研究等業績 - 原著論文 - 三島 和夫
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Novel hypnotics use and hip fracture risk in middle-aged and older adults: A large, population-based cohort study in Japan.
Nana Shibata, Kazuhisa Yoshizawa, Masahiro Takeshima, Shingo Kitamura, Masaya Ogasawara, Mizuki Kudo, Yu Itoh, Eru Miyakoshi, Naoko Ayabe, Kazuo Mishima
PCN reports : psychiatry and clinical neurosciences 4 ( 3 ) e70193 2025年09月 [査読有り]
研究論文（学術雑誌）
AIM: To investigate the relationship between the prescription of novel hypnotics (melatonin receptor agonists [MRAs] and orexin receptor antagonists [ORAs]) and the risk of hip fractures in a large cohort of Japanese patients. METHODS: In this retrospective study, we analyzed data from a large health insurance claims database. Among subscribers aged ≥50 years between April 2014 and September 2021, those assigned the disease code of hip fracture were included. Each patient's prescription history for hypnotics was examined to identify the exposure and non-exposure periods. The relationship between exposure to hypnotics and the development of hip fractures was analyzed using the Mayo-updated Cox proportional hazards regression model. RESULTS: In total, 269,097 patients developed hip fractures. The prescription of any hypnotic was significantly associated with hip fracture incidence (adjusted hazard ratio [aHR], 2.30; 95% confidence interval [CI], 2.27-2.32). In the analysis by class of hypnotics, the hazard ratio was highest for ORAs (aHR, 3.09; 95% CI, 3.03-3.16), followed by that for MRAs (aHR, 2.45; 95% CI, 2.38-2.52). CONCLUSION: Novel hypnotics use was significantly associated with the development of hip fractures, and patients prescribed ORAs and MRAs should be cautioned about the risk of hip fractures.
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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 : the official scientific journal of the Korean College of Neuropsychopharmacology 23 ( 3 ) 379 - 390 2025年08月 [査読有り]
研究論文（学術雑誌） 国内共著
OBJECTIVE: Schizophrenia mainly begins in adolescence and leads to impairments of social functioning. Alterations in the immune system, as represented by cytokine levels, has been linked to the pathophysiology of schizophrenia. Among a variety of cytokines, transforming growth factor-β (TGF-β) plays a role in several neural events, e.g., neurogenesis and synapse formation. To date, few studies have evaluated the relationship between cytokine concentrations and social functioning in subjects with ultra-high-risk state for psychosis (UHR). In this study, we investigated the ability of serum levels of TGF-β to predict the change of social functioning in UHR subjects. METHODS: Fifty-two UHR subjects were recruited at 7 hospitals. We measured social function with the Specific Levels of Functioning scale (SLOF) at baseline, 4, 16, 28, 40, and 52 weeks after sampling blood to measure TGF-β levels. RESULTS: TGF-β1 concentration at baseline was correlated with changes from baseline in the SLOF scores at 4, 28, and 40 weeks. Mixed model for repeated measures analyses revealed that serum levels of TGF-β1 at baseline associated positively with changes from baseline in the SLOF scores, which was most evident at the 40-week time point. CONCLUSION: These results suggest that peripheral levels of TGF-β1 might be associated with longitudinal course of functional outcomes in UHR subjects.
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Common Neural Correlates for Subjective and Objective Sleepiness Indices: A Functional Connectivity Study.
Yuki Motomura, Shingo Kitamura, Kentaro Oba, Ruri Katsunuma, Yuri Terasawa, Akiko Hida, Yoshiya Moriguchi, Kazuo Mishima
Nature and science of sleep 17 1345 - 1359 2025年06月 [査読有り]
研究論文（学術雑誌） 国内共著
PURPOSE: This study examined the neural correlates in functional brain connectivity common to subjective and objective sleepiness. Because functional connectivity can be measured at rest and during tasks, it is well suited for exploring the commonalities between sleepiness during psychomotor vigilance task (PVT) and at rest with measurement of The Karolinska Sleepiness Scale (KSS). Serial resting and task-based fMRI measurements across various states of arousal may reveal a common neural substrate that does not vary with task demands. The neural basis shared by the PVT, an objective measure highly sensitive to sleep debt, and subjective reports of sleepiness may be robust markers for sleepiness and contribute to an improved understanding of the brain mechanisms underlying sleepiness. PARTICIPANTS AND METHODS: The participants were 16 healthy right-handed (self-reported) adult men who, after a 2-week home examination, participated in a 14-day/13-night experiment that included 9 days of extended sleep (12 h per night), followed by one night of total sleep deprivation (0 h), and recovery sleep. KSS and the PVT were used as subjective and objective measures of sleepiness, respectively. Functional connectivity in the brain during each condition were measured using fMRI. In particular, the association between the inverse of the reaction time to the PVT task and resting-state functional connectivity was analyzed using a general linear mixed model. RESULTS: Functional connectivity in six pairs of regions commonly associated with the KSS and PVT were identified. These included the anterior cingulate cortex-posterior cingulate cortex (part of the default mode network) and thalamus-middle temporal cortex, indicating that connectivity in these brain regions were strongly associated with sleepiness. CONCLUSION: These results suggest a common neural substrate for subjective and objective sleepiness, which may be an important indicator of sleepiness. In addition, the functional connectivity between the thalamus and the middle temporal cortex may be a new network that deserves further attention in sleep research. The results of this study provide valuable insights into the effects of sleep deprivation and total sleep deprivation experienced in daily life on the brain and offer a new perspective on the expression of sleepiness in the brain.
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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.
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Development, reliability, and validity of the quality of life scale for insomnia: a health-related quality of life instrument for insomnia.
Naoko Ayabe, Isa Okajima, Wataru Yamadera, Hisateru Tachimori, Hidehisa Yamashita, Naohisa Uchimura, Ken Inada, Yuichi Inoue, Kazuo Mishima
Frontiers in psychiatry 16 1538148 - 1538148 2025年05月 [査読有り]
研究論文（学術雑誌） 国内共著
BACKGROUND: Insomnia is a quality of life (QOL) disorder complicated by various mental or physical daytime dysfunctions in addition to nocturnal insomnia symptoms. This study aimed to develop and examine the reliability and validity of a self-administered scale that can sensitively and easily assess QOL disturbances in patients with insomnia. METHODS: From 122 patients with primary insomnia (mean age 53.8 ± 17.1 years), 11 items correlated with sleep-related clinical indices were extracted and designated the QOL Scale for insomnia (QOL-I). The QOL-I reliability and validity were evaluated. RESULTS: The analysis included 93 patients with chronic insomnia (mean age 54.2 ± 16.0 years) and 228 healthy participants (45.0 ± 15.7 years). The QOL-I showed high reliability (Cronbach α=0.92). Factor analysis showed that the QOL-I has a one-factor structure. Correlation analysis between the QOL-I and other variables indicated criterion-related validity (p<0.001). CONCLUSION: The QOL-I demonstrated good reliability and validity and is expected to be a valuable tool for clinically assessing the QOL of patients with insomnia.
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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.
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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 34 ( 1 ) e14302 2025年02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.
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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
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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.
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Ryoya Aoki, Takashi Miyachi, Yuta Sugano, Choichiro Kanke, Teiichiro Yamazaki, Kazuo Mishima, Kyoko Nomura
Journal of Occupational Health ( Oxford University Press (OUP) ) 2025年01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. -
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.
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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
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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.
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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.
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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.
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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.
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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
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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.
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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.