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Non-restorative sleep (NRS) affects not only individuals' health, but also company productivity, highlighting the importance of measures in the workplace to improve sleep. This study aimed to examine the clustering of the presence of restorative sleep (RS) and lifestyle habits in a Japanese working population and to explore the characteristics of these clusters. The subjects were 58,150 Japanese working men aged 40−59 years who underwent health check-ups across the country from April 2015 to March 2016. Data for the presence of RS, the frequency and amount of drinking, smoking/exercise habits, and body mass index obtained from health check-ups were clustered with latent class analysis. In addition, the characteristics of each cluster were examined from the perspectives of lifestyle-related disease-associated blood test results obtained from health check-ups and the status of medical treatment at medical institutions as determined from medical claims data. Consequently, RS and lifestyle habits were found to form five clusters. The "NRS, no exercise, drinkers" cluster showed the highest probability of not achieving RS. An "Obese, occasional binge drinkers" cluster with a higher percentage of patients with sleep-apnea syndrome and a "Nondrinkers" cluster with proportions of those taking sleeping pills/anxiolytics and antidepressants/antipsychotics were observed. Furthermore, the "Daily smokers and drinkers" and "RS and drinkers" clusters showed a relatively high probability of achieving RS. These findings suggest that some individuals may not be aware of the sleep disorders caused by their drinking and smoking habits. Measures to improve sleep must be tailored to the characteristics of each cluster. [ABSTRACT FROM AUTHOR]

Several medications are associated with delirium; however, studies with adequate statistical power are limited, and it is difficult to determine the effects of the various concomitant medications used in clinical practice. Therefore, in this study, we aimed to comprehensively evaluate the safety signals of delirium-associated drugs using a spontaneous adverse event reporting system. The JAPIC AERS (Food and Drug Administration Adverse Event Reporting System pre-processed by the Japan Pharmaceutical Information Center) was used for the analysis in this pharmacovigilance study. The reporting odds ratio (ROR) for delirium was adjusted for using multivariate logistic regression analysis with sex, age, indication, and melatonin receptor agonist use, and 22 drug categories were targeted as covariates. After excluding patients with missing information, 7,527,568 patients were included in the study. Delirium signals were detected even after adjusting for covariates in 17 drug categories, including benzodiazepines (adjusted ROR, 1.76; 95% confidence interval [CI], 1.64–1.89), opioids (adjusted ROR, 4.42; 95% CI, 4.21–4.64), and tricyclic antidepressants (adjusted ROR, 2.44; 95% CI, 2.20–2.71). These findings suggest that many drug classes, such as benzodiazepines, are independent risk factors for delirium and strengthen the evidence of an association between delirium and medications. [ABSTRACT FROM AUTHOR]

The article discusses research which examined the effects of policy interventions on psychotropics polypharmacy among Japanese older adults. The study determined the proportion of patients prescribed with psychotropics, antidepressants, antipsychotics, hypnotics and anxiolytics. Study limitations include the use of the DeSC Healthcare Inc. database, estimated number of patients who switched medications, and impact of the coronavirus pandemic.

Background: It is unclear how primary care physicians manage insomnia after the introduction of novel hypnotics such as orexin receptor antagonists and melatonin receptor agonists. This Web-based questionnaire survey aimed to examine treatment strategies for insomnia in Japanese primary care practice. Methods: One-hundred-and-seventeen primary care physicians were surveyed on the familiarity of each management option for insomnia on a binary response scale (0 = "unfamiliar"; 1 = "familiar") and how they managed insomnia using a nine-point Likert scale (1 = "I never prescribe/perform it"; 9 = "I often prescribe/perform it"). Physicians who were unfamiliar with a management option were deemed to have never prescribed or performed it. Results: Regarding medication, most physicians were familiar with novel hypnotics. Suvorexant was the most used hypnotic, followed by lemborexant and ramelteon. These novel hypnotics averaged 4.8–5.4 points and 4.0–4.7 points for sleep onset and sleep maintenance insomnia, respectively. By contrast, most benzodiazepines were seldom used below two points. Regarding psychotherapy, only approximately 40% of the physicians were familiar with cognitive behavioral therapy for insomnia (CBT-I) and they rarely implemented it, at an average of 1.5–1.6 points. More physicians were familiar with single-component psychotherapies (i.e., relaxation, sleep restriction therapy, and stimulus control) compared to CBT-I, and 48–74% of them implemented it slightly more often, with scores ranging from 2.6 to 3.4 points. Conclusion: This study suggests that Japanese primary care physicians seldom use CBT-I to treat insomnia. In addition, they use novel sleep medications more frequently than benzodiazepines in terms of pharmacotherapy. The use and availability of CBT-I in Japanese primary care might be facilitated by: educating primary care physicians, implementing brief or digital CBT-I, and/or developing collaborations between primary care physicians and CBT-I specialists. [ABSTRACT FROM AUTHOR]

Background: Bipolar disorder is a mental illness characterized by recurring episodes of mania and depression and is known to cause social impairment. Additionally, it has been revealed that bipolar disorder increases the risk of divorce and loss of family member support, which can worsen the prognosis. However, there is limited evidence regarding the predictive factors of divorce among patients with bipolar disorder in real-world settings. Methods: This study utilized an observational approach and involved psychiatrists from 176 member clinics of the Japanese Association of Neuro-Psychiatric Clinics. They were requested to conduct a retrospective review of medical records and complete a questionnaire focused on patients diagnosed with bipolar disorder. The data collection period for baseline patient characteristics spanned from September to October 2017. Next, we investigated the incidence of divorce over a 2-year period, ranging from baseline to September to October 2019. Results: A total of 1071 outpatients with bipolar disorder were included in the analysis, and 2.8% (30/1071) experienced divorce during the first 2 years of observation. The incidence of divorce in this population was considerably higher than that in the general Japanese population. Binomial logistic regression analysis confirmed that a younger baseline age and lower BMI values were statistically significant predictors of divorce occurrence for all study participants. The predictors of divorce were then examined separately by sex. The results revealed that for men, a younger age at baseline and having bipolar I disorder compared to bipolar II disorder were statistically significant predictors of divorce. In contrast, for women, having a lower BMI and using anxiolytics emerged as statistically significant predictors of divorce. Conclusions: In this study, a younger baseline age and lower BMI values were statistically significant predictors of divorce in patients with bipolar disorder. Notably, the predictors of divorce varied significantly between men and women. These findings provide important insights from a family perspective regarding social support for individuals with bipolar disorder in real-world clinical settings. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation (AF) is the most common sustained arrhythmia among older people and has a significant impact on quality of life. However, it is not always perceived as a serious mental health risk. This study investigated the understanding, perceptions, and attitudes toward the risk of depressive state associated with older patients with AF. Methods: We conducted a quantitative survey in April–June 2021 among patients with AF aged ≥65 years (n = 156), and physicians or cardiologists attending at least 10 older patients with AF annually (n = 158). Results: In total, 45% of patients considered AF a cause of a depressive state. In contrast, 16% of physicians reported that they considered AF a cause of a depressive state. Fifty‐two percent of the patients had experienced a depressive state. Of these, 98% expressed that a depressive state lowered their quality of life. Two of the three patients reported that they would consult their physicians if they felt depressed. By contrast, 30% of physicians responded that even if they perceived their patients as depressed, they prescribe anti‐anxiety medication but do not refer the patient to psychiatrists. Of the physicians, 50% stated that they did not regard the association of AF and depressive state as serious, although both physicians and patients understood that negative anxiety, such as fear of AF attacks, strokes, or heart failure, was the most important contributor to a depressive state. Conclusion: Establishing mental healthcare involving physicians together with psychiatrists is necessary to improve the mental and physical health outcomes for older patients with AF. Geriatr Gerontol Int 2023; 23: 543–548. [ABSTRACT FROM AUTHOR]

Background and Objective: The use of benzodiazepines and nonbenzodiazepines increases the risk for hip fracture, but the effect of suvorexant, an orexin receptor antagonist, is not clear. The objective of this study was to investigate the association between suvorexant use and hip fractures in older adults. Methods: A case–control study was conducted using real-world data (RWD) from Medical Data Vision Co., Ltd. with patients hospitalized between January 2019 and December 2020. Patients were aged 65–84 years and had been prescribed suvorexant at least once. Patients with hip fracture (cases) and those without (controls) were identified by matching up to 1:4 for sex, age (± 2 years), and hospital size category. Suvorexant exposure was identified the day before hospitalization. Hip fracture risk associated with suvorexant was presented as adjusted odds ratios (aOR) with 95% confidence intervals (CI) using conditional logistic regression analysis. Results: Matching identified 389 cases and 1509 controls. The risk of hip fracture was not increased in patients treated with suvorexant [aOR: 0.86, 95% confidence interval (CI) 0.61–1.20]. Additionally, concomitant use of suvorexant with other hypnotics did not increase the risk. Benzodiazepines (1.01, 0.46–2.22), nonbenzodiazepines (1.16, 0.57–2.34), and melatonin (1.80, 0.82–3.94) were combined with suvorexant. The risk was increased for the use of benzodiazepine without suvorexant (1.88, 1.10–3.21). Conclusions: Using RWD in Japanese older adults, we showed that sleep therapy with suvorexant was not associated with an increased risk of hip fracture. The results provide evidence-based drug safety information for the selection of hypnotics for sleep disorders, which increase with age. [ABSTRACT FROM AUTHOR]

Kamishoyosan (KSS) is a traditional Japanese Kampo medicine that is prescribed for hormonal change-induced mood disorders including premenstrual syndrome (PMS). In clinical studies, KSS exhibited ameliorative effects on mood symptoms of PMS, such as anxiety and irritability. However, the mechanism underlying the beneficial effects of KSS is unclear. In the present study, we investigated the involvement of serotonergic machinery in the anxiolytic effects of KSS on hormonally-induced anxiety-like behavior in progesterone withdrawal (PWD) rats, which were used as a model of PMS. Female rats were injected with progesterone daily for 21 days. At 48 h after the final progesterone injection, anxiety-like behavior was evaluated using the elevated plus maze. KSS was administered orally to PWD rats 1 h prior to the test and significantly attenuated PWD-induced anxiety-like behavior. This ameliorative effect of KSS was reversed by WAY-100635, a serotonin (5-HT)1A receptor antagonist. The effect of KSS on serotonergic transmission in the prefrontal cortex of PWD rats was also evaluated using an in vivo microdialysis procedure. KSS significantly increased the extracellular 5-HT level in the prefrontal cortex of PWD rats. In conclusion, our results suggest that KSS alleviates PWD-induced anxiety-like behavior at least partly by activating 5-HT1A receptors and enhancing serotonergic transmission. [ABSTRACT FROM AUTHOR]

Summary: In Japanese patients who experienced an osteoporotic fracture, 10.8% and 18.6% had a subsequent fracture within 1 and 2 years of follow-up, respectively. Although the burden of hip and vertebral fractures has been reported widely, we found that patients with non-hip non-vertebral (NHNV) fractures had a 26% higher risk of subsequent fracture than patients with hip fractures; therefore, NHNV fractures should also be considered an important risk factor for subsequent fracture. Introduction: To investigate imminent risk and odds of subsequent osteoporotic fractures and associated risk factors in patients who experienced an initial osteoporotic fracture. Methods: Patients aged ≥ 50 years with ≥ 1 osteoporotic fracture were analyzed from Japan's Medical Data Vision (MDV) database of claims from acute-care hospitals (January 2012–January 2017). Multivariable models were constructed to explore the impact of key comorbidities and medications on the subsequent fracture risk: Cox proportional hazards model for time to subsequent fracture and logistic regression models for odds of subsequent fracture within 1 and 2 years from index fracture. Results: In total, 32,926 patients were eligible with a median follow-up duration of 12.3 months. The percentage of patients experiencing subsequent fractures was 14.1% across the study duration, and 10.8% and 18.6% in patients with 1 and 2 years of follow-up, respectively. In the Cox proportional hazards model, patients with vertebral or NHNV index fractures had a higher subsequent fracture risk than patients with a hip index fracture (adjusted hazard ratio [aHR] 1.11 and 1.26, respectively); subsequent fracture risk was lower in males than females (aHR 0.89). Patients with baseline claims for tranquilizers and glucocorticoids had a higher subsequent fracture risk than those without (aHR 1.14 and 1.08, respectively). Additionally, baseline claims for anti-Parkinson's medications, alcoholism, and stage 4/5 chronic kidney disease were significantly associated with higher odds of subsequent fracture in the logistic regression models. Conclusion: Several clinical and demographic factors were associated with a higher risk and odds of subsequent fracture. This may help to identify patients who should be prioritized for osteoporosis treatment. [ABSTRACT FROM AUTHOR]

What is known and Objective: Compared with the general adult population, pharmacokinetics and changes in drug responsiveness occur to a greater extent in the elderly. Interactions may occur between drugs used in combination to treat various diseases and may cause adverse events (AEs). We conducted a cross‐sectional risk assessment of AEs in elderly patients based on information gathered from Japanese medical practices with the goal of obtaining information that will contribute to optimizing pharmacotherapy. Methods: The Japanese Adverse Drug Event Report database was used to determine the incidence of AEs in elderly patients (aged 80 years or older) compared with patients aged less than 80 years old by evaluating the reporting odds ratio using the data obtained from reports. Results and discussion: Hypnotics and anxiolytics, as well as anticoagulants and theophylline, were identified as groups of drugs that warrant special attention in the elderly. Hypnotics and anxiolytics, especially those that are short‐acting, tend to cause delirium and geriatric syndromes including falls and fractures. With respect to anticoagulants, no increase in the risk of bleeding was evident and the dose was believed to be properly adjusted; however, there was an increased risk of anemia. Theophylline toxicity tended to occur more frequently in the elderly, suggesting the need for drug monitoring. What is new and Conclusion: Based on these cross‐sectional studies, the evaluation of the risk of AEs for drugs commonly used in the elderly based on near real‐world information was achieved. [ABSTRACT FROM AUTHOR]

What is known and Objective: The use of hypnotics, especially benzodiazepines (BZs), increases the risk of falls. Regarding the association of orexin receptor antagonists with fall risk, consistent results have not been obtained for suvorexant, and studies of lemborexant have not been reported. Therefore, this study investigated whether orexin receptor antagonists, including lemborexant, increase the risk of falls. Methods: Data were obtained from the medical records of patients hospitalized at Saga University Hospital in Japan between July 2020 and April 2021. Patients were retrospectively divided into the fall and non‐fall groups, and the groups were compared for medication usage. Results and Discussion: The fall and non‐fall groups included 132 and 6857 patients respectively. A significantly higher proportion of patients in the fall group used hypnotics (40.2% vs. 21.7%; p < 0.0001). Hypnotics remained significantly associated with a higher risk of falls after adjusting for confounders (adjusted odds ratio [OR] = 1.67, 95% confidence interval [CI] = 1.13–2.48, p = 0.01). In particular, the use of benzodiazepines was associated with a significantly higher risk of falls (adjusted OR = 2.08, 95% CI = 1.38–3.15, p = 0.0005). Meanwhile, suvorexant use was not linked to the risk of falls, and lemborexant use was associated with a significantly lower risk of falls (adjusted OR = 0.27, 95% CI = 0.09–0.84, p = 0.02). What is new and Conclusion: The use of hypnotics is a risk factor for falls, but orexin receptor antagonists may represent a safe option for patients requiring hypnotics. Our results provide evidence supporting the safety of these drugs. [ABSTRACT FROM AUTHOR]

The number of working-age individuals undergoing cancer treatment has been increasing. In these patients, transdermal fentanyl is the preferred treatment. However, it is known to have (1) pharmacodynamic interactions with benzodiazepines and (2) fever-induced pharmacokinetic variations. The aim of this study is to clarify the frequency of co-administration of benzodiazepine and the predictors for fever among working-age patients with cancer using transdermal fentanyl. We used a large claims data source including over 3.6 million patients. Finally, 759 working-age patients aged 20 to 60 years undergoing cancer treatment, in whom transdermal fentanyl was initiated, were analyzed. The proportion of patients receiving co-administration of benzodiazepines with the first administration of transdermal fentanyl was 16.5% (n = 125). This increased to 39.3% (n = 298) within 30 days. Predictive factors for fever using patients' baseline characteristics were male sex, gastrointestinal cancer, hematological cancer, and renal disease. To provide adequate pharmacotherapy to working-age patients undergoing cancer treatment with transdermal fentanyl, medical staff should pay attention to (1) avoid adding benzodiazepines easily and (2) monitor patients having predictors for fever to avoid fentanyl-related adverse events. [ABSTRACT FROM AUTHOR]

Purpose: Benzodiazepines (BZDs) are prescribed to treat psychiatric diseases. However, many guidelines recommend limiting the use of BZDs because of side effects and lack of evidence regarding long-term efficacy. Moreover, reducing BZDs' use is difficult because of dependency and the severity of withdrawal symptoms. The efficacy of cognitive behavioral therapy (CBT) for mood and anxiety disorders has been demonstrated. However, there is scant evidence that CBT has effectively reduced BZDs use, especially in Japan, where the BZDs prescription rate is high. Therefore, we sought to examine the impact of CBT on reducing BZDs use in a Japanese psychiatric setting. Patients and Methods: Participants were outpatients with mood and anxiety disorders who were prescribed BZD anxiolytics. We retrospectively reviewed changes in BZD anxiolytics prescription dosages during CBT (66 patients; mean number of CBT sessions, 14.6) from our hospital record between April 2015 and September 2017. We checked prescriptions at four time points: at first interview for judging adaptation of CBT (baseline), at the first CBT session, at the last CBT session, and 3 months after the last CBT session. Results: A total of 13 of 66 patients discontinued BZD anxiolytics during CBT, and 21 of 66 reduced their prescribed dosage by 50%. The association between discontinuation and dose-reduction and assessment period was modeled simultaneously using Bayesian hierarchical hurdle model. Results from the modeling showed a significant discontinuation at post-CBT and at 3 months post-CBT session compared to baseline (estimated median odds ratio [OR] post-CBT = 9.79 [95% CI: 4.65– 20.45]; OR at 3 months post-CBT = 11.53 [95% CI: 6.06– 22.33]). Moreover, a significant dose reduction was observed post-intervention (estimated median relative risk = 0.845 [95% CI: 0.729– 0.982]), with a median reduction of 1.7 mg (diazepam conversion) in BZD use. Conclusion: Our results suggest that CBT possibly aids in reducing and discontinuing BZD anxiolytics use for Japanese patients. [ABSTRACT FROM AUTHOR]

Introduction: Benzodiazepine anxiolytics are believed to cause urination disorders due to their anticholinergic effects. Objective: This study was carried out to investigate the potential inhibitory effects of 15 clinically available anxiolytics in Japan on acetylcholine (ACh)-induced contractions in rat detrusor smooth muscle (DSM) to predict whether these anxiolytics could induce urination disorders. Methods: -Effects of anxiolytics on contractions induced by ACh and 80 mmol/L KCl solution in rat DSM and effects of anxiolytics on specific binding of [N-methyl-3H]scopolamine ([3H]NMS) in mouse cerebral cortex were investigated. Results and Conclusions: ACh-induced contractions in rat DSM were inhibited by clotiazepam and diazepam (benzodiazepine anxiolytics) at concentrations that were clinically relevant. These contractions were also significantly inhibited by paroxetine, escitalopram (selective serotonin reuptake inhibitors -[SSRIs]), and hydroxyzine (a histamine H1 receptor antagonist), albeit at concentrations that substantially exceeded clinically achievable blood levels. At a concentration of 10–5 mol/L, paroxetine, escitalopram, and hydroxyzine inhibited 80 mmol/L high-KCl solution-induced rat DSM contractions but not clotiazepam and diazepam. Paroxetine, escitalopram, and hydroxyzine also inhibited specific binding of [3H]NMS in mouse cerebral cortex but clotiazepam and diazepam did not. In contrast to the effects of the abovementioned anxiolytics, ACh-induced contractions were not significantly affected by tofisopam, alprazolam, lorazepam, bromazepam, oxazolam, chlordiazepoxide, clonazepam, ethyl loflazepate (benzodiazepine anxiolytics), fluvoxamine (an SSRI), or tandospirone (a serotonin 5-HT1A receptor agonist). These findings suggest that most clinically used anxiolytics are not likely to result in anticholinergic-induced urination disorders within their clinically achievable blood concentration ranges. However, clotiazepam and diazepam may induce urination disorders within their clinical dose ranges via nonanticholinergic inhibition of DSM contractility. [ABSTRACT FROM AUTHOR]

Background: Psychotropic polypharmacy is common in clinical practice although supporting evidence is limited. Extrapyramidal syndromes (EPS) are adverse events associated with use of psychotropic drugs, especially antipsychotics. There are quite a few reports that suggest association between each psychotropic drug and EPS; however, the risk of EPS associated with their polypharmacy has not been fully evaluated. This study aimed at examining the influence of psychotropic polypharmacy on EPS occurrence by drug category (anxiolytics, hypnotics, antidepressants, and antipsychotics). Methods: Sequence symmetry analyses were conducted using a large-scale Japanese health insurance claims database. This method assessed asymmetry in the distribution of EPS occurrence defined as both a diagnosis of EPS and a prescription for antiparkinsonian drugs before and after initiation of psychotropic drugs. The adjusted sequence ratio (ASR) and its 95% confidence interval (CI) were calculated. Results: All categories of psychotropic drugs (anxiolytics, hypnotics, antidepressants, and antipsychotics) were significantly associated with EPS, and the tendency was stronger in polypharmacy associated with them. A clearer association between polypharmacy of BZs and EPS was indicated. In the analyses by subclasses of drugs, BZs, tetracyclic antidepressants, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, typical and atypical antipsychotics were significantly associated with EPS. The ASR of atypical antipsychotics (ASR 11.3, 95% CI 7.95-16.4) was higher than that of typical ones (ASR 2.96, 95% CI 2.06-4.33). Conclusions: The association between psychotropic polypharmacy and EPS was indicated. Further investigation is needed to confirm these findings because of the pharmacoepidemiologic nature of this study. [ABSTRACT FROM AUTHOR]

• The escalating population of older adults and increasing life expectancy have brought attention to the critical issue of managing age-related chronic conditions and their associated polypharmacy and potentially inappropriate medications (PIMs). • Despite a slight decrease in the prevalence of polypharmacy and PIMs in Taiwan between 2014 and 2019, the rates remain significantly higher than those observed in Japan. • There is a call to improve the quality of pharmacotherapy and develop systematic approaches to ensure appropriate prescriptions for older populations. Polypharmacy and potentially inappropriate medications (PIM) are widely recognized as vital quality indicators of pharmacotherapy in older adults. As Taiwan and Japan grapple with the ongoing challenges of population aging, obtaining an accurate understanding of the prevalence of these indicators is crucial for developing effective strategies to optimize pharmacotherapy in older populations. The present study aims to comprehensively evaluate the prevalence of polypharmacy and PIMs in Taiwan and two Japanese cohorts, shedding light on the similarities and differences in prescribing practices across these populations. This study employed a cross-sectional design to investigate individuals aged ≥65 years in Taiwan, as well as two Japanese cohorts: Japan Cohort 1 (dispensing data from chain pharmacies; year 2014 and 2019) and Japan Cohort 2 (claims data; year 2017 and 2019). The prescription records of these participants were collected from the national claims database in Taiwan for the years 2014, 2017, and 2019. To identify polypharmacy and hyper-polypharmacy, the study defined the use of 5–9 and 10+ drugs, respectively. Furthermore, the study identified PIMs based on the STOPP-J criteria. Notably, the study further explored the most frequently used PIMs (by categories) in Taiwan. In the year 2019, the prevalence of polypharmacy exhibited similar rates in Taiwan (35.4%) and Japan Cohort 2 (33.1%), while surpassing that of Japan Cohort 1 (25.6%). Nonetheless, the incidence of PIMs in Taiwan was the highest (66.5%), exceeding those of the two Japanese cohorts (Cohort 1: 43.7% and Cohort 2: 40.2%) in the same year. Notably, the top three categories of commonly used PIMs in Taiwan comprised non-steroidal anti-inflammatory drugs (NSAIDs), antithrombotic drugs, and benzodiazepines. This study highlights the varying prevalence of polypharmacy and PIMs between Taiwan and Japan, but emphasizes the need for collaborative efforts towards optimizing pharmacotherapy in older adults. [ABSTRACT FROM AUTHOR]

Aim: Limited information is available on the prevalence of drug–drug interactions (DDI) in residents of long‐term care facilities who often receive multiple drugs. This study aimed to evaluate the prevalence of clinically relevant cytochrome P450‐mediated potential DDI in residents of intermediate care facilities for older adults (called Roken) in Japan. Methods: A nationwide drug utilization study was carried out for Roken residents in 2015 (up to five residents per facility). Potential DDI were identified with an explicit list of drugs that can be involved in clinically relevant cytochrome P450‐mediated DDI in Japan. Logistic regression was used to evaluate the association of the number of drugs prescribed with the presence of potential DDI, adjusted for age, sex and long‐term care needs level. Results: The study included 1222 residents of 348 Roken who were prescribed two or more active drug substances. The participants who received ≥6 and ≥10 drugs represented 49% and 10% of total participants, respectively. In total, 42 two‐drug combinations involving potential DDI were identified in 33 participants (2.7%) – benzodiazepines, proton pump inhibitors, calcium channel blockers and anti‐epileptic drugs were frequently involved. The adjusted odds ratios for potential DDI were 2.84 (95% confidence interval 1.15–7.02) or 7.82 (95% confidence interval 2.96–20.70) in residents receiving six to nine drugs or ≥10 drugs, compared with those receiving two to five drugs. Conclusions: Approximately 3% of Roken residents were at risk for clinically relevant DDI. Reducing the number of drugs prescribed through medication reviews would mitigate the potential risk. Geriatr Gerontol Int 2019; 19: 513–517. [ABSTRACT FROM AUTHOR]

Aim: Pharmacological treatments are often used in treating the behavioural and psychological symptoms of dementia (BPSD) in nursing homes, despite the fact that non‐pharmacological treatments are recommended as a first‐line treatment and can provide a suitable alternative. Because the course of BPSD is known to fluctuate depending on individual symptoms over time, the frequencies of drug use and BPSD, as well as their association, should be observed over a longer period. We investigated the association between the changes in psychotropic drug (PD) use and BPSD, focusing on the number of symptoms, severity, and care burden over 1 year among long‐term care facility residents. Methods: A 1‐year follow‐up study was conducted among older residents with dementia or similar symptoms (n = 312 at baseline; n = 237 at follow‐up) by using a care staff questionnaire in 10 long‐term care facilities in Hokkaido, Japan. Medication use was determined based on prescription information. The brief questionnaire form of the Neuropsychiatric Inventory was used to assess BPSD. Results: Among residents followed up for 1 year, new users of PD—particularly anxiolytics and hypnotics—had a significantly increased number and severity of BPSD, compared with non‐PD users. Continuing PDs was also related to increased severity over the year. Among residents with any persistent BPSD for 1 year, new use of PDs—particularly anxiolytics and hypnotics—was significantly associated with an increased care burden of BPSD, compared with the non‐use of PDs. The discontinuation of PDs was significantly associated with a decreased care burden, compared with the non‐use of PDs. Conclusions: Our study suggests that PDs, particularly anxiolytics and hypnotics, may be prescribed carefully in response to exacerbation of BPSD in terms of the number of symptoms, severity, and care burden in long‐term care facilities. Continuous monitoring of PDs use and BPSD is important to effectively address BPSD. [ABSTRACT FROM AUTHOR]

Antipsychotic drugs are associated with autonomic nervous system (ANS) dysfunction in patients with schizophrenia, but the effects of individual atypical antipsychotic drugs are not clear. This study investigated how four atypical antipsychotic drugs-risperidone, olanzapine, aripiprazole, and quetiapine-differ in their effects on ANS activity. A total of 241 Japanese patients with schizophrenia participated in this study. All of the participants received an atypical antipsychotic as monotherapy: 90 participants received risperidone, 68 olanzapine, 52 aripiprazole, and 31 quetiapine. ANS activity was assessed by means of a power spectral analysis of heart rate variability. The quetiapine group showed significantly diminished sympathetic and parasympathetic activity compared with the risperidone and aripiprazole groups and significantly lower sympathetic activity relative to olanzapine. In addition, multiple regression analysis showed that the type of antipsychotic drug significantly influenced ANS activity. We suggest that, among the antipsychotics examined-risperidone, olanzapine, aripiprazole and quetiapine-quetiapine has the strongest effect on ANS activity. [ABSTRACT FROM AUTHOR]

Background: This study aimed to evaluate whether selecting mirtazapine as the first choice for current depressive episode instead of selective serotonin reuptake inhibitors (SSRIs) reduces benzodiazepine use in patients with major depressive disorder (MDD). We concurrently examined the relationship between clinical responses and serum mature brain-derived neurotrophic factor (BDNF) and its precursor, proBDNF. Methods: We conducted an open-label randomized trial in routine psychiatric practice settings. Seventy-seven MDD outpatients were randomly assigned to the mirtazapine or predetermined SSRIs groups, and investigators arbitrarily selected sertraline or paroxetine. The primary outcome was the proportion of benzodiazepine users at weeks 6, 12, and 24 between the groups. We defined patients showing a ≥50 % reduction in Hamilton depression rating scale (HDRS) scores from baseline as responders. Blood samples were collected at baseline, weeks 6, 12, and 24. Results: Sixty-five patients prescribed benzodiazepines from prescription day 1 were analyzed for the primary out- come. The percentage of benzodiazepine users was significantly lower in the mirtazapine than in the SSRIs group at weeks 6, 12, and 24 (21.4 vs. 81.8 %; 11.1 vs. 85.7 %, both P < 0.001; and 12.5 vs. 81.8 %, P = 0.0011, respectively). No between-group difference was observed in HDRS score changes. Serum proBDNF levels were significantly decreased (χ² = 8.5, df = 3, P = 0.036) and serum mature BDNF levels were temporarily significantly decreased (F = 3.5, df = 2.4, P = 0.027) in the responders of both groups at week 24. Conclusion: This study demonstrated mirtazapine as the first-choice antidepressant for current depressive episodes may reduce benzodiazepine use in patients with MDD. Trial registration UMIN000004144. Registered 2nd September 2010. The date of enrolment of the first participant to the trial was 24th August 2010. This study was retrospectively registered 9 days after the first participant was enrolled [ABSTRACT FROM AUTHOR]

Background: Respiratory symptoms, dyspnea, cough, and death rattle, are common and distressing in advanced cancer patients. Palliation of respiratory symptoms is important to improve quality of life in cancer patients and their families/caregivers. Currently published clinical guidelines for the management of these respiratory symptoms in cancer patients did not cover the topics comprehensively or were not based on formal process for the development of clinical guidelines. Methods: The Japanese Society for Palliative Medicine (JSPM) decided to develop comprehensive clinical guidelines for the management of respiratory symptoms in cancer patients following the formal guideline developing process. Results: This article provides a summary of the recommendations with the rationales, as well as a short summary of the developing process, of the JSPM respiratory symptom management guidelines. We established 26 recommendations and all recommendations are based on the best available evidences and expert consensus. Discussion: More future clinical researches and continuous guideline updates are required to improve the quality of respiratory symptom management in cancer patients. [ABSTRACT FROM AUTHOR]

Background: Although pharmacotherapy is one of the most important treatments for schizophrenia, the prominent levels of antipsychotic polypharmacy and high-dose regimens used in Japan are thought to be inconsistent with treatment regimens used in other countries. In this study, we evaluated the effect of pharmacist intervention on physician prescribing in patients with chronic schizophrenia.Methods: Participants comprised 52 inpatients at Sawa Hospital (Osaka, Japan), treated with at least one antipsychotic agent, who received pharmacist intervention for 1 year (2012). We compared the dose and the number of antipsychotics prescribed, and the rate of concurrent prescribing of anti-Parkinson, benzodiazepine and mood-stabilizer medication, pre- and post-pharmacist intervention. As an indicator of psychosis symptoms, the rate of seclusion room use was recorded. Additionally, we evaluated the impact of pharmacist intervention on medicine costs. Continuous variables were analyzed by Wilcoxon signed-rank sum tests, and categorical data were analyzed using Fisher's exact tests.Results: Compared with pre-intervention, the dose (982.6 mg pre vs. 857.6 mg post; p < 0.01) and the number of antipsychotics (2.0 pre vs. 2.0 post; p < 0.05) at 1 year were significantly lower post-intervention. The seclusion room use rate was not significantly different but tended to be lower post-intervention than pre-intervention (p < 0.1). The cost (in USD) for all medicines (10.33 pre vs. 8.76 post; p < 0.05), antipsychotics (8.04 pre vs. 6.48 post; p < 0.05), and psychotropics (9.24 pre vs. 7.68 post; p < 0.01) were significantly lower post-intervention than pre-intervention.Conclusion: Pharmacist intervention has the potential to optimize medication prescribing and reduce medication costs in patients with chronic schizophrenia. It might be suggested that clinical practitioners as well as medical hospital administrators consider the pharmacists' ability to rationalize medication therapy in schizophrenia. [ABSTRACT FROM AUTHOR]

Objective: Older people are more likely to have insomnia. One of the most prescribed hypnotics in Japan is triazolam. Although some studies showed the possibility of adverse effects of triazolam in older people, there have been few studies investigating these effects in a clinical setting. The aim of this study was to determine whether patients who used triazolam regularly had increased risks of pneumonia, trauma, and pressure ulcers.Methods: The research design was a retrospective cohort study using claim data. The subjects of the study were patients who were insured by Fukuoka Late Stage Elderly Healthcare Insurance. We defined patients who had received triazolam for 180 days or longer during fiscal year 2011 as the triazolam group, and those who had not received any hypnotics during the period as the non-triazolam group. Each patient in the triazolam group was then matched with a unique control from the non-triazolam group according to propensity score. Multivariate conditional logistic regression analyses were used to obtain adjusted odds ratios for pneumonia, trauma, and pressure ulcer in the triazolam group compared with the non-triazolam group.Results: The number of patients in the triazolam and non-triazolam groups in the unmatched cohort was 13,015 and 411,610, respectively. Adjusted odds ratios show that the risks for pneumonia, trauma, and pressure ulcer in the matched cohort increased by approximately 40%, 30%, and slightly less than 30%, respectively (all statistically significant).Conclusions: Regular use of triazolam is a risk factor for pneumonia, trauma, and pressure ulcer in older people. [ABSTRACT FROM AUTHOR]

Background: Little is known about the use of multiple prescribers for benzodiazepines, which might reflect fragmented patient care and increases the risk of hospital admission for drug dependence or poisoning. Therefore, we aimed to identify the prevalence, prescribed quantities, and trajectory of multiple prescriber episodes for benzodiazepines.Methods: We conducted a 2-year cohort study of 1178,361 recipients aged 0-74 years using a large health insurance claims database in Japan. We quantified multiple prescriber episodes for benzodiazepines occurring in ambulatory care settings in a baseline and subsequent year by (1) counting the number of unique providers within a 12-month period, (2) calculating the maximum number of unique providers within a single month, and (3) identifying consecutive overlapping prescriptions of over 30 days duration.Results: Among 58,314 patients with a benzodiazepine prescription during the baseline year, 282 (0.5%) filled prescriptions from four or more providers within a 12-month period, 439 (0.8%) filled prescriptions from three or more providers within a single month, and 757 (1.3%) filled consecutive overlapping prescriptions. The odds for multiple prescriber episodes were significantly higher among patients with multiple chronic conditions. Consecutive overlapping prescriptions had the best accuracy to detect patients with potentially questionable prescribed quantities as well as to predict those with multiple prescriber episodes in the subsequent year.Conclusions: These results highlight the need for pharmacists to increase their involvement in prescription oversight and for health insurance agencies to implement a prescription monitoring program to screen for patients with multiple prescriber episodes for benzodiazepines. [ABSTRACT FROM AUTHOR]

Introduction: Although hyperlipidemia is a well known adverse event of atypical antipsychotic (AAP) medication, there are few studies that have quantitatively compared the risks of various AAPs.Objective: Our aim was to comparatively evaluate the risk of hyperlipidemia associated with the use of AAPs approved in Japan through a consecutive epidemiological study.Methods: We conducted a sequence symmetry analysis (SSA) using health insurance claims data to analyze the following nine AAPs approved for use in Japan: risperidone, paliperidone, perospirone hydrochloride hydrate, blonanserin, clozapine, olanzapine, quetiapine fumarate, aripiprazole, and zotepine. Exposed cases were identified from drug dispensing records as those who had been administered both AAPs and antihyperlipidemic drugs. The adjusted sequence ratio (ASR) and 95 % confidence interval (CI) for each individual AAP and for all AAPs were calculated while controlling for time trends in dispensing patterns.Results: Olanzapine was significantly associated with increased hyperlipidemia occurrence (ASR 1.56; 95 % CI 1.25-1.95). The ASRs obtained for risperidone (1.01; 95 % CI 0.80-1.27), perospirone hydrochloride hydrate (0.93; 95 % CI 0.63-1.39), blonanserin (0.83; 95 % CI 0.52-1.33), quetiapine fumarate (0.93; 95 % CI 0.73-1.18), and aripiprazole (1.02; 95 % CI 0.82-1.26) were approximately 1.0. Unstable estimates (wide CIs) were obtained for paliperidone and zotepine due to the small sample sizes.Conclusions: Among the AAPs used in Japan, only olanzapine was found to have an elevated risk of hyperlipidemia. In contrast, risperidone, perospirone hydrochloride hydrate, blonanserin, quetiapine fumarate, and aripiprazole had relatively low risks. [ABSTRACT FROM AUTHOR]

A rapid and sensitive method was developed for the determination of benzodiazepines and benzodiazepine-like substances (BZDs) by matrix-assisted laser desorption ionization (MALDI)-time-of-flight (TOF)-mass spectrometry (MS). In this method, α-cyano-4-hydroxy cinnamic acid was used as the matrix to assist the ionization of BZDs. Determination of 8 BZDs (with two of their metabolites) belonging to top 12 medical drugs detected in poisonous cases in Japan, was performed using diazepam-d 5 as the internal standard. The limit of detection of zolpidem was 0.07 ng/ml with its quantification range of 0.2–20 ng/ml in blood, in the best case, and the limit of detection of flunitrazepam was 2 ng/ml with its quantification range of 6–200 ng/ml in blood, in the worst case. The spectra of zopiclone in MALDI-MS and MS/MS were different from those in electrospray ionization MS and MS/MS. Present method provides a simple and high throughput method for the screening of these BZDs using only 20 μl of blood. The developed method was successfully used for the determination of BZDs in biological fluids obtained from two victims. [ABSTRACT FROM AUTHOR]

Objectives: Various aging associated factors, such as functional decline, psychosocial problems, and cognitive dysfunction, are risk factors for somatoform disorders (SDs) in the elderly. The aim of the present study was to evaluate how cognition is correlated with the severity of late-life SDs from a neuropsychological viewpoint.Methods: Fifty-three patients over 60 years of age who had been diagnosed as having SDs were examined in this study. The severity of the somatic symptoms was assessed using the Hamilton Anxiety Rating Scales (HAMA). Cognitive functions were assessed using the Mini-Mental State Examination (MMSE), the Frontal Assessment Battery (FAB), and the Japanese version of the Neurobehavioral Cognitive Examination (J-COGNISTAT).Results: The J-COGNISTAT subtest score for attention was below the cutoff point (8 points) but was not correlated with the severity of the somatic symptoms in the patients with late-life SDs. The severity of anxiety as assessed using the HAMA was significantly correlated with the calculation scores (P < 0.005) among the J-COGNISTAT subtests, the FAB total (P < 0.05), and the FAB subtest scores (similarities and motor series) (P < 0.01). Other factors, including the benzodiazepine dosage, antidepressant dosage, the duration of illness, and the onset age, were not significantly correlated with the symptomatic severities.Conclusion: Patients with late-life SDs showed attention deficits, but no correlation was seen between the attention deficits and symptomatic severities. Attention deficits might be associated with the appearance of symptoms. Executive dysfunction and working memory might be associated with the severity of symptoms. [ABSTRACT FROM AUTHOR]

Aim The aim of this study was to clarify the clinical features of designer-drug-abusing patients through comparisons with methamphetamine-abusing patients and hypnotics/anxiolytics-abusing patients. Methods Information on 126 designer-drug-abusing patients, 138 methamphetamine-abusing patients, and 87 hypnotics/anxiolytics-abusing patients was extracted from the 2012 database of 'The Nationwide Mental Hospital Survey on Drug-related Psychiatric Disorders' and the clinical variables of designer-drug-abusing patients compared with those of the other two groups. Results Multivariate analysis indicated the following significant differences between designer-drug-abusing patients and the other two types of patients: designer-drug-abusing patients were younger, included more men, had higher education and fewer relationships with antisocial groups, and included more patients meeting ICD-10 F1 sub-classification categories of 'Harmful use' and 'Psychotic disorders' than methamphetamine-abusing patients. Compared with hypnotics/anxiolytics-abusing patients, designer-drug-abusing patients were younger, included more men and more patients meeting criteria for 'Psychotic disorders', and more frequently cited 'peer pressure', 'unable to refuse', and 'seeking stimulation' as reasons for using the drug. Conclusion The advent of designer drugs has created a new class of drug abuse, and abuse of designer drugs may carry a strong psychosis-inducing risk, exceeding that of methamphetamine. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Yokukansan, a traditional Japanese medicine (Kampo), has been reported in the treatment of behavioral and psychological symptoms of dementia (BPSD) such as aggression, anxiety and depression in patients with Alzheimer’s disease and other forms of senile dementia. Aims of the study: In the present study, we investigated the anxiolytic effects of yokukansan on anxiety-related behaviors in rats that have experienced aversive stress. Materials and methods: We used male Wistar/ST rats which received an electrical footshock as aversive stress. Yokukansan at a dose of 1.0g/kg was administered orally once a day for 14 or 16 day before behavioral tests. To evaluate the anxiolytic effects, we used the contextual fear conditioning (CFC) test and elevated plus-maze (EPM) test. And we also investigated effects of yokukansan on locomotor activity in the Open-field (OF) test and on the change in plasma corticosterone after CFC stress, in rats that had experienced footshock stress. Results: In the CFC test, rats that had experienced footshock showed significant freezing behavior on re-exposure to the box 14 day after footshock stress. Yokukansan significantly suppressed freezing behavior in the CFC test. In the EPM test on the 16th day after the CFC test, yokukansan significantly increased the time spent in open arms after footshock stress compared to control rats. However, repeated administration of yokukansan on the 14th day did not affect the decrease in locomotor activity and the increase in plasma corticosterone by re-exposure to the box 14 day after footshock stress in the OF test and determination of serum corticosterone, respectively. These anxiolytic effects by yokukansan were antagonized by WAY-100635, a selective 5-HT1A receptor antagonist, in the CFC test, but not the EPM test. Furthermore, 5-HT1A receptor agonist buspirone significantly suppressed freezing behavior in the CFC test; however, buspirone induced no change in the time spent in open arms in the EPM test. Conclusion: These findings suggested that yokukansan has anxiolytic effects on anxiety-like behaviors induced by both innate fear and memory-dependent fear. In particular, yokukansan produced anxiolytic effects via 5-HT1A receptors in memory-dependent fear induced by aversive stress. Furthermore, yokukansan could be useful as one of the therapeutic drugs for the treatment of anxiety disorders and various mental disorders that have comorbid anxiety. [Copyright &y& Elsevier]

Aim: To assess the maternal and neonatal outcomes of pregnant women with mental disorders in Japan. Material and Methods: We conducted this retrospective cohort study to examine the patients who delivered at Nagoya University Hospital (2005-2009). Thereafter, the patients without any complications other than mental disorders and with several sources of psychiatric information were included in the present series, and the maternal and neonatal outcomes between patients with or without maternal mental disorders were compared. The psychiatric outcomes and the adverse effects of psychotropic drugs were also examined. Results: A total of 1649 women delivered during this period, and 63 of them were complicated by maternal mental disorders. After the selection of patients for comparison purposes, women with mental disorders ( n = 51) had a slightly but significantly shorter gestational age (39.2 ± 0.2 vs 39.8 ± 0.1 weeks, P = 0.003) and smaller birth weight (2993.0 ± 56.7 vs 3152.4 ± 23.6 g, P = 0.010) compared with the control group ( n = 278). Intervention by psychiatrists was required for only 10 patients, and no patients required termination of pregnancy due to exacerbation of mental disorders. In schizophrenia patients who were taking atypical antipsychotics and benzodiazepine, a significant increase in maternal gestational weight gain, and a significant shorter gestational age were detected, respectively, compared with patients who were not receiving any drug treatments. Conclusion: A trend towards a lower birth weight and shorter gestational age was observed in Japanese women with well-controlled mental disorders, but the effect of well-controlled mental disorders on the perinatal outcome was minimal. [ABSTRACT FROM AUTHOR]

Objective: Benzodiazepines (BZDs) have been reported to cause negative impacts on body stability and cognitive functions, which in turn could result in lethal incidents, including falls, especially in the elderly. This fact notwithstanding, no systematic trial has evaluated the feasibility and benefits of discontinuing BZD-derivative hypnotics in this population, which was addressed in this study. Methods: In this 8-week open-label study, subjects aged ±60 living in a nursing home who received BZD as a hypnotic were recruited. The BZD dose was tapered off over 3 weeks. The following assessments were performed 12 h post-dose at baseline and at endpoint: the Clinical Stabilometric Platform (CSP), the Critical Flicker Fusion Test (CFF), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and the Leeds Sleep Evaluation Questionnaire (LSEQ). Results: Thirty subjects were enrolled (mean±SD age¼79.1±8.9 years, mean±SD flurazepam equivalent BZD dose¼19.5±10.9 mg/day). Psychiatric diagnoses (DSM-IV) of subjects were as follows: schizophrenia (n¼12), primary insomnia (n¼9), dementia (n¼7), and bipolar disorder (n¼2). In 26 completers, significant changes were found in a total length and a range of trunk motion with eyes closed. Significant improvements were also observed in the CFF and RBANS immediate memory, language, and attention index scores. Subjective worsening in sleep was not reported in those completers, assessed with the LSEQ. Conclusions: Our results suggest that discontinuation of BZD hypnotics is feasible in a majority of elderly persons and leads to an improvement in the stability of body and a recovery in cognitive functions during the daytime. [ABSTRACT FROM AUTHOR]

Purpose: We evaluated the association of nocturia with fracture and death in a large, community based sample of Japanese individuals 70 years old or older. Materials and Methods: The baseline in this population based study was determined in 2003 by an extensive health interview with each participant. In this study we followed 784 individuals with a mean ± SD age of 76.0 ± 4.6 years (range 70 to 97). Information on mortality and fracture during the study period was provided by the National Health Insurance system and details on fractures were collected from medical records. We compared the risk of bone fracture and death with or without nocturia in a multivariate Cox proportional hazard model. Results: Nocturia (2 or greater voids per night) was present in 359 of the 784 participants (45.7%). Fracture was observed in 41 cases, including 32 fall related cases. For all fractures and fall related fractures with nocturia the HR was 2.01 (95% CI 1.04–3.87) and 2.20 (95% CI 1.04–4.68, each p = 0.04). Death occurred in 53 cases. The mortality rate in individuals with nocturia was significantly higher than in those without nocturia. For mortality in patients with nocturia the age-gender adjusted HR was 1.91 (95% CI 1.07–3.43, p = 0.03). Even when further adjusted for diabetes, smoking status, history of coronary disease, renal disease and stroke, tranquilizers, hypnotics and diuretics, the positive relationship was unchanged (HR 1.98, 95% CI 1.09–3.59, p = 0.03). Conclusions: During a 5-year observation period elderly individuals with nocturia were at greater risk for fracture and death than those without nocturia. [Copyright &y& Elsevier]

Nausea and vomiting are among the most common and distressing symptoms in patients with advanced cancer. Olanzapine, an antipsychotic agent, is known to have an affinity for multiple neurotransmitter receptors. Previous studies have reported olanzapine to be efficacious in the treatment of nausea and vomiting. Although it has been administered at a number of facilities, its applicability to treat nausea and vomiting in patients with advanced cancer is poorly understood. We investigated the use of olanzapine for nausea and vomiting in patients with advanced cancer at multiple centers. This retrospective study was carried out at seven palliative care units and three facilities with palliative care teams in Japan from 2013 to 2015. The dosage of olanzapine, treatment duration, and duration from initial use until death were collected from the medical records. One hundred and eight patients met our inclusion criteria. The average dose of olanzapine was 3.6 mg (2.5 mg, n = 61; 5 mg, n = 46; 10 mg, n = 1) and average treatment duration was 18.7 days. The average duration from initial use until death was 39.0 days. There were no differences in the duration of administration until death between olanzapine doses (2.5 and 5 mg). Our results suggest that olanzapine have been used in patients with poor prognoses for nausea and vomiting in patients with advanced cancer. Conducting a prospective trial would further yield promising results. [ABSTRACT FROM AUTHOR]

Abstract: The traditional Japanese Kampo medicine Yokukansan (YKS, Yi-gan san in Chinese) has been demonstrated to improve the behavioral and psychological symptoms of dementia (BPSD), such as anxiety, hallucinations, agitation and irritability. The aim of this study was to elucidate the mechanism of the anxiolytic-like effects of YKS and Chotoko, which is an active component of YKS. Oral treatment with YKS (300 and 1000mg/kg) significantly increased the number of head-dipping behaviors in mice in the hole-board test. Head-dipping behavior in mice was also significantly increased by treatment with Chotoko (50 and 100mg/kg, p.o.). In addition, oral treatment with the water-extracted fractions from YKS (YKS-W; 250 and 500mg/kg, p.o.) and Chotoko (Chotoko-W; 10 and 30mg/kg) significantly increased the number of head-dipping behaviors in mice. On the other hand, treatment with the methanol-extracted fraction of YKS (YKS-Met; 15 and 30mg/kg, p.o.) did not affect head-dipping behavior. The total distance and number of rearing behaviors were not affected by treatment with any of these drugs. The increase in the number of head-dipping behaviors by treatment with YKS-W (500mg/kg, p.o.) and Chotoko-W (30mg/kg, p.o.) was inhibited by pretreatment with the benzodiazepine receptor antagonist flumazenil (1mg/kg, i.v.). In the elevated plus-maze test, the percentage of time spent in open arms was increased in YKS (1000mg, p.o.) treatment. Based on these results, we suggest that YKS produces an anxiolytic-like effect mediated by the benzodiazepine system. Chotoko is an effective component of YKS for producing an anxiolytic-like effect. The effective compound(s) should be contained, at least in part, in the water-soluble fraction of YKS. [Copyright &y& Elsevier]

To describe the prevalence of illicit and non-medical use of drugs, the age of first use, and their correlates in the general population of Japan, based on data collected between 2002 and 2004 as part of the World Mental Health (WMH) surveys. Participants included were a subsample ( n = 887) of the total 2,436 Japanese-speaking respondents aged ≥20 years, randomly sampled from residents in seven cities/municipalities in Japan. Face-to-face household surveys were conducted using the Japanese version of the fully structured WHO WMH Survey Initiative version of the Composite International Diagnostic Interview. Lifetime prevalence of marijuana and cocaine use, non-medical use of prescribed drugs such as tranquilizers, stimulants and analgesics, and use of other substances was 1.5, 0.3, 6.4 and 2.4%, respectively. Lifetime use of marijuana was significantly greater among men. Prescription drug abuse/misuse was significantly more common among the middle-aged (35–49 years) group and those who were married/cohabitating. The 12-month prevalence of marijuana and non-medical use was 0.3 and 1.9%, respectively. Age of first use was likely to be early adulthood. Non-medical use was significantly related to mood disorder, anxiety disorder, intermittent explosive disorder and alcohol abuse/dependence. The present study confirmed lower prevalence of drug use in Japan than in other countries, such as the United States. However, the non-medical use of psychotropic drugs seems more common in Japan. [ABSTRACT FROM AUTHOR]

Sleep disorders are among the most common symptoms in both peri- and post-menopausal women. Kamishoyosan (KSS) is a Kampo medicine prescribed for the treatment of sleep disorders in menopausal women in Japan. However, its precise mechanism of action remains unclear. In the present study, we developed a new animal model of menopausal sleep disorders by inducing social isolation stress in ovariectomized mice. Using pentobarbital-induced sleeping time as an index, we aimed to investigate the effects of KSS and involvement of the benzodiazepine receptors. Eight-week-old, female ddY mice were ovariectomized or subjected to a sham operation (control) and housed in social isolation or groups for 9 weeks. The animals were divided into four groups, group-housed sham-operated, isolated sham-operated, group-housed ovariectomized, and socially isolated ovariectomized. Pentobarbital (50 mg/kg) was administered intraperitoneally (i.p.). Sleeping time was considered the period between the loss of righting reflex and its return (up to 180 min). KSS was administered orally (p.o.) 60 min before the test. Diazepam and flumazenil were administered i.p. 30 and 45 min before the test, respectively. On the day after administration, the mice were euthanized, and their uteri were weighed. Socially isolated, ovariectomized mice had shorter sleeping times than mice in all other groups. In mice with intact ovaries, diazepam (1 mg/kg, i.p.) considerably prolonged the pentobarbital-induced sleeping time, but KSS (30–1000 mg/kg, p.o.) did not. However, KSS (100 mg/kg, p.o.) significantly prolonged the pentobarbital-induced sleeping time in socially isolated ovariectomized mice. The prolongation of sleeping time mediated by KSS was reversed by flumazenil (3 mg/kg, i.p.). KSS potentiated pentobarbital-induced sleep in socially isolated, ovariectomized mice, and the benzodiazepine receptors are possibly involved in its pharmacological mechanism. These findings suggest that KSS is beneficial for the treatment of menopausal sleep disorders. [Display omitted] • Socially isolated ovariectomized mice showed the shortest sleeping time. • Kamishoyosan did not affect the sleeping time in intact mice. • Kamishoyosan prolonged the sleeping time in socially isolated ovariectomized mice. • The prolongation of sleeping time by kamishoyosan was reversed by flumazenil. [ABSTRACT FROM AUTHOR]

Abstract: Kamishoyosan (KSS), a Kampo formula used to treat menopausal psychotic syndromes in women, consists of ten crude herbal drugs. The anxiolytic effect of KSS was investigated by the social interaction (SI) test using mice, and whether the effect of KSS was due to the stimulating and/or sedating effects was examined by the open field locomotion test. Furthermore, the present study examined the effect of individual crude drugs in KSS by the SI test to clarify its active components. Oral administration of KSS increased the total SI time in a dose-dependent manner (50–200 mg/kg), but this effect was not observed over a dose of 300 mg/kg. On the other hand, there were no significant changes observed for the open field locomotion test. These results suggest that the appearance of KSS-induced SI behavior is due to an anxiolytic effect. The unaltered results of the open field test indicated that KSS was neither a stimulant nor sedative. To identify the essential herbs in KSS, the effects of “the component herbs in KSS” and “KSS minus one component herb” using the SI test were examined. An increase in the SI time was observed for hot water extracts of Menthae herba and Gardeniae Fructus, the same as for the KSS treatment. On the other hand the effect of KSS on the SI time was reduced to the control level for KSS minus Gardeniae Fructus, KSS minus Paeoniae Radix, KSS minus Glycyrrhizae Radix and KSS minus Hoelen. Oral administration of Gardeniae Fructus-extract or its common constituent, geniposide increased the SI time in a dose-dependent manner. These results indicate that Gardeniae Fructus and geniposide play a role in the anxiolytic effect of KSS. [Copyright &y& Elsevier]

1: Ingestion of a poisonous mushroom Clitocybe acromelalga is known to cause severe tactile pain (allodynia) in the extremities for a month and acromelic acid (ACRO), a kainate analogue isolated from the mushroom, produces selective damage of interneurons of the rat lower spinal cord when injected either systemically or intrathecally. Since ACRO has two isomers, ACRO-A and ACRO-B, here we examined their acute and late effects on induction of allodynia. 2: Intrathecal administration of ACRO-A and ACRO-B provoked marked allodynia by the first stimulus 5?min after injection, which lasted over the 50-min experimental period. Dose-dependency of the acute effect of ACRO-A on induction of allodynia showed a bell-shaped pattern from 50?ag?kg-1 to 0.5?pg?kg-1 and the maximum effect was observed at 50?fg?kg-1. On the other hand, ACRO-B induced allodynia in a dose-dependent manner from 50?pg?kg-1 to 50?ng?kg-1. 3: N-methyl-D-aspartate (NMDA) receptor antagonists and Joro spider toxin, a Ca2+-permeable AMPA receptor antagonist, inhibited the allodynia induced by ACRO-A, but not by ACRO-B. However, other AMPA/kainate antagonists did not affect the allodynia induced by ACRO. 4: Whereas no neuronal damage was observed in the spinal cord in ACRO-A-treated mice, induction of allodynia by ACRO-A (50?fg?kg-1) and ACRO-B (50?ng?kg-1) was selectively lost 1 week after i.t. injection of a sublethal dose of ACRO-A (50?ng?kg-1) or ACRO-B (250?ng?kg-1). Higher doses of ACRO-A, however, could evoke allodynia dose-dependently from 50?pg?kg-1 to 500?ng?kg-1 in the ACRO-A-treated mice. The allodynia induced by ACRO-A (500?ng?kg-1) was not inhibited by Joro spider toxin or NMDA receptor antagonists. These properties of the late allodynia induced by ACRO-A were quite similar to those of the acute allodynia induced by ACRO-B. 5: ACRO-A could increase [Ca2+]i in the deeper laminae, rather than in the superficial laminae, of the spinal cord. This increase was not blocked by the AMPA-preferring antagonist GYKI52466 and Joro spider toxin. 6: Taken together, these results demonstrate the stereospecificity of ACRO for the induction of allodynia and suggest the presence of a receptor specific to ACRO.British Journal of Pharmacology (2004) 142, 679-688. doi:10.1038/sj.bjp.0705834 [ABSTRACT FROM AUTHOR]

Presents letters by physicians on various medical topics. Reactions to a paper about dichlorodiphenyltrichloroethane (DDT); Critique of the methods used in a study which suggested that endotoxin exposure early in life may protect against allergen sensitisation; Discussion of the difficulty of developing new anxiolytics, including benzodiazepine-receptor partial agonists, in Japan; Question as to the findings of a study on the management of unstable angina and myocardial infarction; More.

Presents the results of trials of serotonin 1A receptor selective agents buspirone, ipsapirone, and tandospirone in anxiety disorders in Japan. Absence of positive results in buspirone and ipsapirone; Tandospirone's clinical efficacy in anxiety; Possibility for marketing of tandospirone for treatment of anxiety disorders in Japan.

Aim The use of potentially inappropriate medications (PIMs) for older patients is a major public health problem. However, there is little information regarding PIMs in Japanese primary care settings, and the association between psychological problems and PIMs is unknown. The present study was carried out to explore the prevalence of PIMs among older patients in a primary care setting in Tokyo, and to assess the association between PIMs and depression and anxiety. Methods A cross-sectional study in a Japanese outpatient clinic providing primary care was carried out. Data were collected from January 2016 to March 2016. A total of 740 patients aged ≥65 years with chronic diseases were enrolled. Information regarding sociodemographic status, comorbidities, and prescription and psychological status was collected using a questionnaire that patients were required to complete, and by reviewing the patients' medical records. Results The Screening Tool of Older Person's Prescriptions criteria version 2 revealed PIM prescription for 32.3% of patients. Benzodiazepines, hypnotic Z-drugs and proton pump inhibitors accounted for a majority of PIMs. After adjusting for age, sex, comorbidities, estimated glomerular filtration rate and the number of medications, anxiety was identified as a predictor for PIMs. Conclusions PIMs among older patients are common in Japanese primary care settings, and prescription of benzodiazepines or hypnotic Z-drugs and proton pump inhibitors was frequent as PIMs. PIMs might be associated with anxiety; therefore, their association should be focused on and addressed to reduce PIMs. Geriatr Gerontol Int 2017; 17: 2520-2526. [ABSTRACT FROM AUTHOR]