Comparison of metabolic parameters between oral and total parenteral nutrition in children with severe eating disorders.

BACKGROUND: This study investigated changes of lipid parameters in children with severe eating disorders during refeeding in order to explore the optimal timing for lipid preparation administration. METHODS: We prospectively assessed the physical conditions of patients with eating disorders after the start of nutrition therapy. The assessments were performed at admission and at 2 and 4 weeks. Lipid metabolism was assessed based on triglyceride (TG), total cholesterol (TC), and free carnitine (FC) levels, as well as acylcarnitine/free carnitine (AC/FC) ratio. RESULTS: A total of 18 patients were included. Of these, 12 and 6 received an oral diet (OD group) and total parenteral nutrition (TPN group), respectively. The mean body mass indexes at hospital admission were 12.8 kg/m2 in the OD group and 12.7 kg/m2 in the TPN group. At 2 weeks after the start of refeeding, TC, TG, and AC/FC levels were significantly lower in the TPN group than in the OD group. Other blood test results did not show any significant differences between the two groups. CONCLUSIONS: Fat-free glucose-based nutrition promoted lipid metabolism over a 2-week period after the start of refeeding, suggesting that balanced energy and lipid intake are essential, even in TPN.

Comparison of metabolic parameters between oral and total parenteral nutrition in children with severe eating disorders.

BACKGROUND: This study investigated changes of lipid parameters in children with severe eating disorders during refeeding in order to explore the optimal timing for lipid preparation administration. METHODS: We prospectively assessed the physical conditions of patients with eating disorders after the start of nutrition therapy. The assessments were performed at admission and at 2 and 4 weeks. Lipid metabolism was assessed based on triglyceride (TG), total cholesterol (TC), and free carnitine (FC) levels, as well as acylcarnitine/free carnitine (AC/FC) ratio. RESULTS: A total of 18 patients were included. Of these, 12 and 6 received an oral diet (OD group) and total parenteral nutrition (TPN group), respectively. The mean body mass indexes at hospital admission were 12.8 kg/m2 in the OD group and 12.7 kg/m2 in the TPN group. At 2 weeks after the start of refeeding, TC, TG, and AC/FC levels were significantly lower in the TPN group than in the OD group. Other blood test results did not show any significant differences between the two groups. CONCLUSIONS: Fat-free glucose-based nutrition promoted lipid metabolism over a 2-week period after the start of refeeding, suggesting that balanced energy and lipid intake are essential, even in TPN.

Harmonizing multisite data with the ComBat method for enhanced Parkinson's disease diagnosis via DAT-SPECT.

Background: Dopamine transporter single-photon emission computed tomography (DAT-SPECT) is a crucial tool for evaluating patients with Parkinson's disease (PD). However, its implication is limited by inter-site variability in large multisite clinical trials. To overcome the limitation, a conventional prospective correction method employs linear regression with phantom scanning, which is effective yet available only in a prospective manner. An alternative, although relatively underexplored, involves retrospective modeling using a statistical method known as "combatting batch effects when combining batches of gene expression microarray data" (ComBat). Methods: We analyzed DAT-SPECT-specific binding ratios (SBRs) derived from 72 healthy older adults and 81 patients with PD registered in four clinical sites. We applied both the prospective correction and the retrospective ComBat correction to the original SBRs. Next, we compared the performance of the original and two corrected SBRs to differentiate the PD patients from the healthy controls. Diagnostic accuracy was assessed using the area under the receiver operating characteristic curve (AUC-ROC). Results: The original SBRs were 6.13 ± 1.54 (mean ± standard deviation) and 2.03 ± 1.41 in the control and PD groups, respectively. After the prospective correction, the mean SBRs were 6.52 ± 1.06 and 2.40 ± 0.99 in the control and PD groups, respectively. After the retrospective ComBat correction, the SBRs were 5.25 ± 0.89 and 2.01 ± 0.73 in the control and PD groups, respectively, resulting in substantial changes in mean values with fewer variances. The original SBRs demonstrated fair performance in differentiating PD from controls (Hedges's g = 2.76; AUC-ROC = 0.936). Both correction methods improved discrimination performance. The ComBat-corrected SBR demonstrated comparable performance (g = 3.99 and AUC-ROC = 0.987) to the prospectively corrected SBR (g = 4.32 and AUC-ROC = 0.992) for discrimination. Conclusion: Although we confirmed that SBRs fairly discriminated PD from healthy older adults without any correction, the correction methods improved their discrimination performance in a multisite setting. Our results support the utility of harmonization methods with ComBat for consolidating SBR-based diagnosis or stratification of PD in multisite studies. Nonetheless, given the substantial changes in the mean values of ComBat-corrected SBRs, caution is advised when interpreting them.

Post-Disaster Community Transition of Psychiatric Inpatients: Lessons from the Fukushima Nuclear Accident.

This study sought to explore factors related to community transition after the mandatory evacuation of psychiatric inpatients to other hospitals owing to the Fukushima Daiichi Nuclear Power Plant accident. A retrospective cohort design was adopted and 391 psychiatric patients were examined. Univariate and multivariate analyses were conducted to confirm the association between the achievement or non-achievement of discharge to community living and their backgrounds (age, gender, evacuation destination, psychiatric diagnoses, and physical complications). Multivariate analysis indicated that patients with psychiatric diagnoses of schizophrenia, schizotypal, and delusional disorders (International Statistical Classification of Diseases and Related Health Problems 10th revision, F20-29), and those with physical diagnoses of the circulatory (I00-95) and digestive (K00-93) systems showed a significant association with the non-attainment of community transition. From these results, we hypothesized that difficulties in the management of medication during and immediately after the extremely chaotic settings of evacuation could have negative effects on the community transitions. Furthermore, another possible concern was that individuals' persistent psychotic status before the accident had been carried over to the destination hospitals. Therefore, pre-disaster daily cooperation across hospitals and challenges for vulnerable psychiatric patients' future community lives are also essential.

Marked alteration of phosphoinositide signaling-associated molecules in postmortem prefrontal cortex with bipolar disorder.

AIM: The etiology of bipolar disorder (BD) remains unknown; however, lipid abnormalities in BD have received increasing attention in recent years. In this study, we examined the expression levels of enzyme proteins associated with the metabolic pathway of phosphoinositides (PIs) and their downstream effectors, protein kinase B (Akt1) and glycogen synthase kinase 3ß (GSK3ß), which have been assumed to be the targets of mood stabilizers such as lithium, in the postmortem brains of patients with BD. METHODS: The protein expression levels of phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1C), phosphatidylinositol 4-kinase alpha (PIK4CA), phosphatase and tensin homolog deleted from chromosome 10 (PTEN), Akt1, and GSK3ß were measured using enzyme-linked immunosorbent assays and multiplex fluorescent bead-based immunoassays in the prefrontal cortex (PFC). Specifically, PTEN, Akt1, GSK3ß, and PIP5K1C were measured in seven BD patients and 48 controls. Additionally, PIK4CA was analyzed in 10 cases and 34 controls. RESULTS: PTEN expression levels were markedly decreased in the PFCs of patients with BD, whereas those of Akt and GSK3ß were prominently elevated. Moreover, patients medicated with lithium exhibited higher Akt1 expression levels and lower PTEN expression levels in comparison with the untreated group. CONCLUSION: Our results suggest that the expression levels of Akt1/GSK3ß and its upstream regulator PTEN are considerably altered.

Effect of lemborexant on pharmacokinetics of clozapine: A potential drug-drug interaction mediated by time-dependent inhibition of CYP3A4.

Clozapine (CLZ) is extensively used for treatment-resistant schizophrenia (TRS) with caution to avoid serious adverse events such as agranulocytosis and drug-drug interactions (DDIs). In the current report, we present a case of a 35-year-old male non-smoking TRS patient whose steady-state plasma trough concentrations (Ctrough ) of CLZ and its active metabolite, N-desmethylclozapine (NDMC), were significantly increased after initiating oral administration of lemborexant (LEM), a dual orexin receptor antagonist, for the treatment of insomnia. The patient experienced oversedation with sleepiness and fatigue while maintaining high levels of Ctrough of CLZ. The increased concentrations of CLZ returned to normal ranges after the discontinuation of LEM dosing, implying a pharmacokinetic DDI between CLZ and LEM. To gain insight into possible mechanisms, we performed in vitro assays of CYP1A2- and CYP3A4-mediated CLZ metabolism by measuring the formations of NDMC and clozapine N-oxide (CNO). In accordance with previous studies, the incubation of CLZ with each enzyme resulted in the production of both metabolites. LEM had only a weak inhibitory effect on CYP1A2- and CYP3A4-mediated CLZ metabolism. However, the preincubation of LEM with CYP3A4 in the presence of NADPH showed a significant enhancement of inhibitory effects on CLZ metabolism with IC50 values for the formations of CNO and NDMC of 2.8 µM and 4.1 µM, respectively, suggesting that LEM exerts as a potent time-dependent inhibitor for CYP3A4. Taken together, the results of the current study indicate that co-medication of CLZ with LEM may lead to increase in exposure to CLZ and risks of CLZ-related adverse events.

Relationship between evacuation after the Great East Japan Earthquake and new-onset hyperuricemia: A 7-year prospective longitudinal study of the Fukushima Health Management Survey.

INTRODUCTION: On March 11, 2011, the Great East Japan Earthquake occurred in Japan, with a nuclear accident subsequently occurring at the Fukushima Daiichi Nuclear Power Plant. The disaster forced many evacuees to change particular aspects of their lifestyles. However, the effect of evacuation on the new-onset of hyperuricemia have not been sufficiently elucidated. This study assessed the association between evacuation and new-onset hyperuricemia after the earthquake based on the Fukushima Health Management Survey from a lifestyle and socio-psychological perspective. MATERIALS AND METHODS: This is a 7-year prospective longitudinal study included 18,140 residents (6,961 men and 11,179 women) with non-hyperuricemia who underwent both the Comprehensive Health Check and the Mental Health and Lifestyle Survey in fiscal year 2011. Associations between new-onset hyperuricemia and lifestyle- and disaster-related factors, including evacuation, were estimated using a Cox proportional hazards regression model analysis. Hyperuricemia was defined as uric acid levels > 7.0 mg/dL for men and > 6.0 mg/dL for women. RESULTS: During a median follow-up of 4.3 years, 2,996 participants (1,608 men, 23.1%, 1,388 women, 12.4%) newly developed hyperuricemia. Significant associations were observed between evacuation and onset of hyperuricemia in women (adjusted hazard ratio 1.18, 95% confidence interval, 1.05-1.32, p = 0.007), but not in men (adjusted hazard ratio 1.11, 95% confidence interval, 0.99-1.24, p = 0.067). DISCUSSION: Evacuation after a natural disaster is an independent risk factor for the new-onset of hyperuricemia in women. The possibility of hyperuricemia developing in response to natural disasters should be considered.

Evidence for increased DNA damage repair in the postmortem brain of the high stress-response group of schizophrenia.

Background: Schizophrenia (SZ) is a disorder diagnosed by specific symptoms and duration and is highly heterogeneous, clinically and pathologically. Although there are an increasing number of studies on the association between genetic and environmental factors in the development of SZ, the actual distribution of the population with different levels of influence of these factors has not yet been fully elucidated. In this study, we focused on stress as an environmental factor and stratified SZ based on the expression levels of stress-responsive molecules in the postmortem prefrontal cortex. Methods: We selected the following stress-responsive molecules: interleukin (IL) -1ß, IL-6, IL-10, tumor necrosis factor-α, interferon-γ, glucocorticoid receptor, brain-derived neurotrophic factor, synaptophysin, S100 calcium-binding protein B, superoxide dismutase, postsynaptic density protein 95, synuclein, apolipoprotein A1 (ApoA1), ApoA2, and solute carrier family 6 member 4. We performed RNA sequencing in the prefrontal gray matter of 25 SZ cases and 21 healthy controls and conducted a hierarchical cluster analysis of SZ based on the gene expression levels of stress-responsive molecules, which yielded two clusters. After assessing the validity of the clusters, they were designated as the high stress-response SZ group and the low stress-response SZ group, respectively. Ingenuity Pathway Analysis of differentially expressed genes (DEGs) between clusters was performed, and Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining was conducted on four cases each in the high and low stress-response SZ groups to validate DNA damage. Results: We found higher prevalence of family history of SZ in the low stress-response SZ group (0/3 vs. 5/4, p = 0.04). Pathway analysis of DEGs between clusters showed the highest enrichment for DNA double-strand break repair. TUNEL staining showed a trend toward a lower percentage of TUNEL-positive cells in the high stress-response SZ group. Conclusion: Our results suggest that there are subgroups of SZ with different degrees of stress impact. Furthermore, the pathophysiology of these subgroups may be associated with DNA damage repair. These results provide new insights into the interactions and heterogeneity between genetic and environmental factors.

Ethnicity-dependent effect of rs1799971 polymorphism on OPRM1 expression in the postmortem brain and responsiveness to antipsychotics.

Schizophrenia is associated with aberration of inhibitory neurons. Although the mu-opioid receptor (MOR) is an essential modulator of inhibitory neurons, the effect of rs1799971 polymorphism in the MOR gene on risk of schizophrenia is controversial. Moreover, the disturbance of opioids systems in patients with schizophrenia has not been fully examined. We firstly conducted preliminary meta-analyses integrating Asian and European populations separately over 12,000 subjects to assess the effect of rs1799971 on risk of schizophrenia. Based on the above result, we also investigated the effect on the expression levels of MOR mRNA in the prefrontal cortex (PFC) and caudate nucleus of 41 postmortem brains. In addition, we determined whether these levels were related to antemortem schizophrenia symptoms and pharmacotherapeutic effects. The rs1799971 G-allele reduced the risk of schizophrenia in Asian populations (OR: 0.56, 95%CI: 0.32-0.98, p = 0.042) but increased it in European populations (OR: 1.66, 95%CI: 1.08-2.56, p = 0.022). It decreased MOR mRNA levels in PFC in the Japanese population (p = 0.031). Increased MOR mRNA level in PFC correlated with higher total score of antemortem schizophrenia symptoms (p = 0.017). Furthermore, the pharmacotherapeutic effect of first-generation antipsychotics was higher for genotype AA than AG/GG of rs1799971 (p = 0.036). The rs1799971 affects risk of schizophrenia and MOR mRNA expression and the effect varies according to ethnicity. Overexpression of MOR might induce severe schizophrenia symptoms. Therefore, MOR modulation may be the key clue for treating antipsychotics-resistant schizophrenia, and genotyping rs1799971 may provide a better pharmacotherapeutic strategy.

Quadripulse transcranial magnetic stimulation inducing long-term depression in healthy subjects may increase seizure risk in some patients with intractable epilepsy.

Objective: This study aimed to assess the efficacy and safety of quadripulse transcranial magnetic stimulation-50 (QPS-50) in patients with intractable epilepsy. Methods: Four patients were included in the study. QPS-50, which induces long-term depression in healthy subjects, was administered for 30 min on a weekly basis for 12 weeks. Patients' clinical symptoms and physiological parameters were evaluated before, during, and after the repeated QPS-50 period. We performed two control experiments: the effect in MEP (Motor evoked potential) size after a single QPS-50 session with a round coil in nine healthy volunteers, and a follow-up study of physiological parameters by repeated QPS-50 sessions in four other healthy participants. Results: Motor threshold (MT) decreased during the repeated QPS-50 sessions in all patients. Epileptic symptoms worsened in two patients, whereas no clinical worsening was observed in the other two patients. In contrast, MT remained unaffected for 12 weeks in all healthy volunteers. Conclusions: QPS-50 may not be effective as a treatment for intractable epilepsy. Significance: In intractable epilepsy patients, administering repeated QPS-50 may paradoxically render the motor cortex more excitable, probably because of abnormal inhibitory control within the epileptic cortex. The possibility of clinical aggravation should be seriously considered when treating intractable epilepsy patients with non-invasive stimulation methods.

Impact of Lifestyle and Psychosocial Factors on the Incidence of Hepatobiliary Enzyme Abnormalities After the Great East Japan Earthquake: Seven-Year Follow-up of the Fukushima Health Management Survey.

OBJECTIVE: Residents who lived near the Fukushima Power Plant accident were forced to change their lifestyle after the 2011 accident. This study aimed to elucidate the association of resident lifestyle and psychological factors with onset of hepatobiliary enzyme abnormalities (HEA) after the accident. METHODS: This longitudinal study included 15705 residents who underwent a comprehensive health check, as well as a mental health and lifestyle survey between June 2011 and March 2012. Follow-up surveys were conducted between June, 2012 and March 2018. Risk factors for new HEA onset were evaluated using the Cox proportional hazards model, moreover, population attributable risks for new HEA onset were calculated. RESULTS: HEA developed in 29.7% of subjects. In addition to metabolic factors such as overweight, hyperglycemia, and hyperlipidemia; there were differences in alcohol intake, evacuation, unemployment, educational background, and psychological distress between subjects with and without HEA onset. After we adjusted for potential confounding factors, an association of being overweight, hypertension, and dyslipidemia, as well as alcohol consumption, evacuation, and psychological distress with increased risk of HEA onset was realized. Among these identified risk factors, evacuation accounted for the greatest share. CONCLUSIONS: Metabolic characteristics and disaster-related lifestyle aspects, including mental status, were risk factors for HAE onset after the Fukushima Power Plant accident.

The influence of tissue pH and RNA integrity number on gene expression of human postmortem brain.

Background: Evaluating and controlling confounders are necessary when investigating molecular pathogenesis using human postmortem brain tissue. Particularly, tissue pH and RNA integrity number (RIN) are valuable indicators for controlling confounders. However, the influences of these indicators on the expression of each gene in postmortem brain have not been fully investigated. Therefore, we aimed to assess these effects on gene expressions of human brain samples. Methods: We isolated total RNA from occipital lobes of 13 patients with schizophrenia and measured the RIN and tissue pH. Gene expression was analyzed and gene sets affected by tissue pH and RIN were identified. Moreover, we examined the functions of these genes by enrichment analysis and upstream regulator analysis. Results: We identified 2,043 genes (24.7%) whose expressions were highly correlated with pH; 3,004 genes (36.3%) whose expressions were highly correlated with RIN; and 1,293 genes (15.6%) whose expressions were highly correlated with both pH and RIN. Genes commonly affected by tissue pH and RIN were highly associated with energy production and the immune system. In addition, genes uniquely affected by tissue pH were highly associated with the cell cycle, whereas those uniquely affected by RIN were highly associated with RNA processing. Conclusion: The current study elucidated the influence of pH and RIN on gene expression profiling and identified gene sets whose expressions were affected by tissue pH or RIN. These findings would be helpful in the control of confounders for future postmortem brain studies.

Lipid-correlated alterations in the transcriptome are enriched in several specific pathways in the postmortem prefrontal cortex of Japanese patients with schizophrenia.

AIMS: Schizophrenia is a chronic relapsing psychiatric disorder that is characterized by many symptoms and has a high heritability. There were studies showing that the phospholipid abnormalities in subjects with schizophrenia (Front Biosci, S3, 2011, 153; Schizophr Bull, 48, 2022, 1125; Sci Rep, 7, 2017, 6; Anal Bioanal Chem, 400, 2011, 1933). Disturbances in prefrontal cortex phospholipid and fatty acid composition have been reported in subjects with schizophrenia (Sci Rep, 7, 2017, 6; Anal Bioanal Chem, 400, 2011, 1933; Schizophr Res, 215, 2020, 493; J Psychiatr Res, 47, 2013, 636; Int J Mol Sci, 22, 2021). For exploring the signaling pathways contributing to the lipid changes in previous study (Sci Rep, 7, 2017, 6), we performed two types of transcriptome analyses in subjects with schizophrenia: an unbiased transcriptome analysis solely based on RNA-seq data and a correlation analysis between levels of gene expression and lipids. METHODS: RNA-Seq analysis was performed in the postmortem prefrontal cortex from 10 subjects with schizophrenia and 5 controls. Correlation analysis between the transcriptome and lipidome from 9 subjects, which are the same samples in the previous lipidomics study (Sci Rep, 7, 2017, 6). RESULTS: Extraction of differentially expressed genes (DEGs) and further sequence and functional group analysis revealed changes in gene expression levels in phosphoinositide 3-kinase (PI3K)-Akt signaling and the complement system. In addition, a correlation analysis clarified alterations in ether lipid metabolism pathway, which is not found as DEGs in transcriptome analysis alone. CONCLUSIONS: This study provided results of the integrated analysis of the schizophrenia-associated transcriptome and lipidome within the PFC and revealed that lipid-correlated alterations in the transcriptome are enriched in specific pathways including ether lipid metabolism pathway.

Prediction of the prognosis of somatoform disorders using the Minnesota Multiphasic Personality Inventory.

BACKGROUND: Somatoform disorders are frequently resistant to treatment. This study aimed to determine the utility of the Minnesota Multifaceted Personality Inventory (MMPI) in predicting the prognosis of somatoform disorders. METHODS: Overall, 125 patients diagnosed with somatoform disorders between January 1, 2013 and December 31, 2017 in the psychiatric department of Fukushima Medical University Hospital were included. Patients with positive outcomes were identified based on a subjective estimation regarding (1) pain and (2) social functions, including activities of daily living. They were divided into the improved group (IG) and the non-improved group (NIG). Each factor was then descriptively compared between the two groups, and the sensitivity and specificity were determined. RESULTS: The NIG had significantly higher scores but only on the Hy scale. Thus, the optimal Hy scale cutoff score was calculated. The cutoff point was 73.5, with a sensitivity of 55.7% and a specificity of 71.7%. CONCLUSION: An MMPI Hy scale score higher than a cutoff value of 73.5 predicts a poor response to conventional supportive psychotherapy or drug therapy in patients with somatoform disorders. This cutoff point may be used as an important index for selecting treatment for somatoform disorders.

Switching to lemborexant for the management of insomnia in mental disorders: the SLIM study.

STUDY OBJECTIVES: We conducted a retrospective study to investigate the efficacy and safety of switching from other hypnotics, including benzodiazepines and Z-drugs, suvorexant, ramelteon, mirtazapine, trazodone, and antipsychotics, to lemborexant, a dual orexin receptor antagonist, for 3 months. METHODS: Clinical data obtained from the medical records of 61 patients treated at the Horikoshi Psychosomatic Clinic between December 2020 and February 2022 were analyzed, including the Athens Insomnia Scale, Epworth Sleepiness Scale, and Perceived Deficits Questionnaire-5. The primary outcome was the mean change in Athens Insomnia Scale score after 3 months. Secondary outcomes were the mean changes in the Epworth Sleepiness Scale and Perceived Deficits Questionnaire-5 scores over 3 months. We also compared pre- and post-diazepam equivalents. RESULTS: The mean Athens Insomnia Scale score decreased over 3 months after switching to lemborexant (1 mo: -2.98 ± 5.19, P < .001; 2 mo: -3.20 ± 5.64, P < .001; 3 mo: -3.38 ± 5.61, P < .001). Mean Epworth Sleepiness Scale score did not change from baseline to 1 month (-0.49 ± 3.41, P = 0.27), 2 months (0.082 ± 4.62, P = .89), or 3 months (-0.64 ± 4.80, P = .30). Mean Perceived Deficits Questionnaire-5 score did improve from baseline to 1 month (-1.17 ± 2.47, P = .004), 2 months (-1.05 ± 2.97, P = .029), and 3 months (-1.24 ± 3.06, P = .013). There was also a reduction in the total diazepam equivalent (baseline vs 3 mo: 14.0 ± 20.2 vs 11.3 ± 20.6, P < .001). CONCLUSIONS: Our study showed that, by switching to lemborexant from other hypnotics, the risks associated with benzodiazepines and Z-drugs may be reduced. CITATION: Horikoshi S, Miura I, Suzuki Y, et al. Switching to lemborexant for the management of insomnia in mental disorders: the SLIM study. J Clin Sleep Med. 2023;19(10):1753-1758.

Identification of schizophrenia symptom-related gene modules by postmortem brain transcriptome analysis.

Schizophrenia is a multifactorial disorder, the genetic architecture of which remains unclear. Although many studies have examined the etiology of schizophrenia, the gene sets that contribute to its symptoms have not been fully investigated. In this study, we aimed to identify each gene set associated with corresponding symptoms of schizophrenia using the postmortem brains of 26 patients with schizophrenia and 51 controls. We classified genes expressed in the prefrontal cortex (analyzed by RNA-seq) into several modules by weighted gene co-expression network analysis (WGCNA) and examined the correlation between module expression and clinical characteristics. In addition, we calculated the polygenic risk score (PRS) for schizophrenia from Japanese genome-wide association studies, and investigated the association between the identified gene modules and PRS to evaluate whether genetic background affected gene expression. Finally, we conducted pathway analysis and upstream analysis using Ingenuity Pathway Analysis to clarify the functions and upstream regulators of symptom-related gene modules. As a result, three gene modules generated by WGCNA were significantly correlated with clinical characteristics, and one of these showed a significant association with PRS. Genes belonging to the transcriptional module associated with PRS significantly overlapped with signaling pathways of multiple sclerosis, neuroinflammation, and opioid use, suggesting that these pathways may also be profoundly implicated in schizophrenia. Upstream analysis indicated that genes in the detected module were profoundly regulated by lipopolysaccharides and CREB. This study identified schizophrenia symptom-related gene sets and their upstream regulators, revealing aspects of the pathophysiology of schizophrenia and identifying potential therapeutic targets.

Disease specific brain capillary angiopathy in schizophrenia, bipolar disorder, and Alzheimer's disease.

Schizophrenia (SZ) and bipolar disorder (BD), which are both psychiatric disorders, share some common clinical evidence. We recently discovered that brain capillary angiopathy is another common feature of these psychiatric disorders using fibrin accumulation in vascular endothelial cells as an indicator. This study aimed to characterize the similarities and differences in cerebral capillary injuries in various brain diseases to provide new diagnostic methods for SZ and BD and to develop new therapeutic strategies. We evaluated whether discrepancies exist in the degree of vascular damage among SZ and BD and other brain disorders (amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD)) using postmortem brains. Our results demonstrate that fibrin was strongly accumulated in the capillaries of the grey matter (GM) of brains of patients with SZ and AD and in the capillaries of the white matter (WM) in those of patients with SZ, BD, and AD when compared with control subjects without any psychiatric or neurological disease history. However, ALS and PD brains did not present a significant increase in the amount of accumulated fibrin, either in the capillaries of WM or GM. Furthermore, significant leakage of fibrin into the brain parenchyma, indicating a vascular physical disruption, was observed in the brains of patients with AD but not in the brains of other patients compared with control subjects. In conclusion, our work reveals that Fibrin-accumulation in the brain capillaries are observed in psychiatric disorders, such as SZ, BD, and AD. Furthermore, fibrin-accumulating, nonbreaking type angiopathy is characteristic of SZ and BD, even though there are regional differences between these diseases.

Effects of disaster-related traumatic events on worry about radiation and COVID-19: A decade after the Fukushima nuclear power plant accident.

Community residents exposed to nuclear power plant (NPP) accidents have long-term worry about the effects of radiation. After the 2011 Fukushima NPP accident, those who experienced traumatic events during the Great East Japan Earthquake (GEJE) tended to have greater worry about radiation. Along with the prolonged worry about radiation, there may also be cognitive changes caused by the traumatic events. We hypothesized that if there were cognitive changes underlying the prolonged worry about radiation, those who experienced the traumatic events would tend to have greater worry about other issues unrelated to radiation. We examined the effects of the traumatic events during the GEJE on community residents' worry about radiation and COVID-19 a decade after the Fukushima NPP accident. Using the data of a longitudinal questionnaire survey following a random sample of 4900 community residents outside the evacuation zone in Fukushima, this study analyzed 774 responses (15.8%). The traumatic events consisted of (1) injury, (2) injury or death of a family member, and (3) the loss of a house or other property. We developed a mediation model drawing paths from the traumatic events to worry about radiation and COVID-19, including posttraumatic stress symptoms (PTSS) as a mediator, using structural equation modeling. The traumatic events directly affected worry about radiation. Although it did not directly affect worry about COVID-19, it did so indirectly through worry about radiation and PTSS. Traumatic events can increase trauma-related worry independently of PTSS and increase trauma-unrelated worry indirectly through trauma-related worry and PTSS.

Disrupted structural connectivity and less efficient network system in patients with the treatment-naive adult attention-deficit/hyperactivity disorder.

Introduction: Attention-deficit/hyperactivity disorder (ADHD) is a neuropsychiatric disorder whose primary symptoms are hyperactivity, impulsivity, and inattention. Historically, ADHD was recognized as a disease of childhood and adolescence. However, many patients are known to have persistent symptoms into adulthood. Many researchers consider the neuropathology of ADHD to be based on abnormalities in multiple parallel and intersecting pathways rather than a single anatomical area, but such alterations remain to be clarified. Methods: Using diffusion tensor imaging, we investigated differences in the global network metrics estimated by graph theory and the degree of connectivity between adjacent voxels within a white matter (WM) fascicle defined by the density of the diffusing spins (connectometry) between 19 drug-naive Japanese patients with adult ADHD and 19 matched healthy controls (HCs). In adult patients with ADHD, we examined the relationships between the symptomatology of ADHD and global network metrics and WM abnormalities. Results: Compared with HCs, adult patients with ADHD showed a reduced rich-club coefficient and decreased connectivity in widely distributed WMs such as the corpus callosum, the forceps, and the cingulum bundle. Correlational analyses demonstrated that the general severity of ADHD symptoms was associated with several global network metrics, such as lower global efficiency, clustering coefficient, small worldness, and longer characteristic path length. The connectometry revealed that the severity of hyperactive/impulsive symptoms was associated with overconnectivity in the corticostriatal, corticospinal, and corticopontine tracts, the inferior fronto-occipital fasciculus, and the extreme capsule but dysconnectivity in the cerebellum. The severity of inattentive symptoms was associated with dysconnectivity in the intracerebellar circuit and some other fibers. Conclusion: The results of the present study indicated that patients with treatment-naive adult ADHD showed disrupted structural connectivity, which contributes to less efficient information transfer in the ADHD brain and pathophysiology of ADHD. Trial registration: UMIN Clinical Trials Registry (UMIN-CTR) UMIN000025183, Registered: 5 January 2017.