Research Achievements - Original paper -
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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 2025.02 [Refereed]
Research paper (journal) Domestic Co-author
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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 2025.01 [Refereed]
Research paper (journal) Domestic Co-author
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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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 2024.12 [Refereed]
Research paper (journal)
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 2024.12 [Refereed]
Research paper (journal) Domestic Co-author
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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 2024.11 [Refereed]
Research paper (journal) Domestic Co-author
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 2024.08 [Refereed]
Research paper (journal) International Co-author
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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Pharmacokinetics, safety, and efficacy of daridorexant in Japanese subjects: Results from phase 1 and 2 studies.
Makoto Uchiyama, Kazuo Mishima, Tomoko Yagi, Tatsuya Yoshihara, Takashi Eto, Clemens Muehlan, Osamu Togo, Yuichi Inoue
Journal of sleep research e14302 2024.08 [Refereed]
Research paper (journal) Domestic Co-author
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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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 2024.08 [Refereed]
Research paper (journal) Domestic Co-author
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 2024.07 [Refereed]
Research paper (journal) Domestic Co-author
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 2024.07 [Refereed]
Research paper (journal) Domestic Co-author
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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 2024.06 [Refereed]
Research paper (journal) Domestic Co-author
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 2024.06 [Refereed]
Research paper (journal) Domestic Co-author
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.
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Association between sleep state misperception and bedtime behavior in patients with chronic insomnia.
Mizuki Kudo, Naoko Ayabe, Masahiro Takeshima, Masaya Ogasawara, Yu Itoh, Kazuhisa Yoshizawa, Shingo Kitamura, Kazuo Mishima
Scientific reports 14 ( 1 ) 13991 - 13991 2024.06 [Refereed]
Research paper (journal) Domestic Co-author
Previous studies on sleep state misperception have objectively evaluated sleep status in special environments using polysomnography. There is a paucity of data from studies that evaluated habitual sleep status in home environments. The present study aimed to investigate sleep state misperception in the home environment of patients with chronic insomnia using a lumbar-worn actigraphy to identify sleep habits associated with sleep state misperception severity. Thirty-one patients and 42 healthy volunteers were included in the insomnia and non-insomnia group, respectively. Participants recorded subjective assessments in sleep diaries, objective assessments with an actigraphy worn for 14 days, and self-assessments using questionnaires. Both groups had similar objective sleep ratings; however, insomnia group had significantly worse subjective ratings (total sleep time, wake after sleep onset, and sleep onset latency). A significant correlation was found between subjective and objective total sleep time scores in non-insomnia group but not in insomnia group. Insomnia group had earlier bedtimes, significantly longer bedtimes, and impaired daytime functioning (Sheehan Disability Scale score); additionally, they underestimated their total sleep time, particularly with earlier bedtimes and longer laying durations. Monitoring the sleep status and habits of individuals in home environments could be instrumental in identifying key points for targeted interventions on sleep hygiene and cognitive behavioral therapy for insomnia.
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Irinaka Keisuke, Takeshima Masahiro, Mishima Kazuo
秋田医学 ( 秋田医学会 ) 51 ( 1 ) 49 - 53 2024.06 [Refereed]
Research paper (journal) Domestic Co-author
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Efficacy of Lemborexant in Adults ≥ 65 Years of Age with Insomnia Disorder.
Valerie Arnold, Sonia Ancoli-Israel, Thien Thanh Dang-Vu, Kazuo Mishima, Kate Pinner, Manoj Malhotra, Margaret Moline
Neurology and therapy 2024.05 [Refereed]
Research paper (journal) International Co-author
BACKGROUND: Pharmacologic treatments are available to treat insomnia, a common and burdensome sleep disorder, but may be contraindicated in older adults who are prone to side effects from sleep-promoting drugs. These analyses of sleep diary data from Study E2006-G000-303 (Study 303) investigated the benefits of lemborexant 5 mg (LEM5) and 10 mg (LEM10) in the subgroup age ≥ 65 years with insomnia. METHOD: Study 303, a 12-month, double-blind study of LEM5 and LEM10 in adults (age ≥ 18 years) with insomnia disorder (sleep onset and/or maintenance difficulties) assessed subject-reported (subjective) sleep-onset latency (sSOL), sleep efficiency (sSE), wake after sleep onset (sWASO), and total sleep time (sTST). Morning sleepiness/alertness, insomnia severity (Insomnia Severity Index [ISI]), fatigue (Fatigue Severity Scale [FSS]), perceptions of sleep-related medication effects (Patient Global Impression-Insomnia [PGI-I] questionnaire), and safety were also evaluated. RESULTS: In this subgroup of older adults (≥ 65 years; n = 262), there were significantly larger changes from baseline for sSOL, sSE, sTST, and sWASO with LEM5 and LEM10 versus placebo through month 6 (except sWASO month 1), indicating improvement; these improvements were sustained through month 12. Subject-reported increases in morning alertness were significantly greater with one or both LEM doses versus placebo through month 6 and sustained through month 12. There were significantly larger ISI total and daytime functioning score decreases (improvement) from baseline with LEM versus placebo at months 1, 3, and 6 (total score: both doses; daytime functioning: LEM5 month 1 and both doses months 3 and 6) and decreases from baseline FSS at months 1 and 3 (LEM5) and month 6 (both doses), sustained to month 12. Compared with placebo, more subjects reported that LEM (both doses) positively impacted ability to sleep, time to fall asleep, and TST through month 6, sustained to month 12, with no rebound after drug withdrawal. LEM was well tolerated to month 12; mild somnolence was the most common treatment-emergent adverse event. CONCLUSIONS: Improvements in subject-reported efficacy in LEM-treated adults age ≥ 65 years with insomnia were observed as early as the first week of treatment and sustained through end of month 12. LEM was well tolerated. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT02952820: E2006-G000-303; Study 303; SUNRISE-2 (First posted: October 2016); EudraCT 2015-001463-39 (First posted: November 2016).
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Treatment Failure and Long-Term Prescription Risk for Guideline-Recommended Hypnotics in Japan.
Masahiro Takeshima, Kazuhisa Yoshizawa, Masaya Ogasawara, Mizuki Kudo, Yu Itoh, Naoko Ayabe, Kazuo Mishima
JAMA network open 7 ( 4 ) e246865 2024.04 [Refereed]
Research paper (journal) Domestic Co-author
IMPORTANCE: Although insomnia guidelines recommend the use of several individual hypnotics, the most useful hypnotic for treating insomnia in a clinical setting remains unclear. OBJECTIVE: To determine which guideline-recommended hypnotics have lower risks of monotherapy failure and which hypnotics have a higher risk of long-term prescription for insomnia treatment. DESIGN, SETTING, AND PARTICIPANTS: This retrospective observational cohort study used data from the Japan Medical Data Center Claims Database from April 1, 2005, to March 31, 2021. Participants included adults whose first prescribed pharmaceutical treatment for insomnia was guideline-recommended hypnotic monotherapy. Data were analyzed from December 24, 2022, to September 26, 2023. EXPOSURES: Suvorexant, ramelteon, eszopiclone, zolpidem, and triazolam monotherapy. MAIN OUTCOMES AND MEASURES: The primary outcome was monotherapy failure, defined as a change in hypnotic or having an additional hypnotic prescribed for insomnia within 6 months of the first prescription of a guideline-recommended hypnotic monotherapy. The secondary outcome was monotherapy discontinuation, defined as no prescription of any hypnotic for 2 consecutive months within 6 months after prescribing a guideline-recommended hypnotic in patients for whom monotherapy did not fail. Monotherapy failure and discontinuation were compared using Cox proportional hazards and logistic regression models, respectively. RESULTS: The study included 239 568 adults (median age, 45 [IQR, 34-55] years; 50.2% women) whose first prescription for insomnia was guideline-recommended hypnotic monotherapy. During the 6-month follow-up period, 24 778 patients (10.3%) experienced failure of monotherapy with a guideline-recommended hypnotic. In comparison with eszopiclone, there were more cases of monotherapy failure for ramelteon (adjusted hazard ratio [AHR], 1.23 [95% CI], 1.17-1.30; P < .001), fewer cases for zolpidem (AHR, 0.84 [95% CI, 0.81-0.87]; P < .001) and triazolam (AHR, 0.82 [95% CI, 0.78-0.87]; P < .001), and no significant difference between suvorexant and eszopiclone. Among those without monotherapy failure, monotherapy was discontinued in 84.6% of patients, with more discontinuations for ramelteon (adjusted odds ratio [AOR], 1.31 [95% CI, 1.24-1.40]; P < .001) and suvorexant (AOR, 1.20 [95% CI, 1.15-1.26]; P < .001) than for eszopiclone and no significant difference between zolpidem or triazolam and eszopiclone. CONCLUSIONS AND RELEVANCE: Due to uncontrolled confounding factors in this cohort study, no conclusions regarding the pharmacologic properties of guideline-recommended hypnotics can be drawn based on these results. Further studies accounting for confounding factors, including diagnoses of chronic vs acute insomnia disorder, insomnia and psychiatric symptom severity, and physician attitudes toward hypnotic prescription, are needed.
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Impact of aripiprazole discontinuation in remitted major depressive disorder: a randomized placebo-controlled trial.
Masahiro Takeshima, Akise Umakoshi, Yuki Omori, Kazuhisa Yoshizawa, Masaya Ogasawara, Mizuki Kudo, Yu Itoh, Naoko Ayabe, Kazuo Mishima
Psychopharmacology 2024.03 [Refereed]
Research paper (journal) Domestic Co-author
RATIONALE: The efficacy and safety of antidepressant augmentation therapy with aripiprazole (AATA) has been established; however, the ongoing effects of continuing aripiprazole after remission remain unclear because no studies have examined this issue. OBJECTIVES: We aimed to explore the effect of AATA discontinuation on the major depressive disorder (MDD) recurrence risk in patients with remitted MDD after AATA. METHODS: This 24-week, multicenter, placebo-controlled, double-blind, randomized trial evaluated recurrence risk in patients with MDD who achieved remission with AATA. Differences in MDD recurrence, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, between the two groups were compared using survival analysis. The differences in depressive symptom severity and social functioning between the two groups were compared using a mixed model with repeated measures. Extrapyramidal symptoms and akathisia were also assessed. RESULTS: Twenty-three participants were randomized and treated. Two patients in each group experienced recurrence during the study. Kaplan-Meier analysis with Log-rank comparison showed no difference in recurrence between groups (p = 0.642). No significant difference in interactions between group and period was observed in the 17-item Hamilton depression rating scale (p = 0.492) or the Social and Occupational Functioning Assessment Scale (p = 0.638). No patients developed extrapyramidal symptoms or akathisia. CONCLUSIONS: Definitive conclusions could not be drawn owing to the small sample size. This study represents a starting point for investigating the safety of aripiprazole discontinuation on recurrence in patients with MDD who have achieved remission with AATA. Future studies with appropriate sample sizes calculated based on this study are needed.
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Development and acceptability testing of a decision aid for considering whether to reduce antipsychotics in individuals with stable schizophrenia
Aoki, Y. Takaesu, Y. Matsui, K. Tokumasu, T. Tani, H. Takekita, Y. Kanazawa, T. Kishimoto, T. Tarutani, S. Hashimoto, N. Takeuchi, H. Mishima, K. Inada, K.
Neuropsychopharmacol Rep ( Wiley ) 2023.07 [Refereed]
Research paper (journal) Domestic Co-author
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Feasibility of a wrist-worn wearable device for estimating mental health status in patients with mental illness.
Kazuyuki Nakagome, Manabu Makinodan, Mitsuhiro Uratani, Masaki Kato, Norio Ozaki, Seiko Miyata, Kunihiro Iwamoto, Naoki Hashimoto, Atsuhito Toyomaki, Kazuo Mishima, Masaya Ogasawara, Masahiro Takeshima, Kazumichi Minato, Toshikazu Fukami, Mari Oba, Kazuyoshi Takeda, Hideki Oi
Frontiers in psychiatry 14 1189765 - 1189765 2023.07 [Refereed]
Research paper (journal) Domestic Co-author
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.