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.

Mental Health Problems among University Students under the Prolonged COVID-19 Pandemic in Japan: A Repeated Cross-Sectional Survey.

Numerous studies have investigated the impact of the coronavirus disease 2019 (COVID-19) pandemic on mental health among university students within a year of its onset, but few have examined the impact of a prolonged pandemic on university life. This study aimed to evaluate the impact of the COVID-19 pandemic on the mental health of students in a large university community. Online questionnaire surveys were conducted on students from March 24 to April 14 (first survey, n = 3,357) and December 2-23, 2021 (second survey, n = 2,604). The questionnaires included items on demographic data, living conditions, and mental health status as measured using the Patient Health Questionnaire-9 for depressive symptoms and the Generalized Anxiety Disorder-7 scale for anxiety symptoms. The results showed that, compared with undergraduate students, graduate students, except those in Medicine, Dentistry, and Pharmaceutical Science courses, had more anxiety symptoms. Furthermore, among undergraduate students, depressive and anxiety symptoms were significantly higher in fourth- than in first-year students. Logistic regression analyses of data from both surveys revealed the seven risk factors associated with depressive or anxiety symptoms that affected the mental health of university students throughout the COVID-19 pandemic: 1) female or nonbinary gender, 2) graduate student, 3) quarantine experience due to COVID-19, 4) isolation from friends and acquaintances, 5) disorganized pattern of daily life, 6) worse financial situation, and 7) no availability of consultations regarding health, life, and finances. These findings suggest that mental health measures for university students need to be designed specific to each course.

Review of Mental Health Consequences of the Great East Japan Earthquake through Long-Term Epidemiological Studies: The Shichigahama Health Promotion Project.

After the Great East Japan Earthquake, Tohoku University began to provide mental health services during the acute phase of the disaster in cooperation with Shichigahama Town, one of the municipalities located in the coastal area of the Miyagi Prefecture that was severely damaged by the earthquake and tsunami; it continued to be providing long-term mental health activities, incorporating annual surveys for affected residents in the town for 10 years. Ten years of combination of surveys and outreach activities first depicted detailed longitudinal alterations in the mental health conditions of communities affected by a catastrophe. While posttraumatic stress reaction had recovered year by year after the year following the Great East Japan Earthquake, recovery from psychological distress retreated between 2014 and 2017, probably due to the relocation from temporal to eternal housing conditions. The annual cycles of assessment and provision of mental health support and promotion activities continued for 10 years can be an initial model for evidence-based, long-term post-disaster mental health and psychosocial support for the affected communities. Data regarding subsequent disasters should be collected in comparable ways, in order to improve the accuracy and usefulness of the accumulated data for planning and providing evidence-based post-disaster mental health and psychosocial support.

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.

Five-Year Psychosocial Impact of Living in Postdisaster Prefabricated Temporary Housing.

OBJECTIVE: This study aims to evaluate the long-term impact of living in postdisaster prefabricated temporary housing on social interaction activities and mental health status. METHODS: A total of 917 adult residents in a coastal town, whose residences were destroyed by the tsunami caused by the Great East Japan Earthquake (GEJE), were enrolled for the assessment held 5 y after the disaster. They answered questions about their experience and consequence of living in prefabricated temporary housing after the disaster. Their present scores on 5 types of self-reported measures regarding the psychosocial or psychiatric status and their present and recalled social interaction activities were cross-sectionally collected. RESULTS: A total of 587 (64.0%) participants had a history of living in prefabricated temporary housing, while the other 330 (36.0%) had not. The prevalence of social interaction activities significantly decreased after the GEJE. However, the experience of living in prefabricated temporary housing did not adversely affect the subsequent social interaction activities or mental conditions of the participants 5 y after the disaster. CONCLUSIONS: Living in postdisaster prefabricated temporary housing may not negatively impact subsequent psychosocial conditions or social interaction activities 5 y later.

Impact of type of reconstructed residence on social participation and mental health of population displaced by disasters.

After disasters, people are often forced to reconstruct or move to new residences. This study aimed to reveal the association between the types of reconstructed residences and psychosocial or psychiatric conditions among the population. A total of 1071 adult residents in a coastal town, whose houses were destroyed by the tsunami caused by the Great East Japan Earthquake, enrolled in the study five years after the disaster. The type of reconstructed post-disaster residences (reconstructed on the same site/disaster-recovery public condominium/mass-translocation to higher ground/privately moving to remote areas) and the current psychosocial indicators were investigated. The results revealed that individuals living in public condominiums showed significantly worse scores on the Lubben Social Network Scale-6 (p < 0.0001) and the Center for Epidemiologic Studies Depression Scale (p < 0.0001), and slightly worse scores on the Kessler Psychological Distress Scale (p = 0.035) and the Impact of Event Scale-Revised (p = 0.028). Lower psychosocial indicator scores in the public condominium group were more remarkable in younger adults aged < 65 years. Insomnia evaluated using the Athens Insomnia Scale was not different among the four residential types. In summary, residents moving into disaster-recovery public condominiums are likely to have less social interaction, be more depressed, and may need additional interventions.

Five-year Psychosocial Impact of Living in Post-Disaster Prefabricated Temporary Housing.

OBJECTIVE: This study aims to evaluate the long-term impact of living in post-disaster prefabricated temporary housing on social interaction activities and mental health status. METHODS: A total of 917 adult residents in a coastal town, whose residences were destroyed by the tsunami caused by the Great East Japan Earthquake (GEJE), were enrolled for the assessment held five years after the disaster. They answered questions about their experience and consequence of living in prefabricated temporary housing after the disaster. Their present scores on five types of self-reported measures regarding the psychosocial or psychiatric status and their present and recalled social interaction activities were cross-sectionally collected. RESULTS: A total of 587 (64.0%) participants had a history of living in prefabricated temporary housing, while the other 330 (36.0%) had not. The prevalence of social interaction activities significantly decreased after the GEJE. However, the experience of living in prefabricated temporary housing did not adversely affect the subsequent social interaction activities or mental conditions of the participants five years after the disaster. CONCLUSIONS: Living in post-disaster prefabricated temporary housing may not negatively impact subsequent psychosocial conditions or social interaction activities five years later.

Impact of the Great East Japan Earthquake on the Employment Status and Mental Health Conditions of Affected Coastal Communities.

The Great East Japan Earthquake devasted the old community in coastal areas characterized by primary industry. The number of unemployed people increased from 150,000 to 190,000 after the earthquake. All of the adult residents of Shichigahama (18 years old or older), located in the coastal area of the Miyagi prefecture, whose houses were totally or majorly damaged, were recruited for a survey conducted in October 2011. All of the residents who responded with written informed consent were included in this study. Among 904 individuals who had a job before the Great East Japan Earthquake, 19% became unemployed. Concerning gender and age, 9% of young men, 34% of elderly men, 21% of young women, and 49% of elderly women became unemployed. Concerning the type of industry, 38%, 15%, and 16% of people who had belonged to the primary, secondary, and tertiary industries, respectively, before the disaster became unemployed. Those who became unemployed exhibited a significantly higher risk of insomnia compared to those who maintained jobs. The study pointed out the severe impact of the Great East Japan Earthquake on populations who had belonged to the primary industry, especially among elderly women, and its effect on sleep conditions.

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.

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.