Kazuo Mishima

Study Objectives: To investigate the prescription patterns for hypnotics among patients <18 years in Japan. Methods: We conducted a descriptive epidemiologic study using a claims database in Japan. We included patients aged 0–17 years with first-time prescriptions for hypnotics between June 2021 and June 2023. Hypnotics were classified as melatonin, melatonin receptor agonists (MRAs), dual orexin receptor antagonists (DORAs), Z-drugs, and benzodiazepines. We described the types of hypnotics, dosages, prescription duration, comorbidities, and concomitant medications for overall and by age groups. Results: The study included 21 145 patients; 1983 aged 0–6 years, 3901 aged 7–11 years, 6664 aged 12–14 years, and 8597 aged 15–17 years. The initial prescribed hypnotics were melatonin (33.9%), MRAs (30.9%), DORAs (18.8%), Z-drugs (10.1%), and benzodiazepines (6.3%). Melatonin was more likely to be prescribed to patients age 0–11 years, MRAs to those aged 0–17 years, and DORAs to patients ages 15–17 years. The most common mental health-related comorbidities were autism spectrum disorder (32.5%), depression (23.4%), attention-deficit hyperactivity disorder (19.8%), and anxiety disorder (18.2%). Conclusions: Melatonin was most frequently prescribed in children for a longer duration than other hypnotics, while MRAs were prescribed across all age groups and DORAs mainly to adolescents. These age-specific patterns suggest that the drug selection was conducted according to patient’s age, since pediatric insomnia might be correlated with psychiatric disorders related to developmental stage. Future research should investigate the long-term effects of hypnotic prescriptions with consideration of comorbid conditions.

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.

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. Clin Psychopharmacol Neurosci 2025;23:379-90. https://doi.org/10.9758/cpn.24.1258

Objectives: This study aimed to investigate how many male truck drivers have sleep disorders and what factors are 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, third edition, sleep apnea syndrome (SAS) with a simple 4-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% 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, lifestyle modification and stress relief may be key to address insomnia.

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. Clin Psychopharmacol Neurosci 2025;23:266-77. https://doi.org/10.9758/cpn.24.1239

Background: We previously demonstrated that sleep apnea (SA) can be detected using acceleration and gyroscope signals from an inertial measurement unit (IMU) embedded in a wristwatch device. This study aimed to explore whether an IMU embedded in non-wristwatch devices, such as smartphones, can also be used to detect SA, when worn during sleep. Methods: During polysomnography (PSG) examinations, patients wore an IMU-embedded GPS device (Amue Link®) and/or smartphones (Xperia® or iPhone®) on their abdomen. Triaxial acceleration and gyroscope signals from the IMU of each device were recorded overnight. The data were divided into training and test groups in a 2:1 ratio. An algorithm to extract respiratory movements (0.13-0.70 Hz) and detect respiratory events was developed using the training group and its performance was validated in the test group. Results: The estimated respiratory event frequency from the IMU signals of Amue Link, Xperia, and iPhone correlated with the PSG apnea-hypopnea index (AHI), with correlation coefficients of 0.90, 0.93, and 0.96, respectively, in the test group. Using cutoff values derived from the training groups, moderate-to-severe SA (AHI ≥15) was identified with areas under the receiver-operating characteristic curve of 0.95, 0.98, and 0.94, and accuracies of 87%, 94%, and 92%, respectively, in the test groups. Conclusions: SA can be quantitatively detected by IMUs embedded in non-wristwatch devices, including smartphones, when worn during sleep.

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.

Keisuke Irinaka, Yu Itoh, Kazuhisa Yoshizawa, Masaya Ogasawara, Naoko Ayabe, Kazuo Mishima, Masahiro Takeshima. Clin Psychopharmacol Neurosci 2024;22:688-96. https://doi.org/10.9758/cpn.24.1185