Analyzing changes in help-seeking from mental and physical health professionals during COVID-19 in Japan.

Japan witnessed the outbreak of coronavirus disease (COVID-19) in March - May 2020. We examined whether the impact of COVID-19 on people seeking help from mental and physical health professionals varied with changes in employment (from full-time employment to unemployment or leave of absence) and psychological predisposition to new-type depression (Interpersonal Sensitivity [IS]/Privileged Self [PS]) associated with the pandemic. An online survey was conducted in June 2020 (after the outbreak of COVID-19) among people who were full-time employees as of April 2019. Data from 1,053 individuals were analyzed. The survey asked about regular visits to health professionals one year prior to the survey (June 2019) and at the time of the survey. Employment status, personality traits, and demographic characteristics were also examined. We found that consultation rates changed little before and after the pandemic. Logistic regression analysis showed that after controlling for age and gender, being unemployed or absent from work after the pandemic and having higher scores for IS/PS were positively associated with regular visits to health professionals. Considering that COVID-19 has been shown to increase the incidence of physical and mental illness, the finding that the rate of consultations remained unchanged implies that consultations were withheld. Joblessness/absence from work and IS/PS had negative effects on physical and mental health, leading to fewer visits.

A gut-restricted glutamate carboxypeptidase II inhibitor reduces monocytic inflammation and improves preclinical colitis.

There is an urgent need to develop therapeutics for inflammatory bowel disease (IBD) because up to 40% of patients with moderate-to-severe IBD are not adequately controlled with existing drugs. Glutamate carboxypeptidase II (GCPII) has emerged as a promising therapeutic target. This enzyme is minimally expressed in normal ileum and colon, but it is markedly up-regulated in biopsies from patients with IBD and preclinical colitis models. Here, we generated a class of GCPII inhibitors designed to be gut-restricted for oral administration, and we interrogated efficacy and mechanism using in vitro and in vivo models. The lead inhibitor, (S)-IBD3540, was potent (half maximal inhibitory concentration = 4 nanomolar), selective, gut-restricted (AUCcolon/plasma > 50 in mice with colitis), and efficacious in acute and chronic rodent colitis models. In dextran sulfate sodium-induced colitis, oral (S)-IBD3540 inhibited >75% of colon GCPII activity, dose-dependently improved gross and histologic disease, and markedly attenuated monocytic inflammation. In spontaneous colitis in interleukin-10 (IL-10) knockout mice, once-daily oral (S)-IBD3540 initiated after disease onset improved disease, normalized colon histology, and attenuated inflammation as evidenced by reduced fecal lipocalin 2 and colon pro-inflammatory cytokines/chemokines, including tumor necrosis factor-α and IL-17. Using primary human colon epithelial air-liquid interface monolayers to interrogate the mechanism, we further found that (S)-IBD3540 protected against submersion-induced oxidative stress injury by decreasing barrier permeability, normalizing tight junction protein expression, and reducing procaspase-3 activation. Together, this work demonstrated that local inhibition of dysregulated gastrointestinal GCPII using the gut-restricted, orally active, small-molecule (S)-IBD3540 is a promising approach for IBD treatment.

Comparison between olanzapine and aripiprazole treatment for 104 weeks after hospital discharge in schizophrenia spectrum disorders: a multicenter retrospective cohort study in a real-world setting.

RATIONALE: The long-term effectiveness of olanzapine and aripiprazole in real clinical conditions at flexible doses in patients after hospital discharge has not been evaluated yet. OBJECTIVES: This study was a multicenter retrospective cohort study. Patients with schizophrenia (n = 398) were prescribed olanzapine (n = 303) or aripiprazole (n = 95) at hospital discharge. The continuation of olanzapine or aripiprazole at 26, 52, or 104 weeks after the hospital discharge were compared using a Cox proportional hazards model and adjusted for possible confounders. RESULTS: The Kaplan-Meier survival curves revealed that the continuation of olanzapine at 26 (P = 0.001) and 52 weeks (P = 0.018) was significantly higher than that of aripiprazole but not at 104 weeks. Olanzapine was better than aripiprazole in efficacy at 26 (hazard ratio: 0.321, 95% confidence interval: 0.159-0.645, P = 0.001), 52 (hazard ratio: 0.405, 95% confidence interval: 0.209-0.786, P = 0.008), and 104 weeks (hazard ratio: 0.438, 95% confidence interval: 0.246-0.780, P = 0.005). Aripiprazole was better than olanzapine in tolerability at 104 weeks (hazard ratio: 4.574, 95% confidence interval: 1.415-14.787, P = 0.011). Rates after two years continuation of olanzapine and aripiprazole were not significantly different in patients with less than five years' duration of illness, but olanzapine was more commonly maintained for more than two years in those patients who had been ill for over five years' due to its greater efficacy. CONCLUSION: Olanzapine treatment showed better continuation rates at 26 and 52 after hospital discharge than aripiprazole, whereas maintenance with the two antipsychotics did not differ significantly at 104 weeks, due reduced tolerability of long-term olanzapine treatment.

Initial Outcomes of the Safe and Sound Protocol on Patients with Adult Autism Spectrum Disorder: Exploratory Pilot Study.

Sensory impairments are common features of autism spectrum disorder (ASD) and are associated with its social impairments. However, there is no established treatment for these impairments in adults with ASD. The Safe & Sound Protocol (SSP) is a listening program designed to improve social communication skills by reducing auditory hypersensitivity. We investigated the effectiveness of the SSP for adults with ASD. We administered the SSP to six participants with ASD aged 21-44 years old, and the effects were assessed using the Social Responsiveness Scale, Second Edition (SRS-2). Secondary outcomes were assessed using the Center for Epidemiological Studies Depression Scale (CES-D), State-Trait Anxiety Inventory (STAI), WHO Quality of Life 26 (WHOQOL-BREF), and Adolescent/Adult Sensory Profile (A/ASP). In this study, only the Social Awareness scale of the SRS-2 Family-Report showed a significant improvement after the intervention. In addition, it was significantly correlated with physical health of WHOQOL-BREF (r = -0.577, p = 0.012), state and trait anxiety of STAI (r = 0.576, p = 0.012; r = 0.708, p = 0.00009, respectively), and CES-D (r = 0.465, p = 0.05). In conclusion, the SSP has a partial effect on social impairments in adults with ASD, specifically on the Social Awareness subscale of the SRS-2.

Dectin-1 signaling on colonic γδ T cells promotes psychosocial stress responses.

The intestinal immune system interacts with commensal microbiota to maintain gut homeostasis. Furthermore, stress alters the microbiome composition, leading to impaired brain function; yet how the intestinal immune system mediates these effects remains elusive. Here we report that colonic γδ T cells modulate behavioral vulnerability to chronic social stress via dectin-1 signaling. We show that reduction in specific Lactobacillus species, which are involved in T cell differentiation to protect the host immune system, contributes to stress-induced social-avoidance behavior, consistent with our observations in patients with depression. Stress-susceptible behaviors derive from increased differentiation in colonic interleukin (IL)-17-producing γδ T cells (γδ17 T cells) and their meningeal accumulation. These stress-susceptible cellular and behavioral phenotypes are causally mediated by dectin-1, an innate immune receptor expressed in γδ T cells. Our results highlight the previously unrecognized role of intestinal γδ17 T cells in the modulation of psychological stress responses and the importance of dectin-1 as a potential therapeutic target for the treatment of stress-induced behaviors.

Development of the "Belief of Affective Perspective-Taking Ability Scale".

This study aimed to develop the Belief of Affective Perspective-Taking Ability Scale (BAPTAS). The belief of affective perspective-taking ability is defined as the tendency of individuals to believe people are generally capable of taking others' perspectives and imagining others' emotions, and we developed 17 items for BAPTAS. The participants in the study comprised 151 university students, who answered the BAPTAS, Experience of Receiving Empathy Scale (ERES), perspective-taking tendency, Interpersonal Trust Scale (ITS), and UCLA loneliness scale in Japanese (ULS-J). Thus, 13 items were constructed, and the scores of BAPTAS showed a normal distribution (M = 4.52, SD = 0.97). BAPTAS is positively related to ERES, a perspective-taking tendency and ITS, and it is negatively related to ULS-J. The relations between BAPTAS and other scales correspond to our previous expectations. We discussed both the potential contribution of BAPTAS to perspective-taking and empathy research and the need to examine its validity experimentally. Our hypothesis was supported, and the validity and reliability of BAPTAS were confirmed.

A Hybrid Intelligent Simulation System for Building IoT Networks: Performance Comparison of Different Router Replacement Methods for WMNs Considering Stadium Distribution of IoT Devices.

As the Internet of Things (IoT) devices and applications proliferate, it becomes increasingly important to design robust networks that can continue to meet user demands at a high level. Wireless local area networks (WLANs) can be a good choice as IoT infrastructure when high throughput is required. On the other hand, wireless mesh networks (WMNs), which are WLANs with mesh topology following the IEEE802.11s standard, have many advantages compared to conventional WLANs. Nevertheless, there are some problems that need solutions. One of them is the node placement problem. In this work, we propose and implement a hybrid intelligent system that solves this problem by determining the position of mesh nodes by maximizing the mesh connectivity and the coverage of IoT devices. The system is based on particle swarm optimization (PSO), simulated annealing (SA), and distributed genetic algorithm (DGA). We compare the performance of three router replacement methods: constriction method (CM), random inertia weight method (RIWM), and rational decrement of Vmax method (RDVM). The simulation results show that RIWM achieves better performance compared to CM and RDVM because it achieves the highest connectivity while covering more clients than the other two methods.

The validity of atypical psychosis diagnostic criteria to detect anti-NMDA receptor encephalitis with psychiatric symptoms.

Anti-NMDAR encephalitis has a psychotic presentation that is difficult to distinguish from primary psychosis. An atypical psychosis that is similar to schizophrenia, mood disorder, and epilepsy is unique, and the original diagnostic criteria exist only in Japan. The clinical symptoms and courses of anti-NMDAR encephalitis and atypical psychosis are very similar. We investigated whether the diagnostic criteria of atypical psychosis are useful to increase the detection rate of anti-NMDAR encephalitis with psychiatric symptoms. The presence of anti-NR1/NR2B IgG antibodies in the cerebrospinal fluid of 218 newly admitted inpatients initially diagnosed with schizophrenia (n = 151), mood disorder (n = 47), or epilepsy with psychiatric symptoms (n = 20) was assessed by cell-based assay. Of 218 patients, 123 (36.3 years ± SD 17.2, 69.9 % females) fulfilled the diagnostic criteria of category B for atypical psychosis. All 12 patients (9.8 %, 12/123) with anti-NR1/NR2B IgG antibodies fulfilled category B of atypical psychosis statistically better than the patients without anti-NR1/NR2B IgG antibodies (P = 0.0009). Of the 12 patients with anti-NMDAR antibodies, two did not fulfill either criteria of catatonia (DSM-5) or Graus' diagnostic criteria of anti-NMDAR encephalitis during the time course, and 11 patients showed good prognosis with early immunotherapies. In ROC analysis, abnormal electroencephalogram findings showed the highest sensitivity (0.833) for detection of anti-NR1/NR2B IgG antibodies, and 31.3 % of patients with category B atypical psychosis and abnormal electroencephalogram findings had anti-NMDAR antibodies. Lumbar puncture and detection of anti-NMDAR antibodies should be considered for patients who fulfill atypical psychosis diagnosis criteria with an abnormal electroencephalogram.

Risk factors of hikikomori among office workers during the COVID-19 pandemic: A prospective online survey.

The global pandemic of COVID-19 has forced people to restrict their outings. In Japan, self-restraint behavior (SRB) has been requested by the government, and some of those decreasing their outings may shift to pathological social withdrawal; hikikomori. The purpose of this study was to examine the risk factors of hikikomori conducting an online prospective survey. An online survey was conducted in June 2020 and December 2020; (1) SRB-related indicators (degree of SRB, motivation for SRB, stigma and self-stigma toward COVID-19, anxiety and depressive feelings toward COVID-19) and (2) general mental health (hikikomori tendency, depressive symptoms, modern type depression (MTD) tendency, internet addiction) were collected. A cross-lagged effects model was performed to examine the association between these variables. Lack of emotional support and lack of socialization in June 2020 increased isolation in December 2020. Besides, MTD and hikikomori interacted with each other. Interestingly, although hikikomori tendency increased depressive tendencies, SRB itself did not have a significant path on any mental health-related variables. Poor interpersonal relationships, rather than SRB per se, are suggested to be a risk factor for increased isolation among office workers in the COVID-19 pandemic. Appropriate early interventions such as interpersonal or emotional support may prevent the transition to pathological hikikomori. The association between MTD and hikikomori seems to reveal the interesting possibility that MTD is a gateway to increased risk of hikikomori, and that hikikomori is a gateway to MTD as well. Future research is required to elucidate the relationship between hikikomori and MTD.

Glutamine antagonist JHU083 improves psychosocial behavior and sleep deficits in EcoHIV-infected mice.

Combined antiretroviral therapy ushered an era of survivable HIV infection in which people living with HIV (PLH) conduct normal life activities and enjoy measurably extended lifespans. However, despite viral control, PLH often experience a variety of cognitive, emotional, and physical phenotypes that diminish their quality of life, including cognitive impairment, depression, and sleep disruption. Recently, accumulating evidence has linked persistent CNS immune activation to the overproduction of glutamate and upregulation of glutaminase (GLS) activity, particularly in microglial cells, driving glutamatergic imbalance with neurological consequences. Our lab has developed a brain-penetrant prodrug of the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON), JHU083, that potently inhibits brain GLS activity in mice following oral administration. To assess the therapeutic potential of JHU083, we infected mice with EcoHIV and characterized their neurobehavioral phenotypes. EcoHIV-infected mice exhibited decreased social interaction, suppressed sucrose preference, disrupted sleep during the early rest period, and increased sleep fragmentation, similar to what has been reported in PLH but not yet observed in murine models. At doses shown to inhibit microglial GLS, JHU083 treatment ameliorated all of the abnormal neurobehavioral phenotypes. To explore potential mechanisms underlying this effect, hippocampal microglia were isolated for RNA sequencing. The dysregulated genes and pathways in EcoHIV-infected hippocampal microglia pointed to disruptions in immune functions of these cells, which were partially restored by JHU083 treatment. These findings suggest that upregulation of microglial GLS may affect immune functions of these cells. Thus, brain-penetrable GLS inhibitors like JHU083 could act as a potential therapeutic modality for both glutamate excitotoxicity and aberrant immune activation in microglia in chronic HIV infection.

Clinical moderators of response to nalmefene in a randomized-controlled trial for alcohol dependence: An exploratory analysis.

BACKGROUND: Nalmefene is the only medication marketed to reduce the consumption of alcohol in patients with alcohol dependence, but it remains unclear which patients could most benefit from it. This study aimed to identify clinical moderators that affect treatment response to nalmefene in patients with alcohol dependence. METHODS: In a multicenter, randomized, controlled, double-blind, phase 3 study of nalmefene on Japanese patients with alcohol dependence, the relationship between the reduction of heavy drinking days (HDD) and total alcohol consumption (TAC) at 12 and 24 weeks of treatment and baseline variables of the participants were analyzed in a linear regression and multiple adjusted analysis. RESULTS: Age < 65, no family history of problem drinking, age at onset of problem drinking ≥ 25, and not currently smoking were possible positive moderators. Nalmefene showed a significant HDD reduction in patients with age < 65 or no family history of problem drinking, and a significant TAC reduction in patients with age at onset of problem drinking ≥ 25 or who were not currently smoking. After multiple adjusted analyses, age < 65 (p = .028), no family history of problem drinking (p = .047), and age at onset of problem drinking ≥ 25 (p = .030) were statistically significant. Not currently smoking (p = .071) was marginally significant. In combination, these moderators indicated synergistic effects. CONCLUSIONS: Alcohol-dependent patients with favorable prognostic factors such as non-smoking status, no family history of problem drinking, and a late-onset of problem drinking selectively benefit from nalmefene. Further research is needed to validate these exploratory results.

Association between depression in chronic phase and future clinical outcome of patients with schizophrenia.

RATIONALE: Depression in schizophrenia is an important symptom. We investigated whether depression and suicidal symptoms in the chronic phase are related to remote future clinical outcomes in patients with schizophrenia and whether psychotropics improved clinical outcomes. OBJECTIVES: The subjects included 462 outpatients of working age (15 to 64 years old) with schizophrenia treated at Okayama University Hospital from January 2010 to December 2011. We investigated the relationship between the Clinical Global Impression-Severity score at the last visit (average 19.2 years) and the existence of previous depression, suicidal ideas, and suicide attempts. We adjusted by several possible confounders including medical history using multiple regression analysis or logistic regression analysis. RESULTS: Of 462 patients, 168 (36.4%) presented with depression 2 years after schizophrenia onset. A history of suicidal ideas and attempts was related to worse clinical outcome. In males, a history of depression was related to worse clinical outcome, but not in females. Lithium carbonate was related to better clinical outcome in all schizophrenia patients with depression, especially in males. Treatment with antidepressants was related to better clinical outcome only in males. CONCLUSIONS: A history of depression or suicidal symptoms in the chronic phase predicted the future worse clinical outcome in patients with schizophrenia. The administration of lithium carbonate or antidepressants might be recommended, especially to male schizophrenia patients with depression.

Impairment of early neuronal maturation in anti-NMDA-receptor encephalitis.

RATIONALE: Adequate immunotherapies for anti-NMDAR encephalitis during pregnancy produce a relatively good clinical outcome for pregnant mothers and their infants, but there are no reports about the future growth of their babies. The damage of anti-NMDAR antibodies to early neuronal development is still unknown. OBJECTIVES: Serum or cerebrospinal fluid from one patient with anti-NMDAR encephalitis (the index patient) and one patient with schizophrenia (the control patient) was administered to primary cultures of dissociated rat cortical neurons, and dendritic outgrowth, centrosome elimination, and branching of dendrites were investigated. For rescue experiments, serum of the index patient was replaced with normal culture media after 3 days' administration of the index patient. RESULTS: Serum and cerebrospinal fluid of the index patient statistically significantly impaired dendritic outgrowth of cultured rat cortical primary neurons. Serum of the index patient also statistically significantly delayed centrosome elimination. Impaired dendritic outgrowth and delayed centrosome elimination were not perfectly rescued by changing to normal culture media. Serum of the index patient also statistically significantly reduced the branching of dendrites. CONCLUSIONS: This is the first demonstration of the damage by anti-NMDAR antibodies on early dendritic development in vitro. As a strategy to protect embryonic neurons, our findings may support the efficacy of early immunotherapy for anti-NMDAR encephalitis in pregnancy.

Mirtazapine Was Effective for a Patient With Benzodiazepine Dependence.

OBJECTIVE: Benzodiazepine (BZD) dependence has become a social problem and results in poor outcomes. Only a few evidence-based treatments for pharmacotherapy, including antidepressants, are recommended. METHODS: We reported about a 71-year-old man with onset of blindness at 50 years of age due to pigmentary degeneration of the retina developed insomnia at age 59 years, characterized by nocturnal and early morning awakenings. RESULTS: Mirtazapine was effective to not only treat sleep disturbance but also a craving for BZD. CONCLUSIONS: The increases of dopamine, norepinephrine, and serotonin signaling by mirtazapine may be related to the effectiveness in reducing BZD dependence.

Lamotrigine in the maintenance treatment of bipolar disorder.

BACKGROUND: Bipolar disorder is a chronic mental disorder with repetitive mania/hypomania as well as depressive episodes, which eventually results in marked impairment in overall functioning and health-related quality of life.  A worldwide prevalence rate of 2.4% has been reported. The risk of suicide is higher in people with bipolar disorder than those with other mental disorders. Therefore, effective management of bipolar disorder in the maintenance period is warranted to minimize the risk of relapse or recurrence. Although lithium has been the standard treatment of bipolar disorder for many years, it is associated with adverse effects and teratogenicity. Lamotrigine is approved to be expected for prevention of recurrence for the maintenance treatment of bipolar disorder. In addition, lamotrigine is as effective as lithium. Therefore, we performed a systematic review to confirm the efficacy and safety of lamotrigine in the maintenance treatment of bipolar disorder. OBJECTIVES: To assess the efficacy and tolerability of lamotrigine in the maintenance treatment of bipolar disorder. SEARCH METHODS: We searched Ovid MEDLINE, Embase, PsycINFO, the Cochrane Common Mental Disorders Group's Specialized Register (CCMDCTR) and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to 21 May 2021. We also searched international trial registries and contacted experts in the field. SELECTION CRITERIA: We included randomized controlled trials enrolling adults with bipolar disorder who were treated with lamotrigine, placebo or lithium. DATA COLLECTION AND ANALYSIS: Two reviews authors independently checked the eligibility of studies and extracted data using a standardized form. Data extracted included study characteristics, participant characteristics, intervention details, settings, and outcome measures in the term of efficacy and tolerability. Study information were then entered into RevMan web. MAIN RESULTS: We included 11 studies with a total of 2314 participants in this review; 1146 were randomized to lamotrigine, 869 were randomized to placebo and, 299 to lithium. We rated all studies as having an unclear risk of bias in at least one domain of Cochrane's tool for assessing risk of bias, with the most commonly observed weakness being selection bias (random sequence generation and allocation concealment). We judged five studies to be at a high risk of detection bias (blinding of outcome assessment). These potential biases pose as major threat to the validity of the included studies in this review. Outcomes of efficacy showed a possible advantage of lamotrigine over placebo. The estimated risk ratio (RR) for recurrence of manic symptom at one year as measured by the Young Mania Rating Scale (YMRS) was 0.67, (95% confidence interval (CI) 0.51 to 0.87; 3 studies, 663 participants; low-certainty evidence) in favor of lamotrigine. The RR of clinical worsening with the need for additional psychotropic treatment (RR 0.82, 95% CI 0.70 to 0.98; 4 studies, 756 participants) based on moderate-certainty evidence. The possible benefits of lamotrigine were also seen for the outcome of treatment withdrawal due to any reason at 6-12 months after treatment (RR 0.88, 95% CI 0.78 to 0.99; 4 studies, 700 participants; moderate-certainty evidence). Regarding tolerability, our analyses showed that the incidence rates of adverse effects were similar between the lamotrigine group and the placebo group (short-term effect: RR 1.07, 95% CI 0.81 to 1.42; 5 studies, 1138 participants; very low-certainty evidence; long-term effect: RR 0.97, 95% CI 0.77 to 1.23; 4 studies, 756 participants; moderate-certainty evidence). In the comparison between lamotrigine and lithium, efficacy was similar between groups except for recurrence of mania episode at one year. Recurrence of manic symptoms was higher in the lamotrigine group than that of the lithium group (RR 2.13, 95% CI 1.32 to 3.44; 3 studies, 602 participants; moderate-certainty evidence). Analysis of adverse effects at 6-12 months showed that a lower proportion of participants experienced at least one adverse effect when treated with lamotrigine compared to lithium (RR 0.70, 95% CI 0.51 to 0.96; 4 studies, 691 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Low- to moderate-certainty evidence collectively suggests that lamotrigine may be superior to placebo as a treatment modality for bipolar disorder. In comparison to lithium, people with bipolar disorder seem to tolerate lamotrigine better in the long run; however, the demonstrated efficacy in the maintenance of bipolar disorder was similar between the two groups.