Abstract Background Clinicians encounter considerable challenges in the diagnosis and treatment of organophosphate‐induced toxic parkinsonism following acute poisoning. Here, we report the importance of longitudinal evaluation of a patient with organophosphate‐induced toxic parkinsonism using dopamine transporter single‐photon emission computed tomography (DAT‐SPECT). This case may provide crucial insights into the pathophysiology of the syndrome and inform therapeutic decision‐making. Case Presentation We report a case of organophosphate‐induced toxic parkinsonism with persistent parkinsonian symptoms evaluated longitudinally using DAT‐SPECT. A 68‐year‐old woman with a history of bipolar disorder was found collapsed at home on Day 0 with impaired consciousness, miosis, hypersalivation, and bradycardia. Organophosphate poisoning was diagnosed based on markedly reduced cholinesterase levels and the presence of an organophosphate pesticide in a shed at her home. Parkinsonian symptoms gradually emerged from Day 18, including hypophonia and a gait disturbance. On Day 60, DAT‐SPECT showed reduced radiotracer uptake in the bilateral striatum, more pronounced on the right. After toxic parkinsonism was diagnosed, l‐dopa was titrated up to 600 mg/day without clinical benefit and discontinued due to adverse effects. Treatment with amantadine and trihexyphenidyl was then initiated, resulting in partial symptomatic improvement, although symptoms persisted. Despite clinical improvement, follow‐up DAT‐SPECT on Day 131 showed a further reduction in striatal tracer uptake, whereas quantitative improvement was observed on Day 200. Conclusion Parkinsonism is an uncommon sequela of organophosphate poisoning and may be accompanied by abnormal DAT‐SPECT findings. Moreover, amantadine and trihexyphenidyl may represent effective therapeutic options for this condition.

It is known that orexin peptides are involved in nociceptive processing, while little is known about the roles of these peptides in itch processing. To reveal the functions of orexin peptides in pruriceptive processing, orexin A (OX-A) and orexin B (OX-B) were applied before histamine or chloroquine (CQ). The administration of OX-A reduced the numbers of scratching events and c-Fos positive cells induced by histamine and CQ, but not OX-B. To clarify the involvement of orexin receptors in pruriceptive processing, OX-A was administered after the injection of an orexin receptor type 1 (OX1) antagonist (SB334867) or an orexin receptor type 2 (OX2) antagonist (JNJ10397049) before histamine and CQ injections. The attenuating effects of OX-A on histamine- and CQ-induced scratching events were reversed by JNJ1039 and SB334867, respectively. To confirm the role of OX2 receptor, an OX2 receptor agonist (YNT185) was applied before the injection of histamine or CQ. Scratching events and c-Fos expression induced by histamine, but not CQ, were attenuated by the pretreatment with YNT185. These results indicate that OX-A elicits the attenuating effects in pruriceptive processing and that itch signals induced by histamine and CQ appear to be differentially regulated by the OX2 receptors and OX1 receptors.

Enhancing the skills of hikikomori supporters inherently contributes to improving the quality of support provided. However, a comprehensive skills assessment tool for these supporters has not yet been developed. This study aimed to develop a self-rated questionnaire, the Hikikomori Supporter’s Skills Checklist (HSSC). Based on a preliminary survey involving 43 supporters, the HSSC draft was revised. The revised version comprises 39 items addressing various aspects of consultation support. In the main survey, questionnaires were posted to 118 hikikomori community support centers. To assess convergent and discriminant validity and derive clinical insights, respondents completed the HSSC along with measures of stigmatic attitudes toward hikikomori and psychiatric patients, workplace psychological flexibility, burnout, and demographics, including prior experience in hikikomori-related learning and support. Analysis of 238 valid responses revealed a single-factor structure; however, 12 items were removed due to lower item factor loadings. The refined 27-item HSSC demonstrated acceptable internal consistency (Cronbach’s α = 0.74). HSSC scores showed a significant correlation with the number of training sessions undertaken (ρ = 0.24), along with other theoretically consistent but statistically non-significant correlations, supporting the checklist’s validity. Furthermore, in the comparison involving specific questions with relatively low correct response rate, a linear increase in the total HSSC score was observed across the low-, middle-, and high correct response rate groups. However, score distribution deviated from normality due to limited data from lower-scoring participants, restricting parametric analysis. Although further validation is necessary, the HSSC appears valuable for promoting self-reflection among hikikomori supporters and evaluating training outcomes.

AIM:Suvorexant is an orexin receptor antagonist (ORA) for the treatment of insomnia. The antagonistic action of suvorexant on orexin receptors is associated with an increase in rapid eye movement (REM) sleep, which can potentially lead to nightmares depending on the patient's condition. However, the precise risk factors for nightmares among patients taking ORAs, such as suvorexant, have yet to be identified. In this retrospective study, we aimed to identify the risk factors for the development of nightmares in patients treated with suvorexant. METHODS:The risk factors were determined by comparing parameters between the nightmare group and the nonnightmare group. This study included 440 patients who received suvorexant at the University of Miyazaki Hospital from April 2014 to January 2021. RESULTS:We found that 9.1% (n = 40) of the patients experienced suvorexant-induced nightmares. There was a significant difference in the median age, which was lower in the nightmare group than in the nonnightmare group (p < 0.01). Furthermore, both multiple logistic regression analysis and Cox proportional hazards regression analysis revealed increased odds ratios for nightmares for individuals aged 20-39 years. CONCLUSIONS:This study revealed that elderly patients taking suvorexant had fewer nightmares than nonelderly patients did.

Background: As drug-metabolizing enzyme activities are affected by a variety of factors, such as drug-drug interactions, a method to evaluate drug-metabolizing enzyme activities in real time is needed. In this study, we developed a novel SPECT imaging probe for evaluation of hepatic CYP2D activity.Methods: Iodine-123- and 125-labeled 4-iodobenzylmequitazine (123/125I-BMQ) was synthesized with high labeling and purity. CYP isozymes involved in the metabolism of 125I-BMQ in mouse liver microsomes were evaluated, and the utility of 123/125I-was assessed from biological distribution and SPECT imaging evaluation in normal and CYP2D-inhibited mice.Results:In vitro metabolite analysis using mouse liver microsomes showed that 125I-BMQ is specifically metabolized by CYP2D. Biological distribution and SPECT imaging of 123/125I-BMQ in normal mice showed that injection 123/125I-BMQ accumulated early in the liver and was excreted into the gallbladder and intestines. In CYP2D-inhibited mice, accumulation in the liver was increased, but accumulation in the gallbladder and intestines, the excretory organ, was delayed. Since only metabolites of 125I-BMQ are detected in bile, visualization and measuring of the accumulation of metabolites over time in the intestine, where bile is excreted, could predict the amount of metabolites produced in the body and evaluate CYP2D activity, which would be useful in determining the dosage of various drugs metabolized by CYP2D.Conclusion:123/125I-BMQ is useful as a SPECT imaging probe for comprehensive and direct assessment of hepatic CYP2D activity in a minimally invasive and simple approach.

Introduction Behavioral Activation (BA) is a short-term cognitive behavioral therapy modality that stimulates activities that increase patients’ reinforcement experiences. Recent research verified the effect of brief BA. However, despite the short intervention time per session, BA is difficult to implement during hospitalization due to its long implementation period. Objectives To evaluate the clinical effectiveness of a brief BA program for people with depression in an inpatient setting. Methods This study employed a single-group pre-post design. Fifteen patients who met the inclusion criteria participated in the trial after providing oral and written informed consent. In addition to their usual care, participants received four weekly sessions administered by a nurse. The primary outcome measures included the Beck Depression Inventory (BDI-II), which indicated patients’ subjective depression severity. Clinical outcomes were measured at preintervention, immediate postintervention, and one-month postintervention. Results Fourteen participants completed the BA program and were receptive to treatment. For the primary endpoint, BDI-II, there was an improvement in scores (25.60 to 22.73 to 22.06) between the baseline, postintervention, and 1-month postassessment, but not a significant change. For EQ VAS score, there was no significant change, but there was an improvement in EQ VAS score (51.53 to 52.20 to 55.13) between the baseline, postintervention, and 1-month postassessment. The mean total Global Assessment of Functioning score increased from 40.20 to 57.00 across the pre- and postassessment points ( p < .0001). Conclusion The study comprised a brief BA intervention, with results suggesting that participants could complete the program without feeling burdened. Although there was no significant improvement in the general outcome, depression levels, and other outcomes improved. Thus, while there is a need to rethink BA intervention, this program may be a practical approach to improving depression and other outcomes.

Background: Alzheimer’s disease (AD) and dementia have increasingly been conceived of as “complex diseases of aging”, determined by multiple, simultaneous, interacting pathophysiological processes. The condition known as frailty is a phenotype of aging and its comprehensive pathophysiology is thought to be closely related to the incidence of mild cognitive impairment (MCI) and the exacerbation of dementia. Objective: This study aimed to investigate the effect of the multicomponent drug, ninjin’yoeito (NYT), on frailty in MCI and mild AD patients. Methods: This study was an open-label trial. A total of 14 patients, including 9 with MCI and 5 with mild AD, were enrolled. Among them, 11 were frail while 3 were prefrail. NYT (6–9 g/day) was administered orally for 24 weeks, and assessments were carried out at baseline (week 0), and at 4, 8, 16, and 24 weeks. Results: In the primary endpoint, significant early improvements were observed in the anorexia scores according to the Neuropsychiatric Inventory after four weeks of treatment with NYT. The Cardiovascular Health Study score was significantly improved, and no frailty was observed after 24 weeks. The fatigue visual analog scale scores also significantly improved. The Clinical Dementia Rating and the Montreal Cognitive Assessment scores remained at baseline levels during the NYT treatment period. Conclusion: The results suggest that NYT may be effective in the treatment of frailty, especially for anorexia and fatigue, in both MCI and mild AD patients, which would be beneficial for the prognosis of dementia.

Pruritus, including neuropathic and psychogenic pruritus, is an unpleasant feeling that causes a desire to scratch, which negatively impacts physical and psychological aspects of daily life. Nonetheless, little is known about the neural mechanisms involved in pruritus. Glutamate is a predominant excitatory neurotransmitter in the mammalian central nervous system and exerts its effects by binding to various glutamate receptors, including kainate (KA) receptors; however, the precise involvement of each glutamate receptor in pruriceptive processing remains unclear, particularly that of KA receptors. Therefore, the roles of KA receptors in histamine-dependent and -independent itch were investigated using CNQX, an AMPA/KA receptors antagonist, UBP310 and UBP302, antagonists of KA receptors, and small interfering (si)RNAs against KA receptor subunits in mice with acute and chronic pruritus. The effects of KA receptor antagonists on histamine-induced c-Fos expression in the spinal cord were also examined. The intrathecal administration of CNQX reduced the number of scratching events induced by histamine and chloroquine. On the other hand, UBP310 or UBP302 and the siRNAs of KA receptor subunits 1-3 significantly inhibited the induction of scratching events in mice treated with histamine, while no significant change was observed in the induction of spontaneous scratching events in mice with chronic pruritus. In addition, antagonists of KA receptors attenuated c-Fos expression in the superficial layers of the dorsal horn induced by histamine. These results indicate that KA receptors are involved in acute pruriceptive processing in the spinal cord induced by histamine, but not chloroquine or chronic itch.

The involvement of serotonin (5-HT) and/or noradrenaline in acute pruriceptive processing in the central nervous system (CNS) has been reported using antidepressants, such as milnacipran, a serotonin and noradrenaline reuptake inhibitor, and mirtazapine, a noradrenergic and specific serotonergic antidepressant; however, the roles of 5-HT receptor family in acute pruriceptive processing have not been fully elucidated in the CNS. In the present study, scratching behavior induced by chloroquine (CQ) was ameliorated by milnacipran or mirtazapine, and these effects were reversed by SB207266, a 5-HT4 antagonist, or SB258585, a 5-HT6 antagonist, but not by SB258585, a 5-HT5 antagonist. Moreover, CQ-induced scratches were mitigated by intrathecal injection of 5-HT4 agonists, such as BIMU8 and ML10302, and the 5-HT6 agonist, WAY208466. Conversely, histamine-induced scratches were not affected by the 5-HT4 agonists or a 5-HT6 agonist. Similarly, the amelioration of histamine-induced scratches by these antidepressants was not reversed by the 5-HT4, 5-HT5, or 5-HT6 receptor antagonist. Therefore, 5-HT is involved in the amelioration of CQ-induced scratches by milnacipran and mirtazapine, and 5-HT4, 5-HT5, and 5-HT6 receptors play differential roles in acute pruriceptive processing after administration of CQ or histamine.

Abstract Aim Yokukansan is a Japanese herbal medicine used in psychiatry to treat behavioral and psychological symptoms of dementia and other psychiatric symptoms. However, the glycyrrhizic acid included in this medicine can cause pseudoaldosteronism and hypokalemia. We aimed to identify the risk factors for hypokalemia due to yokukansan. Methods A retrospective cohort study was conducted on patients previously treated with yokukansan. The risk factors were determined by comparing the hypokalemia group with the non‐hypokalemia group for each parameter. Results This study included 304 patients who received yokukansan treatment between April 2009 and March 2019. We found that 17.4% (n = 53) of the patients experienced yokukansan‐induced hypokalemia. Risk factors detected as significantly different between patients with and without yokukansan‐associated hypokalemia were low serum potassium concentration before yokukansan administration, dose 7.5 g /day or more, and dementia. Hypokalemia occurred earlier in patients with low albumin, low potassium, and dementia. Conclusion It is necessary to pay attention to hypokalemia onset when administering yokukansan at 7.5 g or more to patients with low potassium levels and dementia. Our findings suggest that potassium levels must be checked early after yokukansan administration, especially in patients with low albumin, low potassium, and dementia.

Abstract Background The optimal treatment strategy for patients with treatment‐resistant schizophrenia (TRS) associated with 22q11.2 deletion syndrome (DS) remains a subject of debate. Case Presentation We present the case of a 40‐year‐old female patient diagnosed with TRS and 22q11.2DS who was effectively treated with clozapine. She was diagnosed with schizophrenia and mild intellectual disability during her adolescence; despite being hospitalized for a period of 10 years beginning in her 30s, she continued to exhibit symptoms of impulsivity, and explosive behavior, requiring periods of isolation. We ultimately decided to switch her medication to clozapine, which was administered with caution and gradually titrated upward, with no discernable adverse effects, resulting in a marked improvement in her symptoms and obviated the need for isolation. Subsequently, the patient's history of congenital heart disease and facial abnormalities prompted initial suspicions of a 22q11.2DS diagnosis, which was subsequently confirmed through genetic testing. Conclusion Clozapine may serve as an efficacious pharmacological intervention for TRS patients with 22q11.2DS, including those of Asian descent.

難治化した三叉神経痛にベンラファキシンを使用し良好な経過を得た1例を経験した。症例は72歳女性,三叉神経痛に対して複数の薬剤による投薬治療や神経ブロック,神経血管減圧術が施行されるも疼痛は再燃を繰り返していた。ペインクリニックを経て当科を受診し,ベンラファキシンと認知行動療法を併用し疼痛は軽減した。慢性疼痛は身体的要因に加え心理社会的要因が絡むことでより難治化する傾向にあり,薬物療法と非薬物療法を効果的に組み合わせて治療を行う事が肝要であると考えた。本邦ではベンラファキシンは疼痛性疾患への保険適応を有していないが,その効果は徐々に明らかになってきており,慢性疼痛治療において有用である可能性が示唆された。

Drug metabolizing enzyme activity is affected by various factors such as drug–drug interactions, and a method to quantify drug metabolizing enzyme activity in real time is needed. In this study, we developed a novel radiopharmaceutical for quantitative imaging to estimate hepatic CYP3A4 and CYP2D6 activity. Iodine-123- and 125-labeled O-desmethylvenlafaxine (123/125I-ODV) was obtained with high labeling and purity, and its metabolism was found to strongly involve CYP3A4 and CYP2D6. SPECT imaging in normal mice showed that the administered 123I-ODV accumulated early in the liver and was excreted into the gallbladder, as evaluated by time activity curves. In its biological distribution, 125I-ODV administered to mice accumulated early in the liver, and only the metabolite of 125I-ODV was quickly excreted into the bile. In CYP3A4- and CYP2D6-inhibited model mice, the accumulation in bile decreased more than in normal mice, indicating inhibition of metabolite production. These results indicated that imaging and quantifying the accumulation of radioactive metabolites in excretory organs will aid in determining the dosages of various drugs metabolized by CYP3A4 and CYP2D6 for individualized medicine. Thus, 123/125I-ODV has the potential to direct, comprehensive detection and measurement of hepatic CYP3A4 and CYP2D6 activity by a simple and less invasive approach.

Suicide prevention is a crucial policy issue in Japan to be addressed nationally. Nevertheless, if there are regional differences in suicide, even in adjacent sub-regions, measures may need to be taken at the sub-regional level. Previous studies have not compared regional differences in suicide based on the size of policy units, such as prefectures, secondary medical areas, and municipalities. This study used the number of suicides from open data for 10 years from 2009 to 2018 to obtain shrinkage estimates of the standardized mortality ratio (SMR) using the Bayesian hierarchical model. We visualized and compared the regional disparities in suicide for each policy unit. For each gender and policy unit, adjacent regions had similar clusters of SMRs and positive spatial autocorrelation of global Moran’s I (p < 0.001 for each). Comparisons between each policy unit showed that even if the SMR was low for the prefectural units, there were regions with high SMRs in municipalities and secondary medical areas, and vice versa. It was found that assessing suicide solely on a prefecture-by-prefecture basis may overlook regional disparities in suicide. This research emphasizes the need to establish suicide indicators at the secondary medical or municipal level and execute individual suicide prevention interventions in neighboring communities. Prefectures can also play a role in developing collaborative cooperation between neighboring regions by acting as actors.

Importance:Although the suicide rate in Japan increased during the COVID-19 pandemic, the reasons for suicide have yet to be comprehensively investigated. Objective:To assess which reasons for suicide had rates that exceeded the expected number of suicide deaths for that reason during the COVID-19 pandemic. Design, Setting, and Participants:This national, population-based cross-sectional study of data on suicides gathered by the Ministry of Health, Labor, and Welfare from January 2020 to May 2021 used a times-series analysis on the numbers of reason-identified suicides. Data of decedents were recorded by the National Police Agency and compiled by the Ministry of Health, Labor, and Welfare. Exposure:For category analysis, we compared data from January 2020 to May 2021 with data from December 2014 to June 2020. For subcategory analysis, data from January 2020 to May 2021 were compared with data from January 2019 to June 2020. Main Outcomes and Measures:The main outcome was the monthly excess suicide rate, ie, the difference between the observed number of monthly suicide deaths and the upper bound of the 1-sided 95% CI for the expected number of suicide deaths in that month. Reasons for suicide were categorized into family, health, economy, work, relationships, school, and others, which were further divided into 52 subcategories. A quasi-Poisson regression model was used to estimate the expected number of monthly suicides. Individual regression models were used for each of the 7 categories, 52 subcategories, men, women, and both genders. Results:From the 29 938 suicides (9984 [33.3%] women; 1093 [3.7%] aged <20 years; 3147 [10.5%] aged >80 years), there were 21 027 reason-identified suicides (7415 [35.3%] women). For both genders, all categories indicated monthly excess suicide rates, except for school in men. October 2020 had the highest excess suicide rates for all cases (observed, 1577; upper bound of 95% CI for expected number of suicides, 1254; 25.8% greater). In men, the highest monthly excess suicide rate was 24.3% for the other category in August 2020 (observed, 87; upper bound of 95% CI for expected number, 70); in women, it was 85.7% for school in August 2020 (observed, 26; upper bound of 95% CI for expected number, 14). Conclusions and Relevance:In this study, observed suicides corresponding to all 7 categories of reasons exceeded the monthly estimates (based on data from before or during the COVID-19 pandemic), except for school-related reasons in men. This study can be used as a basis for developing intervention programs for suicide prevention.

Although Mobitz type II atrioventricular block is typically an arrhythmia arising from a permanent organic disorder of the His-Purkinje system, reversible factors should also be considered. Here, we report the association between a rare reversible Mobitz type II atrioventricular block and antipsychotic medication in a 75-year-old patient with schizophrenia.

INTRODUCTION:Despite the recent global mental health movement of the transition from hospital-centred to integrated community-based services, comprehensive evidence of psychosocial interventions focusing on community-dwelling individuals with schizophrenia is still lacking. To overcome this gap in the current knowledge, we will conduct a systematic review and meta-analysis to assess the efficacy of all types of psychosocial interventions for community-dwelling (non-hospitalised) individuals with schizophrenia when compared with non-active control conditions (eg, treatment as usual). METHODS AND ANALYSIS:This study protocol has been developed according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines. By March 2022, the following sources will have been searched, without restrictions for language or publication period: Embase, PubMed, PsycINFO, CINAHL, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform. We will also try to identify other potentially eligible studies by searching the reference lists of included studies, other relevant systematic reviews and grey literature. All relevant randomised controlled trials from both high-income and low-income to middle-income countries will be allowed. Two independent reviewers will conduct the selection/screening of studies, data extraction and methodological quality assessment of included studies. The primary outcomes are quality of life and psychiatric hospital admission. Standard pairwise meta-analyses with a random-effects model will be conducted. Subgroup and sensitivity analyses will be performed to assess the robustness of the findings. Risk of bias will be assessed with the Revised Cochrane Risk-of-Bias Tool for Randomised Trials. The Grades of Recommendation Assessment, Development and Evaluation approach will be used to assess the quality of evidence. ETHICS AND DISSEMINATION:Ethics approval is not required for this study. The study findings will be disseminated through conference presentations as well as peer-reviewed publications. PROSPERO REGISTRATION NUMBER:CRD42021266187.

統合失調症では,複合的な要因で嚥下障害を呈することがあり,適切な対処が求められる。今回,減薬と口腔ケアが肺炎および肺化膿症の治療に寄与した統合失調症の一例を報告する。症例は破瓜型統合失調症の35歳女性。支離滅裂で衝動的な行動が目立ち,単科精神科病院に長期入院していた。肺炎を繰り返すようになり,精査目的で当科へ転院後,肺化膿症と診断された。抗菌薬治療と併せて,向精神薬の調整や口腔ケアを行った。全身状態が改善するにつれて,精神状態が安定し意味のある発語も見られるようになり,入院第59病日に紹介元へ転院した。統合失調症の症状そのものだけでなく,向精神薬や口腔衛生状態の悪化が誤嚥や肺炎の原因となりうる。肺炎を繰り返す統合失調症患者では,薬剤や口腔環境を改めて評価し,包括的に対応することが重要である。

A 63-year-old male receiving hemodialysis for renal insufficiency developed severe and widespread pruritus, which was unresponsive to antihistamines and severe depression with insomnia, agitation, and anxiety. The oral administration of 7.5 mg mirtazapine daily alleviated his severe pruritus after 4 days and severe depression after 14 days. Mirtazapine has potential as a therapeutic option for patients receiving hemodialysis with depressive disorder and severe pruritus unresponsive to antihistamines.

Venlafaxine has potential as a therapeutic option for patients with depressive disorder, migraine, and pruritus unresponsive to antihistamines.