Faculty Profiles - IWAMOTO, Kunihiro

MR Imaging Indices for Brain Interstitial Fluid Dynamics and the Effects of Orexin Antagonists on Sleep Reviewed International journal

Taoka Toshiaki, Iwamoto Kunihiro, Miyata Seiko, Ito Rintaro, Nakamichi Rei, Nakane Toshiki, Okada Ippei, Ichikawa Kazushige, Kan Hirohito, Kamagata Koji, Kikuta Junko, Aoki Shigeki, Fujimoto Akihiro, Kogo Yuki, Ichinose Nobuyasu, Naganawa Shinji, Ozaki Norio

Magnetic Resonance in Medical Sciences Vol. advpub ( 0 ) 2025.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Japanese Society for Magnetic Resonance in Medicine

Purpose: The purpose of this study was to assess the extent to which improvement in sleep with lemborexant contributed to changes in interstitial fluid dynamics.Methods: The 3 methods including diffusion tensor image analysis along the perivascular space (DTI-ALPS), dynamic contrast-enhanced method to assess tissue vascular permeability (Ktrans), and choroid plexus volume (CPV) were used. Correlations between these imaging indices and sleep parameters (latency to persistent sleep [LPS], wake after sleep onset [WASO], total sleep time [TST], and sleep efficiency [SE]) were evaluated using Pearson correlation analysis. Additionally, multiple regression analysis and linear mixed model analysis were employed to assess the relationship between baseline sleep status and imaging parameter changes. MRI and sleep assessments were performed before treatment initiation (week 0, w0) and at 12 weeks after lemborexant administration (week 12, w12).Results: The ALPS-index was inversely correlated with LPS and positively correlated with TST and SE at w0. In multiple regression analysis, ALPS-index was lower when sleep parameters other than LPS were poor at w0. A linear mixed model analysis suggested that poor sleep status in LPS and SE at w0 may have an effect on greater ALPS-index. In the evaluation of Ktrans measurement, the single regression analysis showed a statistically significant correlation between the reduction in Ktrans and the shortening in LPS. Examination of CPV and sleep parameters showed a significant negative correlation between TST and CPV at w0 and w12. Multiple regression analysis also showed that TST of w12 had a significant effect on CPV at w12.Conclusion: Our results suggested that poor sleep status is related to the greater change of ALPS-index and CPV improvement after lemborexant administration may be related to in part to sleep parameter improvement.

DOI： 10.2463/mrms.mp.2024-0176

CiNii Research

Second-generation antipsychotic-induced dystonia: Analysis using the Japanese Adverse Drug Event Report (JADER) database. Reviewed International journal

Takumi Ebina, Kunihiro Iwamoto, Masahiko Ando, Masashi Ikeda

Psychiatry and clinical neurosciences Vol. 79 ( 3 ) page： 117 - 124 2025.1

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

AIM: This study aimed to explore the comparative risks for dystonia among different second-generation antipsychotics (SGAs), the influence of sex, and the relationship between the time-to-onset of dystonia and its outcomes. METHODS: We analyzed data from the Japanese Adverse Drug Event Report database from April 2004 to November 2023. Cases involving oral SGAs, excluding clozapine, were extracted. We used the odds ratios to assess the reporting proportions among SGAs and sex, analyzed the median time-to-onset and interquartile ranges (IQRs), and conducted a receiver operating characteristic (ROC) curve analysis to investigate the time-to-onset of dystonia and its relationship to outcomes. RESULTS: We extracted 9837 cases involving oral SGAs. Lurasidone was associated with a significantly higher proportion of dystonia reports than risperidone, aripiprazole, quetiapine, and olanzapine. The reporting proportion of dystonia associated with aripiprazole was lower than that of paliperidone and risperidone, but higher than that of quetiapine and olanzapine. Female sex was significantly associated with a higher reporting proportion of dystonia compared with males. Among the 148 cases of oral SGA-induced dystonia, the median time-to-onset was 125 days (IQR, 19.75-453.25 days). Divided into the three outcome groups (recovered, improved, and unrecovered/residual), those with better outcomes had a shorter time-to-onset than those with poorer outcomes. ROC curve analysis suggested a threshold of 91.5 days for discriminating outcomes, with a sensitivity of 71.7% and specificity of 69.9%. CONCLUSIONS: The risks of dystonia may vary among SGAs and between sexes. SGA-induced dystonia often manifests in the tardive form.

DOI： 10.1111/pcn.13785

Copy number variations in RNF216 and postsynaptic membrane-associated genes are associated with bipolar disorder: a case-control study in the Japanese population. Reviewed International journal

Masahiro Nakatochi, Itaru Kushima, Branko Aleksic, Hiroki Kimura, Hidekazu Kato, Toshiya Inada, Youta Torii, Nagahide Takahashi, Maeri Yamamoto, Kunihiro Iwamoto, Yoshihiro Nawa, Shuji Iritani, Nakao Iwata, Takeo Saito, Kohei Ninomiya, Tomo Okochi, Ryota Hashimoto, Hidenaga Yamamori, Yuka Yasuda, Michiko Fujimoto, Kenichiro Miura, Kazutaka Ohi, Toshiki Shioiri, Kiyoyuki Kitaichi, Masanari Itokawa, Makoto Arai, Mitsuhiro Miyashita, Kazuya Toriumi, Tsutomu Takahashi, Michio Suzuki, Takahiro A Kato, Shigenobu Kanba, Hideki Horikawa, Kiyoto Kasai, Tempei Ikegame, Seiichiro Jinde, Tadafumi Kato, Chihiro Kakiuchi, Bun Yamagata, Shintaro Nio, Yasuto Kunii, Hirooki Yabe, Yasunobu Okamura, Shu Tadaka, Ueno Fumihiko, Taku Obara, Yasuyuki Yamamoto, Yuko Arioka, Daisuke Mori, Masashi Ikeda, Norio Ozaki

Psychiatry and clinical neurosciences Vol. 79 ( 1 ) page： 12 - 20 2025.1

Language：English Publishing type：Research paper (scientific journal)

AIM: Bipolar disorder (BD) is a common psychiatric disorder characterized by alterations between manic/hypomanic and depressive states. Rare pathogenic copy number variations (CNVs) that overlap with exons of synaptic genes have been associated with BD. However, no study has comprehensively explored CNVs in synaptic genes associated with BD. Here, we evaluated the relationship between BD and rare CNVs that overlap with synaptic genes, not limited to exons, in the Japanese population. METHODS: Using array comparative genome hybridization, we detected CNVs in 1839 patients with BD and 2760 controls. We used the Synaptic Gene Ontology database to identify rare CNVs that overlap with synaptic genes. Using gene-based analysis, we compared their frequencies between the BD and control groups. We also searched for synaptic gene sets related to BD. The significance level was set to a false discovery rate of 10%. RESULTS: The RNF216 gene was significantly associated with BD (odds ratio, 4.51 [95% confidence interval, 1.66-14.89], false discovery rate < 10%). The BD-associated CNV that corresponded with RNF216 also partially overlapped with the minimal critical region of the 7p22.1 microduplication syndrome. The integral component of the postsynaptic membrane (Gene Ontology:0099055) was significantly associated with BD. The CNV overlapping with the intron region of GRM5 in this gene set showed a nominal significant association between cases and controls (P < 0.05). CONCLUSION: We provide evidence that CNVs in RNF216 and postsynaptic membrane-related genes confer a risk of BD, contributing to a better understanding of the pathogenesis of BD.

DOI： 10.1111/pcn.13752

Effects of frequently prescribed antiseizure medications on motor vehicle driving performance: Narrative review based on a tiered approach for the assessment of clinically meaningful driving impairment in the Ministry of Health, Labour, and Welfare guideline Reviewed

Kunihiro Iwamoto, Tetsuo Nakabayashi, Akiko Yamaguchi, Yuki Konishi, Momoe Saji, Reiji Yoshimura, Kousuke Kanemoto, Hirofumi Aoki, Masahiko Ando, Norio Ozaki

Neuropsychopharmacology Reports Vol. 44 ( 4 ) page： 682 - 687 2024.12

Effects of Sleep-Disordered Breathing on Daytime Brain Activity in Community-Dwelling Older Adults Reviewed International journal

Shibata, H; Noda, A; Mao, YJ; Iwamoto, K; Okuda, M; Okada, I; Miyata, S; Taoka, T; Yasuma, F

SLEEP SCIENCE 2024.6

Guideline for evaluating the effects of psychotropic drugs on motor vehicle driving performance in Japan: A tiered approach for the assessment of clinically meaningful driving impairment. Reviewed International journal

Tetsuo Nakabayashi, Kunihiro Iwamoto, Akiko Yamaguchi, Yuki Konishi, Momoe Saji, Reiji Yoshimura, Kousuke Kanemoto, Hirofumi Aoki, Masahiko Ando, Norio Ozaki

Neuropsychopharmacology reports Vol. 44 ( 2 ) page： 308 - 313 2024.6

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

In December 2022, the Ministry of Health, Labour and Welfare (MHLW) of Japan issued and implemented the guideline for evaluating the effects of psychotropic drugs on motor vehicle driving performance. This guideline recommends the use of a tiered approach to assess clinically meaningful driving impairment. It is noted that adverse events cannot be solely explained by pharmacokinetics, as the onset and duration of these events vary. Among these adverse events, those affecting alertness, such as drowsiness caused by psychotropic drugs on driving performance, are more frequently observed during initial treatment stages and dose escalation. Hence, when evaluating the effects of psychotropic drugs on driving performance, it becomes crucial to assess the persistence of clinically meaningful impairment. Therefore, the MHLW guideline, developed by the authors, emphasizes the need to assess the temporal profile of adverse events affecting driving in all clinical trials. Additionally, the guideline states that when conducting driving studies, the timing of multiple dosing should consider not only the pharmacokinetics of the investigational drug but also its tolerance.

DOI： 10.1002/npr2.12436

Duloxetine improves chronic orofacial pain and comorbid depressive symptoms in association with reduction of serotonin transporter protein through upregulation of ubiquitinated serotonin transporter protein Reviewed International journal

Mariko Nakamura, Akira Yoshimi, Tatsuya Tokura, Hiroyuki Kimura, Shinichi Kishi, Tomoya Miyauchi, Kunihiro Iwamoto, Mikiko Ito, Aiji Sato-Boku, Akihiro Mouri, Toshitaka Nabeshima, Norio Ozaki, Yukihiro Noda

Pain Vol. 165 ( 5 ) page： 1177 - 1186 2024.5

Language：English Publishing type：Research paper (scientific journal) Publisher：Ovid Technologies (Wolters Kluwer Health)

Abstract

Chronic orofacial pain (COP) is relieved by duloxetine (DLX) and frequently causes depressive symptoms. The aim of this study was to confirm effects of DLX on pain and depressive symptoms, and to associate with their effectiveness in platelet serotonin transporter (SERT) expression, which is a target molecule of DLX and plasma serotonin concentration in COP patients with depressive symptoms. We assessed for the severity of pain and depressive symptoms using the Visual Analog Scale (VAS) and 17-item Hamilton Depression Rating Scale (HDRS), respectively. Chronic orofacial pain patients were classified into 2 groups based on their HDRS before DLX-treatment: COP patients with (COP-D) and without (COP-ND) depressive symptoms. We found that the VAS and HDRS scores of both groups were significantly decreased after DLX treatment compared with those before DLX treatment. Upregulation of total SERT and downregulation of ubiquitinated SERT were observed before DLX treatment in both groups compared with healthy controls. After DLX treatment, there were no differences in total SERT of both groups and in ubiquitinated SERT of COP-D patients compared with healthy controls; whereas, ubiquitinated SERT of COP-ND patients remained downregulated. There were positive correlations between changes of serotonin concentrations and of VAS or HDRS scores in only COP-D patients. Our findings indicate that DLX improves not only pain but also comorbid depressive symptoms of COP-D patients. Duloxetine also reduces platelet SERT through upregulation of ubiquitinated SERT. As the result, decrease of plasma serotonin concentrations may be related to the efficacy of DLX in relieving pain and depression in COP patients.

DOI： 10.1097/j.pain.0000000000003124

Brexpiprazole-related tardive dystonia in a young patient with schizophrenia: A case report. Reviewed International journal

Takumi Ebina, Kunihiro Iwamoto, Masashi Ikeda

Psychiatry and clinical neurosciences Vol. 78 ( 5 ) page： 334 - 335 2024.5

Effect of single-administration of D-sorbitol pretreatment on the bitterness and continued willingness to take asenapine: a randomized, single-blind, placebo-controlled, crossover trial. Reviewed International journal

Shuhei Wada, Kunihiro Iwamoto, Hiroki Okumura, Hirotake Hida, Shuichi Hiraoka, Aya Kamei, Daisuke Mori, Kiyofumi Yamada, Masahiko Ando, Norio Ozaki, Masashi Ikeda

BMC psychiatry Vol. 24 ( 1 ) page： 81 - 81 2024.1

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Asenapine has unique orally-related side effects, such as a bitter taste induced by sublingual administration, which often results in discontinuation of the medication. While the FDA has approved black-cherry-flavored asenapine, several countries have prescribed only unflavored versions. Specifically, Asians commonly report experiencing the bitterness of asenapine because they are more sensitive to bitter tastes than other ethnic groups. In this study, with the aim of improving adherence by reducing the bitterness of asenapine, we investigated the effects of D-sorbitol, which reduced the bitterness parameters of taste sensors in our previous basic study on the bitterness and continuity of asenapine among patients with schizophrenia. METHODS: Twenty adult patients with schizophrenia were included in this single-blind, placebo-controlled, crossover trial. Participants rinsed their mouths with single-administration of D-sorbitol or a placebo prior to each administration of asenapine. We then conducted the questionnaires and assessed changes in the bitterness of asenapine (primary end point) and willingness to continue its use (secondary end point). RESULTS: D-sorbitol significantly improved the bitterness of asenapine (p = 0.038). Although it did not significantly increase the willingness to continue asenapine (p = 0.180), it did show improvement over the placebo in enhancing willingness to continue, especially in patients who were not accustomed to its taste. CONCLUSION: Our findings indicate that single-administration of D-sorbitol significantly reduces the bitterness of asenapine. In countries where flavored asenapine is not available, this finding could benefit patients who were not accustomed to its bitter taste. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials (jRCTs041210019) on May 14, 2021.

DOI： 10.1186/s12888-024-05549-x

Assessment of cognitive function and sleep-wake rhythms in community-dwelling older adults Reviewed International journal

Okuda, M; Noda, A; Iwamoto, K; Hishikawa, N; Miyata, S; Yasuma, F; Taoka, T; Ozaki, N; Suhr, JA; Miyazaki, S

SLEEP AND BIOLOGICAL RHYTHMS Vol. 22 ( 1 ) page： 137 - 145 2024.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Sleep and Biological Rhythms

Disruption of the circadian rhythm and sleep–wake cycles is a consequence of aging and is associated with the cognitive decline and many neurodegenerative conditions. We investigated the bedtime, wake-up time, sleep timing (midpoint between bedtime and wake-up time), and sleep timing standard deviation (SD) using the actigraphy among 80 consecutive volunteers aged ≥ 60 years. Global cognitive function and executive function of detailed cognitive domains were evaluated using the mini-mental state examination (MMSE) and Wisconsin card sorting test (WCST) and subjective daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS). The category achievement (CA), total errors (TE), perseverative errors of Nelson (PEN), non-perseverative errors (NPE), and difficulties in maintaining set (DMS) on the WCST were significantly correlated with sleep timing SD (CA: r = − 0.276, p = 0.013, TE: r = 0.311, p = 0.005, PEN: r = 0.241, p = 0.032, NPE: r = 0.250, p = 0.025, DMS: r = 0.235, p = 0.036), but not with the MMSE score. Multiple regression analyses with the stepwise forward selection method including age, ESS score, bedtime, sleep timing, and sleep timing SD, revealed that the ESS score, and sleep timing SD were significant factors related to CA on the WCST (ESS score: β = − 0.322, p = 0.004; sleep timing SD: β = − 0.250, p = 0.022). Assessment of sleep–wake rhythms, daytime sleepiness, and cognitive function using the MMSE and WCST is valuable for the prediction of cognitive decline in the geriatric population.

DOI： 10.1007/s41105-023-00491-z

Assessing the Real-World, Long-Term Impact of Lemborexant on Sleep Quality in a Home-Based Clinical Study. Reviewed International journal

Seiko Miyata, Kunihiro Iwamoto, Ippei Okada, Akihiro Fujimoto, Yuki Kogo, Daisuke Mori, Manabu Amano, Nao Matsuyama, Kazuki Nishida, Masahiko Ando, Toshiaki Taoka, Shinji Naganawa, Norio Ozaki

Nature and science of sleep Vol. 16 page： 291 - 303 2024

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Both subjective and objective evaluations are essential for the treatment of insomnia. Lemborexant has been shown to be effective in the long-term based solely on a subjective basis, and no long-term objective measures have been evaluated under natural sleep conditions. Small, lightweight sleep electroencephalogram (EEG) monitor was used, instead of polysomnography, to objectively evaluate sleep at home 4 and 12 weeks after lemborexant treatment. PATIENTS AND METHODS: Adults and elderly subjects with insomnia disorder, per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, were enrolled in this open-label, single-arm, single-center trial. Objective and subjective measures of sleep were prospectively assessed. Sleep disturbance, excessive sleepiness, and depressive symptoms were assessed using questionnaires. RESULTS: A total of 45 subjects were screened, of which 33 were enrolled. Paired t-tests were conducted to evaluate changes in sleep variables and compared with the baseline; subjects showed significant improvements in objective sleep efficiency (SE) and subjective sleep parameters at weeks 4 and 12 following treatment with lemborexant. When baseline values were taken into account, a repeated-multivariate analysis of variance (MANOVA) revealed statistically significant changes in the objective measures. Sleep disturbance, excessive sleepiness, and depressive symptoms improved after three months of lemborexant treatment. CONCLUSION: Furthermore, lemborexant therapy improved nocturnal sleep, when measured objectively using sleep EEG monitoring at home, and improved daytime sleepiness and depressive symptoms in older adults with insomnia disorder.

DOI： 10.2147/NSS.S448871

LPS and its relationship with subjective-objective discrepancies of sleep onset latency in patients with psychiatric disorders. Reviewed International journal

Keita Kawai, Kunihiro Iwamoto, Seiko Miyata, Ippei Okada, Motoo Ando, Hiroshige Fujishiro, Masahiko Ando, Akiko Noda, Norio Ozaki

Scientific reports Vol. 13 ( 1 ) page： 22637 - 22637 2023.12

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

Subjective-objective discrepancies in sleep onset latency (SOL), which is often observed among psychiatric patients, is attributed partly to the definition of sleep onset. Recently, instead of SOL, latency to persistent sleep (LPS), which is defined as the duration from turning out the light to the first consecutive minutes of non-wakefulness, has been utilized in pharmacological studies. This study aimed to determine the non-awake time in LPS that is most consistent with subjective sleep onset among patients with psychiatric disorders. We calculated the length of non-awake time in 30-s segments from lights-out to 0.5-60 min. The root mean square error was then calculated to determine the most appropriate length. The analysis of 149 patients with psychiatric disorders showed that the optimal non-awake time in LPS was 12 min. On the other hands, when comorbid with moderate or severe obstructive sleep apnea (OSA), the optimal length was 19.5 min. This study indicates that 12 min should be the best fit for the LPS non-awake time in patients with psychiatric disorders. When there is comorbidity with OSA, however, a longer duration should be considered. Measuring LPS minimizes discrepancies in SOL and provides important clinical information.

DOI： 10.1038/s41598-023-49261-4

Comparison of Polysomnography, Single-Channel Electroencephalogram, Fitbit, and Sleep Logs in Patients With Psychiatric Disorders: Cross-Sectional Study. Reviewed International journal

Keita Kawai, Kunihiro Iwamoto, Seiko Miyata, Ippei Okada, Hiroshige Fujishiro, Akiko Noda, Kazuyuki Nakagome, Norio Ozaki, Masashi Ikeda

Journal of medical Internet research Vol. 25 ( 1 ) page： e51336 2023.12

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Sleep disturbances are core symptoms of psychiatric disorders. Although various sleep measures have been developed to assess sleep patterns and quality of sleep, the concordance of these measures in patients with psychiatric disorders remains relatively elusive. OBJECTIVE: This study aims to examine the degree of agreement among 3 sleep recording methods and the consistency between subjective and objective sleep measures, with a specific focus on recently developed devices in a population of individuals with psychiatric disorders. METHODS: We analyzed 62 participants for this cross-sectional study, all having data for polysomnography (PSG), Zmachine, Fitbit, and sleep logs. Participants completed questionnaires on their symptoms and estimated sleep duration the morning after the overnight sleep assessment. The interclass correlation coefficients (ICCs) were calculated to evaluate the consistency between sleep parameters obtained from each instrument. Additionally, Bland-Altman plots were used to visually show differences and limits of agreement for sleep parameters measured by PSG, Zmachine, Fitbit, and sleep logs. RESULTS: The findings indicated a moderate agreement between PSG and Zmachine data for total sleep time (ICC=0.46; P<.001), wake after sleep onset (ICC=0.39; P=.002), and sleep efficiency (ICC=0.40; P=.006). In contrast, Fitbit demonstrated notable disagreement with PSG (total sleep time: ICC=0.08; wake after sleep onset: ICC=0.18; sleep efficiency: ICC=0.10) and exhibited particularly large discrepancies from the sleep logs (total sleep time: ICC=-0.01; wake after sleep onset: ICC=0.05; sleep efficiency: ICC=-0.02). Furthermore, subjective and objective concordance among PSG, Zmachine, and sleep logs appeared to be influenced by the severity of the depressive symptoms and obstructive sleep apnea, while these associations were not observed between the Fitbit and other sleep instruments. CONCLUSIONS: Our study results suggest that Fitbit accuracy is reduced in the presence of comorbid clinical symptoms. Although user-friendly, Fitbit has limitations that should be considered when assessing sleep in patients with psychiatric disorders.

DOI： 10.2196/51336

Assessment of cognitive function and sleep-wake rhythms in community-dwelling older adults Reviewed International journal

Okuda, M; Noda, A; Iwamoto, K; Hishikawa, N; Miyata, S; Yasuma, F; Taoka, T; Ozaki, N; Suhr, JA; Miyazaki, S

SLEEP AND BIOLOGICAL RHYTHMS 2023.9

Evaluating sleep-wake rhythm using a wearable device in patients with mental disorders. Invited Reviewed International journal

Seiko Miyata, Kunihiro Iwamoto, Norio Ozaki

Psychiatry and clinical neurosciences Vol. 77 ( 8 ) page： 419 - 419 2023.8

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

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 Vol. 14 page： 1189765 - 1189765 2023.7

Language：English Publishing type：Research paper (scientific journal)

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： 10.3389/fpsyt.2023.1189765

The new guideline for evaluating effects of psychotropic drugs on the performance to drive a motor vehicle in Japan: Comparison with US FDA guideline. Reviewed International journal

Kunihiro Iwamoto, Tetsuo Nakabayashi, Akiko Yamaguchi, Yuki Konishi, Momoe Saji, Reiji Yoshimura, Kousuke Kanemoto, Hirofumi Aoki, Masahiko Ando, Norio Ozaki

Neuropsychopharmacology reports Vol. 43 ( 2 ) page： 172 - 176 2023.6

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

In December 2022, the new guideline for evaluating the effect of psychotropic drugs on the performance to drive a motor vehicle was issued by the Ministry of Health, Labour and Welfare (MHLW) and implemented in Japan. Of the safety information, information on the influence of medications on driving performance is particularly important because it can be relevant to the social functioning of patients. In principle, the package inserts of medications are designed based on evidence and provide precautions regarding the operation of heavy machinery such as automobiles in Japan, the United States, and Europe. The effects of medications on driving performance are generally evaluated in a tiered approach involving nonclinical and clinical studies. Because of the wide variety of functional domains involved in automobile driving, the selection of evaluation methods for a given medication depends on their characteristics, which is a complicated method. Therefore, to evaluate the effects of psychotropic drugs on driving performance efficiently and appropriately, we developed the MHLW guideline that specifically defines the evaluation methods used in pharmacological studies, the neuropsychological tests used in pharmacodynamic studies, and the situations in which driving studies are necessary. Regarding the planning of appropriate drug development strategies, we review the background of the MHLW guideline and its differences from the US Food and Drug Administration (FDA) guideline.

DOI： 10.1002/npr2.12339

Response to 'Fluctuation of dopamine transporter availability in psychiatric-onset dementia with Lewy bodies: the dilemma of treatment with antidepressants'. Reviewed International journal

Hiroshige Fujishiro, Rika Matsubayashi, Youta Torii, Kunihiro Iwamoto

Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society Vol. 23 ( 3 ) page： 556 - 557 2023.5

Sensory evaluation of the bitterness of asenapine using D-sorbitol pretreatment: single-blind, placebo-controlled, crossover trial. Reviewed International journal

Shuhei Wada, Kunihiro Iwamoto, Hiroki Okumura, Hirotake Hida, Shuichi Hiraoka, Aya Kamei, Daisuke Mori, Kiyofumi Yamada, Norio Ozaki

BMC psychiatry Vol. 23 ( 1 ) page： 159 - 159 2023.3

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Antipsychotics are essential in the acute treatment of and maintenance therapy for schizophrenia, but medication adherence and long-term treatment continuity are needed to maximize their effectiveness. Each antipsychotic has various side effects, which may affect adherence. Some patients with schizophrenia are reluctant to take asenapine because of its unique oral-related side effects, such as the bitter taste caused by sublingual administration. Our previous basic research found that D-sorbitol lowered the bitterness parameters of the taste sensors. However, whether D-sorbitol has the same effect in patients remains unclear. Therefore, using a D-sorbitol solution, we aim to evaluate changes in the bitterness of asenapine among patients with schizophrenia. METHODS: In this single-blind, placebo-controlled, crossover trial, we plan to recruit 20 adult patients with schizophrenia spectrum disorder who take sublingual asenapine tablets. The participants will be divided into two groups (n = 10 each). Each group will be given a D-sorbitol or placebo solution on the first day for rinsing before taking the sublingual asenapine tablets. After a 1-day interval, the participants will rinse their mouths again with a different liquid. Questionnaires regarding changes in taste and the willingness to continue asenapine will be conducted before the start of the study and after each rinse. The primary and secondary end points will be a taste evaluation of bitterness, and the willingness to continue asenapine, respectively. Differences in questionnaire scores between the D-sorbitol and placebo solutions will be calculated and analyzed using a McNemar test. DISCUSSION: This study aims to determine the efficacy of D-sorbitol in masking the bitter taste of asenapine. To our knowledge, it is the first intervention study using D-sorbitol for bitter taste of asenapine in patients with schizophrenia. Evidence of the efficacy of D-sorbitol could result in D-sorbitol pretreatment being an easy and inexpensive means of improving adherence to asenapine. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials jRCTs041210019, on May 14, 2021. Ethics approval was obtained from the Nagoya University Clinical Research Review Board.

DOI： 10.1186/s12888-023-04664-5

Driving performance of patients with epilepsy undergoing antiepileptic monotherapy Reviewed International journal

Kunihiro Iwamoto, Momoe Saji, Emi Matsuoka, Kousuke Kanemoto

Psychiatry and Clinical Neurosciences Reports Vol. 2 ( 1 ) page： e83 2023.3

Temporal trajectories of proposed biomarkers in psychiatric-onset prodromal dementia with Lewy bodies: a case report. Reviewed International journal

Hiroshige Fujishiro, Shusei Arafuka, Kazuyoshi Ogasawara, Kunihiro Iwamoto, Seiko Miyata, Youta Torii, Shuji Iritani, Norio Ozaki

Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society Vol. 23 ( 1 ) page： 196 - 200 2023.1

Prevalence of obstructive sleep apnea as assessed by polysomnography in psychiatric patients with sleep-related problems. Reviewed International journal

Ippei Okada, Seiko Miyata, Kunihiro Iwamoto, Hiroshige Fujishiro, Akiko Noda, Norio Ozaki

Sleep & breathing = Schlaf & Atmung Vol. 26 ( 4 ) page： 1983 - 1991 2022.12

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Patients with psychiatric disorders often complain of sleep disturbances and are frequently suspected of obstructive sleep apnea (OSA). However, data regarding sleep problems evaluated by attended polysomnography (PSG) remain limited in this population. We analyzed the results of attended PSG from psychiatric patients with sleep-related problems to determine the prevalence and features of sleep disorders among this population. METHODS: We retrospectively investigated the attended PSG results of patients with psychiatric disorders: major depressive disorder, bipolar disorder, neurodevelopmental disorder, schizophrenia, neurocognitive disorder, anxiety disorder, somatic symptom disorder. RESULTS: Of 264 patients, 158 men (60%), mean age was 47 ± 19.9 years. More than half of the patients with major depressive disorder (62%), bipolar disorder (70%), schizophrenia (58%), neurocognitive disorders (55%), and somatic symptom disorder (56%) had OSA. Among the psychiatric patients with OSA, 62% of these patients had moderate to severe OSA. The risk factors for OSA were snoring, male, age, and body mass index. The presence of OSA was not associated with the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale score, or benzodiazepine, antipsychotic, or antidepressant use. Other sleep disorders were insomnia (19%), central disorders of hypersomnia (8%), restless legs syndrome/periodic limb movement of sleep (8%), rapid eye movement sleep behavior disorder (7%), and central sleep apnea syndrome (3%). CONCLUSIONS: PSG revealed that moderate to severe OSA was common in psychiatric patients with or without snoring. Subjective symptoms and psychotropics did not predict OSA. Therefore, PSG is needed to reveal sleep conditions in patients with psychiatric disorders.

DOI： 10.1007/s11325-022-02566-6

Cross-Disorder Analysis of Genic and Regulatory Copy Number Variations in Bipolar Disorder, Schizophrenia, and Autism Spectrum Disorder. Reviewed International journal

Itaru Kushima, Masahiro Nakatochi, Branko Aleksic, Takashi Okada, Hiroki Kimura, Hidekazu Kato, Mako Morikawa, Toshiya Inada, Kanako Ishizuka, Youta Torii, Yukako Nakamura, Satoshi Tanaka, Miho Imaeda, Nagahide Takahashi, Maeri Yamamoto, Kunihiro Iwamoto, Yoshihiro Nawa, Nanayo Ogawa, Shuji Iritani, Yu Hayashi, Tzuyao Lo, Gantsooj Otgonbayar, Sho Furuta, Nakao Iwata, Masashi Ikeda, Takeo Saito, Kohei Ninomiya, Tomo Okochi, Ryota Hashimoto, Hidenaga Yamamori, Yuka Yasuda, Michiko Fujimoto, Kenichiro Miura, Masanari Itokawa, Makoto Arai, Mitsuhiro Miyashita, Kazuya Toriumi, Kazutaka Ohi, Toshiki Shioiri, Kiyoyuki Kitaichi, Toshiyuki Someya, Yuichiro Watanabe, Jun Egawa, Tsutomu Takahashi, Michio Suzuki, Tsukasa Sasaki, Mamoru Tochigi, Fumichika Nishimura, Hidenori Yamasue, Hitoshi Kuwabara, Tomoyasu Wakuda, Takahiro A Kato, Shigenobu Kanba, Hideki Horikawa, Masahide Usami, Masaki Kodaira, Kyota Watanabe, Takeo Yoshikawa, Tomoko Toyota, Shigeru Yokoyama, Toshio Munesue, Ryo Kimura, Yasuko Funabiki, Hirotaka Kosaka, Minyoung Jung, Kiyoto Kasai, Tempei Ikegame, Seiichiro Jinde, Shusuke Numata, Makoto Kinoshita, Tadafumi Kato, Chihiro Kakiuchi, Kazuhiro Yamakawa, Toshimitsu Suzuki, Naoki Hashimoto, Shuhei Ishikawa, Bun Yamagata, Shintaro Nio, Toshiya Murai, Shuraku Son, Yasuto Kunii, Hirooki Yabe, Masumi Inagaki, Yu-Ichi Goto, Yuto Okumura, Tomoya Ito, Yuko Arioka, Daisuke Mori, Norio Ozaki

Biological psychiatry Vol. 92 ( 5 ) page： 362 - 374 2022.9

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25-0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.

DOI： 10.1016/j.biopsych.2022.04.003

ドライビングシミュレーターによる健常者の運転技能と視線特性との関係性 Reviewed

田中陽子, 宮田聖子, 岩本邦弘, 山本真江里, 三浦健一郎, 橋本亮太, 尾崎紀夫

日本安全運転医療学会誌 Vol. 2 ( 1 ) page： 46 - 53 2022.8

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：日本安全運転医療学会

道路交通法により体調不良時の自動車運転は禁止されているが,患者に運転の可否を指導する上での医学的なエビデンスは乏しく,適切な指導のもと患者が自動車社会で生活するためには,運転技能に関わる医学的知見を蓄積することが求められる.運転技能に必須である視覚,認知機能,運動機能の中でも,とりわけ視覚情報は運転中に得られる情報の90%にも及び,視覚を支える視線を促えることが運転技能を予測する上で有用な可能性がある.そこで,本研究では,視線の基本的特性と運転技能との関連にっいて検討を行うため,同一被験者にて運転と視線計測を行った健常者36名を対象に運転と視線の関連にっいて解折した.運転課題は車線維持課題(横揺れの指標),急ブレーキ課題(反応時間の指標)を実施し,視線課題では,フリービューイング課題,固視課題,パシュート課題を実施した.運転の指標と視線の指標との相関解析により,横揺れの指標はフリービュ一イング課題におけるフィクセーション,サッケード関連指標,視線移動の総距離,およびパシュート課題におけるサッケード,垂直方向の視線移動に関する指標と有意な相関を示した.また,反応時間の指標はパシュート課題におけるサッケー一ドおよび垂直方向の視線移動の指標と有意な相関を示した.以上より,視線解析におけるサッケードや視線移動距離といった指標は,運転技能を予測できる可能性が示された.(著者抄録)

Polysomnographic characteristics and predictors of positional obstructive sleep apnea in Japanese elderly Reviewed International journal

Miyata Seiko, Otake Hironao, Fujishiro Hiroshige, Iwamoto Kunihiro, Noda Akiko, Sone Michihiko, Ozaki Norio

SLEEP AND BIOLOGICAL RHYTHMS Vol. 20 ( 3 ) page： 403 - 411 2022.7

Driving performance of euthymic outpatients with bipolar disorder undergoing real-world pharmacotherapy. Reviewed International journal

Akiko Yamaguchi, Kunihiro Iwamoto, Masahiko Ando, Kiyoshi Fujita, Motonori Yokoyama, Tsuyoshi Akiyama, Yoshio Igarashi, Norio Ozaki

Psychiatry and clinical neurosciences Vol. 76 ( 5 ) page： 172 - 178 2022.5

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: Medications for the treatment of bipolar disorder (BD) could affect patients' cognitive function. Patients with BD present with neurocognitive impairment even in a remission state. Little research is available on the daily functioning, especially driving performance, of stable outpatients with BD under pharmacological treatment. METHODS: In total, 58 euthymic outpatients with BD undergoing real-world pharmacotherapy and 80 sex- and age-matched healthy controls (HCs) were enrolled. Three driving tasks using a driving simulator-road-tracking, car-following, and harsh-braking-and three cognitive tasks-Continuous Performance Test, Wisconsin Card Sorting Test, and Trail-Making Test-were evaluated. Symptom assessment scales-Young Mania Rating Scale, Structured Interview Guide for the Hamilton Depression Rating Scale, Beck Depression Inventory-II, Social Adaptation Self-evaluation Scale, and Stanford Sleepiness Scale-were also completed. RESULTS: Car-following and road-tracking performance were significantly impaired in patients with BD compared with HCs after adjusting for demographic variables, but these performances generally overlapped. Broad neurocognitive functions were significantly lower in the patients with BD compared to HCs, but car-following performance was significantly negatively correlated with sustained attention only. Although most patients received multiple medications rather than monotherapy, no relationship between prescriptions and driving performance was found. CONCLUSION: Euthymic patients with BD under steady-state pharmacotherapy had impaired driving performance compared with HCs, but the overlapping distributions of driving performance suggested that driving performance is not always deteriorated in patients with BD. Therefore, attentional function may be a useful clinical feature for judging driving aptitude in patients with BD. This article is protected by copyright. All rights reserved.

DOI： 10.1111/pcn.13332

Atezolizumab, an immune checkpoint inhibitor, caused precedent depressive symptoms related to limbic encephalitis. Reviewed International journal

Shuhei Wada, Kunihiro Iwamoto, Norio Ozaki

Psychiatry and clinical neurosciences Vol. 76 ( 4 ) page： 125 - 126 2022.4

Residual effects of zopiclone on driving performance using a standardized driving simulator among healthy volunteers. Reviewed International journal

Kunihiro Iwamoto, Mari Iwata, Daiji Kambe, Yumiko Imadera, Naoki Tachibana, Yu Kajiyama, Masahiko Ando, Norio Ozaki

Psychopharmacology Vol. 239 ( 3 ) page： 841 - 850 2022.3

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

RATIONALE: The effects of hypnotics on automobile driving have been attracting increasing attention. However, few driving simulators (DSs) have been confirmed to have acceptable reliability and validity for assessing the next-day residual effects of zopiclone as a positive control on driving performance. OBJECTIVE: To investigate whether a new DS could permit detection of the next-day residual effects of zopiclone on driving performance. METHODS: In this double-blind, randomized, placebo-controlled crossover trial, 28 healthy males received zopiclone 7.5 mg at bedtime on days 1 and 8 and placebo on the other days over a period of 16 days. The participants took part in three driving tasks-road-tracking, car-following, and harsh-braking-using a DS on days 2 and 9 at 9-h post-dosing. Scores on the Karolinska Sleepiness Scale and Profile of Mood States-Second Edition were then assessed, as was the serum concentration of zopiclone. RESULTS: The estimated differences in the standard deviation of lateral position (cm) in the road-tracking task between the zopiclone and placebo groups on days 2 and 9 were 3.75 cm (90% confidence interval (CI): 1.71-5.79) and 4.07 cm (90% CI: 2.02-6.11), respectively. The estimated differences in the distance coefficient of variation in the car-following task and in the brake reaction time in the harsh-braking task between the zopiclone and placebo groups on day 2 were 4.31 (90% CI: 1.94-6.69) and 24.6 ms (90% CI: 12.7-36.4), respectively. CONCLUSIONS: The DS used in this study has sufficient sensitivity to detect the next-day residual effects of zopiclone on driving performance.

DOI： 10.1007/s00213-022-06075-y

A Study of Factors Causing Sleep State Misperception in Patients with Depression. Reviewed International journal

Keita Kawai, Kunihiro Iwamoto, Seiko Miyata, Ippei Okada, Motoo Ando, Hiroshige Fujishiro, Akiko Noda, Norio Ozaki

Nature and science of sleep Vol. 14 page： 1273 - 1283 2022

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

Purpose: Sleep state misperception, which is the discrepancy between subjective and objective sleep, is often observed in patients with depression. This phenomenon may delay the remission of depression. Previous studies have focused on the total sleep time (TST) misperception, with many of these studies using actigraphy. Thus, our study investigated depressed patients with the exploratory aim of clarifying factors associated with the sleep state misperception including the wake after sleep onset (WASO) misperception, with their objective sleep additionally evaluated by polysomnography (PSG). Patients and Methods: We conducted a cross-sectional study. Before undergoing overnight PSG monitoring, 40 patients with depression completed questionnaires that included the Beck Depression Inventory (BDI), Epworth sleepiness scale, Temperament and Character Inventory, and the Pittsburgh sleep quality index. Patients were also asked to estimate their subjective sleep duration after they woke up in the morning. Based on this data, we calculated the misperception using the following formula: subjective sleep duration minus objective sleep duration. We compared each factor between negative and positive misperception groups and the multiple regression analysis was performed for TST and WASO misperception, respectively. Results: Although sleep architectures, age, severity of depression and obstructive sleep apnea (OSA) exhibited differences in underestimating or overestimating the WASO, only sex differences were associated with underestimating or overestimating their total sleep time (TST). Moreover, BDI, the severity of OSA, sleep architectures (N1% and N2%), and benzodiazepine (BZD) use were significantly correlated with WASO misperception, whereas only OSA severity was significantly correlated with TST misperception. A subsequent multiple regression analysis demonstrated the BDI was independently correlated with the WASO misperception (β=0.341, p=0.049). Conclusion: In clinical practice, interventions especially for OSA, and the reduction of depressive symptoms are an important method for improving patient sleep perception. Moreover, current results suggest that BZD prescriptions should be avoided as well.

DOI： 10.2147/NSS.S366774

FLUID study: study protocol for an open-label, single-centre pilot study to investigate the efFect of Lemborexant on sleep management in Japanese sUbjects aged 50 years and older with Insomnia Disorder. Reviewed International journal

Ippei Okada, Kunihiro Iwamoto, Seiko Miyata, Akihiro Fujimoto, Masaki Tanaka, Manabu Amano, Nao Matsuyama, Toshiaki Taoka, Shinji Naganawa, Norio Ozaki

BMJ open Vol. 11 ( 11 ) page： e054885 2021.11

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: Bidirectional associations have been reported between sleep disturbance and both cognitive impairment, including Alzheimer's disease and amyloid beta-peptide (Aβ) accumulation. These relationships can be explained by the glymphatic system, which acts as a garbage drainage system in the brain. As interstitial fluid dynamics are suggested to increase during sleep, clearance of Aβ can be influenced by sleep disturbance or deprivation. We hypothesised that using lemborexant, an orexin receptor antagonist, to improve sleep quality would also improve the function of the glymphatic system. We plan to examine the effect of lemborexant on sleep quality and the glymphatic system among patients with insomnia disorder. METHODS AND ANALYSIS: This pilot study is designed as an open-label, single-arm, single-centre trial. Thirty patients aged 50 years and over with insomnia will be recruited. The participants will take lemborexant (5 mg) at bedtime for 12 weeks and undergo a home-based sleep study at baseline and weeks 4 and 12, as well as MRI examinations to evaluate the glymphatic system at baseline and week 12. The primary outcome will be changes in objective sleep parameters as evaluated using a sleep monitoring system. The secondary outcomes will be changes in subjective sleep parameters. The relationships between changes in sleep parameters and the glymphatic system will be evaluated using diffusion tensor image analysis along the perivascular space, which is called the ALPS-index. Sleep parameters and the ALPS-index will be analysed using a paired t-test or Pearson's correlation coefficient. ETHICS AND DISSEMINATION: The study protocol was approved by Nagoya University Certified Review Board. The findings from this research will be published in peer-reviewed journals and be presented at local, national and international conferences. TRIAL REGISTRATION NUMBER: jRCTs041210024.

DOI： 10.1136/bmjopen-2021-054885