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.

Post-disaster mental health and psychosocial support in the areas affected by the Great East Japan Earthquake: a qualitative study.

BACKGROUND: Few studies exploring the actual practices implemented for long-term mental health and psychosocial support after a natural disaster have been published. This study aimed to reveal (1) the types of activities that were actually provided as mental health and psychosocial support (MHPSS) in the long-term phase after the Great East Japan Earthquake (GEJE) and (2) the problems that must be addressed to provide post-disaster MHPSS activities. METHODS: An open-ended questionnaire was sent to organizations in the Iwate, Miyagi and Fukushima prefectures that were potentially involved in providing MHPSS to communities affected by the GEJE. The organizations were asked to describe their activities and the problems that needed to be addressed to provide these support activities. The collected statements were analysed using content analysis with NVivo11. RESULTS: The support activities conducted to provide MHPSS in the long-term phase after the catastrophe were diverse and classified into 7 major categories, namely, (1) one-on-one support for individuals in need of assistance, (2) support for collective activities, (3) support around living conditions and income, (4) increasing public awareness about mental health, (5) human resource development to improve response capabilities for MHPSS, (6) support for MHPSS providers, and (7) facilitating collaborations among the MHPSS activities provided to affected communities. Problems with human resources and funding were the most frequently mentioned concerns among the organizations participating in the survey. CONCLUSIONS: The establishment of systems to collect and share sufficient and relevant knowledge and to coordinate organizations for long-term post-disaster postventions would be desirable.

Post-traumatic growth of children affected by the Great East Japan Earthquake and their attitudes to memorial services and media coverage.

AIMS: Post-traumatic growth (PTG) refers to positive changes that result from coping with a major life crisis or a traumatic event. Factors influencing PTG in youth have not been well characterized but could have a great impact on overall maturation. METHODS: Fourth to ninth graders (n = 3337) attending elementary or junior high schools located in a district severely damaged by the Great East Japan Earthquake completed a questionnaire, including the revised Posttraumatic Growth Inventory for Children (PTGI-C-R) along with the Post Traumatic Stress Symptoms for Children 15 items (PTSSC-15), 31 months after the event. Experience of the disaster, prior traumatic experiences, and attitudes toward memories of the disaster (rumination) were scored by their caregivers and teachers, and effects of these factors on PTG were evaluated. RESULTS: There were no significant associations between PTGI-C-R and sex or experiences of the disaster. However, PTGI-C-R was negatively correlated with age (r = -0.132, P < 0.001). There was significant but very weak negative correlation between PTGI-C-R and PTSSC-15 among the children (r = -0.096, P < 0.001). PTGI-C-R was significantly associated with positive attitudes to memorial services (P < 0.001) and media coverage (P < 0.05). CONCLUSION: Positive attitudes to deliberate rumination may facilitate PTG in children following natural disasters.

[Factors associated with the psychological impact of the Great East Japan earthquake on high school students 1 year and 4 months after the disaster].

The purpose of this study was to investigate factors associated with the psychological impact of the Great East Japan Earthquake on high school students 1 year and 4 months after the disaster, and clarify support needs of the students. In the outreach program for students of three high schools in coastal areas of southern Miyagi Prefecture, Japan, 1,973 students were surveyed after obtaining informed consent for participation. Questionnaires included: the Quick Inventory of Depressive Symptomatology (QIDS-J), Self-rating Anxiety Scale (SAS), Impact of Event Scale-revised (IES-R), and Connor-Davidson Resilience Scale (CD-RISC10). All scores were compared using SPSS 20.0 J between school grades, locations of the schools, and extent of damage due to the Great East Japan Earthquake. Our analysis showed a significant positive correlation between school grades and the level of anxiety. PTSR scores, but not anxiety nor depressive scores, of students whose lives have suffered extensive damage were significantly higher than those of students who have not. Students of high schools which have suffered extensive damage and use temporary buildings showed significantly higher levels of depression and anxiety, and significantly lower resilience, compared to students of high schools which were not damaged. Although previous findings demonstrated that younger children have a higher risk of being influenced by disasters, symptoms related to PTSR and depression were found frequently in the high school students as well. Among the high school students, our analysis showed a positive correlation between the level of anxiety and school grades, probably because the disaster has affected an influential and pivotal point in their lives.

Physical and psychological outcome in long-term survivors of childhood malignant solid tumor in Japan.

PURPOSE: Few studies have assessed physical and psychological status in long-term survivors of childhood solid tumors in Japan. For children with such diseases diagnosed and treated in our hospital, our purpose was to clarify the physical and psychological status of long-term survivors and their parents. METHODS: Subjects were 56 patients who were diagnosed at our institution as having a childhood malignant solid tumor between 1982 and 2005 and had been alive for at least 5 years after treatment. Surveys were sent and returned by mail. RESULTS: Of the 56 patients surveyed, 32 responded. The current health condition and psychosocial status of survivors were evaluated as good by their parents. However, psychological tests revealed psychosocial problems in 28.1% of the children. Severe posttraumatic stress associated with the child's disease and its treatment was present in 15.6% of the parents. CONCLUSION: Physical status of long-term survivors of childhood malignant solid tumors was good in general. However, psychological tests revealed psychosocial problems in some of the children and posttraumatic stress in the parents. Considering the diversity of both the diseases and their clinical course, a qualitative study is warranted for further analysis.

The Impact of Health Consciousness on the Association Between Walking Durations and Mental Health Conditions After a Disaster: a Cross-Sectional Study.

BACKGROUND: In communities affected by a disaster, walking can be a feasible form of physical exercise to improve physical and mental health conditions. However, there is limited evidence to support relationships between walking habits and mental health conditions in post-disaster settings. Cross-sectional epidemiological data obtained from a questionnaire survey (conducted in October 2017) of a community affected by the 2011 Great East Japan Earthquake (GEJE) was analyzed to evaluate the relationships. METHODS: Participants included individuals over 20 years of age (N = 718) from Shichigahama town in Miyagi prefecture, whose houses were significantly damaged by the GEJE. Their mental health conditions were assessed by the Kessler Psychological Distress Scale (K6), the Center for Epidemiologic Studies Depression Scale (CES-D), and the Impact of Event Scale-Revised (IES-R). Additionally, the questionnaire asked the participants spent duration walking on average and their walking purpose by the following items: (1) longer than 60 min per day, (2) between 30 and 60 min per day, or (3) less than 30 min per day, and whether they walked to maintain healthy living habits (health-conscious walkers) or merely for transportation without considering health consequences (non-health-conscious walkers). These information and mental health indicators were analyzed using analysis of covariance (ANCOVA). RESULTS: Among the three walking duration groups of health-conscious walkers, there were significant differences in CES-D and K6 scores (p = 0.01 and p = 0.04), but not in IES-R scores, considering age, gender, and alcohol drinking habits as covariates. CES-D score was significantly higher among short walkers (p = 0.004). Among the three walking duration groups of non-health-conscious walkers, there were significant differences in avoidance symptoms, the subdomain of IES-R (p = 0.01), but not in CES-D, K6, and total IES-R scores, considering the variants. CONCLUSION: Our study suggests that walking durations may positively affect mood, but not PTSR, only when walking is performed with the purpose of maintaining healthy living habits. Walking durations were negatively associated with avoidance symptoms among non-health-conscious walkers in the community affected by the GEJE, indicating that the disaster may have had a long-lasting impact on walking habits.

[The case of a living liver donor who was underage: psychiatric issues and evaluation].

We report a case in which a healthy 18-year-old girl acted as a liver donor for her mother, who had a terminal hepatic illness with a one-year survival probability of 2% without liver transplantation. The daughter, who was the only relative to have a blood type compatible with her mother, offered to donate after the surgeons explained the situation. Our ethical committee required a psychiatrist to evaluate her psychiatric status and competence, and address ethical concerns. We assessed elements of informed consent: disclosure of information, competence, and voluntariness, as well as psychiatric problems and the psychosocial status. The disclosure of information was adequate. The girl's competence was of a sufficient level for her to appreciate that the procedure could have negative results on both her and her mother. She was able to logically assess the consequences of having the operation and those of declining it. It was very difficult to evaluate whether she was undergoing the procedure completely voluntarily, because she was the only one with a blood type compatible with her mother, who was near death, and because the girl was underage. Psychological issues related to her age were that she depended on her family economically and psychologically, and that the opinions of her family influenced her. In this case, we concluded that she had consented voluntarily, because there was no coercion and no unjust pressure to donate, and because she understood that consent could be withdrawn at any time. Although she was underage and the psychological assessment revealed that she experienced some conflict in this difficult situation, her competence was considered intact. Medical evaluation and laboratory testing were satisfactory, and the ethical committee determined that she was suitable to donate. The operation was performed and was successful. The Japanese Transplantation Society has since established ethical guidelines regarding potential living donors who are underage; one precondition for donation is that a psychiatrist must evaluate whether or not the competence of the donor is equal to that of an adult. As the literature contains no reports of the evaluation of potential donors who are underage, we need to consider the format and contents of such psychiatric evaluations and ethical concerns.

[Establishment of a comprehensive anti-suicide project in an urban city].

For the establishment of an effective comprehensive anti-suicide policy, a multifaceted strategy including primary, secondary, and tertiary prevention measures is needed. In urban cities, however, there are many obstacles to projects such as comprehensive programs for suicide prevention. In Sendai city, which has a population of approximately 1,000,000, a comprehensive anti-suicide project was launched as a public enterprise as a pioneer among ordinance-designated cities in Japan. This project was supported by several important factors. 1) A series of epidemiological observation and intervention studies on depression among the elderly had previously been conducted in a large residential district. As a result, a comprehensive community program for depression among the elderly was implemented as a public enterprise and a subsequent decreasing trend in the later-life suicide rate was found. 2) The municipal authorities recognized the importance of the anti-suicide program and made an effort to reorganize the existing health-related programs in terms of suicide prevention. 3) the action of the municipality was facilitated by the passing of an anti-suicide law by the National Diet in 2006 and the establishment of fundamental principles for a comprehensive anti-suicide policy by the National Diet in 2007. 4) The activities of nongovernmental groups also influenced the municipality. In order to establish a comprehensive anti-suicide program in urban cities with a large population, an interaction model in which various governmental and nongovernmental networks influence and activate each other should be considered.