Prevalence of and factors influencing Hikikomori in Osaka City, Japan: A population-based cross-sectional study.

OBJECTIVES: Hikikomori is commonly defined as a social condition in which individuals avoid social participation and relationships beyond their family members by confining themselves to a room or their house for 6 months or longer. Hikikomori has been predominantly considered a problem among young people; however, as the population is ageing, hikikomori has also emerged as a social issue among adults. Nevertheless, no comparative studies have examined the differences in the factors associated with hikikomori among teenagers/young adults and middle-aged/older adults. Thus, this phenomenon has not been thoroughly examined, and it remains unclear whether the risk factors vary between teenagers/young adults and middle-aged/older adults. Based on the Japan Cabinet Office's definition of hikikomori, this cross-sectional study evaluated the prevalence and related factors of hikikomori among the working age population (15-64 years), utilising univariate and multivariate analyses. The study also compared differences in the prevalence of and factors related to hikikomori between teenagers/young adults and middle-aged/older adults. METHODS: We distributed self-administered questionnaires to individual participants and their families between 24 December 2020 and 18 January 2021. RESULTS: Data from an anonymised sample of 3,092 individuals (split into two groups of 15-39 and 40-64 years) were subjected to analysis. The results revealed a hikikomori prevalence of 2.3% in the target population; the prevalence rate was 2.12% among individuals aged 15 to 39 years and 2.42% among those aged 40 to 64 years. The analysis demonstrated strong correlations between hikikomori and several factors, including unemployment, truancy, a history of psychiatric consultation or hospitalisation, being male and the absence of ibasho, which is defined as a place where individuals can feel peace, security, acceptance and belonging. The factors associated with hikikomori differed between teenagers/young adults and middle-aged/older adults. CONCLUSION: Our findings, thus, contribute to existing research by providing a comparative analysis of risk factors across different age groups.

Oxytocin-induced increases in cytokines and clinical effect on the core social features of autism: Analyses of RCT datasets.

Although oxytocin may provide a novel therapeutics for the core features of autism spectrum disorder (ASD), previous results regarding the efficacy of repeated or higher dose oxytocin are controversial, and the underlying mechanisms remain unclear. The current study is aimed to clarify whether repeated oxytocin alter plasma cytokine levels in relation to clinical changes of autism social core feature. Here we analyzed cytokine concentrations using comprehensive proteomics of plasmas of 207 adult males with high-functioning ASD collected from two independent multi-center large-scale randomized controlled trials (RCTs): Testing effects of 4-week intranasal administrations of TTA-121 (A novel oxytocin spray with enhanced bioavailability: 3U, 6U, 10U, or 20U/day) and placebo in the crossover discovery RCT; 48U/day Syntocinon or placebo in the parallel-group verification RCT. Among the successfully quantified 17 cytokines, 4 weeks TTA-121 6U (the peak dose for clinical effects) significantly elevated IL-7 (9.74, 95 % confidence interval [CI] 3.59 to 15.90, False discovery rate corrected P (PFDR) < 0.001), IL-9 (56.64, 20.46 to 92.82, PFDR < 0.001) and MIP-1b (18.27, 4.96 to 31.57, PFDR < 0.001) compared with placebo. Inverted U-shape dose-response relationships peaking at TTA-121 6U were consistently observed for all these cytokines (IL-7: P < 0.001; IL-9: P < 0.001; MIP-1b: P = 0.002). Increased IL-7 and IL-9 in participants with ASD after 4 weeks TTA-121 6U administration compared with placebo was verified in the confirmatory analyses in the dataset before crossover (PFDR < 0.001). Furthermore, the changes in all these cytokines during 4 weeks of TTA-121 10U administration revealed associations with changes in reciprocity score, the original primary outcome, observed during the same period (IL-7: Coefficient = -0.05, -0.10 to 0.003, P = 0.067; IL-9: -0.01, -0.02 to -0.003, P = 0.005; MIP-1b: -0.02, -0.04 to -0.007, P = 0.005). These findings provide the first evidence for a role of interaction between oxytocin and neuroinflammation in the change of ASD core social features, and support the potential role of this interaction as a novel therapeutic seed. Trial registration: UMIN000015264, NCT03466671/UMIN000031412.

Effect of a novel nasal oxytocin spray with enhanced bioavailability on autism: a randomized trial.

Although intranasal oxytocin is expected to be a novel therapy for the core symptoms of autism spectrum disorder, which has currently no approved medication, the efficacy of repeated administrations was inconsistent, suggesting that the optimal dose for a single administration of oxytocin is not optimal for repeated administration. The current double-blind, placebo-controlled, multicentre, crossover trial (ClinicalTrials.gov Identifier: NCT03466671) was aimed to test the effect of TTA-121, a new formulation of intranasal oxytocin spray with an enhanced bioavailability (3.6 times higher than Syntocinon® spray, as assessed by area under the concentration-time curve in rabbit brains), which enabled us to test a wide range of multiple doses, on autism spectrum disorder core symptoms and to determine the dose-response relationship. Four-week administrations of TTA-121, at low dose once per day (3 U/day), low dose twice per day (6 U/day), high dose once per day (10 U/day), or high dose twice per day (20 U/day), and 4-week placebo were administered in a crossover manner. The primary outcome was the mean difference in the reciprocity score (range: 0-14, higher values represent worse outcomes) on the Autism Diagnostic Observation Schedule between the baseline and end point of each administration period. This trial with two administration periods and eight groups was conducted at seven university hospitals in Japan, enrolling adult males with high-functioning autism spectrum disorder. Enrolment began from June 2018 and ended December 2019. Follow-up ended March 2020. Of 109 males with high-functioning autism spectrum disorder who were randomized, 103 completed the trial. The smallest P-value, judged as the dose-response relationship, was the contrast with the peak at TTA-121 6 U/day, with inverted U-shape for both the full analysis set (P = 0.182) and per protocol set (P = 0.073). The Autism Diagnostic Observation Schedule reciprocity score, the primary outcome, was reduced in the TTA-121 6 U/day administration period compared with the placebo (full analysis set: P = 0.118, mean difference = -0.5; 95% CI: -1.1 to 0.1; per protocol set: P = 0.012, mean difference = -0.8; 95% CI: -1.3 to -0.2). The per protocol set was the analysis target population, consisting of all full analysis set participants except those who deviated from the protocol. Most dropouts from the full analysis set to the per protocol set occurred because of poor adherence to the test drug (9 of 12 in the first period and 8 of 15 in the second period). None of the secondary clinical and behavioural outcomes were significantly improved with the TTA-121 compared with the placebo in the full analysis set. A novel intranasal spray of oxytocin with enhanced bioavailability enabled us to test a wide range of multiple doses, revealing an inverted U-shape dose-response curve, with the peak at a dose that was lower than expected from previous studies. The efficacy of TTA-121 shown in the current exploratory study should be verified in a future large-scale, parallel-group trial.

No adverse events were observed in clozapine-treated patients on extended hematologic monitoring intervals during the coronavirus pandemic in four psychiatric centers in Japan.

AIM: As an emergency measure during the coronavirus disease pandemic, the monitoring interval for clozapine use was temporarily extended beyond the regulatory requirement in Japan, which is the safest monitoring interval worldwide. In this study, we aimed to explore the effect of this measure on patients undergoing clozapine treatment. METHODS: This retrospective chart review study included patients with treatment-resistant schizophrenia (TRS) who were undergoing clozapine treatment at four psychiatric institutions in Japan. Demographic characteristics and clinical information of these patients were collected on April 27, 2020, when Japanese psychiatrists were virtually allowed to prescribe clozapine beyond the regulatory requirement. Furthermore, information of adverse events related to the emergency measure was collected and analyzed. RESULTS: Of the 41 patients with TRS included in this study, 19 patients underwent extended hematological monitoring during clozapine treatment. No psychiatric or hematological adverse events were observed in the patients during the extended monitoring interval. CONCLUSION: This study suggested that there were few adverse events of clozapine-treated patients related to emergency measures in Japan. However, hematological monitoring intervals during clozapine treatment have been emergently extended worldwide; hence, it is necessary to verify the results of these measures.

A Case of Neurosarcoidosis-Induced Syndrome of Inappropriate Secretion of Antidiuretic Hormone Diagnosed with Neuroendoscopy.

We treated a patient with neurosarcoidosis, which caused the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), in whom diagnosis was performed using neuroendoscopy. The patient was a 56-year-old female who was hospitalized for hyponatremia and diagnosed with SIADH based on a detailed examination. During the course, she developed impaired consciousness due to acute hydrocephalus, which improved after ventricular drainage. Head magnetic resonance imaging (MRI) confirmed nodular lesions at the floor of the third ventricle and the cerebral aqueduct. Neuroendoscopic biopsy led to the diagnosis of neurosarcoidosis. Her hyponatremia improved after steroid therapy. Neurosarcoidosis can cause SIADH, and complication of hydrocephalus may lead to a poor prognosis. Neuroendoscopy appears to be effective for the diagnosis of neurosarcoidosis with hydrocephalus and helps in deciding the treatment modality.

The possibility of the treatment for long-acting injectable antipsychotics induced severe side effects.

We present the case of a 47-year-old man with schizophrenia who developed acute and persistent circulatory failure after receiving injections of paliperidone palmitate. We measured blood concentrations of paliperidone and performed resection of hip tissues, where paliperidone palmitate was suspected to be present, in order to reduce the side effects. Unfortunately, the resection could not save the patient from prolonged and severe side effects and he died of multiple organ failure. We suggest that resection of the tissues suspected of containing paliperidone palmitate can help reduce its severe side effects. However, identifying the site of injection is essential.

Possible factors influencing the duration of hospital stay in patients with psychiatric disorders attempting suicide by jumping.

BACKGROUND: Patients with psychiatric disorders have a high rate of suicide. The present study investigated factors influencing hospital stays for Japanese patients with psychiatric disorders attempting suicide by jumping. METHODS: We diagnosed all suicide attempts (n = 113) by jumping based on the International Classification of Diseases 10th Revision (ICD-10) and investigated the mean hospital stays of patients with each diagnosis based on the ICD-10 code. We then analyzed differences in the demographic and clinical characteristics between the diagnostic groups to identify factors influencing the duration of hospital stay. RESULTS: Patients diagnosed with schizophrenia (F2 code) were the most frequent (32.7%) of all diagnoses; therefore, we divided the diagnostic groups into schizophrenia group (n = 37) and other psychiatric diagnoses group (n = 76). The patients with schizophrenia showed a significantly longer hospital stay (125.7 ± 63.9 days) compared with the patients with other psychiatric diagnoses (83.6 ± 63.2) (ß ± SE = 42.1 ± 12.7, p = 0.0013), whereas there was no difference in the jump height between the two groups (the average was the 3rd to 4th floor; p > 0.05). The number of injured parts, particularly lower-limb fractures, was significantly higher (p = 0.017) in patients with schizophrenia than in patients with other psychiatric diagnoses. The duration of psychiatric treatment in patients with schizophrenia were significantly longer (z = 3.4, p = 0.001) than in patients with other psychiatric diagnoses. CONCLUSION: Our findings indicate that the number of injuries and the body parts injured in patients with schizophrenia are associated with a longer duration of hospital stay following a suicide attempt by jumping. The current use of antipsychotics and a longer duration of taking antipsychotics might contribute to the risk of bone fracture via hyperprolactinemia. Further cognitive impairment in patients with schizophrenia might prevent rehabilitation for the management of lower-limb fractures. From these results, we suggest that clinicians should monitor the level of prolactin and cognitive function in patients with schizophrenia in future studies on managing of lower-limb fractures.

Paliperidone Induced Hypoglycemia by Increasing Insulin Secretion.

We report the case of a 41-year-old woman with schizophrenia who developed persistent hypoglycemia following paliperidone administration. After discontinuing paliperidone, the hypoglycemia resolved, but symptoms of diabetes emerged. Therefore, it appears that the hypoglycemia induced by paliperidone may mask symptoms of diabetes. Paliperidone may induce hypoglycemia by increasing insulin secretion. This report could help elucidate the relationship between atypical antipsychotics and glucose metabolism.

A case of "hidden" diabetic nephropathy diagnosed by a combination of renal biopsy findings and continuous glucose monitoring system.

Although diabetic nephropathy is a microvascular complication of diabetes mellitus, some reports suggest that renal biopsy often shows this pathological change without a diagnosis of diabetes mellitus. Here, we report a case of a 65-year-old man who presented with proteinuria, hypoalbuminemia and hypertension without a diagnosis of diabetes mellitus. He drank alcohol regularly and was a heavy smoker. Renal biopsy revealed a diffuse increase in the mesangial area, mesangial nodules or well-developed hyalinosis, interstitial fibrosis, and arteriosclerosis consistent with the changes of diabetic nephropathy. Although we had initially diagnosed him with idiopathic nodular glomerulosclerosis, use of a continuous glucose monitoring system (CGMS) revealed that the changes in his daily blood glucose concentrations met with the diagnostic criteria of diabetes mellitus. Accordingly, we diagnosed him with diabetic nephropathy and initiated treatment for diabetes mellitus. This case suggests that some cases of diabetic nephropathy may be hidden among patients with impaired glucose tolerance, who are not diagnosed with diabetes mellitus. Use of a CGMS may be helpful in diagnosing this type of "hidden" diabetes mellitus. In addition to diet therapy, smoking control, treatment for hypertension, and strict control of hyperglycemia may be important for these patients.