研究等業績 - 原著論文 - 三島　和夫

Identification of Factors to Predict Transition to Schizophrenia in Subjects with Ultra-high Risk for Psychosis: A Protocol for a Multicenter, Longitudinal Study of Sleep Parameters and Cytokine Levels.

Yuji Yamada, Kazuo Mishima, Takashi Ohnishi, Michio Suzuki, Takahiro Nemoto, Masafumi Mizuno, Toshifumi Kishimoto, Hiroaki Tomita, Motohiro Ozone, Shingo Kitamura, Kenji Hashimoto, Kazuyuki Nakagome, Tomiki Sumiyoshi

Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology   23 ( 2 ) 266 - 277   2025年05月  [査読有り]

研究論文（学術雑誌）   国内共著

OBJECTIVE: Schizophrenia is a major psychiatric illness which mostly begins in adolescence and leads to impairments of social functioning. Some patients with schizophrenia have been associated with ultra-high risk state for psychosis (UHR), a condition used to operationally represent the prodromal stage of the illness. In previous studies, the UHR and the progression to overt psychosis has been reported to be accompanied with alterations in the quality of sleep and the immune system, as represented by change of blood levels of cytokines. Currently, biomarkers to predict the development of psychosis in persons at UHR have not yet reached a steady consensus. Therefore, we present a study protocol to explore predictors of transitions to psychosis, in the realm of monitoring of sleep condition and cytokine measurement, in subjects with the UHR. METHODS: This is a multicenter, longitudinal cohort study participated by 7 hospitals in Japan. We will recruit 50 UHR people and 30 healthy volunteers as a control group, and measure positive symptom, depressive symptoms, cognitive function, and social function. Blood cytokines levels and sleep indices, as well as actigraphy data will be monitored. After the baseline assessment, clinical symptoms, sleep indices, and cytokine levels will be measured every 12 weeks for 52 weeks. Actigraphy devices will continue to be worn for 52 weeks, while social function will be assessed over 104 weeks. The results of this study are expected to facilitate the development of novel intervention therapies to reduce the risk of psychosis and improve functional outcomes.

DOI PubMed

Detection of sleep apnea using smartphone-embedded inertial measurement unit.

Junichiro Hayano, Masahiro Takeshima, Aya Imanishi, Masaya Ogasawara, Yasuko Yamada, Emi Yuda, Kazuo Mishima

Scientific reports   15 ( 1 ) 14923 - 14923   2025年04月  [査読有り]

研究論文（学術雑誌）   国内共著

We previously demonstrated that sleep apnea (SA) can be detected using acceleration and gyroscope signals from smartwatches. This study investigated whether an inertial measurement unit (IMU) embedded in non-wristwatch devices, such as smartphones, can also detect SA when worn during sleep. During polysomnography (PSG), subjects wore an IMU-embedded GPS device (Amue Link®) and/or smartphones (Xperia® or iPhone®) on their abdomen. Triaxial acceleration and gyroscope signals were recorded overnight. Data were split into training and test groups (2:1) for each device. An algorithm was developed in the training groups to extract respiratory movements (0.13-0.70 Hz) and detect respiratory events, which were validated in the test groups. IMU-derived respiratory events showed breath-by-breath concordance with PSG apnea-hypopnea events, yielding F1 scores of 0.786, 0.821, and 0.796, respectively. Regression model derived from IMU signals correlated with PSG AHI in the test groups (r = 0.90, 0.93, and 0.96), with limits of agreement of -16.7 to 25.9, -17.4 to 22.5, and - 18.4 to 20.5. Using cutoff values from the training groups, moderate-to-severe SA (AHI ≥ 15) was identified in the test groups with AUCs of 0.95, 0.98, and 0.94 and F1 scores of 0.89, 0.96, and 0.92, respectively. IMUs embedded in non-wristwatch devices, including smartphones, can quantitatively detect SA when worn during sleep.

DOI PubMed

Transforming growth factor-β serum levels associated with social function in subjects at ultra-high risk for psychosis: A multicenter study

Yuji Yamada, Naoko Kishimoto, Hiromi Tagata, Tsubasa Morimoto, Kazuho Tomimoto, Yutaro Sato, Yuko Higuchi, Hiroshi Hiejima, Hayato Ohshima, Takao Kato, Mari S. Oba, Shoki Izumi, Yui Tomo, Shingo Kitamura, Andrew Stickley, Toshifumi Kishimoto, Takahiro Nemoto, Masafumi Mizuno, Hiroaki Tomita, Michio Suzuki, Motohiro Ozone, Kenji Hashimoto, Kazuo Mishima, Takashi Ohnishi, Kazuyuki Nakagome, Tomiki Sumiyoshi

Clinical Psychopharmacology and Neuroscience     2025年02月  [査読有り]

研究論文（学術雑誌）   国内共著

How many truck drivers would have sleep disorders? : Investigation on lifestyle and stress on insomnia among Japanese male truck drivers

Ryoya Aoki, Takashi Miyachi, Yuta Sugano, Choichiro Kanke, Teiichiro Yamazaki, Kazuo Mishima, Kyoko Nomura

Journal of Occupational Health ( Oxford University Press (OUP) )    2025年02月  [査読有り]

研究論文（学術雑誌）  

Abstract

Objectives: This study aimed to investigate how many drivers would have sleep disorders and what factors would be most associated with chronic insomnia symptoms.

Methods: A cross-sectional study of 505 truck drivers in Akita prefecture was conducted using a self-administered questionnaire and health checkup data. We defined insomnia based on the International Classification of Sleep Disorders, 3rd edition (ICSD-3), sleep apnea syndrome (SAS) with a simple four-variable screening tool, and restless legs syndrome (RLS) with RLS/Willis-Ekbom disease diagnostic criteria. Investigated factors included sleep duration, driving characteristics, caffeine types (foods and beverage) and amounts, caffeine intake timing, state-trait anxiety inventory (STAI), individual stress, and other covariates.

Results: The prevalence of suspected SAS was 23.2% (n = 154), and that of RLS was 0.8% (n = 5). After excluding those, chronic insomnia symptoms were present in 36/505 drivers (7.1%). After adjusting for covariates, a logistic model demonstrated that drinking habits (Odds ratio, OR 6.21, 95% Confidence Interval, CI:1.07–35.8), caffeine intake before sleep (OR 2.65, 95% CI:1.09–6.45), sleep duration on days off (OR 1.44, 95% CI: 1.01–2.05), and STAI score (OR 12.8, 95% CI: 2.53–64.2) were significantly associated with chronic insomnia symptoms. STAI was significantly positively correlated with individual stress, such as family worries (r = 0.22), relationships with non-partners (r = 0.28), and health (r = 0.23).

Conclusions: Our study revealed that one fourth of male truck drivers had sleep disorders that require further medical evaluation. For male truck drivers, a lifestyle modification and stress relief may be a key to address insomnia.

DOI

Familial adenomatous polyposis family with clustering of psychiatric disorders.

Masako Funaki, Atsuko Noguchi, Hayahito Ishikawa, Rie Noutomi, Koji Fukuda, Kazuhiro Shimazu, Taichi Yoshida, Daiki Taguchi, Hanae Shinozaki, Naoaki Kodama, Kazuo Mishima, Hiroshi Nanjo, Tsutomu Takahashi, Hiroyuki Shibata

Japanese journal of clinical oncology     2025年01月  [査読有り]

研究論文（学術雑誌）   国内共著

Familial adenomatous polyposis (FAP) is an inherited disorder that follows an autosomal dominant inheritance pattern and is caused by a germline pathogenic variant in the APC gene. FAP also has extracolonic manifestations, including osteomas, brain tumors, and congenital hypertrophy of the retinal pigmented epithelium. Desmoid tumor is a rare soft-tissue tumor often associated with FAP. APC is a WNT signal transduction molecule that is abundantly expressed in the central nervous system. The truncation mutations of the APC gene are responsible for FAP. Further, the C-terminal domains of APC associate with proteins such as EB1 and hDLG, which are involved in central nervous system functions. In recent years, several reports have indicated an association between FAP and mental disorders. We have identified a family with FAP that has a cluster of mental disorders. The female probrand experienced FAP and desmoid tumors in her thirties. She underwent a total colectomy and tumor resection. Her genetic test revealed a pathogenic germline pathogenic variant in the APC gene, c.3183_3187del. Her maternal grandmother and great-grandmother had colorectal polyposis. She has some mental disorders, and her son and daughter both have autism spectrum disorder (ASD). It was reported that her younger sister and her two daughters have intellectual disability and symptoms of ASD. For these situations, we found that mental health care is crucial when providing genetic counseling and medical care, especially to younger patients with FAP and carriers of pathological variants of the APC gene.

DOI PubMed

Association between polypharmacy and the long-term prescription of hypnotics in Japan: a retrospective cross-sectional study.

Munehiro Komatsu, Masahiro Takeshima, Kazuhisa Yoshizawa, Masaya Ogasawara, Mizuki Kudo, Eru Miyakoshi, Yu Itoh, Nana Shibata, Naoko Ayabe, Kazuo Mishima

Frontiers in psychiatry   15   1471457 - 1471457   2024年12月  [査読有り]

研究論文（学術雑誌）  

INTRODUCTION: Hypnotic polypharmacy and its long-term prescriptions constitute the inappropriate use of hypnotics. However, the relationship between hypnotic polypharmacy and prolonged prescriptions remains unclear. This study aimed to elucidate the association between hypnotic polypharmacy and the duration of hypnotic prescriptions. METHODS: This retrospective, cross-sectional study utilized a large dataset from the Japan Medical Data Center. The study population included adults who had been prescribed hypnotics between April 2020 and March 2021, with a focus on those receiving hypnotics in March 2021. Hypnotic polypharmacy was defined as the concurrent prescription of two or more hypnotics in March 2021. The duration of hypnotic prescriptions was measured by calculating the number of months between April 2019 and March 2021 during which hypnotics were prescribed. A binary logistic regression analysis was conducted to assess the relationship between hypnotic polypharmacy and long-term hypnotic prescriptions, adjusting for relevant covariates. RESULTS: We included 112,256 patients (mean age: 49.5 years, females: 47.1%). Among them, 67.9% received hypnotic monotherapy, and 32.1% received hypnotic polypharmacy. Compared with adults who were prescribed hypnotics for 1 month, the association with polypharmacy was stronger in those who were prescribed hypnotics for ≥4 months as the duration of the prescription increased (adjusted odds ratio [aOR]: 1.15, 95% confidence interval [CI]: 1.04-1.27, p=0.006 for 4-6 months; aOR 1.35, 95% CI 1.23-1.49, p<0.001 for 7-9 months; aOR 1.58, 95% CI 1.43-1.73, p<0.001 for 10-12 months; and aOR 3.24, 95% CI 2.99-3.52 for 13-24 months). CONCLUSIONS: This study demonstrated a significant association between hypnotic polypharmacy and long-term prescriptions of hypnotics. Initiating insomnia treatment with hypnotic monotherapy may reduce the likelihood of long-term prescriptions, and limiting the duration of hypnotic prescriptions could potentially prevent polypharmacy.

DOI PubMed

Circadian clock gene variants in two Japanese families with familial advanced sleep phase.

Motoki Ukai, Akiko Hida, Shingo Kitamura, Yuichi Inoue, Kazuo Mishima

Sleep     2024年12月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI PubMed

Identification of Factors to Predict Transition to Schizophrenia in Subjects with Ultra-high risk for Psychosis: A Protocol for a Multicenter, Longitudinal Study of Sleep Parameters and Cytokine Levels

Yuji Yamada, Kazuo Mishima, Takashi Ohnishi, Michio Suzuki, Takahiro Nemoto, Masafumi Mizuno, Toshifumi Kishimoto, Hiroaki Tomita, Motohiro Ozone, Shingo Kitamura, Kenji Hashimoto, Kazuyuki Nakagome, Tomiki Sumiyoshi

Clinical Psychopharmacology and Neuroscience     2024年12月  [査読有り]

研究論文（学術雑誌）   国内共著

Successful Electroconvulsive Therapy for Tardive Dyskinesia and Tardive Dystonia Refractory to Valbenazine Treatment: A Case Report and Narrative Literature Review.

Keisuke Irinaka, Yu Itoh, Kazuhisa Yoshizawa, Masaya Ogasawara, Naoko Ayabe, Kazuo Mishima, Masahiro Takeshima

Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology   22 ( 4 ) 688 - 696   2024年11月  [査読有り]

研究論文（学術雑誌）   国内共著

Tardive dyskinesia and dystonia are intractable extrapyramidal symptoms caused by the blockade of dopamine receptors by antipsychotic drugs. In addition to the reduction or discontinuation of the causative drug, valbenazine for tardive dyskinesia and botulinum toxin for tardive dystonia have been reported to be effective. However, their efficacy has not been fully demonstrated. In this study, we report the case of a female patient with bipolar disorder, valbenazine-resistant tardive dystonia, and tardive dyskinesia who achieved improvement in extrapyramidal symptoms with electroconvulsive therapy. Additionally, we conducted a narrative literature review on the safety and efficacy of electroconvulsive therapy for tardive dyskinesia and dystonia.

DOI PubMed

Efficacy and safety of insomnia treatment with lemborexant in older adults: analyses from three clinical trials.

Mark H Gotfried, Sanford H Auerbach, Thien Thanh Dang-Vu, Kazuo Mishima, Dinesh Kumar, Margaret Moline, Manoj Malhotra

Drugs & aging     2024年08月  [査読有り]

研究論文（学術雑誌）   国際共著

BACKGROUND: Insomnia is more common as people age. Several common hypnotics used to treat insomnia often do not adequately alleviate sleep issues in older adults and may be associated with negative residual effects such as an increased risk of falls, cognitive impairment, automobile accidents, and lack of response to auditory stimuli. The objective of these analyses of three clinical studies was to investigate the efficacy and safety of the dual orexin-receptor antagonist lemborexant (LEM) in older adults. METHODS: Study E2006-G000-304 (Study 304; NCT02783729) was a randomized, double-blind, placebo (PBO)-controlled, active-comparator trial where subjects with insomnia disorder received LEM 5 mg (LEM5), LEM 10 mg (LEM10), zolpidem tartrate extended-release 6.25 mg (ZOL), or PBO for 30 days. In crossover Study E2006-E044-106 (Study 106; NCT02583451), healthy subjects (good sleepers) received LEM 2.5 mg, LEM5, LEM10, or PBO for eight nights or zopiclone on days 1 and 8 (and PBO on days 2-7). In crossover Study E2006-A001-108 (Study 108; NCT03008447), healthy subjects received a single dose of LEM5, LEM10, PBO, or ZOL. Sleep assessments included polysomnography-based latency to persistent sleep (LPS), wake after sleep onset (WASO), WASO in the second half of the night (WASO2H), sleep efficiency, postural stability, middle-of-the-night and next-day cognitive performance, middle-of-the-night auditory awakening threshold and return-to-sleep latency, and driving performance. RESULTS: Overall, 453 of 1006 (45%; Study 304), 24 of 48 (50%; Study 106), and 28 of 56 (50%; Study 108) subjects were aged ≥ 65 years. In Study 304, LEM decreased (improved) LPS, WASO, and WASO2H from baseline more than ZOL and PBO; subjects treated with LEM had greater increases in sleep efficiency (improved) than with ZOL or PBO. In both Studies 304 and 108, postural stability was not impaired at waketime in subjects who received LEM compared with PBO. At waketime, LEM did not impair memory compared with PBO. In Study 108, following middle-of-the-night awakening, LEM and ZOL did not affect subjects' ability to awaken to auditory stimuli; LEM did not affect tests of memory and attention. In Study 106, LEM did not impair next-day driving performance in healthy elderly compared with PBO. LEM was well tolerated in subjects aged ≥ 65 years. CONCLUSIONS: LEM provided benefits on sleep variables without next-morning residual effects in subjects aged ≥ 65 years, supporting LEM as a treatment option for older adults with insomnia. TRIAL REGISTRATION NUMBERS AND DATES OF REGISTRATION: Study 304: ClinicalTrials.gov identifier, NCT02783729, date of registration, 26 May 2016. Study 106: ClinicalTrials.gov identifier, NCT02583451, date of registration, 22 October 2015. Study 108: ClinicalTrials.gov identifier, NCT03008447, date of registration, 2 January 2017.

DOI PubMed

Pharmacokinetics, safety, and efficacy of daridorexant in Japanese subjects: Results from phase 1 and 2 studies.

Makoto Uchiyama, Kazuo Mishima, Tomoko Yagi, Tatsuya Yoshihara, Takashi Eto, Clemens Muehlan, Osamu Togo, Yuichi Inoue

Journal of sleep research     e14302   2024年08月  [査読有り]

研究論文（学術雑誌）   国内共著

Daridorexant is a dual orexin receptor antagonist for the treatment of insomnia. We report results from the first two randomised, double-blind clinical studies of daridorexant in Japanese subjects. In the Phase 1 study, daridorexant (10, 25, 50 mg) or placebo were administered in the morning for 4 days in 24 young (mean age 26.9 years) and 24 older (mean age 69.7 years) healthy Japanese adults. Daridorexant reached a peak plasma concentration within 1.0 h across every dose and age group. For all doses, the mean plasma concentration of daridorexant showed a similar change between the age groups. Exposure parameters increased dose-dependently with minimal/no accumulation upon repeated dosing. The terminal half-life was ~8 h. In the Phase 2, four-period, four-way crossover study, 47 Japanese subjects (mean age 50.4 years) with insomnia disorder were randomised to receive four treatments (daridorexant 10, 25, 50 mg, placebo) during four treatment periods, each consisting of two treatment nights (5-12 day washout between treatment periods). Subjects continued their fourth treatment for 12 further days. A statistically significant dose-response relationship (multiple-comparison procedure-modelling, p < 0.0001) was found in the reduction of polysomnography-measured wake after sleep onset (WASO; primary endpoint) and latency to persistent sleep (secondary endpoint) from baseline to days 1/2. Statistically significant dose-response relationships were also observed for secondary subjective endpoints from baseline to days 1/2 (sWASO, latency to sleep onset). All daridorexant doses were well tolerated, with no treatment discontinuations and no next-morning residual effects. These results supported further investigation of daridorexant in Japanese patients with insomnia disorder.

DOI PubMed

Evaluation of prescribing patterns of switching to and add-on lemborexant in patients treated with hypnotic medication: a nationwide claims database study in Japan.

Sachiko Tanaka-Mizuno, Kenichi Fujimoto, Kazuo Mishima, Yukinori Sakata, Toshiki Fukasawa, Kayoko Mizuno, Satomi Yoshida, Mika Ishii, Takehiro Taninaga, Naoki Kubota, Margaret Moline, Koji Kawakami

Expert opinion on pharmacotherapy     2024年08月  [査読有り]

研究論文（学術雑誌）   国内共著

BACKGROUND: When considering changing hypnotic pharmacotherapy, lemborexant has attracted attention as a candidate due to its effectiveness and safety profile. However, few studies have investigated switching patterns in clinical practice. RESEARCH DESIGN AND METHODS: We conducted a retrospective cohort study using a nationwide claims database. Patients prescribed a single hypnotic who either subsequently switched to (switching cohort) or were additionally prescribed (add-on cohort) lemborexant between July 2020 and December 2021 were identified. Proportion of successful switching was defined as remaining on lemborexant alone or without any hypnotic at six months after lemborexant initiation. RESULTS: Success proportion was 70.1% in the switching cohort (n = 4,861) and 38.6% in the add-on cohort (n = 9,423). In the add-on cohort, success proportion was lower in patients with a hypnotic history of ≥180 days (31.4%) and in patients whose prescribed hypnotic was a benzodiazepine or non-benzodiazepine (31.5% and 37.6%, respectively). CONCLUSION: Proportion of successful switching was higher in patients who switched to lemborexant than in those who added lemborexant as a concomitant treatment. The lower success proportion in the add-on cohort might be related to clinically more severe insomnia, and/or a concomitant prescription of a benzodiazepine or non-benzodiazepine, from which discontinuation may be challenging.

DOI PubMed

Association between benzodiazepine anxiolytic polypharmacy and concomitant psychotropic medications in Japan: a retrospective cross-sectional study.

Masahiro Takeshima, Kazuhisa Yoshizawa, Masaya Ogasawara, Mizuki Kudo, Yu Itoh, Naoko Ayabe, Nana Shibata, Kazuo Mishima

Frontiers in psychiatry   15   1405049 - 1405049   2024年07月  [査読有り]

研究論文（学術雑誌）   国内共著

INTRODUCTION: Guidelines for various psychiatric disorders recommend short-term use of benzodiazepine anxiolytic monotherapy in few cases. Contrarily, benzodiazepine anxiolytic polypharmacy (BAP) is not recommended in any case. However, BAP is often used in real world. Therefore, this study aimed to determine the association between BAP and concomitant use of psychotropic medications. METHOD: This retrospective cross-sectional study used claims data from the Japan Medical Data Center. Medical information of health insurance subscribers treated with benzodiazepine anxiolytics in June 2019 was extracted. Prescription of two or more benzodiazepine anxiolytics was defined as BAP. Binary logistic regression analysis was performed to investigate the factors associated with BAP, using age group, sex, type of subscriber, and number of concomitant hypnotics, antidepressants, and antipsychotics (none, one, and two or more) as covariates. RESULT: The eligible participants were 104,796 adults who were prescribed benzodiazepine anxiolytics. Among them, 12.6% were prescribed two or more drugs. Logistic regression analysis revealed that BAP was significantly associated with those who received hypnotic monotherapy (adjusted odds ratio [aOR]: 1.04, 95% confidence interval [CI]: 1.001-1.09, p=0.04), antidepressant monotherapy and polypharmacy (aOR: 1.57, 95% CI: 1.51-1.63, p<0.001 and aOR: 1.98, 95% CI: 1.88-2.09, p<0.001, respectively), and antipsychotic monotherapy and polypharmacy (aOR: 1.12, 95% CI: 1.07-1.19, p<0.001 and aOR: 1.41, 95% CI: 1.30-1.54, p<0.001, respectively). Conversely, lower BAP was associated with those who received hypnotic polypharmacy (aOR: 0.86, 95% CI: 0.81-0.91, p<0.001). DISCUSSION: This study showed that the greater the number of concomitant antidepressants and antipsychotics, the greater the association with BAP. Since combination therapy with antidepressants or antipsychotics is generally not recommended, patients receiving combination therapy with these medications may be resistant to pharmacotherapy. Therefore, implementing the recommended non-pharmacological treatments may reduce BAP.

DOI PubMed

Effects of policy interventions on psychotropic polypharmacy in Japanese older adults.

Masahiro Takeshima, Kazuhisa Yoshizawa, Masaya Ogasawara, Mizuki Kudo, Yu Itoh, Naoko Ayabe, Kazuo Mishima

Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society     2024年07月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI PubMed

Safety and Efficacy of Lemborexant in Insomnia Patients: Results of a Postmarketing Observational Study of Dayvigo® Tablets.

Kazuo Mishima, Kenichi Fujimoto, Akira Endo, Mika Ishii

Drugs in R&D     2024年06月  [査読有り]

研究論文（学術雑誌）   国内共著

BACKGROUND AND OBJECTIVE: A prospective, postmarketing observational study was conducted to evaluate the safety and efficacy of lemborexant (LEM) tablets in daily clinical practice in Japan. No other studies of a similar size have been conducted since the marketing approval of LEM, making this the first report of its kind. METHODS: Insomnia patients (n = 550) administered LEM (5-10 mg daily) for the first time were enrolled. Adverse events were collected for target events (somnolence, parasomnia, narcolepsy and associated conditions, suicidal ideation and suicidal behavior). Overall improvement of insomnia symptoms was assessed by the investigator based on the patient's complaint. Subjective sleep onset latency (sSOL) and subjective total sleep time (sTST) were investigated as sleep parameters. RESULTS: A case report form was obtained from 539 patients. The incidence of adverse drug reactions (ADRs) was 7.65% for somnolence, 1.76% for nightmares, 0.59% for abnormal dreams, and 0.20% for sleep paralysis. No serious ADRs or ADRs related to suicidal ideation or suicidal behavior were observed. The efficacy rate at the final evaluation was 80.83%. Decreased sSOL and increased sTST were observed as assessed starting from Week 8 of treatment. CONCLUSION: Based on the results of this study, the safety result was consistent with the safety profile described in the current package insert. Efficacy results also indicated that LEM is clinically useful.

DOI PubMed

Treatment strategies for insomnia in Japanese primary care physicians' practice: A Web-based questionnaire survey.

Masahiro Takeshima, Hitoshi Sakurai, Ken Inada, Yumi Aoki, Kenya Ie, Morito Kise, Eriko Yoshida, Kentaro Matsui, Tomohiro Utsumi, Akiyoshi Shimura, Isa Okajima, Nozomu Kotorii, Hidehisa Yamashita, Masahiro Suzuki, Kenichi Kuriyama, Eiji Shimizu, Kazuo Mishima, Koichiro Watanabe, Yoshikazu Takaesu

BMC primary care   25 ( 1 ) 219 - 219   2024年06月  [査読有り]

研究論文（学術雑誌）   国内共著

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.

DOI PubMed

Association between sleep state misperception and bedtime behavior in patients with chronic insomnia.

Mizuki Kudo, Naoko Ayabe, Masahiro Takeshima, Masaya Ogasawara, Yu Itoh, Kazuhisa Yoshizawa, Shingo Kitamura, Kazuo Mishima

Scientific reports   14 ( 1 ) 13991 - 13991   2024年06月  [査読有り]

研究論文（学術雑誌）   国内共著

Previous studies on sleep state misperception have objectively evaluated sleep status in special environments using polysomnography. There is a paucity of data from studies that evaluated habitual sleep status in home environments. The present study aimed to investigate sleep state misperception in the home environment of patients with chronic insomnia using a lumbar-worn actigraphy to identify sleep habits associated with sleep state misperception severity. Thirty-one patients and 42 healthy volunteers were included in the insomnia and non-insomnia group, respectively. Participants recorded subjective assessments in sleep diaries, objective assessments with an actigraphy worn for 14 days, and self-assessments using questionnaires. Both groups had similar objective sleep ratings; however, insomnia group had significantly worse subjective ratings (total sleep time, wake after sleep onset, and sleep onset latency). A significant correlation was found between subjective and objective total sleep time scores in non-insomnia group but not in insomnia group. Insomnia group had earlier bedtimes, significantly longer bedtimes, and impaired daytime functioning (Sheehan Disability Scale score); additionally, they underestimated their total sleep time, particularly with earlier bedtimes and longer laying durations. Monitoring the sleep status and habits of individuals in home environments could be instrumental in identifying key points for targeted interventions on sleep hygiene and cognitive behavioral therapy for insomnia.

DOI PubMed

QUESTIONNAIRE SURVEY ON VENOUS THROMBOEMBOLISM MANAGEMENT AT HOSPITALS WITH PSYCHIATRIC BEDS IN AKITA PREFECTURE: COMPARISON BETWEEN GENERAL HOSPITALS AND PSYCHIATRIC HOSPITALS

Irinaka Keisuke, Takeshima Masahiro, Mishima Kazuo

秋田医学 ( 秋田医学会 )  51 ( 1 ) 49 - 53   2024年06月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI CiNii Research

Efficacy of Lemborexant in Adults ≥ 65 Years of Age with Insomnia Disorder.

Valerie Arnold, Sonia Ancoli-Israel, Thien Thanh Dang-Vu, Kazuo Mishima, Kate Pinner, Manoj Malhotra, Margaret Moline

Neurology and therapy     2024年05月  [査読有り]

研究論文（学術雑誌）   国際共著

BACKGROUND: Pharmacologic treatments are available to treat insomnia, a common and burdensome sleep disorder, but may be contraindicated in older adults who are prone to side effects from sleep-promoting drugs. These analyses of sleep diary data from Study E2006-G000-303 (Study 303) investigated the benefits of lemborexant 5 mg (LEM5) and 10 mg (LEM10) in the subgroup age ≥ 65 years with insomnia. METHOD: Study 303, a 12-month, double-blind study of LEM5 and LEM10 in adults (age ≥ 18 years) with insomnia disorder (sleep onset and/or maintenance difficulties) assessed subject-reported (subjective) sleep-onset latency (sSOL), sleep efficiency (sSE), wake after sleep onset (sWASO), and total sleep time (sTST). Morning sleepiness/alertness, insomnia severity (Insomnia Severity Index [ISI]), fatigue (Fatigue Severity Scale [FSS]), perceptions of sleep-related medication effects (Patient Global Impression-Insomnia [PGI-I] questionnaire), and safety were also evaluated. RESULTS: In this subgroup of older adults (≥ 65 years; n = 262), there were significantly larger changes from baseline for sSOL, sSE, sTST, and sWASO with LEM5 and LEM10 versus placebo through month 6 (except sWASO month 1), indicating improvement; these improvements were sustained through month 12. Subject-reported increases in morning alertness were significantly greater with one or both LEM doses versus placebo through month 6 and sustained through month 12. There were significantly larger ISI total and daytime functioning score decreases (improvement) from baseline with LEM versus placebo at months 1, 3, and 6 (total score: both doses; daytime functioning: LEM5 month 1 and both doses months 3 and 6) and decreases from baseline FSS at months 1 and 3 (LEM5) and month 6 (both doses), sustained to month 12. Compared with placebo, more subjects reported that LEM (both doses) positively impacted ability to sleep, time to fall asleep, and TST through month 6, sustained to month 12, with no rebound after drug withdrawal. LEM was well tolerated to month 12; mild somnolence was the most common treatment-emergent adverse event. CONCLUSIONS: Improvements in subject-reported efficacy in LEM-treated adults age ≥ 65 years with insomnia were observed as early as the first week of treatment and sustained through end of month 12. LEM was well tolerated. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT02952820: E2006-G000-303; Study 303; SUNRISE-2 (First posted: October 2016); EudraCT 2015-001463-39 (First posted: November 2016).

DOI PubMed

Treatment Failure and Long-Term Prescription Risk for Guideline-Recommended Hypnotics in Japan.

Masahiro Takeshima, Kazuhisa Yoshizawa, Masaya Ogasawara, Mizuki Kudo, Yu Itoh, Naoko Ayabe, Kazuo Mishima

JAMA network open   7 ( 4 ) e246865   2024年04月  [査読有り]

研究論文（学術雑誌）   国内共著

IMPORTANCE: Although insomnia guidelines recommend the use of several individual hypnotics, the most useful hypnotic for treating insomnia in a clinical setting remains unclear. OBJECTIVE: To determine which guideline-recommended hypnotics have lower risks of monotherapy failure and which hypnotics have a higher risk of long-term prescription for insomnia treatment. DESIGN, SETTING, AND PARTICIPANTS: This retrospective observational cohort study used data from the Japan Medical Data Center Claims Database from April 1, 2005, to March 31, 2021. Participants included adults whose first prescribed pharmaceutical treatment for insomnia was guideline-recommended hypnotic monotherapy. Data were analyzed from December 24, 2022, to September 26, 2023. EXPOSURES: Suvorexant, ramelteon, eszopiclone, zolpidem, and triazolam monotherapy. MAIN OUTCOMES AND MEASURES: The primary outcome was monotherapy failure, defined as a change in hypnotic or having an additional hypnotic prescribed for insomnia within 6 months of the first prescription of a guideline-recommended hypnotic monotherapy. The secondary outcome was monotherapy discontinuation, defined as no prescription of any hypnotic for 2 consecutive months within 6 months after prescribing a guideline-recommended hypnotic in patients for whom monotherapy did not fail. Monotherapy failure and discontinuation were compared using Cox proportional hazards and logistic regression models, respectively. RESULTS: The study included 239 568 adults (median age, 45 [IQR, 34-55] years; 50.2% women) whose first prescription for insomnia was guideline-recommended hypnotic monotherapy. During the 6-month follow-up period, 24 778 patients (10.3%) experienced failure of monotherapy with a guideline-recommended hypnotic. In comparison with eszopiclone, there were more cases of monotherapy failure for ramelteon (adjusted hazard ratio [AHR], 1.23 [95% CI], 1.17-1.30; P < .001), fewer cases for zolpidem (AHR, 0.84 [95% CI, 0.81-0.87]; P < .001) and triazolam (AHR, 0.82 [95% CI, 0.78-0.87]; P < .001), and no significant difference between suvorexant and eszopiclone. Among those without monotherapy failure, monotherapy was discontinued in 84.6% of patients, with more discontinuations for ramelteon (adjusted odds ratio [AOR], 1.31 [95% CI, 1.24-1.40]; P < .001) and suvorexant (AOR, 1.20 [95% CI, 1.15-1.26]; P < .001) than for eszopiclone and no significant difference between zolpidem or triazolam and eszopiclone. CONCLUSIONS AND RELEVANCE: Due to uncontrolled confounding factors in this cohort study, no conclusions regarding the pharmacologic properties of guideline-recommended hypnotics can be drawn based on these results. Further studies accounting for confounding factors, including diagnoses of chronic vs acute insomnia disorder, insomnia and psychiatric symptom severity, and physician attitudes toward hypnotic prescription, are needed.

DOI PubMed

Impact of aripiprazole discontinuation in remitted major depressive disorder: a randomized placebo-controlled trial.

Masahiro Takeshima, Akise Umakoshi, Yuki Omori, Kazuhisa Yoshizawa, Masaya Ogasawara, Mizuki Kudo, Yu Itoh, Naoko Ayabe, Kazuo Mishima

Psychopharmacology     2024年03月  [査読有り]

研究論文（学術雑誌）   国内共著

RATIONALE: The efficacy and safety of antidepressant augmentation therapy with aripiprazole (AATA) has been established; however, the ongoing effects of continuing aripiprazole after remission remain unclear because no studies have examined this issue. OBJECTIVES: We aimed to explore the effect of AATA discontinuation on the major depressive disorder (MDD) recurrence risk in patients with remitted MDD after AATA. METHODS: This 24-week, multicenter, placebo-controlled, double-blind, randomized trial evaluated recurrence risk in patients with MDD who achieved remission with AATA. Differences in MDD recurrence, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, between the two groups were compared using survival analysis. The differences in depressive symptom severity and social functioning between the two groups were compared using a mixed model with repeated measures. Extrapyramidal symptoms and akathisia were also assessed. RESULTS: Twenty-three participants were randomized and treated. Two patients in each group experienced recurrence during the study. Kaplan-Meier analysis with Log-rank comparison showed no difference in recurrence between groups (p = 0.642). No significant difference in interactions between group and period was observed in the 17-item Hamilton depression rating scale (p = 0.492) or the Social and Occupational Functioning Assessment Scale (p = 0.638). No patients developed extrapyramidal symptoms or akathisia. CONCLUSIONS: Definitive conclusions could not be drawn owing to the small sample size. This study represents a starting point for investigating the safety of aripiprazole discontinuation on recurrence in patients with MDD who have achieved remission with AATA. Future studies with appropriate sample sizes calculated based on this study are needed.

DOI PubMed

精神科で本当に必要な薬は何か? 精神科領域の安定確保医薬品に関する意識調査

稲垣 中, 橋本 亮太, 稲田 健, 坪井 貴嗣, 三島 和夫, 小路 純央, 齊尾 武郎, 安田 由華, 横井 優磨, 小田 陽彦, 加藤 正樹, 岸田 郁子, 岸本 泰士郎, 齊藤 卓弥, 冨田 哲, 古郡 規雄, 松尾 幸治, 渡邊 衡一郎, 木下 利彦, 三木 和平, 三野 進, 三村 將

精神神経学雑誌 ( (公社)日本精神神経学会 )  125 ( 11 ) 932 - 943   2023年11月  [査読有り]

研究論文（学術雑誌）   国内共著

近年,医薬品の安定供給に疑念を抱かせるような事例が多発するようになったため,2020年に厚生労働省は10種類の向精神薬を含めた506種類の安定確保医薬品を指定した.しかしながら,このときには時間的な制約から精神科のステークホルダー全体のコンセンサスに基づいて10種類の向精神薬を選定できず,少数のエキスパートたちのコンセンサスに基づいて決定せざるをえなかった.今回われわれは精神科医,薬剤師,当事者・家族を対象としたweb媒体のアンケート調査を実施したうえで,第118回日本精神神経学会学術総会の際に開催されたシンポジウムにおいてデルファイ法に準じた方法により精神科のステークホルダー全体を反映したコンセンサスの形成を試みた.アンケート調査の結果,精神科医,薬剤師,当事者・家族の大半が10種類の向精神薬を安定確保医薬品に指定することを容認していることが示された.また,デルファイ法に準じた方法による意見集約の結果,リスペリドン,アリピプラゾール,オランザピン,クエチアピン,ミルタザピン,エスシタロプラム,バルプロ酸ナトリウム,炭酸リチウム,ロラゼパム,レンボレキサントの10種類の向精神薬がより妥当な安定確保医薬品として選択された.(著者抄録)

不眠症患者におけるレンボレキサントの安全性および有効性の検討 デエビゴ錠一般使用成績調査結果報告

三島 和夫, 藤本 健一, 遠藤 亮, 石井 美佳

睡眠医療 ( (株)ライフ・サイエンス )  17 ( 3 ) 351 - 363   2023年09月  [査読有り]

研究論文（学術雑誌）   国内共著

不眠症患者を対象にしたレンボレキサント(デエビゴ錠)の一般使用成績調査を実施し,日常診療下の安全性および有効性について539例の調査票を収集し検討を行った.本剤の製造販売承認後に同程度の規模の研究はほかになく,最初の報告となる.副作用の発現状況について検討したところ,「傾眠」の発現割合は7.65%,「悪夢」の発現割合は1.76%,「異常な夢」の発現割合は0.59%,「睡眠麻痺」の発現割合は0.20%であり,自殺念慮および自殺行動に関する副作用の発現はなかった.重篤な副作用の発現は認められなかった.有効割合は最終評価時で80.83%であった.主観的睡眠潜時の短縮,主観的総睡眠時間の延長は本剤投与8週後より認められた.本調査の結果から,安全性について検討した結果,現行の添付文書に記載された安全性プロファイルとの相違はなかった.また有効性について検討した結果,臨床上有用な薬剤であることが示された.(著者抄録)

Development and acceptability testing of a decision aid for considering whether to reduce antipsychotics in individuals with stable schizophrenia

Aoki, Y. Takaesu, Y. Matsui, K. Tokumasu, T. Tani, H. Takekita, Y. Kanazawa, T. Kishimoto, T. Tarutani, S. Hashimoto, N. Takeuchi, H. Mishima, K. Inada, K.

Neuropsychopharmacol Rep ( Wiley )    2023年07月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Feasibility of a wrist-worn wearable device for estimating mental health status in patients with mental illness.

Kazuyuki Nakagome, Manabu Makinodan, Mitsuhiro Uratani, Masaki Kato, Norio Ozaki, Seiko Miyata, Kunihiro Iwamoto, Naoki Hashimoto, Atsuhito Toyomaki, Kazuo Mishima, Masaya Ogasawara, Masahiro Takeshima, Kazumichi Minato, Toshikazu Fukami, Mari Oba, Kazuyoshi Takeda, Hideki Oi

Frontiers in psychiatry   14   1189765 - 1189765   2023年07月  [査読有り]

研究論文（学術雑誌）   国内共著

OBJECT: Real-world data from wearable devices has the potential to understand mental health status in everyday life. We aimed to investigate the feasibility of estimating mental health status using a wrist-worn wearable device (Fitbit Sense) that measures movement using a 3D accelerometer and optical pulse photoplethysmography (PPG). METHODS: Participants were 110 patients with mental illnesses from different diagnostic groups. The study was undertaken between 1 October 2020 and 31 March 2021. Participants wore a Fitbit Sense on their wrist and also completed the State-Trait Anxiety Inventory (STAI), Positive and Negative Affect Schedule (PANAS), and EuroQol 5 dimensions 5-level (EQ-5D-5L) during the study period. To determine heart rate (HR) variability (HRV), we calculated the sdnn (standard deviation of the normal-to-normal interval), coefficient of variation of R-R intervals, and mean HR separately for each sleep stage and the daytime. The association between mental health status and HR and HRV was analyzed. RESULTS: The following significant correlations were found in the wake after sleep onset stage within 3 days of mental health status assessment: sdnn, HR and STAI scores, HR and PANAS scores, HR and EQ-5D-5L scores. The association between mental health status and HR and HRV was stronger the closer the temporal distance between mental health status assessment and HR measurement. CONCLUSION: A wrist-worn wearable device that measures PPG signals was feasible for use with patients with mental illness. Resting state HR and HRV could be used as an objective assessment of mental health status within a few days of measurement.

DOI PubMed

Clinical practice for unspecified anxiety disorder in primary care

Sakurai, H. Takeshima, M. Inada, K. Aoki, Y. Ie, K. Kise, M. Yoshida, E. Tsuboi, T. Yamada, H. Hori, H. Inada, Y. Shimizu, E. Mishima, K. Watanabe, K. Takaesu, Y.

Psychiatry and Clinical Neurosciences Reports ( Wiley )  2 ( 3 )   2023年06月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

The Relationship between Insomnia and Lifestyle-Related Diseases among Japanese Male Truck Drivers.

Tomoka Ando, Takashi Miyachi, Yuta Sugano, Makoto Kamatsuka, Kazuo Mishima, Kyoko Nomura

The Tohoku journal of experimental medicine     2023年06月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI PubMed

Development and acceptability of a decision aid for anxiety disorder considering discontinuation of benzodiazepine anxiolytic

Yumi Aoki, Yoshikazu Takaesu, Ken Inada, Hiroki Yamada, Tomohiko Murao, Toshiaki Kikuchi, Masahiro Takeshima, Masayuki Tani, Kazuo Mishima, Tempei Otsubo

Frontiers in Psychiatry ( Frontiers Media SA )  14   2023年05月  [査読有り]

研究論文（学術雑誌）   国内共著

Aim

We aimed to develop a decision aid (DA) for individuals with anxiety disorders who consider tapering benzodiazepine (BZD) anxiolytics, and if tapering, tapering BZD anxiolytics with or without cognitive behavioral therapy (CBT) for anxiety. We also assessed its acceptability among stakeholders.

Methods

First, we conducted a literature review regarding anxiety disorders to determine treatment options. We cited the results of the systematic review and meta-analysis, which we conducted previously, to describe the related outcomes of two options: tapering BZD anxiolytics with CBT and tapering BZD anxiolytics without CBT. Second, we developed a DA prototype in accordance with the International Patient Decision Aid Standards. We carried out a mixed methods survey to assess the acceptability among stakeholders including those with anxiety disorders and healthcare providers.

Results

Our DA provided information such as explanation of anxiety disorders, options of tapering or not tapering BZD anxiolytics (if tapering, the options of tapering BZD anxiolytics with or without CBT) for anxiety disorder, benefits and risks of each option, and a worksheet for value clarification. For patients (n = 21), the DA appeared to be acceptable language (86%), adequate information (81%), and well-balanced presentation (86%). The developed DA was also acceptable for healthcare providers (n = 10).

Conclusion

We successfully created a DA for individuals with anxiety disorders who consider tapering BZD anxiolytics, which was acceptable for both patients and healthcare providers. Our DA was designed to assist patients and healthcare providers to involve decision-making about whether to taper BZD anxiolytics or not.

DOI

A Comparison between Perceptions of Psychiatric Outpatients and Psychiatrists Regarding Benzodiazepine Use and Decision Making for Its Discontinuation: A Cross-Sectional Survey in Japan

Yumi Aoki, Masahiro Takeshima, Takashi Tsuboi, Eiichi Katsumoto, Ken Udagawa, Ken Inada, Koichiro Watanabe, Kazuo Mishima, Yoshikazu Takaesu

International Journal of Environmental Research and Public Health ( MDPI AG )  20 ( 7 ) 5373 - 5373   2023年04月  [査読有り]

研究論文（学術雑誌）   国内共著

Background: Although long-term use of benzodiazepines and z-drugs (BZDs) is not recommended, little is known about the stakeholders’ perceptions. This study aimed to assess and compare the perceptions of BZD use and decision making regarding its discontinuation between psychiatric outpatients and psychiatrists. Methods: A cross-sectional survey was conducted. Results: Of 104 outpatients, 92% were taking hypnotics and 96% were taking anxiolytics for ≥a year, while 49% were willing to taper hypnotic/anxiolytics within a year of starting. Most psychiatrists felt that “patient and psychiatrist make the decision together on an equal basis” compared to patients (p &lt; 0.001), while more patients felt that “the decision is (was) made considering the psychiatrists’ opinion” compared to psychiatrists (p &lt; 0.001). Of 543 psychiatrists, 79% reported “patients were not willing to discontinue hypnotic/anxiolytic” whereas a certain number of patients conveyed “psychiatrists did not explain in enough detail about hypnotic/anxiolytic discontinuation such as procedure (18.3%), timing (19.2%), and appropriate condition (14.4%)”. Conclusion: The results suggest that the majority of psychiatric outpatients were taking hypnotic/anxiolytics for a long time against their will. There might be a difference in perceptions toward hypnotic/anxiolytic use and decision making for its discontinuation between psychiatric outpatients and psychiatrists. Further research is necessary to fill this gap.

DOI

Treatment Strategy for Insomnia Disorder: Japanese Expert Consensus

Yoshikazu Takaesu, Hitoshi Sakurai, Yumi Aoki, Masahiro Takeshima, Kenya Ie, Kentaro Matsui, Tomohiro Utsumi, Akiyoshi Shimura, Isa Okajima, Nozomu Kotorii, Hidehisa Yamashita, Masahiro Suzuki, Kenichi Kuriyama, Eiji Shimizu, Kazuo Mishima, Koichiro Watanabe, Ken Inada

Frontiers in Psychiatry     2023年04月  [査読有り]

研究論文（学術雑誌）   国内共著

Purpose: There is a lack of evidence regarding answers for clinical questions about treating insomnia disorder. This study aimed to answer the following clinical questions: 1) how to use each hypnotic and non-pharmacological treatment differently depending on clinical situations and 2) how to reduce or stop benzodiazepine hypnotics using alternative pharmacological and non-pharmacological treatments.
Methods: Experts were asked to evaluate treatment choices based on 10 clinical questions about insomnia disorder using a nine-point Likert scale (1=“disagree” to 9=“agree”). The responses of 196 experts were collected, and the answers were categorized into first-, second-, and third-line recommendations.
Results: The primary pharmacological treatment, lemborexant (7.3±2.0), was categorized as a first-line recommendation for sleep initiation insomnia, and lemborexant (7.3±1.8) and suvorexant (6.8±1.8) were categorized as the first-line recommendations for sleep maintenance insomnia. Regarding non-pharmacological treatments for primary treatment, sleep hygiene education was categorized as the first-line recommendation for both sleep initiation (8.4±1.1) and maintenance insomnia (8.1±1.5), while multicomponent cognitive behavioral therapy for insomnia was categorized as the second-line treatment for both sleep initiation (5.6±2.3) and maintenance insomnia (5.7±2.4). When reducing or discontinuing benzodiazepine hypnotics by switching to other medications, lemborexant (7.5±1.8) and suvorexant (6.9±1.9) were categorized as first-line recommendations.
Conclusion: Expert consensus indicates that orexin receptor antagonists and sleep hygiene education are recommended as first-line treatments in most clinical situations to treat insomnia disorder.

DOI

Exploratory Validation of Sleep-Tracking Devices in Patients with Psychiatric Disorders.

Masaya Ogasawara, Masahiro Takeshima, Shumpei Kosaka, Aya Imanishi, Yu Itoh, Dai Fujiwara, Kazuhisa Yoshizawa, Norio Ozaki, Kazuyuki Nakagome, Kazuo Mishima

Nature and science of sleep   15   301 - 312   2023年04月  [査読有り]

研究論文（学術雑誌）   国内共著

PURPOSE: Sleep-tracking devices have performed well in recent studies that evaluated their use in healthy adults by comparing them with the gold standard sleep assessment technique, polysomnography (PSG). These devices have not been validated for use in patients with psychiatric disorders. Therefore, we tested the performance of three sleep-tracking devices against PSG in patients with psychiatric disorders. PATIENTS AND METHODS: In total, 52 patients (32 women; 48.1 ± 17.2 years, mean ± SD; 18 patients diagnosed with schizophrenia, 19 with depressive disorder, 3 with bipolar disorder, and 12 with sleep disorder cases) were tested in a sleep laboratory with PSG, along with portable electroencephalography (EEG) device (Sleepgraph), actigraphy (MTN-220/221) and consumer sleep-tracking device (Fitbit Sense). RESULTS: Epoch-by-epoch sensitivity (for sleep) and specificity (for wake), respectively, were as follows: Sleepgraph (0.95, 0.76), Fitbit Sense (0.95, 0.45) and MTN-220/221 (0.93, 0.40). Portable EEG (Sleepgraph) had the best sleep stage-tracking performance. Sleep-wake summary metrics demonstrated lower performance on poor sleep (ice, shorter total sleep time, lower sleep efficiency, longer sleep latency, longer wake after sleep onset). CONCLUSION: Devices demonstrated similar sleep-wake detecting performance as compared with previous studies that evaluated sleep in healthy adults. Consumer sleep device may exhibit poor sleep stage-tracking performance in patients with psychiatric disorders due to factors that affect the sleep determination algorithm, such as changes in autonomic nervous system activity. However, Sleepgraph, a portable EEG device, demonstrated higher performance in mental disorders than the Fitbit Sense and actigraphy.

DOI PubMed

Novel CLOCK and NR1D2 variants in 64 sighted Japanese individuals with non-24-hour sleep-wake rhythm disorder.

Akiko Hida, Aritoshi Iida, Motoki Ukai, Hiroshi Kadotani, Makoto Uchiyama, Takashi Ebisawa, Yuichi Inoue, Shingo Kitamura, Kazuo Mishima

Sleep     2023年03月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI PubMed

Management of unspecified anxiety disorder: Expert consensus.

Hitoshi Sakurai, Ken Inada, Yumi Aoki, Masahiro Takeshima, Kenya Ie, Morito Kise, Eriko Yoshida, Takashi Tsuboi, Hisashi Yamada, Hikaru Hori, Yasushi Inada, Eiji Shimizu, Kazuo Mishima, Koichiro Watanabe, Yoshikazu Takaesu

Neuropsychopharmacology reports     2023年02月  [査読有り]

研究論文（学術雑誌）   国内共著

AIMS: Treatment guidelines with respect to unspecified anxiety disorder have not been published. The aim of this study was to develop a consensus among field experts on the management of unspecified anxiety disorder. METHODS: Experts were asked to evaluate treatment choices based on eight clinical questions concerning unspecified anxiety disorder using a nine-point Likert scale (1 = "disagree" to 9 = "agree"). According to the responses from 119 experts, the choices were categorized into first-, second-, and third-line recommendations. RESULTS: Benzodiazepine anxiolytic use was not categorized as a first-line recommendation for the primary treatment of unspecified anxiety disorder, whereas multiple nonpharmacological treatment strategies, including coping strategies (7.9 ± 1.4), psychoeducation for anxiety (7.9 ± 1.4), lifestyle changes (7.8 ± 1.5), and relaxation techniques (7.4 ± 1.8), were categorized as first-line recommendations. Various treatment strategies were categorized as first-line recommendations when a benzodiazepine anxiolytic drug did not improve anxiety symptoms, that is, differential diagnosis (8.2 ± 1.4), psychoeducation for anxiety (8.0 ± 1.5), coping strategies (7.8 ± 1.5), lifestyle changes (7.8 ± 1.5), relaxation techniques (7.2 ± 1.9), and switching to selective serotonin reuptake inhibitors (SSRIs) (7.0 ± 1.8). These strategies were also highly endorsed when tapering the dosage of or discontinuing benzodiazepine anxiolytic drugs. There was no first-line recommendation regarding excusable reasons for continuing benzodiazepine anxiolytics. CONCLUSIONS: The field experts recommend that benzodiazepine anxiolytics should not be used as a first-line option for patients with unspecified anxiety disorder. Instead, several nonpharmacological interventions and switching to SSRIs were endorsed for the primary treatment of unspecified anxiety disorder and as alternatives to benzodiazepine anxiolytics.

DOI PubMed

Physicians' attitudes toward hypnotics for insomnia;a questionnaire-based study

Masahiro Takeshima, Yoshikazu Takaesu, Yumi Aoki, Kenya Ie,Eiichi, Katsumoto, Eichi Tsuru, Takashi Tsuboi, Ken Inada, Morito Kise, Koichiro Watanabe, Kazuo Mishima

Frontiers in Psychiatry   14   1071962 - 1071962   2023年01月  [査読有り]

研究論文（学術雑誌）   国内共著

INTRODUCTION: Benzodiazepines and non-benzodiazepines are still widely prescribed despite safety concerns and the introduction of novel hypnotics (orexin receptor antagonists [ORA] and melatonin receptor agonists [MRA]), which may be influenced by physicians' attitudes toward hypnotics. METHODS: A questionnaire survey was administered to 962 physicians between October 2021 and February 2022, investigating frequently prescribed hypnotics and the reasons for their selection. RESULTS: ORA were the most frequently prescribed at 84.3%, followed by non-benzodiazepines (75.4%), MRA (57.1%), and benzodiazepines (54.3%). Compared to non-frequent prescribers of hypnotics, a logistic regression analysis showed that frequent ORA prescribers were more concerned with efficacy (odds ratio [OR]: 1.60, 95% confidence interval [CI]: 1.01-2.54, p = 0.044) and safety (OR: 4.52, 95% CI: 2.99-6.84, p < 0.001), frequent MRA prescribers were more concerned with safety (OR: 2.48, 95% CI: 1.77-3.46, p < 0.001), frequent non-benzodiazepine prescribers were more concerned with efficacy (OR: 4.19, 95% CI: 2.91-6.04, p < 0.001), and frequent benzodiazepine prescribers were more concerned with efficacy (OR: 4.19, 95% CI: 2.91-6.04, p < 0.001) but less concerned with safety (OR: 0.25, 95% CI: 0.16-0.39, p < 0.001). DISCUSSION: This study suggested that physicians believed ORA to be an effective and safe hypnotic and were compelled to prescribe benzodiazepine and non-benzodiazepine frequently, choosing efficacy over safety.

DOI PubMed

Effects of Japanese policies and novel hypnotics on long-term prescriptions of hypnotics.

Masahiro Takeshima, Kazuhisa Yoshizawa, Minori Enomoto, Masaya Ogasawara, Mizuki Kudo, Yu Itoh, Naoko Ayabe, Yoshikazu Takaesu, Kazuo Mishima

Psychiatry and clinical neurosciences   77 ( 5 ) 264 - 272   2022年12月  [査読有り]

研究論文（学術雑誌）   国内共著

AIM: This study aimed to examine the effect of Japanese policies for appropriate hypnotics use and novel hypnotics (e.g., melatonin receptor agonist [MRA] and orexin receptor antagonist [ORA]) on long-term prescriptions of hypnotics. METHODS: This retrospective study was conducted using a large-scale health insurance claims database. Among subscribers prescribed hypnotics at least once between April 2005 and March 2021, those prescribed hypnotics for the first time after being included in the database in three periods (period 1, April 2012-March 2013; period 2, April 2016-March 2017; and period 3, April 2018-March 2019) were eligible. These were set considering the timing of the 2014 and 2018 medical fee revisions (2014 for polypharmacy of three or more hypnotics, 2018 for long-term prescription of benzodiazepine receptor agonists for >12 months). The duration of consecutive prescriptions of hypnotics over 12 months was evaluated. Factors associated with short-term prescriptions of hypnotics were also investigated. RESULTS: In total, 186,535 participants were newly prescribed hypnotics. The mean duration of prescriptions was 2.9 months, and 9.3% of participants were prescribed hypnotics for 12 months. Prescription periods were not associated with short-term prescriptions of hypnotics. ORA use was associated with short-term prescriptions of hypnotics (adjusted hazard ratio, 1.077; 95% confidence interval, 1.035-1.120; p<0.001), but MRA use was not. CONCLUSION: Japanese policies had no statistically significant effect on long-term prescriptions of hypnotics. Although this study suggests initiating ORA for insomniacs as a candidate strategy to prevent long-term prescriptions of hypnotics, further research is necessary to draw conclusions. This article is protected by copyright. All rights reserved.

DOI PubMed

Preterm toddlers have low nighttime sleep quality and high daytime activity.

Yoko Asaka, Yusuke Mitani, Hidenobu Ohta, Takayo Nakazawa, Rika Fukutomi, Kyoko Kobayashi, Mayuko Kumagai, Hitomi Shinohara, Michiko Yoshida, Akiko Ando, Yuko Yoshimura, Machiko Nakagawa, Yoshihisa Oishi, Masato Mizushima, Hiroyuki Adachi, Yosuke Kaneshi, Keita Morioka, Yoshitaka Seto, Rinshu Shimabukuro, Michio Hirata, Takashi Ikeda, Miwa Ozawa, Masahiro Takeshima, Atsushi Manabe, Tsutomu Takahashi, Kazuo Mishima, Mitsuru Kikuchi, Hitoshi Yoda, Isao Kusakawa, Kazutoshi Cho

Scientific reports   12 ( 1 ) 20032 - 20032   2022年11月  [査読有り]

研究論文（学術雑誌）   国内共著

A number of studies have been made on the sleep characteristics of children born preterm in an attempt to develop methods to address the sleep problems commonly observed among such children. However, the reported sleep characteristics from these studies vary depending on the observation methods used, i.e., actigraphy, polysomnography and questionnaire. In the current study, to obtain reliable data on the sleep characteristics of preterm-born children, we investigated the difference in sleep properties between 97 preterm and 97 term toddlers of approximately 1.5 years of age using actigraphy. Actigraphy units were attached to the toddlers' waists with an adjustable elastic belt for 7 consecutive days, and a child sleep diary was completed by their parents. In the study, we found that preterm toddlers had more nocturnal awakenings and more daytime activity, suggesting that preterm-born children may have a different process of sleep development in their early development.

DOI PubMed

Attitudes and Difficulties Associated with Benzodiazepine Discontinuation.

Masahiro Takeshima, Yumi Aoki, Kenya Ie, Eiichi Katsumoto, Eichi Tsuru, Takashi Tsuboi, Ken Inada, Morito Kise, Koichiro Watanabe, Kazuo Mishima, Yoshikazu Takaesu

International journal of environmental research and public health   19 ( 23 )   2022年11月  [査読有り]

研究論文（学術雑誌）   国内共著

Long-term use of benzodiazepine receptor agonists (BZDs) may depend on clinicians' BZD discontinuation strategies. We aimed to explore differences in strategies and difficulties with BZD discontinuation between psychiatrists and non-psychiatrists and to identify factors related to difficulties with BZD discontinuation. Japanese physicians affiliated with the Japan Primary Care Association, All Japan Hospital Association, and Japanese Association of Neuro-Psychiatric Clinics were surveyed on the following items: age group, specialty (psychiatric or otherwise), preferred time to start BZD reduction after improvement in symptoms, methods used to discontinue, difficulties regarding BZD discontinuation, and reasons for the difficulties. We obtained 962 responses from physicians (390 from non-psychiatrists and 572 from psychiatrists), of which 94.0% reported difficulty discontinuing BZDs. Non-psychiatrists had more difficulty with BZD discontinuation strategies, while psychiatrists had more difficulty with symptom recurrence/relapse and withdrawal symptoms. Psychiatrists used more candidate strategies in BZD reduction than non-psychiatrists but initiated BZD discontinuation after symptom improvement. Logistic regression analysis showed that psychosocial therapy was associated with less difficulty in BZD discontinuation (odds ratio, 0.438; 95% confidence interval, 0.204-0.942; p = 0.035). Educating physicians about psychosocial therapy may alleviate physicians' difficulty in discontinuing BZDs and reduce long-term BZD prescriptions.

DOI PubMed

Relationship between clozapine exposure and the onset of appendicitis in schizophrenia patients: a retrospective cohort study.

Yuta Kawakita, Masahiro Takeshima, Tomonari Komatsu, Aya Imanishi, Dai Fujiwara, Yu Itoh, Kazuo Mishima

BMC psychiatry   22 ( 1 ) 653 - 653   2022年10月  [査読有り]

研究論文（学術雑誌）   国内共著

OBJECTIVE: Clozapine may cause serious side effects despite benefits in patients with schizophrenia. Thus, an accurate understanding of the side-effect profile of clozapine is extremely important in the management of its administration to patients with schizophrenia. Our aim was to validate the relationship between clozapine exposure and appendicitis onset in patients with schizophrenia. METHODS: In this study, we retrospectively compared the incidence and cumulative incidence of appendicitis in patients with schizophrenia with and without a history of clozapine exposure. Among the patients with schizophrenia who visited our hospital between June 2009 and August 2021, we extracted those with a history of clozapine treatment. Patients with a history of taking clozapine were defined as the clozapine exposure group, while the others were defined as the clozapine non-exposure group. Patients with a history of appendectomy before their initial visit to our hospital or with a history of clozapine use at other hospitals were excluded. RESULTS: There were 65 patients in the clozapine exposure group and 400 patients in the clozapine non-exposure group who met the inclusion criteria. The exposure group exhibited a remarkably higher incidence of appendicitis during the observation period than the non-exposure group (863 cases vs. 124 cases per 100,000 person-years). In particular, if limited to the period of clozapine exposure, the incidence of appendicitis is extremely high, at 2,086 cases per 100,000 person-years. Moreover, multivariable analysis showed that clozapine exposure was an independent factor contributing to the onset of appendicitis. CONCLUSIONS: Clozapine exposure is associated with appendicitis onset in patients with schizophrenia.

DOI PubMed

Development and validation of the Japanese version of the Hyperarousal Scale.

Naoko Ayabe, Shun Nakajima, Isa Okajima, Ken Inada, Wataru Yamadera, Hidehisa Yamashita, Hisateru Tachimori, Yuichi Kamei, Masahiro Takeshima, Yuichi Inoue, Kazuo Mishima

BMC psychiatry   22 ( 1 ) 617 - 617   2022年09月  [査読有り]

研究論文（学術雑誌）   国内共著

BACKGROUND: The objectives of this study were to develop a Japanese version of the Hyperarousal Scale (HAS-J) and investigate its factor structure, reliability, and validity, as well as to calculate a cutoff score for the HAS-J and assess different levels of hyperarousal in insomnia patients and community dwellers. METHODS: We recruited 224 outpatients receiving insomnia treatment (56.3% women; mean age 51.7 ± 15.6 years) and 303 community dwellers aged 20 years or older (57.8% women; mean age 43.9 ± 15.2 years). Exploratory and confirmatory factor analysis was performed to examine the factor structure of the HAS-J. Cronbach's α and McDonald's ω were then used to test internal consistency. To examine the scale's validity, we determined correlations between the HAS-J and other indexes and compared HAS-J scores between insomnia patients and community dwellers. We also compared HAS-J scores between two community-dweller groups (normal and poor sleepers) and two insomnia patient groups (with and without alleviation after treatment). RESULTS: Following exploratory and confirmatory factor analysis, a 20-item measure emerged comprising three factors: "Introspectiveness and Reactivity," "Neuroticism," and "Insomnia." Confirmatory factor analysis showed a generally good fit for the model of the three-factor structure suggested by the exploratory factor analysis loadings (χ2 (163) = 327.423, (p <  0.001), CFI = 0.914, GFI = 0.872, AGFI = 0.835, RMSEA = 0.067). In insomnia patients, internal consistency indicated sufficient reliability of the HAS-J. Correlation analysis showed weak to moderate positive correlations of the HAS-J score with other indexes, indicating concurrent validity of the HAS-J. All HAS-J subscale scores were significantly higher in insomnia patients than in community dwellers. Additionally, the total score in patients with alleviation of insomnia was comparable to that in poor sleepers and significantly higher than that in normal sleepers. CONCLUSIONS: This study demonstrated the reliability and validity of the HAS-J, indicating that it is useful as a clinical scale of hyperarousal. The high level of hyperarousal in insomnia patients who were assessed to be in remission by the Insomnia Severity Index suggests a risk of insomnia recurrence in these patients.

DOI PubMed

Longitudinal survey of depressive symptoms among university students during the COVID-19 pandemic in Japan.

Kyoko Nomura, Teiichiro Yamazaki, Eri Maeda, Junko Hirayama, Kyoichi Ono, Masahito Fushimi, Kazuo Mishima, Fumio Yamamoto

Frontiers in psychology   13   863300 - 863300   2022年08月  [査読有り]

研究論文（学術雑誌）   国内共著

While changes in response to the different stages of the pandemic remain unknown, this study investigated the longitudinal impact of the COVID-19 pandemic on depressive symptoms in Japanese university students and identified factors associated with new onset of depression and suicidal ideation. Two surveys were conducted at one university in Akita, Japan, during the first COVID-19 outbreak period (T1: May-June 2020) and 1 year later (T2: March-May 2021). Moderate depressive symptoms were defined as a Patient Health Questionnaire-9 score ≥ 10 and suicide-related ideation score ≥ 1 on question 9 of the questionnaire. Among 985 students who completed surveys in T1 and T2, participants with moderate depressive symptoms and suicide-related ideation increased from 11 to 17% and from 5.8 to 11.8%, respectively. Among 872 students at risk after excluding those with moderate depressive symptoms at T1, 103 students (11.8%) developed moderate depressive symptoms at T2. Among the 928 students at risk, after excluding those who had suicidal ideation at T1, 79 (8.5%) developed suicidal ideation. Multivariate logistic modeling revealed financial insecurity and academic performance as risk factors (ps < 0.01), while having someone to consult about worries was a coping factor for depressive symptoms and suicidal ideation (ps < 0.001). Our findings demonstrated that socioenvironmental factors may determine depressive symptoms of university students.

DOI PubMed

Development and acceptability of a decision aid for major depressive disorder considering discontinuation of antidepressant treatment after remission.

Yumi Aoki, Yoshikazu Takaesu, Hajime Baba, Jun-Ichi Iga, Hikaru Hori, Takeshi Inoue, Kazuo Mishima, Aran Tajika, Masaki Kato

Neuropsychopharmacology reports   42 ( 3 ) 306 - 314   2022年07月  [査読有り]

研究論文（学術雑誌）   国内共著

AIM: While evidence-based antidepressant treatment is available for major depressive disorder, standard approaches for discontinuation of antidepressants after remission have not yet been established. Decision aids are structured clinical tools that facilitate shared decision-making between patients and healthcare providers. This study aimed to describe the development process and acceptability of decision aids for major depressive disorder following discontinuation of antidepressant treatment after remission. METHODS: We systematically developed a decision aids according to the International Patient Decision Aid Standards. First, a decision aids prototype was created using the results of a systematic review and meta-analysis previously conducted to identify the consequences of continuing and discontinuing antidepressant treatment. Second, a mixed-methods questionnaire (alpha acceptability testing) was administered to patients and healthcare providers to improve the decision aids prototype and develop it into a final version acceptable for clinical settings. RESULTS: Our decision aids consisted of a description of major depressive disorder, the option to continue or discontinue antidepressant treatment, the advantages and disadvantages of each option, the consequences of each option, and value clarification exercises for each option. The patients (n = 22) reported that the decision aids had acceptable language (91%), adequate information (91%), and a well-balanced presentation (95%). Healthcare providers (n = 20) provided favorable feedback. The final decision aids fulfilled all six International Patient Decision Aid Standards qualifying criteria. CONCLUSION: We successfully developed a decision aids for discontinuation of antidepressant treatment after remission, which could be used during the shared decision-making process. Further studies are needed to verify the effects of using the decision aids during the shared decision-making process.

DOI PubMed

Relationship among psychotic features, benzodiazepine receptor agonists, and rehospitalization in patients with electroconvulsive therapy-responsive major depressive disorder: A retrospective 2-year observational study.

Akise Umakoshi, Masahiro Takeshima, Yu Itoh, Mari Yamamoto, Nana Shibata, Masaya Ogasawara, Naoko Ayabe, Kazuo Mishima

Neuropsychopharmacology reports   42 ( 4 ) 449 - 456   2022年07月  [査読有り]

研究論文（学術雑誌）   国内共著

AIM: It is controversial whether psychotic features are a risk factor for relapse in patients with electroconvulsive therapy-responsive major depressive disorder. A recent study reported that benzodiazepine receptor agonists reduce relapse of psychotic depression. As long-term use of these agonists may induce dependence, further research is required. We examined whether psychotic features are associated with rehospitalization in electroconvulsive therapy-responsive major depressive disorder patients. We also investigated whether taking benzodiazepine receptor agonists at the end of electro-convulsive therapy was associated with rehospitalization among patients with psychotic depression. METHODS: This study included 47 hospitalized patients (22 with psychotic depression, 25 with non-psychotic depression) who had responded to electroconvulsive therapy. Rehospitalization for major depressive episodes within two years from the last session was investigated. RESULTS: Twenty-three subjects (49%) were rehospitalized during the two-year follow-up. Kaplan-Meier analysis revealed no difference in rehospitalization between patients with psychotic and non-psychotic depression (Log-rank P = 0.87). Among the 22 responders to electroconvulsive therapy with psychotic depression, there was no difference in benzodiazepine receptor agonist use at the end of electroconvulsive therapy between the rehospitalization and non-rehospitalization groups. CONCLUSION: Our exploratory study found no difference in the benzodiazepine receptor agonists use at the end of electroconvulsive therapy between rehospitalization and non-rehospitalization groups in patients with electroconvulsive therapy-responsive psychotic depression. Thus, the relapse-preventing effect of these agonists in psychotic depression should be investigated in future randomized controlled trials. Further research is also needed to determine whether psychotic features are associated with rehospitalization in these patients.

DOI PubMed

Changes in psychotropic polypharmacy and high-potency prescription following policy change: Findings from a large scale Japanese claims database.

Masahiro Takeshima, Minori Enomoto, Masaya Ogasawara, Mizuki Kudo, Yu Itoh, Kazuhisa Yoshizawa, Dai Fujiwara, Yoshikazu Takaesu, Kazuo Mishima

Psychiatry and clinical neurosciences   76 ( 9 ) 475 - 477   2022年06月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI PubMed

Melatonin Treatment and Adequate Sleep Hygiene Interventions in Children with Autism Spectrum Disorder: A Randomized Controlled Trial

Masaharu Hayashi , Kazuo Mishima , Michio Fukumizu , Hiroyuki Takahashi , Yuko Ishikawa , Izumi Hamada , Hideyuki Sugioka , Osamu Yotsuya , Yushiro Yamashita

J Autism Dev Disord.   52   2784 - 2793   2022年06月  [査読有り]

研究論文（学術雑誌）   国内共著

Cost-effectiveness analysis of lemborexant for treating insomnia in Japan: a model-based projection, incorporating the risk of falls, motor vehicle collisions, and workplace accidents.

Shunya Ikeda, Mie Azuma, Kenichi Fujimoto, Hidetoshi Shibahara, Sachie Inoue, Margaret Moline, Mika Ishii, Kazuo Mishima

Psychological medicine   52 ( 13 ) 1 - 13   2022年05月  [査読有り]

研究論文（学術雑誌）   国内共著

BACKGROUND: Lemborexant has demonstrated statistically significant improvements in sleep onset and sleep maintenance compared with placebo and zolpidem tartrate extended release, measured both objectively using polysomnography and subjectively using sleep diaries, in the phase 3 clinical trial SUNRISE 1. This study evaluated the cost-effectiveness of lemborexant compared with suvorexant, zolpidem immediate release (IR), and untreated insomnia. METHODS: A decision-tree model was developed for falls, motor vehicle collisions, and workplace accidents associated with insomnia and insomnia treatments from a Japanese healthcare perspective and with a 6-month time horizon. The model extracted subjective sleep onset latency treatment responses and disutility values for non-responders from SUNRISE 1. Cost-effectiveness was assessed using incremental cost per quality-adjusted life year (QALY) gained. One-way and probabilistic sensitivity analyses were conducted to evaluate the impact of parameter uncertainty on the results. RESULTS: In the base-case analysis, the mean estimated QALYs for lemborexant, suvorexant, zolpidem-IR, and untreated insomnia were 0.4220, 0.4204, 0.4113, and 0.4163, and expected medical costs were JPY 34 034, JPY 38 371, JPY 38 139, and JPY 15 383, respectively. Lemborexant saved JPY 4337 and JPY 4105 compared with suvorexant or zolpidem-IR, respectively, while conferring QALY benefits. The incremental cost-effectiveness ratio (ICER) of lemborexant compared with that of untreated insomnia was JPY 3 220 975 /QALY. Lemborexant was dominant over suvorexant and zolpidem-IR and was cost-effective when compared with untreated insomnia. Sensitivity analyses supported the results' robustness. CONCLUSIONS: In a Japanese clinical practice setting, lemborexant may represent a better investment for treating insomnia in the healthcare system in Japan.

DOI PubMed

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

Taku Miyagawa, Susumu Tanaka, Mihoko Shimada, Noriaki Sakai, Kotomi Tanida, Nozomu Kotorii, Tatayu Kotorii, Yu Ariyoshi, Yuji Hashizume, Kimihiro Ogi, Hiroshi Hiejima, Takashi Kanbayashi, Aya Imanishi, Azusa Ikegami, Yuichi Kamei, Akiko Hida, Yamato Wada, Masayuki Miyamoto, Masanori Takami, Hideaki Kondo, Yoshiyuki Tamura, Yukari Taniyama, Naoto Omata, Tomoyuki Mizuno, Shunpei Moriya, Hirokazu Furuya, Mitsuhiro Kato, Kayoko Kato, Jun Ishigooka, Kazuhito Tsuruta, Shigeru Chiba, Naoto Yamada, Masako Okawa, Koichi Hirata, Kenji Kuroda, Kazuhiko Kume, Naohisa Uchimura, Masaaki Kitada, Tohru Kodama, Yuichi Inoue, Seiji Nishino, Kazuo Mishima, Katsushi Tokunaga, Makoto Honda

NPJ genomic medicine   7 ( 1 ) 29 - 29   2022年04月  [査読有り]

研究論文（学術雑誌）   国内共著

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.

DOI PubMed

不登校を併存した概日リズム睡眠―覚醒障害に対する高照度光療法の効果：ランダム化比較試験

井上 建, 嶋田 怜士, 春日 晃子, 椎橋 文子, 北島 翼, 松島 奈穂, 荒川 明里, 大戸 佑二, 大谷 良子, 三島 和夫, 作田 亮一

脳と発達 ( 一般社団法人 日本小児神経学会 )  54 ( 2 ) 135 - 137   2022年03月  [査読有り]

研究論文（学術雑誌）   国内共著

<p> 不登校を伴う概日リズム睡眠―覚醒障害に対する高照度光療法（BLT）のパイロット研究を行った．12名（年齢：13～15歳）の被験者を3週間の短期入院療法単独群とBLT併用群の2群に無作為に割り付けた．脱落した2名を除いた全症例では起床・入眠時間は有意に改善した．単独群（5例）は退院2週後に起床時間が後退/再燃したが，併用群（5例）は起床時間を維持できた．さらに併用群は，有意に低い不眠重症度質問票得点を示した．以上からBLTの有効性が示唆された．</p>

DOI CiNii Research

Development and acceptability of a decision aid for chronic insomnia considering discontinuation of benzodiazepine hypnotics.

Aoki, Yumi ; Takaesu, Yoshikazu ; Suzuki, Masahiro; Okajima, Isa ; Takeshima, Masahiro ; Shimura, Akiyoshi ; Utsumi, Tomohiro ; Kotorii, Nozomu ; Yamashita, Hidehisa ; Kuriyama, Kenichi ; Watanabe, Norio ; Mishima, Kazuo

Neuropsychopharmacol Rep.     2022年03月  [査読有り]

研究論文（学術雑誌）   国内共著

Diabetes and anxiety were associated with insomnia among Japanese male truck drivers.

Yuta Sugano, Takashi Miyachi, Tomoka Ando, Toyoto Iwata, Toshikazu Yamanouchi, Kazuo Mishima, Kyoko Nomura

Sleep medicine   90   102 - 108   2022年02月  [査読有り]

研究論文（学術雑誌）   国内共著

OBJECTIVE/BACKGROUND: Insomnia among truck drivers may contribute to traffic accidents. We previously reported that truck drivers had adverse lifestyle habits, including smoking and drinking alcohol, in addition to enforced sedentarism making them more vulnerable to lifestyle-related diseases. This study aimed to investigate the association between insomnia and diabetes, as well as the effect of anxiety related to driving tasks on this association. PATIENTS/METHODS: A total of 755 male truck drivers under 65 years of age who belonged to Akita prefecture Truck Association in Japan were investigated. Insomnia and State-Trait Anxiety Inventory (STAI) score were assessed using a self-administered questionnaire in 2020. Insomnia was defined in accordance with International classification of sleep disorders-third edition. Diabetes was defined as a fasting blood glucose level of ≥126 mg/dL and/or use of anti-diabetic drugs using data obtained from health checkups in 2018. RESULTS: The proportions of truck drivers with insomnia and diabetes were 13.9% and 9.7%, respectively, which were higher than those in the general working population in Japan. After adjusting for age, smoking, drinking, daily hours of driving and sleep, and hypertension, the STAI score (odds ratio [OR] for the highest quartile vs. the lowest: 3.88, 95% confidence interval [CI]: 1.84-8.18) and diabetes (OR: 2.49, 95% CI: 1.11-5.60) were found to be associated with insomnia. A statistical interaction with STAI scores was not observed between diabetes and insomnia. CONCLUSIONS: The present study demonstrated that diabetes and anxiety are independently and significantly associated with insomnia in male Japanese truck drivers.

DOI PubMed

Genome-wide association study of idiopathic hypersomnia in a Japanese population

Kotomi Tanida, Mihoko Shimada, Seik-Soon Khor, Hiromi Toyoda, Kayoko Kato, Nozomu Kotorii, Tatayu Kotorii, Yu Ariyoshi, Takao Kato, Hiroshi Hiejima, Motohiro Ozone, Naohisa Uchimura, Azusa Ikegami, Kazuhiko Kume, Takashi Kanbayashi, Aya Imanishi, Yuichi Kamei, Akiko Hida, Yamato Wada, Kenji Kuroda, Masayuki Miyamoto, Koichi Hirata, Masanori Takami, Naoto Yamada, Masako Okawa, Naoto Omata, Hideaki Kondo, Tohru Kodama, Yuichi Inoue, Kazuo Mishima, Makoto Honda, Katsushi Tokunaga, Taku Miyagawa

SLEEP AND BIOLOGICAL RHYTHMS ( SPRINGER JAPAN KK )  20 ( 1 ) 137 - 148   2022年01月  [査読有り]

研究論文（学術雑誌）   国内共著

Idiopathic hypersomnia (IH) is a rare sleep disorder characterized by excessive daytime sleepiness, great difficulty upon awakening, and prolonged sleep time. In contrast to narcolepsy type 1, which is a well-recognized hypersomnia, the etiology of IH remains poorly understood. No susceptibility loci for IH have been identified, although familial aggregations have been observed among patients with IH. Narcolepsy type 1 is strongly associated with human leukocyte antigen (HLA)-DQB1*06:02; however, no significant associations between IH and HLA alleles have been reported. To identify genetic variants that affect susceptibility to IH, we performed a genome-wide association study (GWAS) and two replication studies involving a total of 414 Japanese patients with IH and 6587 healthy Japanese individuals. A meta-analysis of the three studies found no single-nucleotide polymorphisms (SNPs) that reached the genome-wide significance level. However, we identified several candidate SNPs for IH. For instance, a common genetic variant (rs2250870) within an intron of PDE9A was suggestively associated with IH. rs2250870 was significantly associated with expression levels of PDE9A in not only whole blood but also brain tissues. The leading SNP in the PDE9A region was the same in associations with both IH and PDE9A expression. PDE9A is a potential target in the treatment of several brain diseases, such as depression, schizophrenia, and Alzheimer's disease. It will be necessary to examine whether PDE9A inhibitors that have demonstrated effects on neurophysiologic and cognitive function can contribute to the development of new treatments for IH, as higher expression levels of PDE9A were observed with regard to the risk allele of rs2250870. The present study constitutes the first GWAS of genetic variants associated with IH. A larger replication study will be required to confirm these associations.

DOI

Sleep Apnea Syndrome (SAS) Clinical Practice Guidelines 2020.

Tsuneto Akashiba, Yuichi Inoue, Naohisa Uchimura, Motoharu Ohi, Takatoshi Kasai, Fusae Kawana, Shigeru Sakurai, Misa Takegami, Rho Tachikawa, Takeshi Tanigawa, Shintaro Chiba, Kazuo Chin, Satoru Tsuiki, Morio Tonogi, Hiroshi Nakamura, Takeo Nakayama, Koji Narui, Tomoko Yagi, Motoo Yamauchi, Yoshihiro Yamashiro, Masahiro Yoshida, Toru Oga, Yasuhiro Tomita, Satoshi Hamada, Kimihiko Murase, Hiroyuki Mori, Hiroo Wada, Makoto Uchiyama, Hiromasa Ogawa, Kazumichi Sato, Seiichi Nakata, Kazuo Mishima, Shin-Ichi Momomura

Respiratory investigation   60 ( 1 ) 3 - 32   2022年01月  [査読有り]

研究論文（学術雑誌）   国内共著

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.

DOI PubMed

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

Yu Itoh, Masahiro Takeshima, Yoshitaka Kaneita, Naohisa Uchimura, Yuichi Inoue, Makoto Honda, Wataru Yamadera, Norio Watanabe, Shingo Kitamura, Isa Okajima, Naoko Ayabe, Kyoko Nomura, Kazuo Mishima

Nature and science of sleep   14   61 - 73   2022年01月  [査読有り]

研究論文（学術雑誌）   国内共著

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.

DOI PubMed

Training types associated with knowledge and experience in public health workers.

Zui Narita, Yoshio Yamanouchi, Kazuo Mishima, Yoko Kamio, Naoko Ayabe, Ryoko Kakei, Yoshiharu Kim

Archives of public health = Archives belges de sante publique   80 ( 1 ) 44 - 44   2022年01月  [査読有り]

研究論文（学術雑誌）   国内共著

BACKGROUND: Training non-specialist workers in mental healthcare improves knowledge, attitude, confidence, and recognition of mental illnesses. However, still little information is available on which type of mental health training is important in the improvement of these capacities. METHODS: We studied web-based survey data of 495 public health workers to examine training types associated with knowledge and experience in supporting individuals with mental illness. Multivariable logistic regression analysis was conducted to evaluate the association between a lack of knowledge and experience (outcome) and mental health training (exposure). We fitted three regression models. Model 1 evaluated unadjusted associations. Model 2 adjusted for age and sex. Model 3 adjusted for age, sex, years of experience, mental health full-time worker status, and community population. Bias-corrected and accelerated bootstrap confidence intervals (CIs) were used. RESULTS: For all training types, the association between a lack of knowledge and experience and mental health training attenuated as the model developed. In Model 3, a lack of knowledge and experience was significantly associated with training in specific illness (OR, 0.54; 95% CI, 0.32-0.93) and screening and assessment (OR, 0.63; 95% CI, 0.39-0.99). Non-significant results were produced for training in counseling, psychosocial support, collaborative work, and law and regulation in Model 3. CONCLUSIONS: We believe that the present study provides meaningful information that training in specific illness and screening and assessment may lead to knowledge and experience of public health workers. Further studies should employ a longitudinal design and validated measurements.

DOI PubMed

Cross-sectional survey of depressive symptoms and suicide-related ideation at a Japanese national university during the COVID-19 stay-home order

Nomura K.

Environmental Health and Preventive Medicine ( Environmental Health and Preventive Medicine )  26 ( 1 )   2021年12月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Daytime nap and nighttime breastfeeding are associated with toddlers’ nighttime sleep

Nakagawa M.

Scientific Reports ( Scientific Reports )  11 ( 1 )   2021年12月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Development and acceptability of a decision aid for chronic insomnia considering discontinuation of benzodiazepine hypnotics.

Yumi Aoki, Yoshikazu Takaesu, Masahiro Suzuki, Isa Okajima, Masahiro Takeshima, Akiyoshi Shimura, Tomohiro Utsumi, Nozomu Kotorii, Hidehisa Yamashita, Kenichi Kuriyama, Norio Watanabe, Kazuo Mishima

Neuropsychopharmacology reports   42 ( 1 ) 10 - 20   2021年11月  [査読有り]

研究論文（学術雑誌）   国内共著

AIM: To describe the development and acceptability of a decision aid (DA) for chronic insomnia considering discontinuation of benzodiazepine (BZD) and benzodiazepine receptor agonist (BZRA) hypnotics, and if discontinuing, tapering with or without cognitive behavioral therapy for insomnia (CBT-I). METHODS: We reviewed relevant literature describing chronic insomnia to identify options. We used the results of the systematic review and meta-analysis conducted previously to determine the related outcomes of two options: discontinuation of BZD/BZRA hypnotics by gradual tapering alone and discontinuation of BZD/BZRA hypnotics by gradual tapering with CBT-I. We then developed a prototype of DA following the International Patient Decision Aid Standards. A mixed methods survey was conducted to assess the acceptability among patients and healthcare providers. RESULTS: The prototype consisted of a description of insomnia, options of continuing or discontinuing BZD/BRZA hypnotics (if discontinuing, the options of tapering hypnotics with or without CBT-I), pros and cons of each option, and a value clarification exercise. Patients (n = 24) reported that the DA had acceptable language (79%), adequate information (71%), and well-balanced presentation (91%). Healthcare providers (n = 20) also provided favorable feedback. CONCLUSION: We developed a DA for chronic insomnia considering discontinuation of BZD/BRZA hypnotics, which was acceptable for stakeholders. The developed DA was designed to support patients and healthcare providers to make a decision about whether to discontinue BZD/BRZA hypnotics.

DOI PubMed

Aripiprazole as a new treatment for the prolonged nocturnal sleep of patient with idiopathic hypersomnia.

Aya Imanishi, Yuki Omori, Hideaki Ishido, Yohei Sagawa, GoEun Han, Kazuo Mishima, Takashi Kanbayashi, Hideaki Kondo

Psychiatry and clinical neurosciences   75 ( 10 ) 320 - 322   2021年10月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI PubMed

Pregabalin withdrawal in patients without psychiatric disorders taking a regular dose of pregabalin: A case series and literature review.

Hayahito Ishikawa, Masahiro Takeshima, Hiroyasu Ishikawa, Naoko Ayabe, Hidenobu Ohta, Kazuo Mishima

Neuropsychopharmacology reports   41 ( 3 ) 434 - 439   2021年09月  [査読有り]

研究論文（学術雑誌）   国内共著

Pregabalin is a drug that can cause psychiatric symptoms via pregabalin withdrawal. Prior reports on pregabalin withdrawal have mainly focused on cases with pregabalin dependence or abuse, and little attention has been paid to patients who are prescribed regular doses of pregabalin. Herein, we report three cases of pregabalin withdrawal in patients without psychiatric disorders, taking regular doses of pregabalin, who developed psychiatric symptoms such as insomnia and anxiety after abrupt discontinuation of pregabalin. In addition, we conducted a systematic review of six case reports (previous studies) of pregabalin withdrawal under regular doses of pregabalin. Among the six cases, three patients had no comorbid mental or substance use disorders, the dose of pregabalin ranged from 150 to 600 mg/d, and the duration of pregabalin use ranged from a few weeks to many years. Of these six cases of pregabalin withdrawal, five had psychopathological symptoms, three had vegetative symptoms, and three had neurologic and physical complications. We concluded that since pregabalin withdrawal can occur even with regular doses and short-term use, clinicians must carefully reduce pregabalin doses when reducing or discontinuing treatment, paying close attention to withdrawal symptoms. Our case series sheds light on the scant evidence from previous research on physical dependence in patients who are taking regular doses of pregabalin. Furthermore, our cases were also valuable in demonstrating that pregabalin withdrawal can occur even after a relatively short period of 2 months.

DOI PubMed

Sleep maturation influences cognitive development of preterm toddlers.

Akiko Ando, Hidenobu Ohta, Yuko Yoshimura, Machiko Nakagawa, Yoko Asaka, Takayo Nakazawa, Yusuke Mitani, Yoshihisa Oishi, Masato Mizushima, Hiroyuki Adachi, Yosuke Kaneshi, Keita Morioka, Rinshu Shimabukuro, Michio Hirata, Takashi Ikeda, Rika Fukutomi, Kyoko Kobayashi, Miwa Ozawa, Masahiro Takeshima, Atsushi Manabe, Tsutomu Takahashi, Kazuo Mishima, Isao Kusakawa, Hitoshi Yoda, Mitsuru Kikuchi, Kazutoshi Cho

Scientific reports   11 ( 1 ) 15921 - 15921   2021年08月  [査読有り]

研究論文（学術雑誌）   国内共著

Our recent study on full-term toddlers demonstrated that daytime nap properties affect the distribution ratio between nap and nighttime sleep duration in total sleep time but does not affect the overall total amount of daily sleep time. However, there is still no clear scientific consensus as to whether the ratio between naps and nighttime sleep or just daily total sleep duration itself is more important for healthy child development. In the current study, to gain an answer to this question, we examined the relationship between the sleep properties and the cognitive development of toddlers born prematurely using actigraphy and the Kyoto scale of psychological development (KSPD) test. 101 premature toddlers of approximately 1.5 years of age were recruited for the study. Actigraphy units were attached to their waist with an adjustable elastic belt for 7 consecutive days and a child sleep diary was completed by their parents. In the study, we found no significant correlation between either nap or nighttime sleep duration and cognitive development of the preterm toddlers. In contrast, we found that stable daily wake time was significantly associated with better cognitive development, suggesting that sleep regulation may contribute to the brain maturation of preterm toddlers.

DOI PubMed

Attention-deficit/hyperactivity disorder symptoms and sleep problems in preschool children: the role of autistic traits

Andrew Stickley, Aya Shirama, Shingo Kitamura, Yoko Kamio, Hidetoshi Takahashi, Aya Saito, Hideyuki Haraguchi, Hirokazu Kumazaki, Kazuo Mishima, Tomiki Sumiyoshi

Sleep Medicine ( Elsevier BV )  83   214 - 221   2021年07月  [査読有り]

研究論文（学術雑誌）   国内共著

BACKGROUND: Sleep problems are elevated in children with attention-deficit/hyperactivity disorder (ADHD). However, until now there has been comparatively little research on the role of autistic traits in this association. The current study examined the association between ADHD symptoms and sleep problems in Japanese preschool children and whether autistic traits might also be important for this relationship. METHODS: Data were analyzed from 1053 children (average age 64.14 months, range 58-71; 50.3% male) that were drawn from the Tama Children's Survey (TCS). Parent-reported information was obtained on ADHD symptoms using the Strengths and Difficulties Questionnaire (SDQ) and autistic traits with the Social Responsiveness Scale Second Edition (SRS-2). Parents also provided information on three different categories of sleep problems experienced by their children - parasomnias, sleep disordered breathing and awakening/daytime problems. Ordinal logistic regression analysis was used to examine the associations. RESULTS: In analyses adjusted for sociodemographic factors, the mother's mental health and child's emotional problems, compared to children with no ADHD symptoms or autistic traits, children with only ADHD symptoms had significantly increased odds for only one of 11 individual sleep problems - waking in a negative mood. In contrast, children with comorbid ADHD symptoms and autistic traits had elevated odds for five sleep problems with odds ratios ranging from 2.10 (takes time to become alert in the morning) to 3.46 (excessive body movement while sleeping). CONCLUSIONS: Sleep problems may be especially elevated in children with comorbid ADHD symptoms and autistic traits.

DOI PubMed

Association between sleep habits/disorders and emotional/behavioral problems among Japanese children.

Masahiro Takeshima, Hidenobu Ohta, Tomoko Hosoya, Masakazu Okada, Yukako Iida, Aiko Moriwaki, Hidetoshi Takahashi, Yoko Kamio, Kazuo Mishima

Scientific reports ( NATURE RESEARCH )  11 ( 1 ) 11438 - 11438   2021年06月  [査読有り]

研究論文（学術雑誌）   国内共著

Actual sleep status and the association between sleep habits/disorders and emotional/behavioral problems among children in the development stage have not been fully clarified. A questionnaire survey was conducted on the sleep habits/disorders (Brief Child Sleep Questionnaire; BCSQ) and emotional/behavioral problems (Strengths and Difficulties Questionnaire; SDQ) of 87,548 children enrolled in ordinary classes in nine grade levels from the first grade of elementary school to the third grade of junior high school from December 2009 to April 2010. As school grade increased, children's bedtimes were delayed and sleep duration was reduced by 2.0 h over the nine grade levels. Based on the BCSQ, 18.3% of children were judged to have some type of sleep disorder, and about 30% to 40% of children had sleep symptoms at bedtime, during sleep, and at wake time. Multiple regression analysis showed that emotional and behavioral problems were associated with presence of any sleep symptom, longer sleep latency, and longer awake time after sleep onset, whereas total sleep time was not. Sleep symptoms at wake time were most strongly associated with emotional and behavioral problems. Status of sleep habits/disorders should be considered when interpreting emotional/behavioral problems in school-age children.

DOI PubMed

Development and validation of the Benzodiazepine Hypnotics Withdrawal Symptom Scale (BHWSS) based on item response theory.

Hajime Narisawa, Yuichi Inoue, Mina Kobayashi, Isa Okajima, Takashi Kikuchi, Tatsuo Kagimura, Kentaro Matsui, Ken Inada, Kazuo Mishima

Psychiatry research   300   113900 - 113900   2021年06月  [査読有り]

研究論文（学術雑誌）   国内共著

This study aimed to refine and validate the Benzodiazepine Hypnotics Withdrawal Symptom Scale (BHWSS). The 12-item prototype version of the BHWSS was administered to a sample of 346 patients with chronic insomnia (161 males and 185 females, mean age: 52.8 ± 16.6 years) who had been taking hypnotics (benzodiazepines [BZDs] or BZD receptor agonists) for at least 3 months. The item information curve indicated that two of the 12 BHWSS items should be excluded. As a result of analyzing the 10-item version of the BHWSS (revised-BHWSS), the contribution rate in the case of the factor 1 was 0.49, Cronbach's α was 0.90, and the reliability coefficient ω was 0.91. An analysis of the item information curve for the revised-BHWSS indicated that the information amount per item increased from 3.90 for the original 12-item BHWSS to 4.37 for the 10-item revised-BHWSS. The receiver operating characteristic curve indicated that 6.5 points on the revised-BHWSS was the most appropriate cutoff for estimating moderate or severe withdrawal symptoms using the Benzodiazepine Dependence Self-Report Questionnaire as a reference. These results suggest that the 10-item revised-BHWSS has sufficient reliability and validity for evaluating the severity of withdrawal symptoms after discontinuing BZDs.

DOI PubMed

The Role of the Thalamus in the Neurological Mechanism of Subjective Sleepiness: An fMRI Study

Yuki Motomura, Shingo Kitamura, Kyoko Nakazaki, Kentaro Oba, Ruri Katsunuma, Yuri Terasawa, Akiko Hida, Yoshiya Moriguchi, Kazuo Mishima

Nature and Science of Sleep ( Informa UK Limited )  Volume 13   899 - 921   2021年06月  [査読有り]

研究論文（学術雑誌）   国内共著

Purpose: The thalamus, the region that forms the attentional network and transmits external sensory signals to the entire brain, is important for sleepiness. Herein, we examined the relationship between activity in the thalamus-seed brain network and subjective sleepiness. Materials and Methods: Fifteen healthy male participants underwent an experiment comprising a baseline evaluation and two successive interventions, a 9-day sleep extension followed by 1-night total sleep deprivation. Pre- and post-intervention tests included the Karolinska sleepiness scale and neuroimaging for arterial spin labeling and functional connectivity. We examined the association between subjective sleepiness and the functional magnetic resonance imaging indices. Results: The functional connectivity between the left or right thalamus and various brain regions displayed a significant negative association with subjective sleepiness, and the functional connectivity between the left and right thalamus displayed a significant positive association with subjective sleepiness. The graph theory analysis indicated that the number of positive functional connectivity related to the thalamus showed a strong negative association with subjective sleepiness, and conversely, the number of negative functional connectivity showed a positive association with subjective sleepiness. Arterial spin labeling analysis indicated that the blood flow in both the left and right thalami was significantly negatively associated with subjective sleepiness. Functional connectivity between the anterior cingulate cortex and salience network areas of the left insular cortex, and that between the anterior and posterior cingulate cortices showed a strong positive and negative association with subjective sleepiness, respectively. Conclusion: Subjective sleepiness and the thalamic-cortical network dynamics are strongly related, indicating the application of graph theory to study sleepiness and consciousness. These results also demonstrate that resting functional connectivity largely reflects the "state" of the subject, suggesting that the control of sleep and conscious states is essential when using functional magnetic resonance imaging indices as biomarkers.

DOI PubMed

Melatonin Treatment and Adequate Sleep Hygiene Interventions in Children with Autism Spectrum Disorder: A Randomized Controlled Trial.

Masaharu Hayashi, Kazuo Mishima, Michio Fukumizu, Hiroyuki Takahashi, Yuko Ishikawa, Izumi Hamada, Hideyuki Sugioka, Osamu Yotsuya, Yushiro Yamashita

Journal of autism and developmental disorders   52 ( 6 ) 2784 - 2793   2021年06月  [査読有り]

研究論文（学術雑誌）   国内共著

Robust clinical evidence has not been available for melatonin, a drug commonly administered for treating sleep problems of children with autism spectrum disorder (ASD). In a phase 3 randomized, placebo-controlled clinical trial, we administered 1-mg melatonin (n = 65), 4-mg melatonin (n = 65), or placebo (n = 66) to196 children with ASD once daily before bedtime under adequate sleep hygiene interventions. The primary outcome was sleep onset latency (SOL) assessed with the electronic sleep diary. SOL shortened significantly in the 1- and 4-mg melatonin groups compared to the placebo group (- 22.0, - 28.0, and - 5.0 min, respectively; p < 0.0001 each). This therapeutic regimen of melatonin is a reasonable clinical approach to cope with ASD-emergent difficulties in children with ASD.

DOI PubMed

Parthenogenetic mosaicism: generation via second polar body retention and unmasking of a likely causative PER2 variant for hypersomnia.

Yohei Masunaga, Masayo Kagami, Fumiko Kato, Takeshi Usui, Takako Yonemoto, Kazuo Mishima, Maki Fukami, Kazushi Aoto, Hirotomo Saitsu, Tsutomu Ogata

Clinical epigenetics   13 ( 1 ) 73 - 73   2021年04月  [査読有り]

研究論文（学術雑誌）   国内共著

BACKGROUND: Parthenogenetic mosaicism is an extremely rare condition identified only in five subjects to date. The previous studies indicate that this condition is mediated by parthenogenetic activation and is free from a specific phenotype ascribed to unmaking of a maternally inherited recessive variant in the parthenogenetic cell lineage. RESULTS: We examined a 28-year-old Japanese 46,XX female with Silver-Russell syndrome and idiopathic hypersomnia. The results revealed (1) predominance of maternally derived alleles for all the differentially methylated regions examined; (2) no disease-related copy-number variant; (3) two types of regions for all chromosomes, i.e., four BAF (B-allele frequency) band regions with single major microsatellite peaks of maternal origin and single minor microsatellite peaks of non-maternal (paternal) origin, and six BAF band regions with single major microsatellite peaks of maternal origin and two minor microsatellite peaks of maternal and non-maternal (paternal) origin; (4) an unmasked extremely rare PER2 variant (c.1403G>A:p.(Arg468Gln)) with high predicted pathogenicity; (5) mildly affected local structure with altered hydrogen bonds of the p.Arg468Gln-PER2 protein; and (6) nucleus-dominant subcellular distribution of the p.Arg468Gln-PER2 protein. CONCLUSIONS: The above findings imply that the second polar body retention occurred around fertilization, resulting in the generation of the parthenogenetic cell lineage by endoreplication of a female pronucleus and the normal cell lineage by fusion of male and female pronuclei, and that the homozygous PER2 variant in the parthenogenetic cells is the likely causative factor for idiopathic hypersomnia.

DOI PubMed

Current state of hypnotic use disorders: Results of a survey using the Japanese version of Benzodiazepine Dependence Self-Report Questionnaire

Yamamoto M.

Neuropsychopharmacology Reports ( Neuropsychopharmacology Reports )  41 ( 1 ) 14 - 25   2021年03月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Prescribing Pattern of Hypnotic Medications in Patients Initiating Treatment at Japanese Hospitals: A Nationwide, Retrospective, Longitudinal, Observational Study Using a Claims Database

Ken Inada, Minori Enomoto, Kentaro Yamato, Kazuo Mishima

Drugs - Real World Outcomes ( Springer Science and Business Media LLC )  8 ( 3 ) 277 - 288   2021年03月  [査読有り]

研究論文（学術雑誌）   国内共著

BACKGROUND: Prolonged treatment of insomnia using benzodiazepine (BZD) receptor agonists, including BZD and non-BZD hypnotic drugs, can cause drug dependence, tolerance, abuse and other adverse events. These side effects are more common and/or severe in older adults taking different hypnotic drugs concomitantly. Therefore, a single prescription is limited to 30 daily doses for most BZD receptor agonists and restrictions apply to the prescription of more than three types of hypnotic drugs in Japan. Little is known, however, about the real-world prescribing pattern of hypnotic drugs in Japan. OBJECTIVE: We analysed prescribing patterns for hypnotic drugs in Japan to evaluate whether real-world use differs from guideline recommendations. METHODS: In this nationwide, retrospective, longitudinal, observational study, we analysed the types of hypnotic drugs prescribed, duration of medication and treatment setting in a subset of hospitals in Japan using a hospital-based administrative claims database (Medical Data Vision). Patients initiating treatment with hypnotic drugs between January 2012 and December 2016 were included in the analyses to assess the duration of medication and occurrence of co-prescription of a second and third hypnotic drug, within a year from prescription of the first hypnotic drugs. RESULTS: In 261,167 patients analysed, the first hypnotic drugs prescribed were BZDs (59.7%), non-BZDs (36.8%), a melatonin receptor agonist [MRA] (3.1%) and an orexin receptor antagonist [ORA] (0.4%). Benzodiazepine and non-BZD hypnotic drugs were mostly prescribed in inpatient settings (57.7% and 63.0%, respectively) and the MRA and ORA mostly in outpatient settings (62.6% and 65.4%, respectively). The departments that prescribed the most patients their first hypnotic drugs were internal medicine (23.6%), general surgery (11.8%), orthopaedic surgery (11.4%) and urology (5.3%). Of the total prescriptions of MRA and ORA as the first hypnotic drugs, 22.0% and 31.8% were in internal medicine, 4.4% each in general surgery, 6.0% and 4.5% in orthopaedic surgery, 9.7% and 4.4% in neurology, and 10.1% and 12.2% in psychiatry departments, respectively. Mean duration of medication was 1.13 months for non-BZDs, 1.15 months for BZDs, 1.29 months for the ORA and 1.83 months for the MRA. Overall, 5.3% (95% confidence interval 5.2-5.4) of patients were prescribed a second hypnotic drug; of these, 8.4% (95% confidence interval 8.0-8.9) were prescribed at least three hypnotic drugs within a year. Patients who were prescribed three or more hypnotic drugs received higher doses of the first drug than patients who received fewer hypnotic drugs. CONCLUSIONS: Benzodiazepine receptor agonists were the most common hypnotic drugs prescribed as the first drug to patients in Japan. Further education and awareness may be needed on the risk of complications and adverse events associated with these therapies. The duration of BZD receptor agonist use was shorter than for the MRA and ORA, in accordance with prescribing guidelines. Long-term use and co-prescribing of hypnotic drugs were also uncommon.

DOI PubMed

Recurrence Rates in Stable Bipolar Disorder Patients after Drug Discontinuation versus Drug Maintenance: A Systematic Review and Meta-analysis - Corrigendum.

Taro Kishi, Yuki Matsuda, Kenji Sakuma, Makoto Okuya, Kazuo Mishima, Nakao Iwata

Psychological medicine   51 ( 15 ) 1 - 1   2021年03月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI PubMed

Decreased activity in the reward network of chronic insomnia patients

Motomura Y.

Scientific Reports ( Scientific Reports )  11 ( 1 )   2021年02月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI リポジトリ

Effect of residual insomnia and use of hypnotics on relapse of depression: a retrospective cohort study using a health insurance claims database

Inada K.

Journal of Affective Disorders ( Journal of Affective Disorders )  281   539 - 546   2021年02月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Discontinuation of antidepressants after remission with antidepressant medication in major depressive disorder: a systematic review and meta-analysis

Kato M.

Molecular Psychiatry ( Molecular Psychiatry )  26 ( 1 ) 118 - 133   2021年01月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Patterns of hypnotic prescribing for residual insomnia and recurrence of major depressive disorder: a retrospective cohort study using a Japanese health insurance claims database

Yamato K.

BMC Psychiatry ( BMC Psychiatry )  21 ( 1 )   2021年01月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Does cognitive behavioral therapy for anxiety disorders assist the discontinuation of benzodiazepines among patients with anxiety disorders? A systematic review and meta-analysis

Takeshima M.

Psychiatry and Clinical Neurosciences ( Psychiatry and Clinical Neurosciences )    2021年  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Effects of a conventional mood stabilizer alone or in combination with second-generation antipsychotics on recurrence rate and discontinuation rate in bipolar I disorder in the maintenance phase: A systematic review and meta-analysis of randomized, placebo-controlled trials

Kishi T.

Bipolar Disorders ( Bipolar Disorders )    2021年  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Tracking intermediate performance of vigilant attention using multiple eye metrics

Abe T.

Sleep ( Sleep )  43 ( 3 )   2021年  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Factors Associated with Insomnia Among Truck Drivers in Japan.

Takashi Miyachi, Kyoko Nomura, Sachiko Minamizono, Kazuki Sakai, Toyoto Iwata, Yuta Sugano, Shun Sawaguchi, Kouhei Takahashi, Kazuo Mishima

Nature and science of sleep   13   613 - 623   2021年  [査読有り]

研究論文（学術雑誌）   国内共著

Purpose: Truck drivers with insomnia are at a high risk of traffic accidents. We aimed to investigate the prevalence of insomnia and identify its associated factors among truck drivers in Japan. Methods: Participants were 2927 male truck drivers younger than 65 years old. Self-administered questionnaires were used to assess insomnia symptoms, State-Trait Anxiety Inventory, drinking, smoking habits, body mass index, caffeine intake, as well as daily driving hours, consecutive days away from home, and driving distance. Insomnia symptoms included difficulty initiating sleep, maintaining sleep and early morning awakening. Insomnia was defined when any of these symptoms were observed with daily tiredness. Results: The prevalence of insomnia among the subjects was 13.3% (n=356), of which 13.5% had difficulty initiating sleep, 78% had difficulty maintaining sleep, and 26.4% had early morning awakening. After adjusting for covariates, drinking habits, daily driving hours, and STAI score were significantly and linearly associated with insomnia; the adjusted odds ratio (OR) of drinking habits for insomnia was 1.74 [95% confidence interval (CI), 1.23-2.47] for heavy drinkers compared to non-drinkers (trend p<0.001); the adjusted OR of daily driving hours was 1.87 (95% CI, 1.00-3.49) for 12 hours or longer in a day compared to <8 hours in a day (trend p<0.001); the adjusted OR of STAI quartiles was 5.30 (95% CI, 3.66-7.67) for the highest quartile compared to the lowest quartile (trend p<0.001). Conclusion: The present study demonstrated that insomnia is prevalent among truck drivers in Japan, and its risk factors include drinking habits, daily driving hours, and anxiety.

DOI PubMed

Severity of Depressive Symptoms is Associated with Venous Thromboembolism in Hospitalized Patients with a Major Depressive Episode.

Kazuhisa Yoshizawa, Masahiro Takeshima, Sayaka Ishino, Masaya Ogasawara, Dai Fujiwara, Yu Itoh, Aya Imanishi, Hidenobu Ohta, Kazuo Mishima

Neuropsychiatric disease and treatment ( DOVE MEDICAL PRESS LTD )  17   2955 - 2963   2021年  [査読有り]

研究論文（学術雑誌）   国内共著

Purpose: A major depressive episode is a risk factor for venous thromboembolism (VTE) in psychiatric inpatients. However, it is unclear whether the severity of depressive symptoms or duration of the current depressive episode is associated with VTE. Further, the VTE prevalence among hospitalized patients with a major depressive episode receiving electroconvulsive therapy is unknown. This retrospective study examined factors associated with VTE among hospitalized patients with a major depressive episode and estimated the prevalence of VTE in such patients who underwent electroconvulsive therapy. Patients and Methods: Patients with a major depressive episode hospitalized in the Department of Neuropsychiatry at Akita University Hospital between January 2018 and December 2020 were included. Data from the first week of hospitalization were extracted from medical records. VTE was diagnosed based on the findings of computed tomography. To evaluate whether the severity of depressive symptoms or duration of the current depressive episode was associated with VTE, logistic regression analysis was conducted after adjusting for covariates with known VTE risk factors (antidepressants, antipsychotics, and physical comorbidities). Results: We analyzed 133 patients; of these, 14 were diagnosed with asymptomatic VTE. The severity of depressive symptoms (odds ratio: 1.220, 95% confidence interval: 1.081-1.377, p = 0.001) was significantly associated with VTE. The prevalence of VTE among those receiving electroconvulsive therapy was 35% (7/20). Conclusion: The prevalence of VTE was 35% among patients receiving in-hospital electroconvulsive therapy for a major depressive episode. VTE should be considered for hospitalized patients with severe depressive symptoms and patients receiving in-hospital electroconvulsive therapy for a major depressive episode.

DOI PubMed

The Usefulness of the Combination of D-Dimer and Soluble Fibrin Monomer Complex for Diagnosis of Venous Thromboembolism in Psychiatric Practice: A Prospective Study.

Masahiro Takeshima, Hiroyasu Ishikawa, Masaya Ogasawara, Munehiro Komatsu, Dai Fujiwara, Yu Itoh, Yuki Wada, Yuki Omori, Hidenobu Ohta, Kazuo Mishima

Vascular health and risk management ( DOVE MEDICAL PRESS LTD )  17   239 - 246   2021年  [査読有り]

研究論文（学術雑誌）   国内共著

Purpose: D-dimer has the advantage of excluding venous thromboembolism (VTE) due to its high sensitivity but is disadvantageous for diagnosing VTE due to its low specificity. A method to increase the usefulness of D-dimer in the diagnosis of VTE is warranted. This study aimed to investigate the usefulness of the combination of D-dimer and soluble fibrin monomer complex (SFMC), which has been suggested as a new candidate marker for VTE, in VTE diagnosis. Patients and Methods: This prospective study in 109 subjects was performed at a psychiatric department between August 1, 2017 and December 31, 2019. Subjects' levels of D-dimer and SFMC were measured simultaneously. Plasma levels of D-dimer and SFMC were measured using NANOPIA® D-dimer and NANOPIA® SF. Subjects with positive D-dimer (≥1.0 µg/mL) results underwent contrast computed tomography for confirmation of VTE within 12 hours of D-dimer measurement. A receiver operating characteristic curve analysis was performed to examine the usefulness of SFMC for the diagnosis of VTE. Results: Only 109 of the 783 subjects without symptoms suggestive of VTE participated in the study. Out of 41 subjects with positive D-dimer results, 17 subjects were diagnosed with VTE. A receiver operating characteristic curve analysis was performed to determine cutoff values. The area under the curves was 0.848 for SFMC (p<0.001, 95% CI 0.722 to 0.974), and the optimal cutoff value was 10.0 µg/mL (sensitivity 58.8%, specificity 100%, positive predictive value 100%, negative predictive value 77.4%). Conclusion: SFMC was useful for diagnosing VTE in the psychiatric patients with positive D-dimer results.

DOI PubMed

Risk factors for low adherence to methylphenidate treatment in pediatric patients with attention-deficit/hyperactivity disorder

Ishizuya A.

Scientific Reports ( Scientific Reports )  11 ( 1 )   2020年12月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Early detection of Niemann-pick disease type C with cataplexy and orexin levels: Continuous observation with and without Miglustat

Imanishi A.

Orphanet Journal of Rare Diseases ( Orphanet Journal of Rare Diseases )  15 ( 1 )   2020年09月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Long-term melatonin treatment for the sleep problems and aberrant behaviors of children with neurodevelopmental disorders

Yuge K.

BMC Psychiatry ( BMC Psychiatry )  20 ( 1 )   2020年09月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Recurrence of Mania or Depression Among Adult Bipolar Patients Who Continued Using Lithium: A Single-group Summary Meta-analysis of Randomized Trials

Kishi T.

Journal of clinical psychopharmacology ( Journal of clinical psychopharmacology )  40 ( 5 ) 468 - 474   2020年09月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Examination of the influence of cedar fragrance on cognitive function and behavioral and psychological symptoms of dementia in Alzheimer type dementia.

Yuya Takahashi, Sho Shindo, Takashi Kanbayashi, Masahiro Takeshima, Aya Imanishi, Kazuo Mishima

Neuropsychopharmacology reports ( Wiley )  40 ( 1 ) 10 - 15   2020年03月  [査読有り]

研究論文（学術雑誌）   国内共著

We examined whether symptoms of dementia are improved by olfactory nerve stimulation in Alzheimer type dementia patients. First, a stick-type olfactory identification ability test was performed in patients with Alzheimer type dementia, to select patients without olfactory dysfunctions. Then, these patients were randomly assigned into the intervention (n = 19) and the control groups (n = 17). To evaluate the effects of olfactory nerve stimulation, we exposed the intervention group to a disinfecting ethanol with added aroma extracts from ceder and the control group to the ethanol without the added aroma extracts. Each group underwent the intervention for 8 weeks, cognitive and behavioral functions were evaluated before and after treatments using the Neuropsychiatric Inventory (NPI), the Japanese version of Zarit Caregiver Burden interview (J-ZBI), and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). A significant improvement was observed in the NPI score and J-ZBI in the intervention group compared to the control group at 4 and 8 weeks. On the other hand, there was no significant difference in the score of ADAS-cog. Exposure to cedar fragrance improved behavioral and psychological symptoms of dementia (BPSD) in Alzheimer type dementia and may reduce the burden of nursing care. In addition to its effectiveness, the procedure is simple and minimally invasive and would be a valuable non-pharmaceutical treatment.

DOI PubMed

Tracking intermediate performance of vigilant attention using multiple eye metrics

Takashi Abe, Kazuo Mishima, Shingo Kitamura, Akiko Hida, Yuichi Inoue, Koh Mizuno, Kosuke Kaida, Kyoko Nakazaki, Yuki Motomura, Kazushi Maruo, Toshiko Ohta, Satoshi Furukawa, David F Dinges, Katsuhiko Ogata

Sleep ( Oxford University Press (OUP) )  43 ( 3 )   2020年03月  [査読有り]

研究論文（学術雑誌）   国内共著

<title>Abstract</title>
Vigilance deficits account for a substantial number of accidents and errors. Current techniques to detect vigilance impairment measure only the most severe level evident in eyelid closure and falling asleep, which is often too late to avoid an accident or error. The present study sought to identify ocular biometrics of intermediate impairment of vigilance and develop a new technique that could detect a range of deficits in vigilant attention (VA). Sixteen healthy adults performed well-validated Psychomotor Vigilance Test (PVT) for tracking vigilance attention while undergoing simultaneous recording of eye metrics every 2 hours during 38 hours of continuous wakefulness. A novel marker was found that measured VA when the eyes were open—the prevalence of microsaccades. Notably, the prevalence of microsaccades decreased in response to sleep deprivation and time-on-task. In addition, a novel algorithm for detecting multilevel VA was developed, which estimated performance on the PVT by integrating the novel marker with other eye-related indices. The novel algorithm also tracked changes in intermediate level of VA (specific reaction times in the PVT, i.e. 300–500 ms) during prolonged time-on-task and sleep deprivation, which had not been tracked previously by conventional techniques. The implication of the findings is that this novel algorithm, named “eye-metrical estimation version of the PVT: PVT-E,” can be used to reduce human-error-related accidents caused by vigilance impairment even when its level is intermediate.

DOI PubMed

Examination of the influence of cedar fragrance on cognitive function and behavioral and psychological symptoms of dementia in Alzheimer type dementia.

Takahashi Y, Shindo S, Kanbayashi T, Takeshima M, Imanishi A, Mishima K.

Neuropsychopharmacol Rep.   9 ( 10 ) 12096   2020年02月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Association Between the Use of Antidepressants and the Risk of Type 2 Diabetes Mellitus: A Large, Population-Based Cohort Study in Japan.

Miidera H, Enomoto M, Kitamura S, Tachimori H, Mishima K.

Diabetes Care   12 ( 10 ) dc19-1175   2020年02月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Tracking intermediate performance of vigilant attention using multiple eye metrics.

Abe T, Mishima K, Kitamura S, Hida A, Inoue Y, Mizuno K, Kaida K, Nakazaki K, Motomura Y, Maruo K, Ohta T, Furukawa S, Dinges DF, Ogata K.

Sleep   43   5733056   2020年02月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Mood stabilizers and/or antipsychotics for bipolar disorder in the maintenance phase: a systematic review and network meta-analysis of randomized controlled trials

Kishi T.

Molecular Psychiatry ( Molecular Psychiatry )    2020年  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Prevalence of asymptomatic venous thromboembolism in depressive inpatients

Takeshima M.

Neuropsychiatric Disease and Treatment ( Neuropsychiatric Disease and Treatment )  16   579 - 587   2020年  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Recurrence rates in stable bipolar disorder patients after drug discontinuation v. drug maintenance: A systematic review and meta-analysis

Kishi T.

Psychological Medicine ( Psychological Medicine )    2020年  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Relationship between Indoor Daytime Light Exposure and Circadian Phase Response under Laboratory Free-Living Conditions

Yoshimura M.

Biological Rhythm Research ( Biological Rhythm Research )    2020年  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Long-term use of hypnotics: Analysis of trends and risk factors.

Enomoto M, Kitamura S, Tachimori H, Takeshima M, Mishima K.

Gen Hosp Psychiatry   62   49 - 55   2019年12月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

A missense variant in PER2 is associated with delayed sleep–wake phase disorder in a Japanese population

Miyagawa T.

Journal of Human Genetics ( Journal of Human Genetics )  64 ( 12 ) 1219 - 1225   2019年12月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Psychosocial intervention for discontinuing benzodiazepine hypnotics in patients with chronic insomnia: A systematic review and meta-analysis.

Takaesu Y, Utsumi T, Okajima I, Shimura A, Kotorii N, Kuriyama K, Yamashita H, Suzuki M, Watanabe N, Mishima K.

Sleep Med Rev.   48   101214   2019年10月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Efficacy and safety of lithium and lamotrigine for the maintenance treatment of clinically stable patients with bipolar disorder: A systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials with an enrichment design

Oya K.

Neuropsychopharmacology Reports ( Neuropsychopharmacology Reports )  39 ( 3 ) 241 - 246   2019年09月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Brexpiprazole as adjunctive treatment for major depressive disorder following treatment failure with at least one antidepressant in the current episode: a systematic review and meta-analysis.

Kishi T, Sakuma K, Nomura I, Matsuda Y, Mishima K, Iwata N.

Int J Neuropsychopharmacol.   27   5539907   2019年07月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Melatonin receptor agonists-ramelteon and melatonin-for bipolar disorder: a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials.

Kishi T, Nomura I, Sakuma K, Kitajima T, Mishima K, Iwata N.

Neuropsychiatr Dis Treat.   15   1479 - 1486   2019年06月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Sleep problem but not chronotype is associated with retirement from shift work: a cross-sectional retrospective study.

Kitamura S, Takahashi M, Mishima K.

Sleep and Biological Rhythms   17   331 - 337   2019年04月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

機械学習を用いた動画解析による生体情報の自動追跡技術 ：瞼裂幅計測に用いた一例

西村 英伍, 元村 祐貴, 勝沼 るり, 吉村 道孝, 三島 和夫, 尾方 義人

日本生理人類学会誌 ( 日本生理人類学会 )  24 ( 1 ) 35 - 45   2019年  [査読有り]

研究論文（学術雑誌）   国内共著

Methods of human motion tracking for acquiring biometric information are needed in order to apply knowledgeof physiological anthropology. However, previous methods have difficulty in control of video shooting conditions.Thus, we developed a more robust motion tracking method using machine learning. In this report, we evaluated theaccuracy of our method by comparing palpebral fissure height measured using manually selected data and trackingdata obtained using YOLOv3. The results indicate that our method has practical accuracy in measuring palpebral fissureheight and suggest that including noise in training data contributes to its accuracy.

DOI

Prevalence of childhood obstructive sleep apnea syndrome and its role in daytime sleepiness.

Tsukada E, Kitamura S, Enomoto M, Moriwaki A, Kamio Y, Asada T, Arai T, Mishima K.

PLoS One   13 ( 10 ) e0204409   2018年10月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

A variant at 9q34.11 is associated with HLA-DQB1 06:02 negative essential hypersomnia.

Miyagawa T, Khor SS, Toyoda H, Kanbayashi T, Imanishi A, Sagawa Y, Kotorii N, Kotorii T, Ariyoshi Y, Hashizume Y, Ogi K, Hiejima H, Kamei Y, Hida A, Miyamoto M, Ikegami A, Wada Y, Takami M, Higashiyama Y, Miyake R, Kondo H, Fujimura Y, Tamura Y, Taniyama Y, Omata N, Tanaka Y, Moriya S, Furuya H, Kato M, Kawamura Y, Otowa T, Miyashita A, Kojima H, Saji H, Shimada M, Yamasaki M, Kobayashi T, Misawa R, Shigematsu Y, Kuwano R, Sasaki T, Ishigooka J, Wada Y, Tsuruta K, Chiba S, Tanaka F, Yamada N, Okawa M, Kuroda K, Kume K, Hirata K, Uchimura N, Shimizu T, Inoue Y, Honda Y, Mishima K, Honda M, Tokunaga K.

J Hum Genet.   28 ( 10 ) 018 - 0518   2018年09月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Evidence for the Efficacy of Bright Light Therapy for Bipolar Depression.

Benedetti F, Avery DH, Bauer M, Bunney WE, Çaliyurt O, Camardese G, Colombo C, Dallaspezia S, Henriksen TE, Kasper S, Kuriyama K, Lam RW, Martiny K, Meesters Y, Mishima K, Schulte R, Suzuki M, Święcicki Ł, Uchiyama M, Veale D, Winkler D, Wu J, Kupeli NY, Yoshiike T, Yu X

Am J Psychiatry ( American Psychiatric Association Publishing )  175 ( 9 ) 905 - 906   2018年09月  [査読有り]

研究論文（学術雑誌）   国際共著

DOI

Association of sleep with emotional and behavioral problems among abused children and adolescents admitted to residential care facilities in Japan.

Okada M, Otaga M, Tsutsui T, Tachimori H, Kitamura S, Higuchi S, Mishima K.

PLoS One   13 ( 6 ) e0198123   2018年06月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Effect of discontinuation v. maintenance of antipsychotic medication on relapse rates in patients with remitted/stable first-episode psychosis: a meta-analysis.

Kishi T, Ikuta T, Matsui Y, Inada K, Matsuda Y, Mishima K, Iwata N.

Psychol Med.   18   1 - 8   2018年06月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Lack of association between PER3 variable number tandem repeat and circadian rhythm sleep-wake disorders.

Hida A, Kitamura S, Kadotani H, Uchiyama M, Ebisawa T, Inoue Y, Kamei Y, Mishima K.

Hum Genome Var.   5   17   2018年06月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Effectiveness of cognitive behavioral therapy for pharmacotherapy-resistant chronic insomnia: a multi-center randomized controlled trial in Japan.

Ayabe N, Okajima I, Nakajima S, Inoue Y, Watanabe N, Yamadera W, Uchimura N, Tachimori H, Kamei Y, Mishima K.

Sleep Med.   50   105 - 112   2018年06月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Effect of discontinuation v. maintenance of antipsychotic medication on relapse rates in patients with remitted/stable first-episode psychosis: a meta-analysis.

Kishi T, Ikuta T, Matsui Y, Inada K, Matsuda Y, Mishima K, Iwata N

Psychol Med.   18   1 - 8   2018年06月  [査読有り]

研究論文（学術雑誌）   国内共著

中枢性過眠症における周期性四肢運動の検討

都留 あゆみ, 亀井 雄一, 木村 綾乃, 三島 和夫

不眠研究 ( メディカルフロントインターナショナル(有) )  2017   72 - 74   2017年10月

研究論文（学術雑誌）   国内共著

過眠症における終夜睡眠ポリグラフ検査(PSG)の所見として、ナルコレプシー(NA)では覚醒反応が多いことや、筋活動抑制を伴わないREM睡眠(RWA)を認めること、特発性過眠症(IH)では睡眠効率が良いことなどが知られている。また、NA患者では健常対照群に比べて睡眠中の周期性四肢運動が多いという報告があるが、IHとの比較はあまり検討されていない。そこで今回、当院のNA患者68例(うちカタプレキシーを伴う者20例)とIH患者60例を対象とし、「PSGにおける覚醒反応指数(Arousal index)」「覚醒を伴う周期性四肢運動となる脚動指数(PLM arousal index)」「周期性四肢運動指数(PLMI)」の群間比較を行った。結果、Arousal indexはNA群とIH群の間で有意差はみられなかったが、NA群のうちカタプレキシー(CA)を伴う群ではIH群に比べて高い傾向にあった。PLM arousal indexもNA群とIH群の間で有意差はなかったが、CAを伴う群ではIH群に比べて有意に高かった。PLMIはNA群がIH群に比べて有意に高かった。

Two Days' Sleep Debt Causes Mood Decline During Resting State Via Diminished Amygdala-Prefrontal Connectivity.

Motomura Y, Katsunuma R, Yoshimura M, Mishima K.

Sleep   40 ( 10 ) pii: zsx133   2017年10月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Unrecognized Sleep Loss Accumulated in Daily Life Can Promote Brain Hyperreactivity to Food Cue

Ruri Katsunuma, Kentaro Oba, Shingo Kitamura, Yuki Motomura, Yuri Terasawa, Kyoko Nakazaki, Akiko Hida, Yoshiya Moriguchi, Kazuo Mishima

SLEEP ( OXFORD UNIV PRESS INC )  40 ( 10 )   2017年10月  [査読有り]

研究論文（学術雑誌）   国内共著

Epidemiological studies have shown that sleep debt increases the risk of obesity. Experimental total sleep deprivation (TSD) has been reported to activate the reward system in response to food stimuli, but food-related responses in everyday sleep habits, which could lead to obesity, have not been addressed. Here, we report that habitual sleep time at home among volunteers without any sleep concerns was shorter than their optimal sleep time estimated by the 9-day extended sleep intervention, which indicates that participants had already been in sleep debt in their usual sleep habits. The amygdala and anterior insula, which are responsible for both affective responses and reward prediction, were found to exhibit significantly lowered activity in the optimal sleep condition. Additionally, a subsequent one-night period of TSD reactivated the right anterior insula in response to food images; however, the activity level of amygdala remained lowered. These findings indicate that (1) our brain is at risk of hyperactivation to food triggers in everyday life, which could be a risk factor for obesity and lifestyle diseases, and (2) optimal sleep appears to reduce this hypersensitivity to food stimuli.

DOI

Validation of Brain-Derived Signals in Near-Infrared Spectroscopy Through Multivoxel Analysis of Concurrent Functional Magnetic Resonance Imaging

Yoshiya Moriguchi, Takamasa Noda, Kosei Nakayashiki, Yohei Takata, Shiori Setoyama, Shingo Kawasaki, Yoshihiko Kunisato, Kazuo Mishima, Kazuyuki Nakagome, Takashi Hanakawa

HUMAN BRAIN MAPPING ( WILEY )  38 ( 10 ) 5274 - 5291   2017年10月  [査読有り]

研究論文（学術雑誌）   国内共著

Near-infrared spectroscopy (NIRS) is a convenient and safe brain-mapping tool. However, its inevitable confounding with hemodynamic responses outside the brain, especially in the frontotemporal head, has questioned its validity. Some researchers attempted to validate NIRS signals through concurrent measurements with functional magnetic resonance imaging (fMRI), but, counterintuitively, NIRS signals rarely correlate with local fMRI signals in NIRS channels, although both mapping techniques should measure the same hemoglobin concentration. Here, we tested a novel hypothesis that different voxels within the scalp and the brain tissues might have substantially different hemoglobin absorption rates of near-infrared light, which might differentially contribute to NIRS signals across channels. Therefore, we newly applied a multivariate approach, a partial least squares regression, to explain NIRS signals with multivoxel information from fMRI within the brain and soft tissues in the head. We concurrently obtained fMRI and NIRS signals in 9 healthy human subjects engaging in an n-back task. The multivariate fMRI model was quite successfully able to predict the NIRS signals by cross-validation (interclass correlation coefficient = similar to 0.85). This result confirmed that fMRI and NIRS surely measure the same hemoglobin concentration. Additional application of Monte-Carlo permutation tests confirmed that the model surely reflects temporal and spatial hemodynamic information, not random noise. After this thorough validation, we calculated the ratios of the contributions of the brain and soft-tissue hemodynamics to the NIRS signals, and found that the contribution ratios were quite different across different NIRS channels in reality, presumably because of the structural complexity of the frontotemporal regions. (C) 2017 Wiley Periodicals, Inc.

DOI PubMed

Reliability and validity of a brief sleep questionnaire for children in Japan.

Okada M, Kitamura S, Iwadare Y, Tachimori H, Kamei Y, Higuchi S, Mishima K.

J Physiol Anthropol.   36 ( 1 ) 35   2017年09月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Pathophysiology and strategic treatment of sighted non-24-h sleep–wake rhythm disorders.

Mishima K.

Sleep and Biological Rhythms   15   11 - 20   2017年09月  [査読有り]

研究論文（学術雑誌）   単著

DOI

Recovery from Unrecognized Sleep Loss Accumulated in Daily Life Improved Mood Regulation via Prefrontal Suppression of Amygdala Activity.

Motomura Y, Kitamura S, Nakazaki K, Oba K, Katsunuma R, Terasawa Y, Hida A, Moriguchi Y, Mishima K.

Front Neurol.   8   306   2017年07月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Validation of brain-derived signals in near-infrared spectroscopy through multivoxel analysis of concurrent functional magnetic resonance imaging.

Moriguchi Y, Noda T, Nakayashiki K, Takata Y, Setoyama S, Kawasaki S, Kunisato Y, Mishima K, Nakagome K, Hanakawa T.

Hum Brain Mapp.   38 ( 10 ) 5274 - 5291   2017年07月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

ASSOCIATION BETWEEN MINDFULNESS TENDENCY ASSESSED BY FIVE FACET MINDFULNESS QUESTIONNAIRE AND REGIONAL GRAY MATTER VOLUME IN A JAPANESE POPULATION

Hiroki Murakami, Ruri Katsunuma, Kentaro Oba, Kazuo Mishima, Yoshiya Moriguchi

PSYCHOSOMATIC MEDICINE ( LIPPINCOTT WILLIAMS & WILKINS )  79 ( 4 ) A61 - A61   2017年05月  [査読有り]

研究論文（学術雑誌）   国内共著

Personal lifestyle as a resource for work engagement.

Nishi D, Suzuki Y, Nishida J, Mishima K, Yamanouchi Y.

J Occup Health.   59 ( 1 ) 17 - 23   2017年01月  [査読有り]

研究論文（学術雑誌）   国内共著

DOI

Evaluation of circadian phenotypes utilizing fibroblasts from patients with circadian rhythm sleep disorders

Hida A.

Translational Psychiatry ( Translational Psychiatry )  7 ( 4 )   2017年  [査読有り]

研究論文（学術雑誌）   国内共著

DOI