Altered Functional Connectivity during Mild Transient Respiratory Impairment Induced by a Resistive Load.

Background: Previous neuroimaging studies have identified brain regions related to respiratory motor control and perception. However, little is known about the resting-state functional connectivity (FC) associated with respiratory impairment. We aimed to determine the FC involved in mild respiratory impairment without altering transcutaneous oxygen saturation. Methods: We obtained resting-state functional magnetic resonance imaging data from 36 healthy volunteers during normal respiration and mild respiratory impairment induced by resistive load (effort breathing). ROI-to-ROI and seed-to-voxel analyses were performed using Statistical Parametric Mapping 12 and the CONN toolbox. Results: Compared to normal respiration, effort breathing activated FCs within and between the sensory perceptual area (postcentral gyrus, anterior insular cortex (AInsula), and anterior cingulate cortex) and visual cortex (the visual occipital, occipital pole (OP), and occipital fusiform gyrus). Graph theoretical analysis showed strong centrality in the visual cortex. A significant positive correlation was observed between the dyspnoea score (modified Borg scale) and FC between the left AInsula and right OP. Conclusions: These results suggested that the FCs within the respiratory sensory area via the network hub may be neural mechanisms underlying effort breathing and modified Borg scale scores. These findings may provide new insights into the visual networks that contribute to mild respiratory impairments.

Efficacy and Safety of Transitioning to Lemborexant from Z-drug, Suvorexant, and Ramelteon in Japanese Insomnia Patients: An Open-label, Multicenter Study.

INTRODUCTION: For patients with chronic insomnia, conventional therapy may not always provide satisfactory efficacy and safety. Thus, switching to an alternative therapeutic agent can be explored. However, there is a lack of prospective studies evaluating the effectiveness of such changes. This prospective, non-randomized, open-label, interventional, multicenter study assessed whether Japanese patients with chronic insomnia dissatisfied with treatment could transition directly to lemborexant (LEM) from four cohorts-non-benzodiazepine sedative-hypnotic (zolpidem, zopiclone, or eszopiclone) monotherapy, dual orexin receptor antagonist (suvorexant) monotherapy, suvorexant + benzodiazepine receptor agonists (BZRAs), and melatonin receptor agonist (ramelteon) combination. We evaluated whether transitioning to LEM improved patient satisfaction based on efficacy and safety. METHODS: The primary endpoint was the proportion of successful transitions to LEM at 2 weeks (titration phase end), defined as the proportion of patients on LEM by the end of the 2-week titration phase who were willing to continue on LEM during the maintenance phase (Weeks 2-14). Patient satisfaction and safety (the incidence of treatment-emergent adverse events [TEAEs]) were assessed at 14 weeks (end of titration and maintenance phases). RESULTS: Among the 90 patients enrolled, 95.6% (95% confidence interval: 89.0-98.8%) successfully transitioned to LEM at 2 weeks. The proportions of patients who successfully continued on LEM were 97.8% and 82.2% at the end of the titration and maintenance phases (Weeks 2 and 14), respectively. The overall incidence of TEAEs was 47.8%; no serious TEAEs occurred. In all cohorts, the proportions of patients with positive responses were higher than the proportions with negative responses on the three scales of the Patient Global Impression-Insomnia version. During the maintenance phase, Insomnia Severity Index scores generally improved at Weeks 2, 6, and 14 of LEM transition. CONCLUSIONS: Direct transition to LEM may be a valid treatment option for patients with insomnia who are dissatisfied with current treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04742699.

A randomized, double-blind, placebo-controlled, crossover study of respiratory safety of lemborexant in moderate to severe obstructive sleep apnea.

STUDY OBJECTIVES: To evaluate the respiratory safety of lemborexant among adults and older adults with moderate to severe obstructive sleep apnea (OSA). METHODS: E2006-A001-113 (Study 113; NCT04647383) was a double-blind, two-period crossover, placebo-controlled study in adults (ages ≥ 45 to ≤ 90 years, n = 33) with moderate (apnea-hypopnea index [AHI] score ≥ 15 to < 30 events/h, n = 13) or severe (AHI ≥ 30 events/h, n = 20) OSA. Participants were randomized to lemborexant 10 mg (LEM10) or placebo (PBO) for two treatment periods of 8 nights with a ≥ 14-day washout period. AHI and peripheral oxygen saturation were evaluated after treatment on Day 1 (after a single dose) and Day 8 (after multiple doses). RESULTS: No significant differences in AHI were observed after single and multiple doses of LEM10 compared with PBO in participants with moderate to severe OSA (least-squares mean: single-dose LEM10, 41.7; PBO, 44.8; multiple-dose LEM10, 44.9; PBO, 45.7). In addition, there were no significant differences between treatments in peripheral oxygen saturation (least-squares mean: single-dose LEM10, 93.0; PBO, 93.1; multiple-dose LEM10, 93.1; PBO, 93.4). Further, there were no significant differences between treatments in percentage of total sleep time with peripheral oxygen saturation < 90%, < 85%, or < 80%. No significant differences were observed between treatments when AHI and peripheral oxygen saturation outcomes were analyzed by OSA severity. Altogether, 6/33 (18.2%) participants receiving LEM10, vs 3/33 (9.1%) PBO, reported treatment-emergent adverse events, mostly mild in severity. CONCLUSIONS: LEM10 demonstrated respiratory safety and was well tolerated with single-dose and multiple-dose administration in participants with moderate to severe OSA. This suggests that LEM may be a treatment option for patients with OSA and comorbid insomnia. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: A Study to Evaluate the Respiratory Safety of Lemborexant in Adult and Elderly Participants With Moderate to Severe Obstructive Sleep Apnea and in Adult and Elderly Participants With Moderate to Severe Chronic Obstructive Pulmonary Disease; URL: https://clinicaltrials.gov/ct2/show/NCT04647383; Identifier: NCT04647383. CITATION: Cheng JY, Lorch D, Lowe AD, et al. A randomized, double-blind, placebo-controlled, crossover study of respiratory safety of lemborexant in moderate to severe obstructive sleep apnea. J Clin Sleep Med. 2024;20(1):57-65.

Trends in the multiple prescriptions of hypnotic drugs in a university outpatient in Japan.

AIMS: In Japan, the daily dosage of hypnotic drugs for insomnia treatment is increasing year by year, and over-dependence on treatment with hypnotic drugs is a major problem. This study aimed to examine the factors related to the elimination of prescriptions of three or more hypnotic drugs within 1 year in our clinic. METHODS: We conducted two surveys. Survey ① assessed the frequency of prescriptions of three or more hypnotic drugs by retrospectively reviewing the medical records of all patients who visited general and psychiatric outpatient clinics from January 2013 to March 2019. Survey ② assessed changes in prescriptions of hypnotic and psychotropic drugs within the subsequent year by retrospectively reviewing the medical records of all patients prescribed three or more hypnotic drugs who visited neuropsychiatric outpatient clinics multiple times between April 2013 and March 2019. RESULTS: The frequency of prescribing three or more hypnotic drugs was six to nine times higher in psychiatry than in other departments. Flunitrazepam and brotizolam were the most common drugs prescribed and had the second lowest discontinuation rate after zolpidem. Conversely, eszopiclone, zopiclone, and suvorexant had the highest discontinuation rates. The success factors for drug reduction were age (odds ratio [OR]: 0.97, p < 0.0037), trazodone addition (OR: 12.86, p < 0.0194) and number of years of psychiatric experience. CONCLUSIONS: The characteristics and success factors in relation to drug reduction in patients with multiple prescriptions of hypnotic drugs identified in this study may contribute to solving the problem of multiple prescriptions of hypnotic drugs.

Pharmacokinetics, pharmacodynamics and safety profile of the dual orexin receptor antagonist vornorexant/TS-142 in healthy Japanese participants following single/multiple dosing: Randomized, double-blind, placebo-controlled phase-1 studies.

The pharmacokinetics, pharmacodynamics and safety profile of vornorexant were investigated in healthy Japanese participants in three double-blind studies: a single ascending dose of 1-30 mg (Study 101; n = 6) and multiple ascending doses of 10-30 mg (Study 102; n = 6). Study 202 consisted of two steps: an open-label, 20 mg repeated-dose in non-elderly individuals (Step 1; n = 12) and a double-blind, 20 mg repeated-dose in elderly individuals (Step 2; n = 8/3 for vornorexant/placebo). Vornorexant was rapidly absorbed and eliminated under fasting conditions, with a time to maximum plasma concentration of 0.500-3.00 h (range) and elimination half-life of 1.32-3.25 h. The area under the plasma concentration-time curve (AUC) of vornorexant increased proportionally with dose increments. Sleepiness-related pharmacodynamic outcome changes (Karolinska sleepiness scale, digit symbol substitution test and psychomotor vigilance task) were generally increased with dose increments at 1 and 4 h post-dose, whereas no consistent dose-related changes were detected the next morning. Food intake did not affect the maximum observed plasma concentration of vornorexant but increased the AUC0-inf . Exposure in elderly individuals was generally comparable to that in non-elderly individuals. Altogether, vornorexant may have a favourable profile for insomnia treatment, including rapid onset of action and minimal next-day residual effects.

A knowledge-based simple education program for patients with epilepsy in Japan: Effects sustained after the program implementation.

PURPOSE: To investigate the effects of an original education program on patients with epilepsy (PWE). The effects on knowledge about epilepsy, attitude to epilepsy, depression scales, and quality of life were investigated. METHOD: Thirty-five PWE participated in a lecture-style educational program using an original knowledge-oriented textbook. All patients were administered a total of four rating scales: the Knowledge about Epilepsy Scale (KES), the Attitude toward Epilepsy Scale (AES), and the Japanese version of the Quality of Life in Epilepsy Inventory (QOLIE-31-P), the Beck Depression Inventory (BDI). The KES and AES of patients (pKES and pAES) were compared to those of medical students (St) and residents (Rd). RESULTS: After education, pKES improved and showed significant differences among pre-and post-education and six months later. Before education, pKES was inferior to St and Rd. However, after education, pKES changed and became superior to St and Rd. Six months later, the advantage was lost, but not significantly. PAES also improved after education, with significant differences before, after, and six months later after education. PAES was statistically inferior to St and Rd before education, but the difference disappeared after education, and the effect persisted after six months. The non-depressed (BDI < 20) and depressed groups (BDI â‰§ 20) improved in the KES after education. About the AES, the non-depressive group has a statistical tendency, but not the depressive group. At six months, the depressed group's AES is significantly lower than the non-depressed group. CONCLUSION: While correct knowledge about epilepsy can improve attitudes and perceptions of epilepsy in PWE, special measures are needed for PWE with depression.

Fatigue on Waking, Insomnia, and Workplace Relationship Problems May Help to Detect Suicidal Ideation among New Middle-Aged Primary Care Patients: A 6-Month Prospective Study in Japan.

Signs of suicidal depression often go undetected in primary care settings. This study explored predictive factors for depression with suicidal ideation (DSI) among middle-aged primary care patients at 6 months after an initial clinic visit. New patients aged 35-64 years were recruited from internal medicine clinics in Japan. Baseline characteristics were elicited using self-administered and physician questionnaires. DSI was evaluated using the Zung Self-Rating Depression Scale and the Profile of Mood States at enrollment and 6 months later. Multiple logistic regression analysis was conducted to calculate adjusted odds ratios for DSI. Sensitivity, specificity, and likelihood ratios for associated factors were calculated. Among 387 patients, 13 (3.4%) were assessed as having DSI at 6 months. Adjusted for sex, age, and related factors, significant odds ratios for DSI were observed for "fatigue on waking ≥1/month" (7.90, 95% confidence intervals: 1.06-58.7), "fatigue on waking ≥1/week" (6.79, 1.02-45.1), "poor sleep status" (8.19, 1.05-63.8), and "relationship problems in the workplace" (4.24, 1.00-17.9). Fatigue on waking, sleep status, and workplace relationship problems may help predict DSI in primary care. Because the sample size in this investigation was small, further studies with larger samples are needed to confirm our findings.

Sleep Structure in Untreated Adults With ADHD: A Retrospective Study.

OBJECTIVE: Polysomnographic findings in neurodevelopmental disorders have been reported, but previous studies have had several limitations. The purpose of this study was to characterize sleep structure in untreated adults diagnosed with ADHD, excluding ADHD-related sleep disorders as determined by polysomnography and multiple sleep latency testing. METHODS: This study included 55 patients aged 18 years or older who visited the Kurume University Hospital Sleep Clinic between April 2015 and March 2020. The diagnosis of ADHD was determined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (ADHD group, n = 28; non-ADHD, n = 27). RESULTS: The ADHD group had significantly longer slow wave sleep (SWS) duration than the non-ADHD group (ADHD: 68.3 ± 31.0 minutes vs. non-ADHD: 43.4 ± 36.6 minutes; p = .0127). CONCLUSIONS: The increased SWS volume observed in drug-naïve adult patients with ADHD may be related to the pathogenesis of this disorder.

Effect of smartphone-based cognitive behavioral therapy app on insomnia: a randomized, double-blind study.

STUDY OBJECTIVES: This study assessed the effects and safety of the smartphone-based cognitive behavioral therapy for insomnia (CBT-I) app compared with the sham app. METHODS: In this multicenter, double-blind, and parallel-group study, 175 patients with insomnia were randomized to a smartphone-based CBT-I app (Active, n = 87) or a sham app (Sham, n = 88) group. The primary endpoint was the change in Athens Insomnia Score (AIS) from baseline after 8 weeks of treatment. RESULTS: The change in AIS (mean ± standard deviation) from baseline, assessed using a modified-intent-to-treat analysis, was -6.7 ± 4.4 in the Active group and -3.3 ± 4.0 in the Sham group. The difference in the mean change between the groups was -3.4 (p < .001), indicating a greater change in the Active group. The change in CGI-I from the baseline was 1.3 ± 0.8 in the Active group and 0.7 ± 0.8 in the Sham group (p < .001). The proportion of patients with an AIS less than 6 was 37.9% in the Active group and 10.2% in the Sham group (p < .001). As for the safety assessment, no adverse reactions or device failures were detected in the Active group. CONCLUSIONS: This study demonstrated the effectiveness of a smartphone-based CBT-I system for treating insomnia. CLINICAL TRIAL REGISTRATION: ID: jRCT2032210071; trial name: Sham (software)-controlled, multicenter, dynamic allocation, double-blinded study of non-medication therapy with a software Yukumi in patients with insomnia disorders (verification study); URL: https://jrct.niph.go.jp/en-latest-detail/jRCT2032210071.

Sleep disturbance has the largest impact on children's behavior and emotions.

Objective: Children's behavior and emotions are affected by sleep disturbances, the parent-child relationship, media viewing time, and the social status of parents and caregivers. We conducted a questionnaire survey to identify the factors that have the greatest impact on children's behavior and emotions and how these factors relate to each other. Methods: A parental questionnaire survey was performed at a public elementary school. The questionnaire comprised questions on the family environment (e.g., family structure, media and game exposure, after-school lessons, and caregiver's work schedule) and physical information, the Strengths and Difficulties Questionnaire (SDQ), the Children's Sleep Habits Questionnaire (CSHQ), and the Pittsburgh Sleep Quality Index (PSQI) for parents' sleep condition. A path diagram was drawn to hypothesize the complex interrelationships among factors, and structural equation modeling was used to estimate the path coefficients. Result: We identified several factors that significantly affected the SDQ score. The CSHQ total score had the largest impact, followed by after-school lessons, single-mother families, and children's sex. In addition, several indirect pathways that led to the CSHQ score (i.e., a pathway from time spent watching television to CSHQ score via children's bedtime and a pathway from single-mother family to CSHQ score via PSQI total score) significantly affected the SDQ score. Conclusion: Children's sleep habits that were influenced by several environmental factors had the greatest impact on children's behavior and emotions, which suggested that children's behavioral problems can be improved by interventions focused on sleep habits, such as sleep hygiene instructions.

Development of a Subclinical Dissociation Scale by Comparing Healthy Controls with Patients.

We developed a Subclinical Dissociation Scale by comparing healthy controls with patients with post-traumatic stress disorder (PTSD) or dissociative disorder. The Dissociative Experiences Scale, Subclinical Dissociation Scale, and General Health Questionnaire were completed by 441 healthy Japanese adolescents (mean age, 19.9 years) and 23 psychiatric inpatients (mean age, 28.8 years) diagnosed with PTSD or dissociative disorder. The initial Subclinical Dissociation Scale included 52 items grouped into five factors: F1, absentmindedness (14 items); F2, immersion or preoccupation (15 items); F3, temporary amnesia (10 items); F4, feelings of unreality (eight items); and F5, feelings of alienation (five items). Factor and correlation analyses revealed the validity and reliability of the Subclinical Dissociation Scale. The final version of the scale that comprised three factors (F1, F2, and F4) and 37 items underwent logistic regression and receiver operating characteristic (ROC) curve analyses to compare healthy controls with patients with PTSD or dissociative disorder. The ROC curve analysis using the Youden Index indicated a cut-off score of 18 for the borderline or abnormal range, which was calculated using the following formula: "(F1) + (F4) - (F2)." This study provides evidence of the partial test-retest reliability and con current validity of the Subclinical Dissociation Scale.

Balance dysfunction the most significant cause of in-hospital falls in patients taking hypnotic drugs: A retrospective study.

PURPOSE: Preventing falls in patients is one of the most important concerns in acute hospitals. Balance disorder and hypnotic drugs lead to falls. The Standing Test for Imbalance and Disequilibrium (SIDE) is developed for the evaluation of static standing balance ability. There have been no reports of a comprehensive assessment of falls risk including hypnotic drugs and SIDE. The purpose of this study was to investigate the fall rate of each patient who took the hypnotic drug and the factor associated with falls. METHODS: Fall rates for each hypnotic drug were calculated as follows (number of patients who fell/number of patients prescribed hypnotic drug x 100). We investigated the hypnotic drugs as follows; benzodiazepine drugs, Z-drugs, melatonin receptor agonists, and orexin receptor antagonists. Hypnotic drug fall rate was analyzed using Pearson's chi-square test. Decision tree analysis is the method we used to discover the most influential factors associated with falls. RESULTS: This study included 2840 patients taking hypnotic drugs. Accidents involving falls were reported for 211 of inpatients taking hypnotic drugs. Z-drug recipients had the lowest fall rate among the hypnotic drugs. We analyzed to identify independent factors for falls, a decision tree algorithm was created using two divergence variables. The SIDE levels indicating balance disorder were the initial divergence variable. The rate of falls in patients at SIDE level ≦ 2a was 14.7%. On the other hand, the rate of falls in patients at SIDE level ≧ 2b was 2.9%. Gender was the variable for the second classification. In this analysis, drugs weren't identified as divergence variables for falls. CONCLUSION: The SIDE balance assessment was the initial divergence variable by decision tree analysis. In order to prevent falls, it seems important not only to select appropriate hypnotic drugs but also to assess patients for balance and implement preventive measures.

Impact of Selected Initial Titration Schedules on Safety and Long-Term Effectiveness of Lamotrigine for the Treatment of Mood Disorders.

PURPOSE: Lamotrigine (LTG) is used for treatment of mood disorders, but it is associated with the risk of rash occurrence in the initial administration phase. Although slow titration reduces this risk, its effectiveness in the treatment of mood disorders has not been verified. The effects of titration method on the safety and effectiveness of LTG for the treatment of mood disorders were examined in this study. METHODS: This retrospective cohort study included 312 patients with mood disorders who underwent initiation of LTG therapy. Data regarding baseline demographics, titration schedules, concomitant medications, and time to and cause of discontinuation of LTG were collected. A multivariate analysis was used to evaluate the effects of the titration schedules. The 12-month effectiveness was also evaluated. RESULTS: The 12-month discontinuation rate of LTG was 16.7%. The most frequent cause of discontinuation was development of a rash (47.7%, n = 312). Fast titration (adjusted odds ratio, 8.15) significantly increased the risk of rash development, and slow titration (adjusted odds ratio, 0.29) significantly decreased this risk. The time to all-cause discontinuation was not significantly different between the slow and standard titration groups (n = 303). After 12 months of treatment, the condition of 46.7% patients were rated much or very much improved using CGI-C. CONCLUSIONS: Although slow titration of LTG reduces the occurrence of a rash, it is not more effective than standard titration in the long term. Optimizing the initial LTG titration schedule for patients with mood disorders is challenging.

A rare genetic variant in the cleavage site of prepro-orexin is associated with idiopathic hypersomnia.

Idiopathic hypersomnia (IH) is a rare, heterogeneous sleep disorder characterized by excessive daytime sleepiness. In contrast to narcolepsy type 1, which is a well-defined type of central disorders of hypersomnolence, the etiology of IH is poorly understood. No susceptibility loci associated with IH have been clearly identified, despite the tendency for familial aggregation of IH. We performed a variation screening of the prepro-orexin/hypocretin and orexin receptors genes and an association study for IH in a Japanese population, with replication (598 patients and 9826 controls). We identified a rare missense variant (g.42184347T>C; p.Lys68Arg; rs537376938) in the cleavage site of prepro-orexin that was associated with IH (minor allele frequency of 1.67% in cases versus 0.32% in controls, P = 2.7 × 10-8, odds ratio = 5.36). Two forms of orexin (orexin-A and -B) are generated from cleavage of one precursor peptide, prepro-orexin. The difference in cleavage efficiency between wild-type (Gly-Lys-Arg; GKR) and mutant (Gly-Arg-Arg; GRR) peptides was examined by assays using proprotein convertase subtilisin/kexin (PCSK) type 1 and PCSK type 2. In both PCSK1 and PCSK2 assays, the cleavage efficiency of the mutant peptide was lower than that of the wild-type peptide. We also confirmed that the prepro-orexin peptides themselves transmitted less signaling through orexin receptors than mature orexin-A and orexin-B peptides. These results indicate that a subgroup of IH is associated with decreased orexin signaling, which is believed to be a hallmark of narcolepsy type 1.

Effects of TS-142, a novel dual orexin receptor antagonist, on sleep in patients with insomnia: a randomized, double-blind, placebo-controlled phase 2 study.

RATIONALE: Novel compound with potent antagonistic activity against orexin receptors may be new treatment option for patients with insomnia. OBJECTIVE: The aim was to investigate the efficacy and safety of single oral doses of the dual orexin receptor antagonist TS-142 in patients with insomnia. METHODS: This multicenter, double-blind, crossover randomized clinical trial included non-elderly patients with insomnia. Patients were randomized to receive single doses of placebo and TS-142 at doses of 5, 10, and 30 mg in one of four different sequences, with a 7-day washout period between treatments. Primary efficacy endpoints were latency to persistent sleep (LPS) and wake time after sleep onset (WASO) measured by polysomnography. RESULTS: Twenty-four patients were included (mean age 50.3 ± 10.5 years; mean duration of insomnia 5.71 ± 8.68 years). Least-squares mean differences (95% confidence interval) from placebo in LPS with 5, 10, and 30 mg TS-142 were - 42.38 (- 60.13, - 24.63), - 42.10 (- 60.02, - 24.17), and - 44.68 (- 62.41, - 26.95) minutes, respectively (all p < 0.001). Least-squares mean differences (95% confidence interval) from placebo in WASO with 5, 10, and 30 mg TS-142 were - 27.52 (- 46.90, - 8.14), - 35.44 (- 55.02, - 15.87), and - 54.69 (- 74.16, - 35.23) minutes, respectively (all p < 0.01). Self-reported aspects of sleep initiation and sleep quality, determined using the Leeds Sleep Evaluation Questionnaire (LSEQ), were also improved with TS-142 administration versus placebo. TS-142 was well tolerated; all adverse events were mild or moderate and none were serious. CONCLUSION: Single-dose TS-142 was well tolerated and had clinically relevant effects on objective and subjective sleep parameters in patients with insomnia. CLINICAL TRIAL REGISTRATION: JapicCTI173570 (www. CLINICALTRIALS: jp); NCT04573725 (www. CLINICALTRIALS: gov).

Optimal dose determination of enerisant (TS-091) for patients with narcolepsy: two randomized, double-blind, placebo-controlled trials.

BACKGROUND: The histamine H3 receptor has emerged as one of the most promising targets of novel pharmacotherapy for narcolepsy. Studies now aim to investigate the optimal dose of enerisant, a novel H3 antagonist/inverse agonist, for the treatment of excessive daytime sleepiness in patients with narcolepsy. METHODS: We conducted two phase 2, fixed-dose, double-blind, randomized, placebo-controlled trials in patients with narcolepsy. The first phase 2 study (Study 1) was conducted to investigate the efficacy and safety of enerisant at dosages of 25, 50, and 100 mg/day administered for 3 weeks based on the results of a phase 1 study conducted on healthy volunteers. The primary endpoint was mean sleep latency in maintenance of wakefulness test (MWT), and the secondary endpoint was the total score on the Epworth Sleepiness Scale (ESS). The dosages of enerisant in the second phase 2 study (Study 2) were set at 5 and 10 mg/day based on the simulation of receptor occupancy results from positron emission tomography study. RESULTS: Forty-six and fifty-three patients were randomized in Study 1 and Study 2, respectively. The efficacy of enerisant was partially confirmed in Study 1 with ESS; however, the doses were not tolerated, and there were many withdrawals due to adverse events (mainly insomnia, headache, and nausea). The doses in Study 2 were well tolerated, with a lower incidence of adverse events in Study 2 than in Study 1, although the efficacy could not be confirmed with MWT and ESS in Study 2. CONCLUSIONS: The optimal dose of enerisant could not be determined in these two studies. Although enerisant has a favorable pharmacokinetic profile, it is thought to have large interindividual variabilities in terms of efficacy and safety, suggesting the necessity of tailored dosage adjustments. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03267303 ; Registered 30 August 2017 (Study 2). Japic identifier: JapicCTI-142529 ; Registered 7 May 2014 (Study 1) and JapicCTI-173689 ; Registered 30 August 2017, https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?clinicalTrialId=29277 (Study 2).

Sleep Apnea Syndrome (SAS) Clinical Practice Guidelines 2020.

The prevalence of sleep disordered breathing (SDB) is reportedly very high. Among SDBs, the incidence of obstructive sleep apnea (OSA) is higher than previously believed, with patients having moderate-to-severe OSA accounting for approximately 20% of adult males and 10% of postmenopausal women not only in Western countries but also in Eastern countries, including Japan. Since 1998, when health insurance coverage became available, the number of patients using continuous positive airway pressure (CPAP) therapy for sleep apnea has increased sharply, with the number of patients about to exceed 500,000 in Japan. Although the "Guidelines for Diagnosis and Treatment of Sleep Apnea Syndrome (SAS) in Adults" was published in 2005, a new guideline was prepared in order to indicate the standard medical care based on the latest trends, as supervised by and in cooperation with the Japanese Respiratory Society and the "Survey and Research on Refractory Respiratory Diseases and Pulmonary Hypertension" Group, of Ministry of Health, Labor and Welfare and other related academic societies, including the Japanese Society of Sleep Research, in addition to referring to the previous guidelines. Because sleep apnea is an interdisciplinary field covering many areas, this guideline was prepared including 36 clinical questions (CQs). In the English version, therapies and managements for SAS, which were written from CQ16 to 36, were shown. The Japanese version was published in July 2020 and permitted as well as published as one of the Medical Information Network Distribution Service (Minds) clinical practice guidelines in Japan in July 2021.

Associations Between the 2011 Great East Japan Earthquake and Tsunami and the Sleep and Mental Health of Japanese People: A 3-Wave Repeated Survey.

PURPOSE: Large-scale natural disasters have an enormous physical and mental impact, immediately after they occur, on people living near the central disaster areas. It is known that, in the early stages, a seismic disaster triggers high rates of symptoms for insomnia, depression, and anxiety. However, little information is available about their medium- to long-term clinical outcomes. In this study, we conducted a repeated cross-sectional nationwide questionnaire survey to clarify changes in the prevalence of insomnia and its background factors after the Great East Japan Earthquake, a huge earthquake with a moment magnitude of 9.0 that occurred on March 11, 2011. METHODS: We conducted a repeated cross-sectional survey in November 2009 (pre-earthquake, 1224 participants), July 2011 (4 months post-earthquake, 1259 participants), and August 2012 (18 months post-earthquake, 1289 participants) using stratified random sampling from 157 Japanese sites. RESULTS: Compared to 2009, the prevalence of insomnia statistically increased nationwide immediately post-disaster (11.7% vs 21.2%; p < 0.001) but significantly decreased in 2012 compared to immediately after the earthquake (10.6% vs 21.2%; p < 0.001). In 2011, insomnia was most frequent in the central disaster area. Multivariable logistic regression models demonstrated the association between the following factors and increased risk of insomnia: being a woman (odds ratio [OR] 1.48, 95% confidence interval [CI]: 1.00-2.19), being employed in 2009 (OR 1.74, 95% CI: 1.15-2.62), and being of younger age group (20-64 years) in 2011 (OR 1.64, 95% CI: 1.12-2.42) and 2012 (OR 2.50 95% CI: 1.47-4.23). Post-earthquake, the prevalence of insomnia symptoms in men increased, while the gender difference decreased and was no longer statistically significant. Additionally, insomnia was associated with psychological distress (scores ≥5 on the Kessler Psychological Distress Scale) in 2011 and 2012. CONCLUSION: This study demonstrated that the prevalence of insomnia was significantly higher after the earthquake. Moreover, individuals with insomnia were more likely to experience psychological distress after the earthquake that continued until 2012.

Verification of sleep scales as predictors of suicidal ideation in Japanese dayworkers: a longitudinal study.

The objective of this study was to verify whether the assessment of poor sleep based on two sleep scales could predict suicidal ideation in Japanese dayworkers. A longitudinal survey was conducted among 446 Japanese dayworkers working at a company in Japan. Questionnaires were administered in 2013 (baseline) and 2014 (follow-up). To evaluate suicidal ideation, we used Question 19 of the Self-rating Depression Scale, categorizing participants who chose response options "some/a good part/most of the time" as suicidal ideation (+), and those who chose option "never or only a little of the time" as suicidal ideation (-). Two sleep scales, the Pittsburgh Sleep Quality Index (PSQI) and the 3-Dimensional Sleep Scale (3DSS), were selected as potential predictors of suicidal ideation. Only participants who were suicidal ideation (-) at baseline were included in the analysis, and suicidal ideation (+) individuals at follow-up were considered to have developed suicidal ideation during the interval between baseline and follow-up surveys. Data from 293 participants (236 men, 57 women) were analyzed. Twenty-two participants (7.5%) became suicidal ideation (+) at follow-up. Multiple logistic regression analysis showed that only sleep quality of the 3DSS subscale significantly predicted suicidal ideation, even after adjusting for depressive symptoms. That is, assessment of poor sleep did not predict suicidal ideation when based on the PSQI, but did when based on the 3DSS. Assessment of sleep quality based on the 3DSS may prove more useful in predicting worker suicidal ideation in industrial settings with limited facilities than PSQI. Supplementary Information: The online version contains supplementary material available at 10.1007/s41105-022-00404-6.