Hypnotic prescription trends and patterns for the treatment of insomnia in Japan: analysis of a nationwide Japanese claims database.

BACKGROUND: There is limited consensus regarding the optimal treatment of insomnia. The recent introduction of orexin receptor antagonists (ORA) has increased the available treatment options. However, the prescribing patterns of hypnotics in Japan have not been comprehensively assessed. We performed analyses of a claims database to investigate the real-world use of hypnotics for treating insomnia in Japan. METHODS: Data were retrieved for outpatients (aged ≥ 20 to < 75 years old) prescribed ≥ 1 hypnotic for a diagnosis of insomnia between April 1st, 2009 and March 31st, 2020, with ≥ 12 months of continuous enrolment in the JMDC Claims Database. Patients were classified as new or long-term users of hypnotics. Long-term use was defined as prescription of the same mechanism of action (MOA) for ≥ 180 days. We analyzed the trends (2010-2019) and patterns (2018-2019) in hypnotics prescriptions. RESULTS: We analyzed data for 130,177 new and 91,215 long-term users (2010-2019). Most new users were prescribed one MOA per year (97.1%-97.9%). In 2010, GABAA-receptor agonists (benzodiazepines [BZD] or z-drugs) were prescribed to 94.0% of new users. Prescriptions for BZD declined from 54.8% of patients in 2010 to 30.5% in 2019, whereas z-drug prescriptions remained stable (~ 40%). Prescriptions for melatonin receptor agonist increased slightly (3.2% to 6.3%). Prescriptions for ORA increased over this time from 0% to 20.2%. Prescriptions for BZD alone among long-term users decreased steadily from 68.3% in 2010 to 49.7% in 2019. Prescriptions for ORA were lower among long-term users (0% in 2010, 4.3% in 2019) relative to new users. Using data from 2018-2019, multiple (≥ 2) MOAs were prescribed to a higher proportion of long-term (18.2%) than new (2.8%) users. The distribution of MOAs according to psychiatric comorbidities, segmented by age or sex, revealed higher proportions of BZD prescriptions in elderly (new and long-term users) and male (new users) patients in all comorbidity segments. CONCLUSION: Prescriptions for hypnotics among new and long-term users in Japan showed distinct patterns and trends. Further understanding of the treatment options for insomnia with accumulating evidence for the risk-benefit balance might be beneficial for physicians prescribing hypnotics in real-world settings.

Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel non-basic 1-(2H-indazole-5-yl)pyridin-2(1H)-one derivatives and mitigation of mutagenicity in Ames test.

To develop non-basic melanin-concentrating hormone receptor 1 (MCHR1) antagonists with a high probability of target selectivity and therapeutic window, we explored neutral bicyclic motifs that could replace the previously reported imidazo[1,2-a]pyridine or 1H-benzimidazole motif. The results indicated that the binding affinity of a chemically neutral 2H-indazole derivative 8a with MCHR1 (hMCHR1: IC50=35nM) was comparable to that of the imidazopyridine and benzimidazole derivatives (1 and 2, respectively) reported so far. However, 8a was positive in the Ames test using TA1537 in S9- condition. Based on a putative intercalation of 8a with DNA, we introduced a sterically-hindering cyclopropyl group on the indazole ring to decrease planarity, which led to the discovery of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-{[5-(trifluoromethyl)thiophen-3-yl]methoxy}pyridin-2(1H)-one 8l without mutagenicity in TA1537. Compound 8l exerted significant antiobesity effects in diet-induced obese F344 rats and exhibited promising safety profile.

Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel 1-(1H-benzimidazol-6-yl)pyridin-2(1H)-one derivatives and design to avoid CYP3A4 time-dependent inhibition.

Melanin-concentrating hormone (MCH) is an attractive target for antiobesity agents, and numerous drug discovery programs are dedicated to finding small-molecule MCH receptor 1 (MCHR1) antagonists. We recently reported novel pyridine-2(1H)-ones as aliphatic amine-free MCHR1 antagonists that structurally featured an imidazo[1,2-a]pyridine-based bicyclic motif. To investigate imidazopyridine variants with lower basicity and less potential to inhibit cytochrome P450 3A4 (CYP3A4), we designed pyridine-2(1H)-ones bearing various less basic bicyclic motifs. Among these, a lead compound 6a bearing a 1H-benzimidazole motif showed comparable binding affinity to MCHR1 to the corresponding imidazopyridine derivative 1. Optimization of 6a afforded a series of potent thiophene derivatives (6q-u); however, most of these were found to cause time-dependent inhibition (TDI) of CYP3A4. As bioactivation of thiophenes to form sulfoxide or epoxide species was considered to be a major cause of CYP3A4 TDI, we introduced electron withdrawing groups on the thiophene and found that a CF3 group on the ring or a Cl adjacent to the sulfur atom helped prevent CYP3A4 TDI. Consequently, 4-[(5-chlorothiophen-2-yl)methoxy]-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (6s) was identified as a potent MCHR1 antagonist without the risk of CYP3A4 TDI, which exhibited a promising safety profile including low CYP3A4 inhibition and exerted significant antiobesity effects in diet-induced obese F344 rats.

Factors Associated with Prescriptions for an Orexin Receptor Antagonist Among Japanese Patients with Insomnia: Analysis of a Nationwide Japanese Claims Database.

BACKGROUND: Few studies have examined the prescribing patterns of orexin receptor antagonists (ORAs) in the real-world clinical setting in Japan. OBJECTIVE: We sought to analyze the factors associated with ORA prescriptions for patients with insomnia in Japan. METHODS: Outpatients (aged ≥ 20 to < 75 years old) prescribed one or more hypnotic for insomnia between April 1, 2018 and March 31, 2020 with continuous enrollment for ≥ 12 months were extracted from the JMDC Claims Database. We performed multivariable logistic regression to identify factors (patient demographics and psychiatric comorbidities) associated with ORA prescription in new or non-new users of hypnotics (patients without or with hypnotics prescription history, respectively). RESULTS: Of 58,907 new users, 11,589 (19.7%) were prescribed ORA at the index date. Male sex (odds ratio [OR] 1.17, 95% confidence interval [CI] 1.12-1.22) and presence of bipolar disorders (OR 1.36, 95% CI 1.20-1.55) were associated with greater odds of ORA prescription. Among 88,611 non-new users, 15,504 (17.5%) were prescribed ORA at the index date. Younger age and several psychiatric comorbidities, such as neurocognitive disorders (OR 1.64, 95% CI 1.15-2.35), substance use disorders (OR 1.19, 95% CI 1.05-1.35), bipolar disorders (OR 1.14, 95% CI 1.07-1.22), schizophrenia spectrum disorders (OR 1.07, 95% CI 1.01-1.14), and anxiety disorders (OR 1.05, 95% CI 1.00-1.10), were associated with greater odds of ORA prescription. CONCLUSION: This is the first study to determine the factors associated with ORA prescriptions in Japan. Our findings could help guide appropriate insomnia treatment using ORAs.

Incremental medical cost of delirium in elderly patients with cognitive impairment: analysis of a nationwide administrative database in Japan.

OBJECTIVES: Delirium is a neuropsychiatric disorder that commonly occurs in elderly patients with cognitive impairment. The economic burden of delirium in Japan has not been well characterised. In this study, we assessed incremental medical costs of delirium in hospitalised elderly Japanese patients with cognitive impairment. DESIGN: Retrospective, cross-sectional, observational study. SETTING: Administrative data collected from acute care hospitals in Japan between April 2012 and September 2020. PARTICIPANTS: Hospitalised patients ≥65 years old with cognitive impairment were categorised into groups-with and without delirium. Delirium was identified using a delirium identification algorithm based on the International Classification of Diseases 10th Revision codes or antipsychotic prescriptions. OUTCOME MEASURES: Total medical costs during hospitalisation were compared between the groups using a generalised linear model. RESULTS: The study identified 297 600 hospitalised patients ≥65 years of age with cognitive impairment: 39 836 had delirium and 257 764 did not. Patient characteristics such as age, sex, inpatient department and comorbidities were similar between groups. Mean (SD) unadjusted total medical cost during hospitalisation was 979 907.7 (871 366.4) yen for patients with delirium and 816 137.0 (794 745.9) yen for patients without delirium. Adjusted total medical cost was significantly greater for patients with delirium compared with those without delirium (cost ratio=1.09, 95% CI: 1.09 to 1.10; p<0.001). Subgroup analyses revealed significantly higher total medical costs for patients with delirium compared with those without delirium in most subgroups except patients with hemiplegia or paraplegia. CONCLUSIONS: Medical costs during hospitalisation were significantly higher for patients with delirium compared with those without delirium in elderly Japanese patients with cognitive impairment, regardless of patient subgroups such as age, sex, intensive care unit admission and most comorbidities. These findings suggest that delirium prevention strategies are critical to reducing the economic burden as well as psychological/physiological burden in cognitively impaired elderly patients in Japan.

Demographic and clinical characteristics of patients with delirium: analysis of a nationwide Japanese medical database.

OBJECTIVES: Delirium commonly occurs during hospitalisation and is associated with increased mortality, especially in elderly patients. This study aimed to determine the demographic and clinical characteristics of patients with delirium in the Japanese real-world clinical setting using a nationwide database comprising claims and discharge abstract data. DESIGN: This was an observational, cross-sectional, retrospective study in hospitalised patients with an incident delirium identified by a diagnosis based on International Classification of Diseases, 10th Revision codes or initiating antipsychotics recommended for delirium treatment in Japan during their hospitalisation. SETTING: Patients from the Medical Data Vision database including more than 400 acute care hospitals in Japan were evaluated from admission to discharge. PARTICIPANTS: Of the 32 910 227 patients who were included in the database between April 2012 and September 2020, a total of 145 219 patients met the criteria for delirium. PRIMARY AND SECONDARY OUTCOME MEASURES: Demographic and baseline characteristics, comorbidities, clinical profiles and pharmacological treatments were evaluated in patients with delirium. RESULTS: The mean (SD) patient age was 76.5 (13.8) years. More than half of the patients (n=82 159; 56.6%) were male. The most frequent comorbidities were circulatory system diseases, observed in 81 954 (56.4%) patients. Potentially inappropriate medications (PIMs) with risk of delirium including benzodiazepines and opioids were prescribed to 76 798 (52.9%) patients. Approximately three-fourths of these patients (56 949; 74.2%) were prescribed ≥4 PIMs. The most prescribed treatment for delirium was injectable haloperidol (n=82 490; 56.8%). Mean (SD) length of hospitalisation was 16.0 (12.1) days. CONCLUSIONS: The study results provide comprehensive details of the clinical characteristics of patients with delirium and treatment patterns with antipsychotics in the Japanese acute care setting. In this patient population, the prescription rate of injectable haloperidol and PIMs was high, suggesting the need for improved understanding among healthcare providers about the appropriate management of delirium, which may benefit patients.

Identification of MK-1925: a selective, orally active and brain-penetrable opioid receptor-like 1 (ORL1) antagonist.

Structure-activity relationship studies directed toward improving the metabolic stability of compound 1 resulted in the identification of 3-[5-(3,5-difluorophenyl)-3-({[(1S,3R)-3-fluorocyclopentyl]amino}methyl)-4-methyl-1H-pyrazol-1-yl]propanenitrile 39 (MK-1925) as a selective, orally available and brain-penetrable opioid receptor-like 1 (ORL1) antagonist. The compound also showed in vivo efficacy after oral dosing. Therefore, compound 39 was selected to undergo further studies as a clinical candidate.

Association between sleep disturbance in Alzheimer's disease patients and burden on and health status of their caregivers.

BACKGROUND: Sleep disturbance in Alzheimer's disease (AD) patients may have a negative impact not only on patients themselves but also on the physical and mental health of their caregivers. Detailed analysis of these issues is lacking. OBJECTIVE: This study investigated the association between sleep disturbance in AD patients and the burden on, and health status of, their caregivers in Japan. METHODS: We conducted a cross-sectional web-based questionnaire survey among caregivers of AD patients with insomnia symptoms in Japan. Demographic data and Sleep Disorders Inventory (SDI) scores for patients, caregiver burden (Burden Index of Caregivers-11 [BIC-11]) and health status, including Pittsburgh Sleep Quality Index, Patient Health Questionnaire-9, and 12-Item Short Form Health Survey v2, were collected. Multivariate analysis was used to examine the association between the burden and health status of caregivers and sleep disturbance in their care recipients with AD. RESULTS: A total of 496 caregivers of AD patients with insomnia symptoms were examined in this study. We found that the BIC-11 total score increased as the SDI score increased, indicating a significant positive association, even after adjusting for confounding factors. We also found an association between sleep disturbances of AD patients and health of caregivers (sleep quality, depression, and physical/mental quality of life). CONCLUSION: This study demonstrated that sleep disturbance in AD patients was associated with an increased burden and poorer health status of caregivers. Our findings highlight the importance of sleep management in AD patients.

Corticotropin-releasing factor modulates maternal separation-induced ultrasonic vocalization in rat pups via activation of CRF1 receptor.

An infant animal isolated from its mother emits vocalizations spanning from the audible to the ultrasonic. These vocalizations are believed to represent distress signals from the pup. However, the neurobiological basis for vocalizations elicited by isolation has not been well characterized under different environmental conditions. The present study was designed to clarify the role of the corticotropin-releasing factor (CRF) system in vocalizations elicited by isolating a rat pup at ambient temperatures of 37 degrees C (temperature of the nest in which the mother and littermates are present) and 24 degrees C (room temperature). Sprague-Dawley rat pups at 7 days old were isolated from their dam, then the number of vocalizations was measured for 5 min. The number of vocalizations increased when ambient temperature was changed from 37 degrees C to 24 degrees C. Systemic administration of CRF (3 or 10 mg/kg) increased the number of vocalizations at 37 degrees C in a dose-dependent manner. CRF-induced increases in the number of vocalizations at 3 mg/kg were completely blocked by a selective CRF1 receptor antagonist, NBI27914 (3 mg/kg), but not by a selective CRF2 receptor antagonist, K41498 (3 mg/kg). NBI27914 (30 mg/kg), but not K41498 (3 mg/kg), suppressed the increased number of vocalizations at 24 degrees C. These results demonstrate involvement of the CRF-CRF1 receptor regulatory system on the modulation of ultrasonic vocalizations by rat pups separated from their dam.

Antipsychotic property of a muscarinic receptor agonist in animal models for schizophrenia.

Pharmacological evidence has implicated cholinergic dysfunction in the manifestation of psychotic symptoms. The purpose of the present study was to clarify the roles of muscarinic and nicotinic receptors in several animal models of schizophrenia. A muscarinic receptor agonist, oxotremorine (0.03-0.3 mg/kg), reversed hyperlocomotion in mice and disruption of prepulse inhibition (PPI) caused by methamphetamine in rats, similar to a typical antipsychotic drug, haloperidol (0.1-0.3 mg/kg). In addition to modulating hyperdopaminergic function, oxotremorine as well as clozapine (3-10 mg/kg) reversed the disruption of PPI caused by ketamine, an N-methyl-D-aspartate antagonist in rats, which mimics the clinical symptoms of schizophrenia. One of the spontaneous mouse models, DBA/2J exhibited lower PPI than C57BL/6J. Oxotremorine (0.03-0.06 mg/kg) increased PPI in DBA/2J but not C57BL/6J. On the other hand, a nicotinic receptor agonist, nicotine (0.06-0.6 mg/kg), exhibited no effects on the four animal models of symptoms of schizophrenia we tested. These findings suggest that muscarinic receptors play important roles in animal models to examine sensory gating which is known to be disrupted in schizophrenic patients, and hence activation of muscarinic receptors may provide an alternative approach for the treatment of psychotic symptoms in addition to classical antipsychotics.