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Maki Nagaoka,1,2 Akihiro Koreki,1– 3 Teppei Kosugi,4 Akira Ninomiya,1,2 Masaru Mimura,2,5 Mitsuhiro Sado1,2,6 1Department of Neuropsychiatry, Keio University School of Medicine, Shinjuku-ku, Japan; 2Mindfulness & Stress Research Center, Keio University, Shinjuku-ku, Japan; 3Department of Psychiatry, National Hospital Organization Shimofusa Psychiatric Medical Center, Chiba, Japan; 4Department of Psychiatry, Gunma Hospital, Takasaki, Japan; 5Keio University Centre for Preventive Medicine, Keio University, Shinjuku-ku, Japan; 6Keio University Health Center, Keio University, Yokohama City, JapanCorrespondence: Mitsuhiro Sado, Keio University Health Center, Keio University, 4-1-1 Hiyoshi, Kouhoku-ku, Yokohama City, Kanagawa, 223-8521, Japan, Tel +81-045-566-1055, Fax +81-045-566-1059, Email mitsusado@keio.jpPurpose: This study aimed to conduct an economic evaluation of mindfulness-based cognitive therapy (MBCT) in healthy participants by performing cost-utility analysis (CUA) and cost-benefit analysis (CBA).Patients and Methods: CUA was carried out from a healthcare sector perspective and CBA was from the employer’s perspective in parallel with a randomized controlled trial. Of the 90 healthy participants, 50 met the inclusion criteria and were randomized to the MBCT group (n = 25) or wait-list control group (n = 25). In the CUA, intervention costs and healthcare costs were included, while the mean difference in the change in quality-adjusted life years (QALYs) between the baseline and 16-week follow-up was used as an indicator of effect. Incremental cost-effectiveness ratio (ICER) was produced, and uncertainty was addressed using non-parametric bootstrapping with 5000 replications. In the CBA, the change in productivity losses was reflected as a benefit, while the costs included intervention and healthcare costs. The net monetary benefit was calculated, and uncertainty was handled with 5000 bootstrapping. Healthcare costs were measured with the self-report Health Service Use Inventory. The purchasing power parity in 2019 was used for currency conversion.Results: In the CUA, incremental costs and QALYs were estimated at JPY 19,700 (USD 189) and 0.011, respectively. The ICER then became JPY 1,799,435 (USD 17,252). The probability of MBCT being cost-effective was 92.2% at the threshold of 30,000 UK pounds per QALY. The CBA revealed that MBCT resulted in increased costs (JPY 24,180) and improved work productivity (JPY 130,640), with a net monetary benefit of JPY 106,460 (USD 1021). The probability of the net monetary benefit being positive was 69.6%.Conclusion: The results suggested that MBCT may be more cost-effective from a healthcare sector perspective and may be cost-beneficial from the employer’s perspective.Keywords: mindfulness, healthy individuals, cost-effectiveness, MBCT

Akihiro Koreki,1– 3 Maki Nagaoka,1,3 Akira Ninomiya,1,3 Masaru Mimura,1,3 Mitsuhiro Sado1,3,4 1Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan; 2Department of Psychiatry, National Hospital Organization Shimofusa Psychiatric Medical Center, Chiba, Japan; 3Center for Stress Research, Keio University, Tokyo, Japan; 4Health Center, Keio University, Tokyo, JapanCorrespondence: Mitsuhiro Sado, Department of Neuropsychiatry, Keio University School of Medicine, Shinanomachi 35, Shinjuku-ku, Tokyo, 160-8582, Japan, Tel +81-3-3353-1211 Ext. 62454, Fax +81-3-5379-0187, Email mitsusado@keio.jpPurpose: Cost-effective analysis is one of the most useful analyses for political decision-making in medicine under a limited budget. Although the data of the ICEpop CAPability measure for Adults (ICECAP-A) is sometimes essential for the measurement of cost effectiveness, such data are often lacking in most clinical trials. Therefore, a conversion formula (ie mapping) derived from the values of clinical assessment scales into utility is required.Patients and Methods: We used an internet survey where 500 general residents were asked to fill in four kinds of self-reported questionnaires [ICECAP-A, the Satisfaction with Life Scale (SWLS), Flourishing Scale (FS), and the Scale of Positive and Negative Experience (SPANE)]. A beta regression was conducted with the utility assessed by ICECAP-A as a dependent variable.Results: We developed several mapping formulae depending on available questionnaires. These mapping formulae were well-validated in our validation sample. The models using a greater number of questionnaires tended to show better mapping.Conclusion: The mapping function of our formula was within the range of other reported mapping studies. We believe this formula is useful for cost effective analyses of several trials where utility data are lacking.Keywords: mapping, well-being, ICECAP, SWLS, FS, SPANE

Mitsuhiro Sado,1,2 Teppei Kosugi,1 Akira Ninomiya,1,2 Sunre Park,3,4 Daisuke Fujisawa,1,4,5 Maki Nagaoka,1 Masaru Mimura1,2 1Department of Neuropsychiatry, Keio University School of Medicine, Shinjuku, Tokyo, Japan; 2Center for Stress Research, Keio University, Shinjuku, Tokyo, Japan; 3Faculty of Nursing and Medicine Care, Keio University, Shinjuku, Tokyo, Japan; 4Palliative Care Center, Keio University Hospital, Shinjuku, Tokyo, Japan; 5Division of Patient Safety, Keio University Hospital, Shinjuku, Tokyo, JapanCorrespondence: Mitsuhiro SadoDepartment of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, JapanTel +81-03-3353-1211Fax +81-03-5379-0187Email mitsusado@keio.jpPurpose: Mindfulness-based cognitive therapy (MBCT) could be an intervention for improving subjective well-being among healthy individuals (HIs). However, MBCT studies for HIs to improve their subjective well-being are rare. The aim of this study was to report the feasibility, safety and effectiveness of MBCT for HIs in comparison with clinical samples.Patients and Methods: We conducted a single-arm, pre-post comparison pilot study offering MBCT to both HIs and people with common mental disorders. Twenty-four participants in total were included in the study. Eight weekly two-hour sessions with six monthly boosters were offered to all participants. Assessment was carried out at baseline, week 4, 8, and during follow-up. The 5-item World Health Organization Well-Being Index (WHO-5) was the primary clinical outcome measure.Results: The results showed the MBCT is sufficiently safe and would be more feasible in HIs compared to in clinical samples (attendance rate: 81.5% vs 61.3%, p=0.06). Although Satisfaction with Life Scale, the other scale of subjective well-being used, improved significantly at week 20 (p=0.01), no significant improvement was seen in WHO-5. The results of the sub-group analysis revealed WHO-5 improved significantly at week 8 and 32 among the subjects whose baseline scores began in the lower half.Conclusion: MBCT is sufficiently safe and would be more feasible with HIs compared to the clinical samples. In designing randomized controlled trials, selecting HIs with lower subjective well-being would be reasonable to minimize the “ceiling effect” on outcomes.Keywords: subjective well-being, mindfulness-based cognitive therapy, feasibility, common mental disorders

Aleksandra Klimkowicz-Mrowiec,1 Pawel Wolkow,2 Malgorzata Sado,3 Anna Dziubek,3 Joanna Pera,1 Tomasz Dziedzic,1 Andrzej Szczudlik,1 Agnieszka Slowik1 1Department of Neurology, Jagiellonian University, School of Medicine, Botaniczna, 2Department of Pharmacology, Jagiellonian University, School of Medicine, Grzegórzecka, 3Department of Neurology, University Hospital, Botaniczna, Krakow, Poland Background: Recent data indicate that the rs1080985 single nucleotide polymorphism of the cytochrome P450 (CYP) 2D6 gene may affect the response to treatment with donepezil in patients with Alzheimer's disease. There is also evidence that the common apolipoprotein E (APOE) polymorphism may affect the response to treatment with donepezil in Alzheimer's disease. We investigated the association between response to donepezil and the rs1080985 single nucleotide polymorphism, the minor allele (G) of which was previously reported to be associated with a poor response to this drug in patients with Alzheimer's disease. The common APOE polymorphism was also assessed for its relevance to the outcome of this treatment. Methods: Analysis of CYP2D6 and APOE polymorphisms was undertaken in 88 naive Caucasian patients with Alzheimer's disease. All patients received treatment with donepezil for at least 10 months, and the response to treatment was then assessed according to the National Institute for Health and Clinical Excellence criteria. Results: No significant differences were observed in distribution of the CYP2D6 rs1080985 single nucleotide polymorphism or common APOE polymorphism between responders (68.2%) and nonresponders (31.8%) to treatment with donepezil. Conclusion: Our results suggest that neither the CYP2D6 nor the APOE polymorphism influences the response to treatment with donepezil in a Polish population with Alzheimer’s disease. Keywords: Alzheimer’s disease, CYP2D6, APOE, donepezil, pharmacogenetics, single nucleotide polymorphism

Mitsuhiro Sado,1 Ataru Inagaki,2 Akihiro Koreki,1 Martin Knapp,3 Lee Andrew Kissane,4 Masaru Mimura,1 Kimio Yoshimura4 1Department of Neuropsychiatry, Keio University School of Medicine, 2Center for Clinical Psychopharmacology, Institute of Neuropsychiatry, Tokyo, Japan; 3Department of Social Policy, London School of Economics and Political Science, London, UK; 4Department of Health Policy and Management, Keio University School of Medicine, Tokyo, Japan Introduction: Schizophrenia is a disorder that produces considerable burdens due to its often relapsing/remitting or chronic longitudinal course. This burden is felt not only by patients themselves, but also by their families and health care systems. Although the societal burden caused by this disorder has been evaluated in several countries, the magnitude of the societal cost of schizophrenia in Japan has never been estimated. The aim of this study is to clarify the societal burden of schizophrenia by estimating the cost of schizophrenia in Japan in 2008. Methods: A human capital approach was adopted to estimate the cost of schizophrenia. The total cost of schizophrenia was calculated as the sum of the direct, morbidity, and mortality costs. Schizophrenia was defined as disorders coded as F20.0–F20.9 according to the International Classification of Diseases-10. The data required to estimate the total cost was collected from publicly available statistics or previously reported studies. Results: The total cost of schizophrenia in Japan in 2008 was JPY 2.77 trillion (USD 23.8 billion). While the direct cost was JPY 0.770 trillion (USD 6.59 billion), the morbidity and mortality costs were JPY 1.85 trillion (USD 15.8 billion) and JPY 0.155 trillion (USD 1.33 billion), respectively. Conclusion: The societal burden caused by schizophrenia is tremendous in Japan, similar to that in other developed countries where published data exist. Compared with other disorders, such as depression or anxiety disorders, the direct cost accounted for a relatively high proportion of the total cost. Furthermore, absolute costs arising from unemployment were larger, while the prevalence rate was smaller, than the corresponding results for depression or anxiety in Japan. Keywords: cost of illness, schizophrenia, societal burden, cost analysis, societal cost

Abstract Background Empirical support for cognitive behavioral therapy (CBT) for treating Japanese patients with major depression is lacking, therefore, a feasibility study of CBT for depression in Japanese clinical settings is urgently required. Findings A culturally adapted, 16-week manualized individual CBT program for Japanese patients with major depressive disorder was developed. A total of 27 patients with major depression were enrolled in a single-group study with the purpose of testing the feasibility of the program. Twenty six patients (96%) completed the study. The mean total score on the Beck Depression Inventory-II (BDI-II) for all patients (Intention-to-treat sample) improved from 32.6 to 11.7, with a mean change of 20.8 (95% confidence interval: 17.0 to 24.8). Within-group effect size at the endpoint assessment was 2.64 (Cohen's d). Twenty-one patients (77.7%) showed treatment response and 17 patients (63.0%) achieved remission at the end of the program. Significant improvement was observed in measurement of subjective and objective depression severity (assessed by BDI-II, Quick Inventory of Depressive Symptomatology-Self Rated, and Hamilton Depression Rating Scale), dysfunctional attitude (assessed by Dysfunctional Attitude Scale), global functioning (assessed by Global Assessment of Functioning of DSM-IV) and subjective well-being (assessed by WHO Subjective Well-being Inventory) (all p values < 0.001). Conclusions Our manualized treatment comprised of a 16-week individual CBT program for major depression appears feasible and may achieve favorable treatment outcomes among Japanese patients with major depression. Further research involving a larger sample in a randomized, controlled trial design is warranted. Trial registration UMIN-CTR UMIN000002542.

Abstract Background Previous studies have demonstrated essential roles for alpha-calcium/calmodulin-dependent protein kinase II (alpha-CaMKII) in learning, memory and long-term potentiation (LTP). However, previous studies have also shown that alpha-CaMKII (+/-) heterozygous knockout mice display a dramatic decrease in anxiety-like and fearful behaviors, and an increase in defensive aggression. These findings indicated that alpha-CaMKII is important not only for learning and memory but also for emotional behaviors. In this study, to understand the roles of alpha-CaMKII in emotional behavior, we generated transgenic mice overexpressing alpha-CaMKII in the forebrain and analyzed their behavioral phenotypes. Results We generated transgenic mice overexpressing alpha-CaMKII in the forebrain under the control of the alpha-CaMKII promoter. In contrast to alpha-CaMKII (+/-) heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in anxiety-like behaviors in open field, elevated zero maze, light-dark transition and social interaction tests, and a decrease in locomotor activity in their home cages and novel environments; these phenotypes were the opposite to those observed in alpha-CaMKII (+/-) heterozygous knockout mice. In addition, similarly with alpha-CaMKII (+/-) heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in aggression. However, in contrast to the increase in defensive aggression observed in alpha-CaMKII (+/-) heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in offensive aggression. Conclusion Up-regulation of alpha-CaMKII expression in the forebrain leads to an increase in anxiety-like behaviors and offensive aggression. From the comparisons with previous findings, we suggest that the expression levels of alpha-CaMKII are associated with the state of emotion; the expression level of alpha-CaMKII positively correlates with the anxiety state and strongly affects aggressive behavior.

Aim: Live two-way video, easily accessible from home via smartphones and other devices, is becoming a new way of providing psychiatric treatment. However, lack of evidence for real-world clinical setting effectiveness hampers its approval by medical insurance in some countries. Here, we conducted the first large-scale pragmatic, randomized controlled trial to determine the effectiveness of long-term treatment for multiple psychiatric disorders via two-way video using smartphones and other devices, which are currently the primary means of telecommunication., Methods: This randomized controlled trial compared two-way video versus face-to-face treatment for depressive disorder, anxiety disorder, and obsessive-compulsive disorder in the subacute/maintenance phase during a 24-week period. Adult patients with the above-mentioned disorders were allocated to either a two-way video group (≥50% video sessions) or a face-to-face group (100% in-person sessions) and received standard treatment covered by public medical insurance. The primary outcome was the 36-Item Short-Form Health Survey Mental Component Summary (SF-36 MCS) score. Secondary outcomes included all-cause discontinuation, working alliance, adverse events, and the severity rating scales for each disorder., Results: A total of 199 patients participated in this study. After 24 weeks of treatment, two-way video treatment was found to be noninferior to face-to-face treatment regarding SF-36 MCS score (48.50 vs 46.68, respectively; p < 0.001). There were no significant differences between the groups regarding most secondary end points, including all-cause discontinuation, treatment efficacy, and satisfaction., Conclusion: Two-way video treatment using smartphones and other devices, was noninferior to face-to-face treatment in real-world clinical settings. Modern telemedicine, easily accessible from home, can be used as a form of health care., (© 2023 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Aim: The coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented stress. Mindfulness-based interventions (MBIs) are known to be effective in reducing stress. However, it is unclear how long-term outcomes differ between those who continue mindfulness practice after MBIs and those who do not. In this study, we hypothesized that those who continued mindfulness practice would have higher stress tolerance, and we examined this hypothesis through a survey of MBI graduates. In this study, we examined the association between the continuation of mindfulness practice among MBI completers and individual stress during the COVID-19 epidemic., Methods: A cross-sectional survey of MBI graduates was conducted. The physical and mental health states were compared between those who established a habit of mindfulness practice (practice group) and those who did not (no practice group)., Results: The data were collected from 95 participants (response rate: 53.7%). Of the total respondents, 66 (69.5%) practiced mindfulness. Although the degree of perceived stress due to the COVID-19 pandemic was not statistically different between the practice and no practice groups, the practice group showed significantly lower levels of depression ( p  = 0.007), higher levels of resilience ( p  = 0.006), higher levels of overall health ( p  = 0.006), and higher levels of mental health ( p  = 0.039). The effect of mindfulness practice on reducing depression was fully mediated by resilience., Conclusion: Among MBI graduates, those who regularly practiced mindfulness had lower levels of depression and higher levels of physical and mental health. Thus, the continuation of mindfulness practice increases resilience, buffers against new stressors such as the COVID-19 pandemic, and has the potential to prevent depression., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors. Psychiatry and Clinical Neurosciences Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Background: Numerous studies have demonstrated the effectiveness of mindfulness-based programs (MBPs) among both clinical and nonclinical populations. These data document positive impacts in the workplace, including reducing perceived stress and burnout and increasing well-being. However, the effectiveness for productivity, which is of most interest to managers and administrators, is still unclear. In addition, MBPs in the workplace tend to be modified by reducing the number of the program sessions or delivering content online to improve accessibility. To date, however, the impact of MBPs that feature these modifications on productivity in the workplace has not been investigated., Objective: The study aims to investigate the effectiveness and cost-effectiveness of online-delivered brief mindfulness-based cognitive therapy (bMBCT) for improving productivity and other work-related outcomes among healthy workers compared to the waitlist control., Methods: We will conduct a 4-week randomized controlled trial (RCT) with a 6-month follow-up. Employees are included in the study if they (1) are between the ages of 20 and 65 years and (2) work longer than 30 hours weekly. Employees are randomly allocated to either the bMBCT group or the waitlist control group. The primary outcome of the study is the mean difference of productivity measured by the World Health Organization Health and Work Performance Questionnaire (WHO-HPQ) between the groups at 4, 16, and 28 weeks. Secondary outcomes include several clinical outcomes and health economics evaluation., Results: We started recruiting participants in August 2021, and the intervention began in October 2021. A total of 104 participants have been enrolled in the study as of October 2021. The intervention is scheduled to be completed in December 2023. Data collection will be completed by the end of January 2024., Conclusions: The novelty of the study is that (1) it will investigate bMBCT's effectiveness on productivity, which is still unclear, and (2) samples are recruited from 3 companies in different industries. The limitations of the study are that (1) all measures assessed are in self-report format and (2) we lack an active control group. This study has the potential to provide new data on the relationship between MBPs and occupational health and productivity., Trial Registration: University Hospital Medical Information Network Clinical Trials Registry UMIN000044721; https://tinyurl.com/4e2fh873., International Registered Report Identifier (irrid): DERR1-10.2196/36012., (©Mitsuhiro Sado, Masashi Yamada, Akira Ninomiya, Maki Nagaoka, Naho Goto, Akihiro Koreki, Atsuo Nakagawa, Zindel Segal, Masaru Mimura. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 13.06.2022.)

Objectives: To deliver mindfulness-based cognitive therapy (MBCT) efficiently, the present study aimed (1) to identify predictors and moderators of patients who benefit from MBCT for psychological distress and (2) to explore the initial treatment reaction to identify the optimal number of sessions that produce a significant clinical effect., Methods: This is the secondary analysis of a randomized controlled trial of MBCT for breast cancer patients (N = 74). We classified the participants into remitters vs. non-remitters, and responder vs. non-responders, according to the total score of the Hospital Anxiety and Depression Scale at the end of the intervention. We conducted multivariate analyses to explore for predictors of response and remission. We adopted generalized estimating equations to explore the optimal number of sessions., Results: Sociodemographic and clinical backgrounds did not have significant influence on the treatment outcomes of the MBCT. Better program adherence, which was represented as the participants' better attendance to the MBCT program, was a significant predictor of both remission and response [odds ratio (OR) = 1.90, 95% confidence interval (CI) 1.25-2.89, p = 0.003, and OR = 1.72, 95% CI 1.12-2.65, p = 0.013, respectively]. It was not until seventh session that the remission rate exceeded 50% and the response rate showed significance., Significance of Results: Sociodemographic and clinical characteristics did not significantly influence the treatment outcomes, while homework minutes and class attendance had significant effects on treatment outcomes. This implies that MBCT is recommended to any cancer patient, if he/she is motivated to the program, regardless of their sociodemographic and clinical characteristics. Patients are encouraged to attend a standard MBCT program (eight sessions) and do the assigned homework as intensely as possible. Further studies with larger sample and objective measurements are desired.

Background: Although higher rates of burnout have been reported during the COVID-19 pandemic, the contribution of the modifiable factors is lesser-known. We investigated how the risk of emotional exhaustion was associated with mindfulness skills and social support in a single medical center in Japan., Methods: We conducted a cross-sectional web survey on mental health for all staff of a national medical hospital from February to March 2021. We examined the association between self-rated emotional exhaustion and levels of mindfulness and social support using multivariate logistic regression., Results: Of the 830 participants, signs of emotional exhaustion were observed in 261 (31%) individuals. Among those highly exposed to the virus at work, individuals with low levels of mindfulness and social support had significantly higher odds of emotional exhaustion [OR 3.46 (95% CI; 1.48-8.09), OR; 3.08 (95% CI; 1.33-7.13), respectively] compared to those with high levels. However, among those not highly exposed to the virus, individuals with both low and moderate levels of mindfulness had significantly higher odds of emotional exhaustion. [OR 3.33 (95% CI; 2.22-5.00), OR; 2.61 (95% CI; 1.73-3.94), respectively]., Conclusion: We found that factors associated with emotional exhaustion differed by exposure to SARS-CoV-2. Building mindfulness skills can help reduce the high burden placed on the staff. Additionally, increasing social support may be useful especially for workers highly exposed to SARS-CoV-2., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sampei, Okubo, Sado, Piedvache, Mizoue, Yamaguchi and Morisaki.)

Background: Augmented mindfulness-based cognitive therapy (MBCT) with treatment as usual (mainly pharmacotherapy) is reported to be effective after treatment for anxiety disorders. However, whether its effectiveness persists in the long term is unclear., Objective: This study aims to examine the feasibility, acceptability, and effectiveness of a follow-up program by conducting a feasibility randomized controlled trial (RCT) that compares augmented MBCT with follow-up sessions and that without follow-up sessions in preparation for a definitive RCT., Methods: The study involves an 8-week MBCT with a 10-month follow-up. Patients aged 20 to 65 years who meet the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria for panic disorder, agoraphobia, or social anxiety disorder, which is not remitted with usual treatment for at least 4 weeks, will be included in the study and randomly allocated to receive augmented MBCT with follow-up sessions or augmented MBCT without follow-up sessions. For this feasibility RCT, the primary outcomes are (1) study inclusion rate, (2) dropout rate, (3) attendance rate, and (4) mean and standard deviation of several clinical measures at 8 weeks and 5, 8, and 12 months., Results: We started recruiting participants in January 2020, and 43 participants have been enrolled up to January 2021. The study is ongoing, and data collection will be completed by May 2022., Conclusions: This study is novel in terms of its design, which compares augmented MBCT with and without follow-up sessions. The limitations of the trial are as follows: (1) mixed participants in terms of the delivery mode of the intervention, and (2) lack of a pharmacotherapy-alone arm. Owing to its novelty and significance, this study will provide fruitful knowledge for future definitive RCTs., Trial Registration: UMIN Clinical Trials Registry UMIN000038626; https://tinyurl.com/2p9dtxzh., International Registered Report Identifier (irrid): DERR1-10.2196/33776., (©Mitsuhiro Sado, Akira Ninomiya, Maki Nagaoka, Akihiro Koreki, Naho Goto, Yohei Sasaki, Chie Takamori, Teppei Kosugi, Masashi Yamada, Sunre Park, Yasunori Sato, Daisuke Fujisawa, Atsuo Nakagawa, Masaru Mimura. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 21.01.2022.)

Background: There is a lack of studies that investigated the effect of a wide range of work environmental factors on stress and depression in Japan., Objectives: To examine the association of work environment factors with stress and depression among workers in Japan., Methods: We conducted questionnaire surveys of workers that mainly engage in desk work in Japan. Stress was assessed through the Perceived Stress Scale (PSS), depression through the Patient Health Questionnaire-9 (PHQ-9), and work environment through physical and psychological workplace environment questionnaires. Workers were divided into low and high stress groups based on PSS score (median split), and divided into non-depressed and depressed groups based on their PHQ-9 score (< 5, and ≥5); these groups were then compared with their working environment. In addition, a multiple regression analysis was performed., Results: Responses were obtained from 210 subjects. Multiple regression analysis showed that "Ability to work at one's own pace" and "Ability to apply personal viewpoint to work," etc., had effect on stress, while "Workplace harassment" and "Support from colleagues," etc., had effect on depression., Conclusions: The results suggest that stress and depression in Japanese workers are related to factors such as job demands, control of work, workplace harassment, and psychological safety.

Introduction: The COVID-19 pandemic has had a profound impact on the mental health of people around the world. Anxiety related to infection, stress and stigma caused by the forced changes in daily life have reportedly increased the incidence and symptoms of depression, anxiety disorder and obsessive-compulsive disorder. Under such circumstances, telepsychiatry is gaining importance and attracting a great deal of attention. However, few large pragmatic clinical trials on the use of telepsychiatry targeting multiple psychiatric disorders have been conducted to date., Methods: The targeted study cohort will consist of adults (>18 years) who meet the DSM-5 diagnostic criteria for either (1) depressive disorders, (2) anxiety disorders, or (3) obsessive-compulsive and related disorders. Patients will be assigned in a 1:1 ratio to either a "telepsychiatry group" (at least 50% of treatments to be conducted using telemedicine, with at least one face-to-face treatment [FTF] within six months) or an "FTF group" (all treatments to be conducted FTF, with no telemedicine). Both groups will receive the usual treatment covered by public medical insurance. The study will utilize a master protocol design in that there will be primary and secondary outcomes for the entire group regardless of diagnosis, as well as the outcomes for each individual disorder group., Discussion: This study will be a non-inferiority trial to test that the treatment effect of telepsychiatry is not inferior to that of FTF alone. This study will provide useful insights into the effect of the COVID-19 pandemic on the practice of psychiatry., Trial Registration: jRCT1030210037, Japan Registry of Clinical Trials (jRCT)., (Copyright © 2021. Published by Elsevier Inc.)

Background: Regular visit to psychiatric clinic is essential for successful treatment of any psychiatric condition including attention-deficit/hyperactivity disorder (AD/HD). However, cancellation of outpatient appointments in patients with AD/HD, which represents a significant medical loss, has not been systematically investigated to our knowledge., Methods: A systematic chart review was conducted for patients visiting the Shimada Ryoiku medical Center for Challenged Children in Japan at the age of ≤15 years from January to December 2013. The primary outcome measure was the cancellation rate, defined as the number of missed visits divided by the number of scheduled visits. The cancellation rates during 24 months after the first visit were compared between outpatients with AD/HD and other psychiatric disorders, including pervasive developmental disorders (PDD), and developmental coordination disorders and/or communication disorders (DCD-CD). A generalized linear model with binomial distribution was used to examine factors associated with cancellation rates exclusively in the AD/HD group., Results: We included 589 patients (mean ± SD age, 5.6 ± 3.4 years; 432 males) in the analysis. The cancellation rate in patients with AD/HD was 12.3% (95% confidence interval [CI]: 10.0-15.1), which was significantly higher than in those with PDD (5.6%, 95% CI: 3.8-8.3) and DCD-CD (5.3%, 95% CI: 3.6-7.8). Prescriptions of osmotic-release oral system-methylphenidate (OROS-MPH) and antipsychotics were associated with fewer cancellations in AD/HD patients (odds ratios: 0.61, 95% CI: 0.39-0.95 and 0.49, 95% CI: 0.25-0.95, respectively), although these significances did not find in the subgroup analysis including only patients with ≥ 6 years old., Conclusions: Patients with AD/HD were more likely to miss appointments compared to those with other psychiatric disorders. The impact of AD/HD medications as well as potential psychiatric symptoms of their parents or caregivers on appointment cancellations needs to be evaluated in more detail in future investigations., Competing Interests: KN has received honoraria (lecture fees) from Janssen Pharmaceutical, Eli Lilly, Shire, and Shionogi within the past three years. RT declares no conflicts of interest associated with this manuscript. KY has received honoraria (manuscript fees) from Sumitomo Dainippon Pharma, fellowship grants from the Japan Research Foundation for Clinical Pharmacology and Azrieli Adult Neurodevelopmental Centre Postdoctoral Fellowship at CAMH, and consultant fees from Signant Health and VeraSci within the past three years. MS has received honoraria (lecture fees) from Meiji Seika Pharma, Shionogi, Kumon Institute of Education, and Mochida Pharma within the past three years. TS has received manuscript or speaker fees from Astellas, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Elsevier Japan, Janssen Pharmaceuticals, Kyowa Yakuhin, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Novartis, Otsuka Pharmaceutical, Shionogi, Shire, Tsumura, Wiley Japan, and Yoshitomi Yakuhin, and research grants from Eisai, Mochida Pharmaceutical, Meiji Seika Pharma, and Shionogi within the past three years. MM has received speaker’s honoraria from Byer Pharmaceutical, Daiichi Sankyo, Dainippon-Sumitomo Pharma, Eisai, Eli Lilly, Fuji Film RI Pharma, Hisamitsu Pharmaceutical, Janssen Pharmaceutical, Kyowa Pharmaceutical, Mochida Pharmaceutical, MSD, Mylan EPD, Nihon Medi-physics, Nippon Chemipher, Novartis Pharma, Ono Yakuhin, Otsuka Pharmaceutical, Pfizer, Santen Pharmaceutical, Shire Japan, Takeda Yakuhin, Tsumura, and Yoshitomi Yakuhin within the past three years. Also, he received grants from Daiichi Sankyo, Eisai, Pfizer, Shionogi, Takeda, Tanabe Mitsubishi and Tsumura within the past three years outside the submitted work. HU has received grants from Eisai, Otsuka Pharmaceutical, Dainippon-Sumitomo Pharma, and Meiji-Seika Pharma, speaker’s honoraria from Otsuka Pharmaceutical, Dainippon-Sumitomo Pharma, Eisai, and Meiji-Seika Pharma, and advisory panel payments from Dainippon-Sumitomo Pharma within the past three years. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Aim: Pharmacotherapy is the primary treatment strategy in major depression. However, two-thirds of patients remain depressed after the initial antidepressant treatment. Augmented cognitive behavioral therapy (CBT) for pharmacotherapy-resistant depression in primary mental health care settings proved effective and cost-effective. Although we reported the clinical effectiveness of augmented CBT in secondary mental health care, its cost-effectiveness has not been evaluated. Therefore, we aimed to compare the cost-effectiveness of augmented CBT adjunctive to treatment as usual (TAU) and TAU alone for pharmacotherapy-resistant depression at secondary mental health care settings., Methods: We performed a cost-effectiveness analysis at 64 weeks, alongside a randomized controlled trial involving 80 patients who sought depression treatment at a university hospital and psychiatric hospital (one each). The cost-effectiveness was assessed by the incremental cost-effectiveness ratio (ICER) that compared the difference in costs and quality-adjusted life years, and other clinical scales, between the groups., Results: The ICERs were JPY -15 278 322 and 2 026 865 for pharmacotherapy-resistant depression for all samples and those with moderate/severe symptoms at baseline, respectively. The acceptability curve demonstrates a 0.221 and 0.701 probability of the augmented CBT being cost-effective for all samples and moderate/severe depression, respectively, at the threshold of JPY 4.57 million (GBP 30 000). The sensitivity analysis supported the robustness of our results restricting for moderate/severe depression., Conclusion: Augmented CBT for pharmacotherapy-resistant depression is not cost-effective for all samples including mild depression. In contrast, it appeared to be cost-effective for the patients currently manifesting moderate/severe symptoms under secondary mental health care., (© 2021 The Authors Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Background: In ageing population, it is desirable to reduce the impact of cognitive decline on daily life. While various types of dementia-friendly environments have been proposed, the question still remains regarding whether analogue or digital clocks are friendlier for people with dementia., Methods: In clinical practice, we normally use our original clock reading test (10 analogue and 10 digital clocks) to assess patients' ability to read a clock. In the present study, a retrospective medical record survey was conducted. Fifty-five participants who had done the test were identified. The result of the test was compared between analogue and digital clocks. Additionally, to assess specific ability to read analogue clocks, an "analogue-digital gap" was defined as the difference between patients' performance for analogue and digital clocks. Univariate and multivariate analyses were conducted to detect significant factors associated with reading ability specific to analogue clocks., Results: The analogue clock proved less readable than the digital clock, even after adjusting for MMSE total score ( p = 0.003). Multivariate analysis revealed reading ability of the analogue clock was significantly associated with MMSE calculation and clock drawing test ( p = 0.009 and 0.040, respectively)., Conclusions: In the present study, the digital clock was friendlier than the analogue clock for patients with dementia. Compared to the digital clock, reading analogue clocks might require more widespread cognition, such as working memory and visuospatial processing. While our finding was a general tendency, and individual assessment is necessary, it might help the development of personalized environmental adjustments., Competing Interests: The authors report no conflicts of interest regarding this study., (Copyright © 2021 by S. Karger AG, Basel.)

The importance of workers' well-being has been recognized in recent years. The assessment of well-being has been subjective, and few studies have sought potential biomarkers of well-being to date. This study examined the relationship between well-being and the LF/HF ratio, an index of heart rate variability that reflects sympathetic and parasympathetic nerve activity. Pulse waves were measured using photoplethysmography through a web camera attached to the computer used by each participant. The participants were asked to measure their pulse waves while working for 4 weeks, and well-being was assessed using self-reported measures such as the Satisfaction With Life Scale (SWLS), the Positive and Negative Affect Schedule (PANAS), and the Flourishing Scale (FS). Each of the well-being scores were split into two groups according to the median value, and the LF/HF ratio during work, as well as the number of times an LF/HF ratio threshold was either exceeded or subceeded, were compared between the high and low SWLS, positive emotion, negative emotion, and FS groups. Furthermore, to examine the effects of the LF/HF ratio and demographic characteristics on well-being, a multiple regression analysis was conducted. Data were obtained from 169 participants. The results showed that the low FS group had a higher mean LF/HF ratio during work than the high FS group. No significant differences were seen between the high and low SWLS groups, the high and low positive emotion groups, or the high and low negative emotion groups. The multiple regression analysis showed that the mean LF/HF ratio during work affected the FS and SWLS scores, and the number of times the mean LF/HF ratio exceeded +3 SD had an effect on the positive emotion. No effect of the LF/HF ratio on negative emotions was shown. The LF/HF ratio might be applicable as an objective measure of well-being., Competing Interests: The authors have declared that no competing interests exist.

Background: It is not clear which method is more cost-effective: To initially provide all depressed patients with combination therapy (COMB; i.e. cognitive behavioural therapy plus pharmacotherapy), followed by antidepressant treatment (AD) for those still in depression; or, to first provide AD for all patients, followed by COMB for non-remission patients. The aim is to investigate whether a COMB-first strategy would be more cost-effective than an AD-first strategy, in treating depression., Methods: A Markov model was developed to perform the analysis. The primary outcome was the incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) at 104 weeks. Probabilistic sensitivity analysis and scenario analysis were performed, to investigate the uncertainty associated with the clinical parameters and the impact of CBT's cost on the results, respectively., Results: The ICER per QALY at 104 week, was JPY 591,822 (USD 5,725) for moderate depression and JPY 499,487 (USD 4,832) for severe one. The scenario analysis revealed the ICER became JPY 1,147,518 (USD 11,101) for moderate and JPY 968,484 (USD 9,369) for severe when the CBT cost was set as JPY 14,400 (USD 139)(i.e. GBP 96: the unit cost of CBT in UK), which is well below the threshold recommended by NICE (i.e. GBP 20,000-30,000)., Limitations: This is a model-based analysis which was conducted from the health insurance perspective. Then, the analysis from the societal perspective would generate different results., Conclusions: The results suggest that a COMB-first strategy would be more cost effective than an AD-first strategy., (Copyright © 2021. Published by Elsevier B.V.)

Objectives: Better subjective and eudaimonic well-being fosters better health conditions. Several studies have confirmed that mindfulness-based interventions are effective for improving well-being; however, the samples examined in these studies have been limited to specific populations, and the studies only measured certain aspects of well-being rather than the entire construct. Additionally, few studies have examined the effect of mindfulness-based cognitive therapy on well-being. The present study examines the feasibility of mindfulness-based cognitive therapy and its effectiveness for improving subjective and eudaimonic well-being among community residents. Methods: The study design featured an 8-week randomized, waiting-list controlled, parallel-group study. 8 weekly mindfulness classes, followed by 2 monthly classes, were provided for healthy individuals aged 20-65 years who had a Satisfaction with Life Scale score of ≤ 24 indicating average to low cognitive aspect of subjective well-being. This trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (ID: UMIN000031885, URL: https://upload.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000036376). Results: The results showed that cognitive aspect of subjective well-being and mindfulness skills were significantly improved at 8 weeks, and this effect was enhanced up to the end of the follow-up period. Positive affective aspect of subjective and eudaimonic well-being were significantly improved at 16 weeks. Conclusions: Eight weeks of mindfulness-based cognitive therapy with a 2-month follow-up period improves cognitive and affective aspects of subjective and eudaimonic well-being in healthy individuals. The order of improvement was cognitive, positive affective, and eudaimonic well-being. To verify these findings, multi-center randomized controlled trials with active control groups and longer follow-up periods are warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kosugi, Ninomiya, Nagaoka, Hashimoto, Sawada, Park, Fujisawa, Mimura and Sado.)

Objective: To assess the effectiveness of mindfulness-based interventions on people with dementia and mild cognitive impairment., Methods: We searched several electronic databases, namely Cochrane Library, EMBASE, and MEDLINE with no limitations for language or document type (last search: 1 February 2020). Randomized controlled trials of mindfulness-based interventions for people with dementia and mild cognitive impairment compared to active-control interventions, waiting lists, or treatment as usual were included. Predefined outcomes were anxiety symptoms, depressive symptoms, cognitive function, quality of life, mindfulness, ADL and attrition. We used the random effects model (DerSimonian-Laird method) for meta-analysis, reporting effect sizes as Standardized Mean Difference. Heterogeneity was assessed with the I2 statistics., Results: Eight randomized controlled trials, involving 276 patients, met the eligibility criteria and were included in the meta-analysis. We found no significant effects for mindfulness-based interventions in either the short-term or the medium- to long-term on any outcomes, when compared with control conditions. The number of included studies and sample sizes were too small. Additionally, the quality of evidence was low for each randomized controlled trial included in the analysis. This is primarily due to lack of intent-to-treat analysis, high risk of bias, and imprecise study results. The limited statistical power and weak body of evidence prevented us from reaching firm conclusions., Conclusions: We found no significant effects of mindfulness-based interventions on any of the outcomes when compared with control conditions. The evidence concerning the efficacy of mindfulness-based interventions in this population is scarce in terms of both quality and quantity. More well-designed, rigorous, and large-scale randomized controlled trials are needed., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Mental disorders are a leading cause of disability worldwide. Depression has a significant impact in the field of occupational health because it is particularly prevalent during working age. On the other hand, there are a growing number of studies on the relationship between "well-being" and employee productivity. To promote healthy and productive workplaces, this study aims to develop a technique to quantify stress and well-being in a way that does not disturb the workplace. Methods and analysis: This is a single-arm prospective observational study. The target population is adult (>20 years old) workers at companies that often engage in desk work; specifically, a person who sits in front of a computer for at least half their work hours. The following data will be collected: (a) participants' background characteristics; (b) participants' biological data during the 4-week observation period using sensing devices such as a camera built into the computer (pulse wave data extracted from the facial video images), a microphone built into their work computer (voice data), and a wristband-type wearable device (electrodermal activity data, body motion data, and body temperature); (c) stress, well-being, and depression rating scale assessment data. The analysis workflow is as follows: (1) primary analysis, comprised of using software to digitalize participants' vital information; (2) secondary analysis, comprised of examining the relationship between the quantified vital data from (1), stress, well-being, and depression; (3) tertiary analysis, comprised of generating machine learning algorithms to estimate stress, well-being, and degree of depression in relation to each set of vital data as well as multimodal vital data. Discussion: This study will evaluate digital phenotype regarding stress and well-being of white-collar workers over a 4-week period using persistently obtainable biomarkers such as heart rate, acoustic characteristics, body motion, and electrodermal activity. Eventually, this study will lead to the development of a machine learning algorithm to determine people's optimal levels of stress and well-being. Ethics and dissemination: Collected data and study results will be disseminated widely through conference presentations, journal publications, and/or mass media. The summarized results of our overall analysis will be supplied to participants. Registration: UMIN000036814., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Izumi, Minato, Shiga, Sugio, Hanashiro, Cortright, Kudo, Fujita, Sado, Maeno, Takebayashi, Mimura and Kishimoto.)

Context: Mindfulness-based interventions have been receiving growing attention in cancer care., Objectives: The purpose of this randomized controlled trial is to examine the effectiveness of mindfulness-based cognitive therapy (MBCT) for psychological distress (anxiety and depression), fear of cancer recurrence (FCR), fatigue, spiritual well-being, and quality of life (QOL) in Japanese ambulatory patients with Stage I-III breast cancer., Methods: A total of 74 patients were randomly assigned to either an eight-week MBCT intervention group (n = 38) or a wait-list control group (n = 36). The primary outcome was psychological distress, measured on Hospital Anxiety and Depression Scale. The secondary outcomes were FCR (Concerns About Recurrence Scale-overall anxiety subscale), fatigue (Brief Fatigue Inventory), spiritual well-being (Functional Assessment of Chronic Illness Therapy-Spiritual), QOL (Functional Assessment of Cancer Therapy-General), and mindfulness skills (Five Facet Mindfulness Questionnaire). The participants were assessed at baseline (T0), Week 8 (T1), and Week 12 (T2). The results were analyzed using a intention-to-treat linear mixed model., Results: The participants in the MBCT group experienced significantly better outcomes in their psychological distress (Cohen's d = 1.17; P < 0.001), FCR (d = 0.43; P < 0.05), fatigue (d = 0.66; P < 0.01), spiritual well-being (d = 0.98; P < 0.001), and QOL (d = 0.79; P < 0.001) compared with the control group. The difference remained significant at T2 (four weeks after completion of the intervention)., Conclusion: MBCT was demonstrated to improve well-being that encompasses psychological, physical, and spiritual domains in Japanese patients with nonmetastatic breast cancer. The favorable effect was maintained up to four weeks after the completion of the intervention., (Copyright © 2020 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Previous studies have indicated that higher subjective well-being works as a protective factor for health. Some studies have already shown the effects of mindfulness-based interventions on improving subjective well-being. However, these studies targeted specific populations rather than the general public. Furthermore, they assessed either life evaluation or affective aspects of subjective well-being rather than the concept as a whole, including the eudemonic aspect of well-being., Objective: This study aims to investigate the effectiveness and cost-effectiveness of mindfulness-based cognitive therapy (MBCT) for improving the wholistic aspects of subjective well-being in healthy individuals., Methods: This study was an 8-week, randomized, parallel-group, superiority trial with a 2-month follow-up. Healthy individuals aged 20-65 years with scores lower than 25 on the Satisfaction With Life Scale (SWLS) were eligible to participate and randomly allocated to the MBCT group or the wait-list control group. The intervention program was developed by modifying an MBCT program to improve the well-being of a nonclinical population. The primary outcome was the difference between the two groups in mean change scores from the baseline on the SWLS. The secondary outcomes included scores on the Flourishing Scale and the Scale of Positive and Negative Experience as well as the incremental cost-effectiveness ratio., Results: This study began recruiting participants in July 2018 and recruitment was completed at the end of September 2019. Data collection and dataset construction was completed by the end of March 2020., Conclusions: This study is unique in that it investigates MBCT's effects on the three different aspects of subjective well-being: life evaluation, affect, and eudemonia. It is limited, as the specific effect attributable to MBCT cannot be detected because of the lack of an active control group., Trial Registration: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) UMIN000031885; https://upload.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000036376., International Registered Report Identifier (irrid): DERR1-10.2196/15892., (©Mitsuhiro Sado, Teppei Kosugi, Akira Ninomiya, Maki Nagaoka, Sunre Park, Daisuke Fujisawa, Joichiro Shirahase, Masaru Mimura. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 08.05.2020.)

Background: A recent technical advance in mRNA in situ hybridization (mRNA-ISH) assays provides simultaneous signal amplification and background suppression with a unique probe design that enables single-molecule visualization. We assessed the utility of the mRNA-ISH assay as a diagnostic tool for detecting anaplastic lymphoma receptor tyrosine kinase ( ALK ) mRNA in non-small-cell lung carcinoma (NSCLC). We compared the mRNA-ISH assay with immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH)., Methods: The study included 279 surgically resected lung adenocarcinomas and 44 transbronchial-biopsied (TBB) adenocarcinomas. mRNA-ISH was conducted using the RNAscope 2.0 system, which includes pre-designed probes for detecting the tyrosine kinase domain encoded in ALK mRNA. IHC was conducted on all 323 samples using ALK-specific antibodies. mRNA-ISH was performed on 279 surgical samples and 6 TBB samples. Break-apart FISH was used to examine samples that were mRNA-ISH-positive or IHC-positive., Results: ALK protein expression was detected in 11 of 279 specimens (3.9%). ALK mRNA was also detected with mRNA-ISH in ALK-positive samples, and 9 of the 11 specimens (81%) were also positive for ALK using break-apart FISH. Using the IHC results as a reference, the sensitivity and specificity of mRNA-ISH was 100%. In the TBB cohort, ALK protein expression was observed in 3 of 44 specimens (6.8%), in which ALK mRNA expression was also detected., Conclusions: The ALK mRNA-ISH data were highly correlated with the IHC data, and ALK mRNA-ISH detected ALK mRNA expression in every FISH-positive sample. We conclude that mRNA-ISH could serve as an alternative or complementary method for diagnosing ALK rearrangements in NSCLC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr.2020.03.04). The authors have no conflicts of interest to declare., (2020 Translational Lung Cancer Research. All rights reserved.)