute in vivo administration of clozapine (20 mg/kg) to adult rats significantly suppressed the basal phosphorylation levels of ErbB4 in the brain, although we failed to detect effects on basal ErbB1 phosphorylation. Altogether with the previous findings that quinazoline inhibitors for ErbB kinases harbor antipsychotic potential in animal models for schizophrenia, our present observations suggest the possibility that the micromolar concentrations of clozapine can attenuate the activity of ErbB receptor kinases, which might illustrate a part of its unique antipsychotic psychopharmacology.

It has long been known that antipsychotic drugs (ATP) causes tachycardia, however details such as the differences between ATP are not well known. In recent years, the relationship between the rise in resting heart rate (RHR) and the increased risk of death in the general population has been garnering attention. In this study, we examined the difference in action on RHR between olanzapine (OLZ) and aripiprazole (ARP). The changes in the RHR on switching from OLZ to ARP and on increasing from the starting OLZ dose to the final one were evaluated in 19 outpatients (Study 1) and in 29 outpatients with schizophrenia (Study 2), respectively. To analyze the RHR, electrocardiographic measurements were obtained. At the same day, the Brief Psychiatric Rating Scale (BPRS) was evaluated, and fasting blood samples were drawn after an overnight fast of at least 8 h to examine electrolytes. Both Study 1 and 2 were conducted with the approval of the Gene Ethics Committee of Niigata University Graduate School of Medical and Dental Sciences, and the patients were treated at the outpatient psychiatric clinic at Niigata University Medical and Dental Hospital. All patients had been diagnosed with schizophrenia based on the DSM-IV-TR. In the Study 1, OLZ of 14.6 ± 9.2mg (mean ± standard deviation) was switched to ARP of 20.8 ± 8.1mg. Significant decreases were observed in the mean RHR after the switch to ARP (73.7 ± 9.7 vs 65.8 ± 10.9 beats/min, p = 0.008). In the Study 2, the starting OLZ dose was 7.2 ± 3.2mg and the increasing OLZ dose was 18.3 ± 7.4mg. Significant increases were observed in the mean RHR after increasing OLZ (69.7 ± 14.0 vs 75.6 ± 14.3 beats/min, p = 0.004). In this study, it was shown that OLZ has a stronger RHR enhancing effect compared to ARP and its effects are dose-dependent. If the increase in RHR increases the mortality rate of patients with schizophrenia, it may be necessary to further investigate the differences between ATP in terms of the effect on RHR of second-generation antipsychotics with a strong anticholinergic action or phenothiazine antipsychotics., Competing Interests: The authors have declared that no competing interests exist.

Objective: Patients with schizophrenia have a higher prevalence of metabolic syndrome (MetS) than the general population. Minimizing weight gain and metabolic abnormalities in a population with an already high prevalence of obesity is of clinical and social importance. This randomized controlled trial investigated the effect of monthly nutritional education on weight change and metabolic abnormalities among patients with schizophrenia in Japan., Methods: From July 2014 to December 2014, we recruited 265 obese patients who had a DSM-IV diagnosis of schizophrenia or schizoaffective disorder. Participants were randomly assigned to a standard care (A), doctor's weight loss advice (B), or an individual nutritional education group (C) for 12 months. The prevalence of MetS and body weight were measured at baseline and 12 months., Results: After the 12-month treatment, 189 patients were evaluated, and the prevalence of MetS based on the ATP III-A definition in groups A, B, and C was 68.9%, 67.2%, and 47.5%, respectively. Group C showed increased weight loss (3.2 ± 4.5 kg) over the 12-month study period, and the change in weight differed significantly from that of group A; additionally, 26.2% of the participants in group C lost 7% or more of their initial weight, compared with 8.2% of those in group A., Conclusion: Individual nutrition education provided by a dietitian was highly successful in reducing obesity in patients with schizophrenia and could be the first choice to address both weight gain and metabolic abnormalities induced by antipsychotic medications., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Users of antipsychotics (APs) have a risk of sudden cardiac death (SCD). Sudden cardiac death in such patients is thought to be largely due to drug-induced QT prolongation. It has been reported that many subjects with drug-induced torsades de pointes (TdP) have risk alleles associated with subclinical congenital long QT syndrome., Methods: We investigated the effects of the risk alleles associated with long QT on the QT interval in patients receiving APs using 24-hour Holter electrocardiograms to take into account the circadian fluctuation of QT intervals. We investigated 8 single-nucleotide polymorphisms identified on a GWAS., Results: We found that increased numbers of risk alleles at rs7188697 in NDRG4 and rs11970286 in PLN were the major predictors of an increased maximum QT interval over 24 hours in users of APs., Conclusions: It could be useful to perform a DNA-based analysis before the initiation of APs to reduce the risk of drug-induced torsades de pointes and SCD.

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.

Among the most important adverse effects of antipsychotics is abnormal glucose metabolism, which includes not only hyperglycemia but hyperinsulinemia and hypoglycemia. We have previously described five patients who experienced hypoglycemia during treatment with antipsychotics. Thus, an anamnesis of gastric surgery, which often causes dumping syndrome, and treatment with antipsychotics may synergistically induce hypoglycemia. We describe here a patient with schizophrenia under treatment of olanzapine and an anamnesis of gastric surgery, who experienced late dumping syndrome, hyperinsulinemia and overactivation of glucose-dependent insulinotropic polypeptide. Dumping syndrome, however, was improved after the patient was switched from olanzapine to quetiapine., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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.

Aim: We examined the difference between the effects of olanzapine (OLZ) and risperidone (RIS) on PR and QT intervals among patients with stable schizophrenia using a cohort analysis., Methods: Twenty-one subjects treated with OLZ were enrolled in the study. Following baseline assessments, which included PR and QT intervals, OLZ was switched to RIS for each subject. The same parameters were evaluated following the switch to RIS., Results: All patients who had been treated with OLZ were successfully switched to RIS. In all patients, we observed a significant decrease in PR interval (t = 2.397, P = 0.029) and no change in either QTc or RR interval. In female patients, the QTc interval was significantly decreased (t = 3.495, P = 0.008) following the switch, while in male patients, the QTc interval did not change. No patients showed a PR interval of >200 ms or a QTc interval of >500 ms., Conclusion: OLZ treatment has a greater prolonging effect on PR and QT intervals compared with RIS. Careful attention may need to be paid to the cardiac conduction system in addition to QT prolongation during OLZ treatment., (© 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.)

Background: There is growing concern about the metabolic abnormalities in patients with schizophrenia., Aims: The aim of this study was to assess the attitudes of psychiatrists toward metabolic adverse events in patients with schizophrenia., Method: A BRIEF QUESTIONNAIRE WAS CONSTRUCTED TO COVER THE FOLLOWING BROAD AREAS: the psychiatrists' recognition of the metabolic risk of antipsychotic therapy, pattern of monitoring patients for physical risks, practice pattern for physical risks, and knowledge of metabolic disturbance. In March 2012, the questionnaire was mailed to 8,482 psychiatrists who were working at hospitals belonging to the Japan Psychiatric Hospitals Association., Results: The overall response rate was 2,583/8,482 (30.5%). Of the respondents, 85.2% (2,200/2,581) reported that they were concerned about prescribing antipsychotics that have a risk of elevating blood sugar; 47.6% (1,201/2,524) stated that their frequency of monitoring patients under antipsychotic treatment was based on their own experiences; and only 20.6% (5,22/2,534) of respondents answered that the frequency with which they monitored their patients was sufficient to reduce the metabolic risks., Conclusions: Psychiatrists practicing in Japan were generally aware and concerned about the metabolic risks for patients being treated with antipsychotics. Although psychiatrists should monitor their patients for metabolic abnormalities to balance these risks, a limited number of psychiatrists answered that the frequency with which they monitored patients to reduce the metabolic risks was sufficient. Promotion of the best practices of pharmacotherapy and monitoring is needed for psychiatrists treating patients with schizophrenia.

Objective: We examined sex differences in the effect of olanzapine (OLZ), risperidone (RIS), aripiprazole (ARP), or quetiapine (QTP) on mean corrected QT (QTc) intervals among 222 patients with schizophrenia., Methods: Subjects were patients with schizophrenia who were treated with either OLZ (n = 69), RIS (n = 60), ARP (n = 62), or QTP (n = 31). Electrocardiographic measurements were conducted, and the QT interval was corrected using Bazett's correction formula., Results: The mean QTc interval of the QTP group was significantly longer than that of the RIS group (p = 0.002) or ARP group (p = 0.029). The mean QTc interval of the OLZ group was also significantly longer than that of the RIS group (p = 0.006). In female participants, the difference in the mean QTc interval among the four second-generation antipsychotic (SGA) groups was statistically significant (p = 0.002), whereas in male patients, there was no significant difference in the mean QTc interval among the four SGA groups. Post hoc analyses showed that sex differences in QTc interval were observed only in OLZ treatment group (p = 0.007)., Conclusion: To our knowledge, this is the first study to demonstrate sex differences in the effect of four SGAs on the QTc interval., (Copyright © 2013 John Wiley & Sons, Ltd.)

Although second-generation antipsychotics (SGAs) are characterized by fewer prolactin (PRL)-related side effects compared with first-generation antipsychotics, the detailed effects of SGAs on the plasma PRL levels still remain unclear. We examined the differences in plasma PRL levels among 268 patients treated for schizophrenia with olanzapine (OLZ), risperidone (RIS), aripiprazole (ARP), quetiapine (QTP), or perospirone (PER). The participants had received antipsychotic monotherapy with stable doses of OLZ, RIS, ARP, QTP, or PER for ≥ 3 weeks, and fasting blood samples were drawn to examine plasma PRL levels. The differences in median plasma PRL levels in all (P<0.001), male (P<0.001) and female patients (P<0.001) among the five SGA groups were statistically significant. A stepwise multiple regression analysis showed that ARP treatment was found to contribute to lower plasma PRL level, while female sex, RIS, OLZ and chlorpromazine equivalent dose were found to contribute to a higher plasma PRL level. The median value of plasma PRL level in the RIS group was twice as much compared with that in the OLZ group, although this was not statistically significant. In this study, OLZ had a considerable effect on plasma PRL level, similar to RIS, while PER did not affect plasma PRL levels, similar to QTP. Further studies are needed to clarify the differences in plasma PRL levels among SGAs., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Atypical antipsychotic drugs are superior to typical antipsychotic drugs in having a lower incidence of extrapyramidal side-effects, so atypical antipsychotic drugs have become the mainstream in the clinic. However, there is growing interest in the effects of antipsychotic treatment on other serious side-effects such as metabolic abnormalities, sexual function and QT prolongation. There is a need for biomarkers that can help in early identification of patients who are at risk for these serious side-effects. Hence, we have conducted psychopharmacological studies using OGTT, measurement of adipokines, holter ECG and genetic methods, aiming to identify key biomarkers to drive personalized medicine and new treatment development.

Objectives: There have so far been few papers studying the metabolic syndrome (MetS) prevalence rate in Japanese patients with schizophrenia. We studied the MetS prevalence rate in Japanese controls and inpatients with schizophrenia and compared the prediction factors for the occurrence of MetS., Methods: The subjects were 319 inpatients with schizophrenia and 154 controls. The predictive utilities of body mass index (BMI) and the individual components of MetS for MetS diagnosis were evaluated., Results: The prevalence of MetS did not differ between schizophrenia and control subjects. Subjects with schizophrenia showed higher prevalences of the MetS criteria for high-density lipoprotein cholesterol (HDL) (p < 0.001) and waist circumference (WC) (p < 0.001). In subjects with schizophrenia, the predictive power was found to be highest for HDL, followed by WC, BMI, triglyceride, diastolic blood pressure (BP), systolic BP and fasting plasma glucose. However, in control subjects, the predictive power was found to be highest for triglyceride, followed by WC, systolic BP, BMI, HDL, diastolic BP and fasting plasma glucose. HDL was the component most predictive of MetS in subjects with schizophrenia treated with antipsychotics., Conclusion: Because, in normal clinical practice, it is difficult to obtain temporal measurements for all of the MetS criteria, measurement of HDL may be useful for predicting the MetS., (Copyright © 2013 John Wiley & Sons, Ltd.)

We implemented a two-step approach to detect potential predictor gene variants for neuroleptic-induced tardive dyskinesia (TD) in schizophrenic subjects. First, we screened associations by using a genome-wide (Illumina HumanHapCNV370) SNP array in 61 Japanese schizophrenia patients with treatment-resistant TD and 61 Japanese schizophrenia patients without TD. Next, we performed a replication analysis in 36 treatment-resistant TD and 138 non-TD subjects. An association of an SNP in the DPP6 (dipeptidyl peptidase-like protein-6) gene, rs6977820, the most promising association identified by the screen, was significant in the replication sample (allelic P=0.008 in the replication sample, allelic P=4.6 × 10(-6), odds ratio 2.32 in the combined sample). The SNP is located in intron-1 of the DPP6 gene and the risk allele was associated with decreased DPP6 gene expression in the human postmortem prefrontal cortex. Chronic administration of haloperidol increased Dpp6 expression in mouse brains. DPP6 is an auxiliary subunit of Kv4 and regulates the properties of Kv4, which regulates the activity of dopaminergic neurons. The findings of this study indicate that an altered response of Kv4/DPP6 to long-term neuroleptic administration is involved in neuroleptic-induced TD.

People with schizophrenia have higher rates of medical illness and mortality than the general population. Cardiovascular disease is a major contributor to premature death in patients with schizophrenia. There has been an increase literature discussing the high prevalence of dyslipidemia, which is one of risk factors for cardiovascular disease, induced by second generation antipsychotic agents. Depression is associated with increased risks of diabetes, hypertension, cardiovascular disease. However, those may not be secondary to the use of antidepressant agents. In order to reduce the risk of cardiovascular disease in patients with schizophrenia receiving antipsychotic agents, obtaining fasting lipid measurements at regular intervals is needed. Further investigations are needed to evaluate the effects of antidepressive agents on lipid profiles.

Objectives: There are few reports regarding quetiapine (QTP)-related QT prolongation. We examined the change in QT interval after switching from aripiprazole (ARP), olanzapine (OLZ), or risperidone (RIS) to QTP., Methods: Twenty subjects treated with ARP, OLZ, or RIS were enrolled in the study. Following baseline assessments, which included QT interval and electrolytes, these three drugs were switched to QTP for each subject. The same parameters were evaluated following a switch to QTP., Results: All 20 patients who had been treated with ARP, OLZ, or RIS were successfully switched to QTP. Significant increases were observed in the total mean corrected QT (QTc) interval after switching (p = 0.014). The coefficient of variation for the extent of change in QTc interval was 1.66. The mean QTc with ARP treatment was significantly increased after QTP treatment (p = 0.004)., Conclusions: Quetiapine might have a greater effect on QTc interval than other second-generation antipsychotics. However, because there was a considerable variability in the extent of QTc prolongation after switch to QTP, further studies are required to clarify the effect of QTP on QTc interval., (Copyright © 2012 John Wiley & Sons, Ltd.)

The development of impaired glucose tolerance induced by antipsychotics (APs) is of concern as a serious adverse effect of psychiatric drug therapy. However, the mechanism by which APs cause dysfunction of the glucose-insulin response is not fully understood. Recent studies have shown that patients treated with APs for schizophrenia were more likely to exhibit impaired glucose tolerance after a glucose load compared with healthy control subjects, even if fasting glucose levels were within the reference range. To explain these findings, we hypothesized that insulin secretion is increased in schizophrenic patients treated with AP, even those normal fasting glucose (NFG) levels. Therefore, oral glucose tolerance tests were conducted in 159 Japanese inpatients with AP-treated schizophrenia and in 90 healthy subjects without schizophrenia. Plasma glucose and serum insulin concentrations were measured before (0 minute) and at 30, 60, 90, and 120 minutes after the oral glucose load. Although insulin levels at 0 minute were similar in both groups of subjects, insulin levels were significantly higher in the patients treated with AP at all times after the glucose load than in the healthy subjects. In analyses of NFG subjects, insulin levels were significantly higher in the patients treated with AP compared with the healthy subjects at all times after glucose loading. Overall, we found that insulin secretion in response to a glucose load was significantly higher in the patients treated with AP, irrespective of NFG. These results suggest that APs affect the glucose-insulin response, which may lead to subclinical insulin resistance before the onset of overt glucose intolerance.

Several studies have shown increased rates of hyperglycemia and diabetes in schizophrenic patients treated with olanzapine. However, the underlying mechanism is poorly understood. Glucose-dependent insulinotropic polypeptide (GIP) is known to affect insulin secretion by pancreatic β cells. Recently, a meta-analysis study reported an association between a GIP receptor (GIPR) gene polymorphism (rs10423928) and insulin secretion measured by an oral glucose tolerance test (OGTT). We assessed the influence of this GIPR gene polymorphism on glucose metabolism in 60 schizophrenic patients treated with olanzapine and 103 healthy controls. The GIPR gene polymorphism was determined using TaqMan methods. We performed repeated-measures analysis of variance (ANOVA) and one-way ANOVA for the glucose and insulin levels during OGTTs in four groups divided by the GIPR gene polymorphism and cohort (schizophrenia or control). We found significant effects of the GIPR gene and cohort on the insulin levels at 30 min. Our findings suggest that schizophrenic patients with the A allele of GIPR rs10423928 are at risk of developing hyperinsulinemia when treated with antipsychotics.

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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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.

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., Case Summary: We present a case of a 22-year-old man with schizophrenia who experienced dyskinesia and dystonia associated with aripiprazole. Switching from olanzapine to aripiprazole resulted in worsening dyskinesia and new onset of dystonia. The patient's dyskinesia and dystonia improved after switching from aripiprazole to quetiapine therapy., What Is New and Conclusion: There were several previous case reports on dyskinesia and dystonia associated with aripiprazole medication. The risk factors for tardive dyskinesia include older age and female sex. However, our case was a male patient who was younger compared with the previous cases and so should have been less at risk for dyskinesia in comparison with the previous cases. The effects of aripiprazole can include tardive movement disorders. Dyskinesia, dystonia and psychotic symptoms were improved with relatively small dose of quetiapine in this case. Whether some second-generation antipsychotics are more effective than others in the treatment of tardive dyskinesia remains unclear., (© 2011 Blackwell Publishing Ltd.)

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 / RR). 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.

Objective: 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., Methods: Steady-state plasma RIS, 9-OH-RIS, and active moiety levels were measured in 64 patients treated with an average dosage of 4.6 mg/day., Results: The number of CYP2D6*10 alleles significantly affected dose-corrected plasma RIS levels (p = 0.001), and the median concentrations in ng/ml/mg were 0.94 (0 allele) vs. 1.73 (1 allele) vs. 3.05 (2 alleles). The number of CYP2D6*10 alleles did not affect plasma 9-OH-RIS or active moiety levels., Conclusion: The present study shows that the number of CYP2D6*10 alleles affected plasma RIS levels but not plasma 9-OH-RIS and plasma active moiety levels. Because the plasma active moiety levels can influence antipsychotic effects or side effects, the genetic screening of the CYP2D6*10 allele for RIS in Asian populations may not be clinically important.

Objective: 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., Methods: The present study evaluated associations between risperidone metabolism and QT interval in 61 psychiatric patients who had been receiving risperidone for ≥4 weeks at an average dosage of 4.7 mg/day. Plasma risperidone and paliperidone levels were measured and electrocardiographic measurements were also obtained., Results: There was no correlation between risperidone dosage and QTc or plasma risperidone levels and QTc. However, there was a significant positive correlation between plasma paliperidone levels and QTc (r = 0.361; p = 0.004). There was no correlation between age and dose-corrected plasma risperidone levels or between age and QTc. There was a significant positive correlation between age and dose-corrected plasma paliperidone levels (r = 0.290; p = 0.023)., Conclusion: Clinically, paliperidone is considered to play a more important role in QT prolongation than risperidone., (Copyright © 2011 John Wiley & Sons, Ltd.)

Objectives: 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., Methods: Twenty-six subjects treated with varying starting doses of OLZ were enrolled in the study. Following baseline assessments, which included completion of the Brief Psychiatric Rating Scale (BPRS), measurements of Body Mass Index (BMI), QT interval, electrolytes, fasting plasma glucose, PRL, hemoglobin A1c (HbA1c), total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), and low density lipoprotein (LDL), the dose of OLZ was increased for each subject. The same parameters were evaluated following the increased dose treatment., Results: A significant decrease was observed in BPRS score (p = 0.01) following treatment with an increased dose of OLZ. Significant increases were observed in BMI (p = 0.032), QTc (p = 0.031), and plasma PRL level (p = 0.028). The mean values of electrolytes, fasting plasma glucose, HbA1c, TC, TG, HDL and LDL treatment were unchanged by the switch to increased-dose OLZ treatment., Conclusion: We have demonstrated the dose-dependent effect of OLZ on the QT interval and the plasma PRL level of patients with schizophrenia., (Copyright © 2011 John Wiley & Sons, Ltd.)

The pathogenesis of schizophrenia has yet to be fully characterized. Gene-environment interactions have been found to play a crucial role in the vulnerability to this disease. Among various environmental factors, inflammatory immune processes have been most clearly implicated in the etiology and pathology of schizophrenia. Cytokines, regulators of immune/inflammatory reactions and brain development, emerge as part of a common pathway of genetic and environmental components of schizophrenia. Maternal infection, obstetric complications, neonatal hypoxia and brain injury all recruit cytokines to mediate inflammatory processes. Abnormal expression levels of specific cytokines such as epidermal growth factor, interleukins (IL) and neuregulin-1 are found both in the brain and peripheral blood of patients with schizophrenia. Accordingly, cytokines have been proposed to transmit peripheral immune/inflammatory signals to immature brain tissue through the developing blood-brain barrier, perturbing structural and phenotypic development of the brain. This cytokine hypothesis of schizophrenia is also supported by modeling experiments in animals. Animals treated with specific cytokines of epidermal growth factor, IL-1, IL-6, and neuregulin-1 as embryos or neonates exhibit schizophrenia-like behavioral abnormalities after puberty, some of which are ameliorated by treatment with antipsychotics. In this review, we discuss the neurobiological mechanisms underlying schizophrenia and novel antipsychotic candidates based on the cytokine hypothesis.

We investigated the effect of gender on plasma prolactin levels in 20 Japanese drug-naïve schizophrenic patients [10 male, 10 female, aged 25.4+/-10.3 (mean+/-S.D.), range = 12-46 years] treated with olanzapine. Plasma prolactin levels were measured at baseline, and weeks 3 and 8 after starting titration of olanzapine. Comparisons of plasma prolactin levels between baseline and week 3, and between baseline and week 8 were made by repeated analysis of variance (ANOVA) and paired t-test. Two-way ANOVA showed a significant difference in olanzapine-induced prolactin changes between male and female patients (P = 0.037). In male patients (n = 10), the plasma concentration of prolactin at week 3 was significantly higher than at baseline (P = 0.016), but there was no significant difference between the plasma concentration of prolactin at week 8 and at baseline or week 3 (P = 0.191). In female patients (n = 10), there was a significant change of prolactin between baseline and week 3 (P = 0.005), and between baseline and week 8 (P = 0.047). Our results indicate the possibility of gender differences in prolactin elevation induced by olanzapine in Japanese drug-naïve schizophrenic patients. These gender-based findings may be helpful for clinicians when deciding the frequency of follow-up visits once a patient starts olanzapine therapy.

The authors have developed and verified the precision and accuracy of new automated cloned enzyme donor immunoassays (CEDIA) for haloperidol and bromperidol, and cross-validations have been performed with conventional semiautomated EIA kits (MARKIT-M) and high-performance liquid chromatographic (HPLC) methods. The CEDIA method provides a quick (about 10 minutes) assay for haloperidol or bromperidol, requiring no serum/plasma pretreatment or predilution. The CEDIA haloperidol/bromperidol assay showed little or no cross reactivity with either their metabolites or many drugs commonly coprescribed. MARKIT-M revealed considerable cross reactivity values proportional to the spiked amounts of reduced metabolites. Precision, accuracy, recovery, and linearity testing for the CEDIA assay were all sufficient for clinical use. Significant linear correlations were found between CEDIA and HPLC in measuring haloperidol (CEDIA = 1.06 x HPLC + 0.869; n = 44, rs = 0.913, P < 0.001) and bromperidol (CEDIA = 1.06 x HPLC + 0.606; n = 56, rs = 0.914, P < 0.001) concentrations. This study has, therefore, demonstrated that the CEDIA assay has a quick run time with high precision and accuracy, and this method is a useful tool for the TDM of haloperidol or bromperidol.

Delirium, which is experienced by 10-30% of inpatients, is commonly seen in daily practice. A survey was conducted of the delirium medications, and results were obtained from 28 psychiatric departments and related facilities. Haloperidol was used in 67% cases for the treatment of delirium. Ninety-seven per cent of facilities considered haloperidol as the drug of first choice, while 57% thought this drug had few side-effects and was easy to use. However, because the use of this drug is not covered by health insurance in Japan, its use is limited. We expect that this study on medication for the treatment of delirium will be a first step in increasing the approved indications for drugs used for the treatment of delirium, and to reduce off-label use.

The authors studied the interactive effects of the coadministration of haloperidol and chlorpromazine on plasma concentrations of haloperidol and reduced haloperidol. The subjects were 43 Japanese male schizophrenic inpatients who were concomitantly treated with chlorpromazine before or after monotherapy with haloperidol. Coadministration of chlorpromazine produced significant increases in the plasma concentrations of haloperidol (P < 0.01) and reduced haloperidol (P < 0.001) by an average of 28.5% +/- 83.3% and 160.8% +/- 288.9%, respectively. However, there were marked interindividual variations in the interactive effects of chlorpromazine. The authors analyzed the importance of five CYP2D6 genotypes, *1/ *1, *1/ *10, *10/ *10, *1/*5, and *5/*10 on the percentage of change in plasma concentrations of haloperidol and reduced haloperidol. Patients with the CYP2D6*5 allele (n = 4) showed a significantly smaller increase in plasma concentrations of haloperidol (P < 0.05) and a slightly smaller increase in those of reduced haloperidol (P = 0.074) in response to the coadministration of chlorpromazine compared than those with the CYP2D6*1/*1 genotype (n = 8). Those with the CYP2D6*1/*1 genotype (n = 8) showed a trend toward greater increases in plasma concentrations of haloperidol than those with other genotypes (P = 0.087).

Measurement of serum sultopride levels was performed using an enzyme immunoassay. Little or no cross-reactivity with metabolites of sultopride and other drugs was found. The results of reproducibility, recovery, and dilution testing were all good enough for clinical use. A comparison between the measurement values of this method (y) with that of high-performance liquid chromatography (x) showed high correlation (n = 211, r = 0.991, p < 0.0001, y = 0.99x + 107.5). In a comparison between the sultopride dose and serum levels in 161 patients, interindividual differences were large (19 times for same doses), implying that the serum level cannot be predicted from the dosage. The method was found to be reliable for serum level measurements of sultopride and useful for monitoring compliance and assessing the optimal dose.

The authors we investigated the relationship between plasma levels of haloperidol (HAL) and the number of CYP2D6*10 (*10) alleles in 66 Japanese inpatients with schizophrenia (male = 61, female = 5) on HAL. Plasma HAL level was determined by an enzyme immunoassay method. Daily dose of HAL was 1.5-36 (mean +/- SD = 12.3 +/- 7.6) mg or 0.02-0.49 (0.21 +/- 0.13) mg/kg body weight. Plasma HAL levels ranged from 1.4 to 47.4 (12.4 +/- 9.5) ng/mL. No significant difference in the plasma HAL levels was observed between the subjects with no, one, and two *10 alleles (one-way analysis of variance: 56.1 +/- 20.3, 61.0 +/- 20.3, and 63.3 +/- 20.3 ng/mL/mg/kg, respectively, F(2,63) = 0.65, p = 0.52). These results are not supportive of the previous report that plasma HAL levels can be predicted by the number of *10 alleles in Asian patients.

Plasma concentrations of bromperidol (BRP) and reduced bromperidol (RBRP) were determined in 31 patients with schizophrenia who were administered BRP for their psychiatric symptoms. Activities of carbonyl reductase in red blood cells were assayed using BRP as a substrate. Plasma concentrations of BRP and RBRP ranged from 2.2 to 23.5 ng/mL and from 0.2 to 8.2 ng/mL, respectively. RBRP-to-BRP ratios in plasma ranged from 0.01 to 0.94 (mean +/- SD: 0.31 +/- 0.20), values notably lower than the previously reported values of reduced haloperidol to haloperidol (HAL) in the plasma from patients on HAL. The activity of BRP reductase in red blood cells was determined as 6.8-12.3 pmol/hr/10(6) red blood cells, which was at approximately the same level as that of HAL reductase. Patients with positive responses to BRP treatment were evaluated using the Brief Psychiatric Rating Scale. We found that the number of patients who had a positive response to BRP did not increase after BRP plasma levels had reached the level of 12 ng/mL. This finding suggests that a therapeutic plateau in BRP pharmacotherapy of schizophrenia occurs, and there is no advantage to raising the dose once this plateau is reached.

We investigated the effect of cytochrome P450 (CYP2D6) genotypes on plasma levels of haloperidol (HAL) and reduced haloperidol (RHAL) in 47 Japanese male schizophrenic inpatients being treated with HAL. Mutation-specific polymerase chain reaction (PCR) analysis was used to detect CYP2D6*10 as the C188C1T mutation in exon 1. A long-PCR analysis method was used to detect CYP2D6*5. Allele frequencies of CYP2D6*5 and CYP2D6*10 were 4.3% and 34.0%, respectively. Plasma concentrations of HAL and RHAL were measured using high-performance liquid chromatography. The ranges of the plasma concentration of HAL and RHAL corrected to the dose were 0.28-1.60 (mean +/- SD, 0.66+/-0.25, n = 47) ng/mL/mg and 0.03-3.00 (mean+/-SD, 0.36+/-0.46, n = 47) ng/mL, respectively. Plasma RHAL/HAL ratios (R/H ratios) ranged from 0.06 to 1.88 (mean +/- SD, 0.48+/-0.32, n = 47). The analysis was performed among the four genotype groups: CYP2D6*1/CYP2D6*1 (n = 11), CYP2D6*1/CYP2D6*10 (n = 11), CYP2D6*10/CYP2D6*10 (n = 6) and those who have CYP2D6*5 allele (CYP2D6*1/ CYP2D6*5 or CYP2D6*5/CYP2D6*10 (n = 4). We observed significant tendency in effects of CYP2D6 genotypes on plasma concentration of HAL and significant effects on plasma concentration of RHAL, and R/H ratio. These results we obtained suggested that the plasma concentration of HAL and RHAL were determined partly by CYP2D6 polymorphic activity.

The impact of smoking on plasma haloperidol (HAL) concentrations was investigated in 66 Japanese male schizophrenic inpatients treated orally with HAL. The subjects consisted of 22 nonsmokers and 44 smokers each smoking ten cigarettes per day. Plasma concentrations of HAL were determined by an enzyme immunoassay method. There were significant positive correlations between the plasma HAL concentration and the daily dose of HAL per kg body weight (Y = 58.1X-0.01 (r = 0.86)). Smokers had significantly lower HAL concentrations per daily dose of HAL/kg body weight than nonsmokers (smokers vs. nonsmokers = 54.3+/-16.6 vs. 70.6+/-23.2 ng/mL/mg/kg). In doses less than 0.2 mg/kg of HAL, smokers showed significantly lower HAL concentrations per daily dose of HAL/kg body weight than nonsmokers (smokers vs. nonsmokers = 55.1+/-14.4 vs. 79.5+/-27.1 ng/mL/mg/kg), whereas no significant difference in HAL concentrations per daily dose of HAL/kg body weight was observed between smokers and nonsmokers when treated with more than 0.2 mg/kg (smokers vs. nonsmokers = 52.9+/-20.7 vs. 60.0+/-11.1 ng/mL/mg/kg). Our results indicate that smoking may induce the enzyme(s) metabolizing HAL, which results in lower plasma HAL concentrations in smokers than in nonsmokers, particularly at low doses of HAL.

We analyzed therapeutic drug monitoring (TDM) data from 231 schizophrenic inpatients (137 men, 94 women) and investigated interindividual differences of plasma haloperidol (HAL) concentrations and drug/drug interactions between HAL and various concomitant drugs. Plasma HAL concentrations were determined by an enzyme immunoassay (EIA) method. Plasma HAL concentrations per daily dose of HAL per body weight (HAL C/D ratio) demonstrated an approximately 11-fold interindividual variation. The patient subjects who received carbamazepine (CBZ) concomitantly had a mean HAL C/D ratio that was 37% lower than that of the patient subjects without CBZ. The patient subjects treated with concomitant phenobarbital (PB) also showed a mean HAL C/D ratio that was 22% lower than those without PB. We concluded that careful evaluation of HAL TDM data and consideration of the impact of concomitant medication such as CBZ or PB that might influence the metabolism of HAL is necessary in daily clinical settings to avoid insufficient clinical response because of lowered concentrations of HAL or adverse effects because of high concentrations of HAL.

Plasma levels of timiperone (TIM) and reduced timiperone (RTIM) were determined in 10 schizophrenic patients who were treated with TIM. Activities of ketone reductase in red blood cells (RBC) were assayed using TIM and haloperidol (HAL) as substrates. Plasma levels of TIM and RTIM ranged from 3.2 ng/mL to 9.5 ng/mL and from 1.7 ng/mL to 7.6 ng/mL, respectively, and approximately four-fold inter-individual variations in RTIM/TIM (0.37-1.43, 0.67 +/- 0.25) were observed. There were significant and positive correlations between plasma levels of TIM or RTIM with the daily doses of TIM (mg/kg body weight); TIM (ng/mL)= 19.5 x daily dose of TIM (mg/kg) + 1.3, r = 0.79, n = 18, P < 0.01; RTIM (ng/mL) = 13.1 x daily dose of TIM (mg/kg) + 0.7, r = 0.73, n = 18, P < 0.001). Given 0.3 mg/kg of TIM, a plasma level of TIM as 7.15 ng/mL was predicted, which is approximately 60% that of HAL. The activity of TIM reductase in RBC was determined as approximately 70% of HAL reductase in RBC, although the correlation between the activities of TIM reductase and HAL reductase in RBC was high (r = 0.98, n = 10, P < 0.001).

This in vitro study using human liver enzymes was undertaken in order to compare the mechanism of metabolic reduction of timiperone, a potent butyrophenone neuroleptic, with that of haloperidol. Conversion of timiperone to reduced timiperone in liver cytosol was confirmed. The carbonyl reductase inhibitors (menadione IC50 5-18 microM; ethacrynic acid IC50 26-51 microM) potently inhibited both timiperone reductase and haloperidol reductase activity, while 4-methylpyrazole (alcohol dehydrogenase inhibitor) had no effect and phenobarbital (aldehyde reductase inhibitor) had a weak inhibitory effect. The formation of reduced timiperone was highly correlated with the formation of reduced haloperidol(r = 0.87, n = 6, P < 0.02). Timiperone reductase activity was approximately 40% lower than haloperidol reductase activity (at a substrate concentration of 100 microM, two-tailed t-test, P < 0.05). The Michaelis-Menten constant (Km) and maximum velocity (Vmax) of reduced timiperone formation were much lower than reduced haloperidol formation (K(m) values: 29.7 +/- 15.1 versus 381.3 +/- 1.1 microM, n = 3, P < 0.01; Vmax: 0.81 +/- 0.19 versus 6.00 +/- 1.47 nmol/mg/min; n = 3, P < 0.05). However, the ratio Vmax/K(m) (clearance) for timiperone was 1.3-2.4 times higher than for haloperidol, indicating that metabolic clearance of timiperone by carbonyl reductase may be similar to or slightly higher than for haloperidol.

It is unclear whether elevated cholesterol level is a complication of panic disorder (PD) or is associated with pharmacotherapy. We compared the total cholesterol (TC) level in 47 PD patients with that in 47 gender- and age-matched normal controls (NC), and we also examined the pre- and post-treatment TC levels. There was no sex difference in TC. Before pharmacotherapy, the mean TC level in the PD group (194.9 +/- 39.6 mg/dl) was non-significantly higher than that in the NC group (190.5 +/- 26.7 mg/dl). The mean TC level in the PD group was significantly reduced following the pharmacotherapy (post-TC: 184.7 +/- 31.0 mg/dl; t = 2.44, P < 0.02), and the subgroup treated with alprazolam (n = 26) showed markedly significant decrease of TC after the treatment (t = 2.36, P < 0.03). The TC level in the PD subgroup with agoraphobia (n = 24, 198.9 +/- 37.9 mg/dl) was slightly higher than that in the group without agoraphobia (n = 23, 190.8 +/- 41.6 mg/dl). These findings suggest that there is a relationship between cholesterol levels and treatment in PD.