Effects of titration speed, gender, obesity and concomitant medications on the risk and onset time of clozapine-associated fever among Japanese patients with schizophrenia: retrospective review of charts from 21 hospitals.

BACKGROUND: Clozapine-induced inflammation, such as myocarditis and pneumonia, can occur during initial titration and can be fatal. Fever is often the first sign of severe inflammation, and early detection and prevention are essential. Few studies have investigated the effects of clozapine titration speed and concomitant medication use on the risk of clozapine-induced inflammation. AIMS: We evaluated the risk factors for clozapine-associated fever, including titration speed, concomitant medication use, gender and obesity, and their impact on the risk of fever and the fever onset date. METHOD: We conducted a case-control study. The medical records of 539 Japanese participants with treatment-resistant schizophrenia at 21 hospitals in Japan who received clozapine for the first time between 2010 and 2022 were retrospectively investigated. Of these, 512 individuals were included in the analysis. Individuals were divided into three groups according to the titration rate recommended by international guidelines for East Asians: the faster titration group, the slower titration group and the ultra-slower titration group. The use of concomitant medications (such as antipsychotics, mood stabilisers, hypnotics and anxiolytics) at clozapine initiation was comprehensively investigated. Logistic regression analysis was performed to identify the explanatory variables for the risk of a fever of 37.5°C or higher lasting at least 2 days. RESULTS: Fever risk significantly increased with faster titration, male gender and concomitant use of valproic acid or quetiapine. No increased fever risk was detected with the use of other concomitant drugs, such as olanzapine, lithium or orexin receptor antagonists. Fever onset occurred significantly earlier with faster titration. Multivariate analysis identified obesity as being a factor that accelerated fever onset. CONCLUSION: A faster titration speed and concomitant treatment with valproic acid and quetiapine at clozapine initiation increased the risk of clozapine-associated fever. Clinicians should titrate clozapine with caution and consider both the titration speed and concomitant medications.

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.

Retina as a potential biomarker in schizophrenia spectrum disorders: a systematic review and meta-analysis of optical coherence tomography and electroretinography.

INTRODUCTION: Abnormal findings on optical coherence tomography (OCT) and electroretinography (ERG) have been reported in participants with schizophrenia spectrum disorders (SSDs). This study aims to reveal the pooled standard mean difference (SMD) in retinal parameters on OCT and ERG among participants with SSDs and healthy controls and their association with demographic characteristics, clinical symptoms, smoking, diabetes mellitus, and hypertension. METHODS: Using PubMed, Scopus, Web of Science, and PSYNDEX, we searched the literature from inception to March 31, 2023, using specific search terms. This study was registered with PROSPERO (CRD4202235795) and conducted according to PRISMA 2020. RESULTS: We included 65 studies in the systematic review and 44 in the meta-analysis. Participants with SSDs showed thinning of the peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell layer- inner plexiform cell layer, and retinal thickness in all other segments of the macula. A meta-analysis of studies that excluded SSD participants with diabetes and hypertension showed no change in results, except for pRNFL inferior and nasal thickness. Furthermore, a significant difference was found in the pooled SMD of pRNFL temporal thickness between the left and right eyes. Meta-regression analysis revealed an association between retinal thinning and duration of illness, positive and negative symptoms. In OCT angiography, no differences were found in the foveal avascular zone and superficial layer foveal vessel density between SSD participants and controls. In flash ERG, the meta-analysis showed reduced amplitude of both a- and b-waves under photopic and scotopic conditions in SSD participants. Furthermore, the latency of photopic a-wave was significantly shorter in SSD participants in comparison with HCs. DISCUSSION: Considering the prior report of retinal thinning in unaffected first-degree relatives and the results of the meta-analysis, the findings suggest that retinal changes in SSDs have both trait and state aspects. Future longitudinal multimodal retinal imaging studies are needed to clarify the pathophysiological mechanisms of these changes and to clarify their utility in individual patient monitoring efforts.

Live two-way video versus face-to-face treatment for depression, anxiety, and obsessive-compulsive disorder: A 24-week randomized controlled trial.

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.

Maternal social isolation and behavioral problems in preschool children: the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

It is essential to clarify factors associated with mental health and behavioral problems in early childhood, because children are critical stages of life for mental health. We aimed to prospectively examine the associations between maternal social isolation and behavioral problems in preschool children. We analyzed data from 5842 mother-child pairs who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. The Lubben Social Network Scale-abbreviated version was used to assess social isolation (defined as scores < 12) one year after delivery. The Child Behavior Checklist 1½-5 was used to assess behavioral problems, and its subscales were used to assess internalizing and externalizing problems in children at 4 years of age. Multiple logistic regression analyses were conducted to examine the associations between social isolation and behavioral problems, after adjustment for age, education, income, work status, marital status, extraversion, neuroticism, depressive symptoms, child sex, and number of siblings. Multiple logistic regression analyses were also conducted for internalizing problems and externalizing problems. The prevalence of maternal social isolation was 25.4%. Maternal social isolation was associated with an increased risk of behavioral problems in children: the odds ratio (OR) was 1.37 (95% confidence interval [CI] 1.14-1.64). Maternal social isolation was also associated with increased risks of internalizing problems and externalizing problems in children: the ORs were 1.33 (95% CI, 1.12-1.59) and 1.40 (95% CI, 1.18-1.66), respectively. In conclusion, maternal social isolation one year after delivery was associated with behavioral problems in children at 4 years of age.

Concomitant use of hydroxyzine and haloperidol did not worsen delirium in patients with cancer: A multicenter, retrospective, observational study.

OBJECTIVES: There is concern that hydroxyzine exacerbates delirium, but a recent preliminary study suggested that the combination of haloperidol and hydroxyzine was effective against delirium. This study examined whether the concomitant use of hydroxyzine and haloperidol worsened delirium in patients with cancer. METHODS: This retrospective, observational study was conducted at 2 general hospitals in Japan. The medical records of patients with cancer who received haloperidol for delirium from July to December 2020 were reviewed. The treatments for delirium included haloperidol alone or haloperidol combined with hydroxyzine. The primary outcome was the duration from the first day of haloperidol administration to the resolution of delirium, defined as its absence for 2 consecutive days. The time to delirium resolution was analyzed to compare the haloperidol group and hydroxyzine combination group using the log-rank test with the Kaplan-Meier method. Secondary outcomes were (1) the total dose of antipsychotic medications, including those other than haloperidol (measured in chlorpromazine-equivalent doses), and (2) the frequencies of detrimental incidents during delirium, specifically falls and self-removal of drip infusion lines. The unpaired t-test and Fisher's exact test were used to analyze secondary outcomes. RESULTS: Of 497 patients who received haloperidol, 118 (23.7%) also received hydroxyzine. No significant difference in time to delirium resolution was found between the haloperidol group and the hydroxyzine combination group (log-rank test, P = 0.631). No significant difference between groups was found in either chlorpromazine-equivalent doses or the frequency of detrimental incidents. SIGNIFICANCE OF RESULTS: This study showed that the concomitant use of hydroxyzine and haloperidol did not worsen delirium in patients with cancer.

Decreased ß-hydroxybutyrate and ketogenic amino acid levels in depressed human adults.

ß-hydroxybutyrate (BHB) is a major ketone body synthesized mainly in the liver mitochondria and is associated with stress and severity of depression in humans. It is known to alleviate depressive-like behaviors in mouse models of depression. In this study, plasma BHB, ketogenic and glucogenic amino acids selected from the Tohoku Medical Megabank Project Community-Based Cohort Study were analysed and measured using nuclear magnetic resonance spectroscopy. The Center for Epidemiologic Studies Depression Scale (CES-D) was utilized to select adult participants with depressive symptoms (CES-D ≥ 16; n = 5722) and control participants (CES-D < 16; n = 18,150). We observed significantly reduced plasma BHB, leucine, and tryptophan levels in participants with depressive symptoms. Using social defeat stress (SDS) mice models, we found that BHB levels in mice sera increased after acute SDS, but showed no change after chronic SDS, which differed from human plasma results. Furthermore, acute SDS increased mitochondrial BHB levels in the prefrontal cortex at 6 h. In contrast, chronic SDS significantly increased the amount of food intake but reduced hepatic mitochondrial BHB levels in mice. Moreover, gene transcriptions of voltage-dependent anion-selective channel 1 (Vdac1) and monocarboxylic acid transporter 1 (Mct1), major molecules relevant to mitochondrial biogenesis and BHB transporter, significantly decreased in the liver and PFC after chronic SDS exposure. These results provide evidence that hepatic and prefrontal mitochondrial biogenesis plays an important role in BHB synthesis under chronic stress and in humans with depressive symptoms.

Retinal layers and associated clinical factors in schizophrenia spectrum disorders: a systematic review and meta-analysis.

INTRODUCTION: The retina shares structural and functional similarities with the brain. Furthermore, structural changes in the retina have been observed in patients with schizophrenia spectrum disorders (SSDs). This systematic review and meta-analysis investigated retinal abnormalities and their association with clinical factors for SSD. METHODS: Studies related to retinal layers in SSD patients were retrieved from PubMed, Scopus, Web of Science, Cochrane Controlled Register of Trials, International Clinical Trials Registry Platform, and PSYNDEX databases from inception to March 31, 2021. We screened and assessed the eligibility of the identified studies. EZR ver.1.54 and the metafor package in R were used for the meta-analysis and a random-effects or fixed-effects model was used to report standardized mean differences (SMDs). RESULTS: Twenty-three studies (2079 eyes of patients and 1571 eyes of controls) were included in the systematic review and meta-analysis. The average peripapillary retinal nerve fiber layer (pRNFL) thickness, average macular thickness (MT), and macular ganglion cell layer-inner plexiform layer (GCL-IPL) thickness were significantly lower in patients than in controls (n = 14, 6, and 3, respectively; SMD = -0.33, -0.49, and -0.43, respectively). Patients also had significantly reduced macular volume (MV) compared to controls (n = 7; SMD = -0.53). The optic cup volume (OCV) was significantly larger in patients than in controls (n = 3; SMD = 0.28). The meta-regression analysis indicated an association between several clinical factors, such as duration of illness and the effect size of the pRNFL, macular GCL-IPL, MT, and MV. CONCLUSION: Thinning of the pRNFL, macular GCL-IPL, MT, and MV and enlargement of the OCV in SSD were observed. Retinal abnormalities may be applicable as state/trait markers in SSDs. The accumulated evidence was mainly cross-sectional and requires verification by longitudinal studies to characterize the relationship between OCT findings and clinical factors.

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.

Maternal postnatal bonding disorder and developmental delays in children: the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

Although there is some evidence regarding an association between maternal bonding disorder and child development, studies have mainly focused on development during the period of infancy. We aimed to examine the associations between maternal postnatal bonding disorder and developmental delays in children beyond 2 years of age. We analyzed data from 8380 mother-child pairs who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Maternal bonding disorder was defined as Mother-to-Infant Bonding Scale score of ≥5 at 1 month after delivery. The Ages & Stages Questionnaires, Third Edition, which consists of five developmental areas, was used to assess developmental delays in children at 2 and 3.5 years of age. Multiple logistic regression analyses were conducted to examine the associations between postnatal bonding disorder and developmental delays after adjustment for age, education, income, parity, feelings toward pregnancy, postnatal depressive symptoms, child's sex, preterm birth, and birth defects. Bonding disorder was associated with developmental delays in children at 2 and 3.5 years of age: the odds ratios (95% confidence intervals) were 1.55 (1.32-1.83) and 1.60 (1.34-1.90), respectively. Bonding disorder was associated with delay in communication only at 3.5 years of age. Bonding disorder was associated with delay in gross motor, fine motor, and problem solving, but not delay in the personal-social domain, at 2 and 3.5 years of age. In conclusion, maternal bonding disorder 1 month after delivery was associated with an increased risk of developmental delays in children beyond 2 years of age.

Maternal social isolation in the perinatal period and early childhood development: the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

PURPOSE: Studies examining the associations between maternal social relationships and early childhood development have mainly focused on social relationships after childbirth. We aimed to prospectively examine the associations between the transition of maternal social isolation from the prenatal to postnatal period and early childhood development. METHODS: We analyzed data for 6692 mother-child pairs who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Social isolation in the prenatal and postnatal periods was assessed by the Lubben Social Network Scale-abbreviated version and categorized into four groups: none, prenatal only, postnatal only, and both. The Ages and Stages Questionnaire, Third Edition, which consists of five developmental areas, was used to assess developmental delays in children at 2 and 3.5 years of age. Multiple logistic regression analyses were conducted to examine the associations between maternal social isolation and developmental delays. RESULTS: The prevalence of social isolation in both the prenatal and postnatal periods was 13.1%. Social isolation in both the prenatal and postnatal periods was associated with developmental delays in children at 2 and 3.5 years of age: the multivariate-adjusted odds ratios (95% confidence intervals) were 1.68 (1.39-2.04) and 1.43 (1.17-1.76), respectively. Social isolation in the prenatal period only and social isolation in the postnatal period only were not associated with developmental delays in children at 2 and 3.5 years of age. CONCLUSION: Maternal social isolation in both the prenatal and postnatal periods was associated with an increased risk of developmental delays in early childhood.

Association between maternal psychological distress and children's neurodevelopment in offspring aged 4 years in Japan: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

AIM: An association between maternal psychological distress and children's development has been reported, but  reports from Japan are limited. This study aimed to examine the association of maternal psychological distress with children's neurodevelopment in Japan. METHODS: The study assessed data of 7646 mother-infant pairs in the Japanese population. We used Kessler Psychological Distress Scale, a screening tool for psychological distress, to assess maternal psychological distress in early pregnancy and 2 years postpartum and divided it into four categories: none in both the pre-natal and post-natal periods, only the pre-natal period, only the post-natal period and both the pre-natal and post-natal periods. Children's neurodevelopment was assessed using the Ages & Stages Questionnaires Third Edition (ASQ-3) at 4 years of age. ASQ-3 comprises five domains (communication, gross motor, fine motor, problem solving and personal-social), and the score of less than -2 standard deviation relative to the mean in reference was defined as having developmental delay. We conducted multivariate logistic regression analysis to examine the association between maternal psychological distress and children's neurodevelopment. RESULTS: The prevalence of developmental delay of communication, gross motor, fine motor, problem solving and personal-social were 4.0%, 4.3%, 4.9%, 3.8% and 4.6%, respectively. Maternal psychological distress in only the postpartum period and both pre-natal and postpartum periods were associated with risks of developmental delay in all domains. Maternal psychological distress in only the pre-natal period was associated with developmental delay in communication. CONCLUSIONS: Maternal psychological distress is associated with risks of children's developmental delay.

Surface translocation of Kir2.1 channel induces IL-1ß secretion in microglia.

One of the major properties of microglia is to secrete cytokines as a reaction to stress such as lipopolysaccharide (LPS) application. The mechanism of cytokine secretion from the microglia upon stress through the inflammasome-mediated release process is well studied, and the voltage-gated Kv1.3 channel is known to play an important role in this process. Most previous studies investigated long-term inflammasome-mediated cytokine release (at least over 4 h) and there are only a few studies on the acute reaction (within minutes order) of the microglia to stress and its cytokine secretion capacity. In this study, we found that LPS induced an increase in Kir2.1 current within 15 min after administration but had no effect on voltage-dependent outward currents. Moreover, cytological and western blot analysis revealed that the increase in the Kir2.1 channel current after LPS administration was induced by the translocation of Kir2.1 from the cytoplasm to the cell surface. From an experiment using the inhibitor and trafficking mutation of Kir2.1, an increase in Kir2.1 was found to contribute to the secretion of the inflammatory cytokine, IL-1ß. Although the physiological significance of this acute IL-1ß secretion remains unclear, our present data imply that Kir2.1 translocation functions as a regulator of IL-1ß secretion, and therefore becomes a potential target to control cytokine release from microglia.

Real-Time Prediction of Medical Demand and Mental Health Status in Ukraine under Russian Invasion Using Tweet Analysis.

Russia's invasion of Ukraine (February 24, 2022) has begun and there are concerns about the impact on health care supply and mental health. This study analyzed tweets in the Ukrainian language to capture the medical needs and mental health conditions in wartime Ukraine by focusing on ostensibly relevant words. The number of tweets containing the keywords and their overall proportion was compared before and after the Russian invasion of Ukraine. The survey period was divided into four phases-the pre-2022 Russian invasion, acute phase (4 weeks), subacute phase (12 weeks), and the chronic phase (8 weeks) up to August 10, 2022. The analysis targeted tweets sent in Ukrainian. The tweets were screened using a set of six classes with 75 key groups and 303 Ukrainian (204 original Japanese) keywords. Overall, 98,526,440 tweets were analyzed, with a pre-invasion and post-onset average of 1,096,976 and 3,328,243 tweets/week (a 3.0-fold increase), respectively. Of these, 3,197,443 tweets contained the keywords, with a pre-invasion and invasion average of 26,241 and 114,640 tweets/week (a 4.4-fold increase), respectively. The post-onset phase witnessed a considerable increase in all classes-medical services, treatment, medical resources, medical situations, and special situations-but not in the symptom class. Keywords related to psychological distress and anxiety immediately increased during the acute phase; those related to depression and post-traumatic stress reactions continued increasing as the invasion persisted, which may have reflected the mental state of those impacted. Analyzing tweets is useful for predicting people's real-time physical and mental health needs during wartime.

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.

Association between low levels of anti-inflammatory cytokines during pregnancy and postpartum depression.

AIM: Previous studies based on a relatively limited number of subjects have indicated potential associations between plasma cytokine concentrations in perinatal women and postpartum depression (PPD). This report aimed to examine alterations in cytokine levels during pregnancy and after delivery by measuring nine cytokines in prenatal and postnatal plasma samples in a large cohort. METHODS: A nested, case-control study was conducted using plasma samples from 247 women with PPD (Edinburgh Postnatal Depression Scale: EPDS ≥9) and 243 age-matched control (EPDS ≤2) women from among perinatal women who participated in the Tohoku Medical Megabank three-generation cohort. Concentrations of nine plasma cytokines (IFN-γ, IL-1ß, IL-4, IL-6, IL-10, IL-12p40, IL-12p70, IL-13, and TNF-α) in plasma collected at the time of enrollment during pregnancy and 1 month after delivery were determined using an immunoassay kit. RESULTS: Cross-sectional comparisons of cytokine levels during pregnancy and after delivery indicated that the PPD group maintained significantly lower plasma IL-4 levels during pregnancy and after delivery than the control group, and that plasma IL-4 levels decreased significantly during pregnancy regardless of PPD status. Plasma IL-10 levels were significantly higher during pregnancy than after delivery only among healthy controls, and plasma IL-10 levels were significantly higher in the control group than in the PPD group. Moreover, IFN-γ, IL-6, IL-12p40, and TNF-α levels were significantly lower during pregnancy compared with after delivery regardless of PPD status. CONCLUSIONS: These results suggest a potential protective effect of the anti-inflammatory cytokines IL-4 and IL-10 during pregnancy against the development of PPD.

N-Acetylcysteine Suppresses Microglial Inflammation and Induces Mortality Dose-Dependently via Tumor Necrosis Factor-α Signaling.

N-acetylcysteine (NAC) is an antioxidant that prevents tumor necrosis factor (TNF)-α-induced cell death, but it also acts as a pro-oxidant, promoting reactive oxygen species independent apoptosis. Although there is plausible preclinical evidence for the use of NAC in the treatment of psychiatric disorders, deleterious side effects are still of concern. Microglia, key innate immune cells in the brain, play an important role in inflammation in psychiatric disorders. This study aimed to investigate the beneficial and deleterious effects of NAC on microglia and stress-induced behavior abnormalities in mice, and its association with microglial TNF-α and nitric oxide (NO) production. The microglial cell line MG6 was stimulated by Escherichia coli lipopolysaccharide (LPS) using NAC at varying concentrations for 24 h. NAC inhibited LPS-induced TNF-α and NO synthesis, whereas high concentrations (≥30 mM) caused MG6 mortality. Intraperitoneal injections of NAC did not ameliorate stress-induced behavioral abnormalities in mice, but high-doses induced microglial mortality. Furthermore, NAC-induced mortality was alleviated in microglial TNF-α-deficient mice and human primary M2 microglia. Our findings provide ample evidence for the use of NAC as a modulating agent of inflammation in the brain. The risk of side effects from NAC on TNF-α remains unclear and merits further mechanistic investigations.

The return of individual genomic results to research participants: design and pilot study of Tohoku Medical Megabank Project.

Certain large genome cohort studies attempt to return the individual genomic results to the participants; however, the implementation process and psychosocial impacts remain largely unknown. The Tohoku Medical Megabank Project has conducted large genome cohort studies of general residents. To implement the disclosure of individual genomic results, we extracted the potential challenges and obstacles. Major challenges include the determination of genes/disorders based on the current medical system in Japan, the storage of results, prevention of misunderstanding, and collaboration of medical professionals. To overcome these challenges, we plan to conduct multilayer pilot studies, which deal with different disorders/genes. We finally chose familial hypercholesterolemia (FH) as a target disease for the first pilot study. Of the 665 eligible candidates, 33.5% were interested in the pilot study and provided consent after an educational "genetics workshop" on the basic genetics and medical facts of FH. The genetics professionals disclosed the results to the participants. All positive participants were referred to medical care, and a serial questionnaire revealed no significant psychosocial distress after the disclosure. Return of genomic results to research participants was implemented using a well-prepared protocol. To further elucidate the impact of different disorders, we will perform multilayer pilot studies with different disorders, including actionable pharmacogenomics and hereditary tumor syndromes.

Sex-Dependent Effects of the APOE ɛ4 Allele on Behavioral Traits and White Matter Structures in Young Adults.

The APOE ɛ4 allele is associated with a risk of Alzheimer's disease in the elderly, with the association being pronounced in females. Conversely, findings of the effects of the APOE ɛ4 allele in young adults are mixed. Here, we investigated the sex-genotype interaction effects of the APOE ɛ4 allele on cognitive functions as well as brain structures among 1258 young adults. After adjusting for multiple comparisons, there were significant effects of the interaction between sex and the number of APOE ɛ4 allele on some speed tasks (e.g., simple processing speed tasks and the reverse Stroop task) as well as on regional white matter volume (rWMV). The observed sex-genotype interaction conferred better cognitive performance and greater rWMV in the anterior frontal and precentral white matter areas in females having more APOE ɛ4 alleles and reduced rWMV in the same areas in male having more APOE ɛ4 alleles. These findings support the long-debated antagonistic pleiotropic effects of the APOE ɛ4 allele in females.

Association of maternal psychological distress and the use of childcare facilities with children's behavioral problems: the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

BACKGROUND: Childcare facilities are a factor that lowers the established association of mother's postnatal psychiatric symptoms with children's behavioral problems. However, no studies have considered the prenatal psychiatric symptoms yet. This study examined whether the use of childcare facilities moderates the association of maternal psychological distress in early pregnancy and at two years postpartum with behavioral problems in children aged four years. METHODS: The present study was based on the data from 23,130 mother-child pairs participating in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. K6 was used to classify maternal psychological distress in early pregnancy and at two years postpartum into four categories: none in both prenatal and postnatal periods (none), only the prenatal period (prenatal only); only the postnatal period (postnatal only); both prenatal and postnatal periods (both). The children's behavioral problems were assessed using the Child Behavior Checklist for Ages 1½-5 (CBCL) aged four years. The clinical range of the externalizing, internalizing, and total problem scales of the CBCL was defined as having behavioral problems. To examine whether availing childcare facilities moderates the association between maternal psychological distress and children's behavioral problems, we conducted a stratified analysis based on the use of childcare facilities or not, at two years of age. The interaction term between maternal psychological distress and use of childcare facilities was included as a covariate in the multivariate logistic regression analysis to confirm the p-value for the interaction. RESULTS: The prevalence of the clinical ranges of externalizing problems, internalizing problems, and clinical range of total problems were 13.7%, 15.4%, and 5.8%, respectively. The association of maternal psychological distress with a high risk of children's behavioral problems was significant; however, the association between prenatal only psychological distress and externalizing problems in the group that did not use childcare facilities was not significant. Interactions between the use of childcare facilities and maternal psychological distress on behavioral problems in children were not significant. CONCLUSIONS: Use of childcare facilities did not moderate the association of maternal psychological distress in early pregnancy and at two years postpartum with behavioral problems in children aged four years.