Differential genetic associations and expression of PAPST1/SLC35B2 in bipolar disorder and schizophrenia.

Lithium's inhibitory effect on enzymes involved in sulfation process, such as inhibition of 3'(2')-phosphoadenosine 5'-phosphate (PAP) phosphatase, is a possible mechanism of its therapeutic effect for bipolar disorder (BD). 3'-Phosphoadenosine 5'-phosphosulfate (PAPS) is translocated from cytosol to Golgi lumen by PAPS transporter 1 (PAPST1/SLC35B2), where it acts as a sulfa donor. Since SLC35B2 was previously recognized as a molecule that facilitates the release of D-serine, a co-agonist of N-methyl-D-aspartate type glutamate receptor, altered function of SLC35B2 might be associated with the pathophysiology of BD and schizophrenia (SCZ). We performed genetic association analyses of the SLC35B2 gene using Japanese cohorts with 366 BD cases and 370 controls and 2012 SCZ cases and 2170 controls. We then investigated expression of SLC35B2 mRNA in postmortem brains by QPCR using a Caucasian cohort with 33 BD and 34 SCZ cases and 34 controls and by in situ hybridization using a Caucasian cohort with 37 SCZ and 29 controls. We found significant associations between three SNPs (rs575034, rs1875324, and rs3832441) and BD, and significantly reduced SLC35B2 mRNA expression in postmortem dorsolateral prefrontal cortex (DLPFC) of BD. Moreover, we observed normalized SLC35B2 mRNA expression in BD subgroups who were medicated with lithium. While there was a significant association of SLC35B2 with SCZ (SNP rs2233437), its expression was not changed in SCZ. These findings indicate that SLC35B2 might be differentially involved in the pathophysiology of BD and SCZ by influencing the sulfation process and/or glutamate system in the central nervous system.

Genetic and molecular risk factors within the newly identified primate-specific exon of the SAP97/DLG1 gene in the 3q29 schizophrenia-associated locus.

The synapse-associated protein 97/discs, large homolog 1 of Drosophila (DLG1) gene encodes synaptic scaffold PDZ proteins interacting with ionotropic glutamate receptors including the N-methyl-D-aspartate type glutamate receptor (NMDAR) that is presumed to be hypoactive in brains of patients with schizophrenia. The DLG1 gene resides in the chromosomal position 3q29, the microdeletion of which confers a 40-fold increase in the risk for schizophrenia. In the present study, we performed genetic association analyses for DLG1 gene using a Japanese cohort with 1808 schizophrenia patients and 2170 controls. We detected an association which remained significant after multiple comparison testing between schizophrenia and the single nucleotide polymorphism (SNP) rs3915512 that is located within the newly identified primate-specific exon (exon 3b) of the DLG1 gene and constitutes the exonic splicing enhancer sequence. When stratified by onset age, although it did not survive multiple comparisons, the association was observed in non-early onset schizophrenia, whose onset-age selectivity is consistent with our recent postmortem study demonstrating a decrease in the expression of the DLG1 variant in early-onset schizophrenia. Although the present study did not demonstrate the previously reported association of the SNP rs9843659 by itself, a meta-analysis revealed a significant association between DLG1 gene and schizophrenia. These findings provide a valuable clue for molecular mechanisms on how genetic variations in the primate-specific exon of the gene in the schizophrenia-associated 3q29 locus affect its regulation in the glutamate system and lead to the disease onset around a specific stage of brain development.

Association study of H2AFZ with schizophrenia in a Japanese case-control sample.

It is widely accepted that malfunction of the N-methyl-D-aspartate (NMDA)-type glutamate receptor may be involved in the pathophysiology of schizophrenia. Several recent microRNA (miRNA) studies have demonstrated that the expression of the glutamate system-related miR-132 and miR-212 is changed in postmortem schizophrenic brains. Here we attempted to obtain further insight into the relationships among schizophrenia, the NMDA receptor, the molecular cascades controlled by these miRNAs and commonly predicted target genes of the two miRNAs. We focused on the H2AFZ (encoding H2A histone family, member Z) gene, whose expression was shown in our screening study to be modified by a schizophrenomimetic NMDA antagonist, phencyclidine. By performing polymerase chain reaction with fluorescent signal detention using the TaqMan system, we examined four tag single nucleotide polymorphisms (SNPs; SNP01-04) located around and within the H2AFZ gene for their genetic association with schizophrenia. The subjects were a Japanese cohort (2,012 patients with schizophrenia and 2,170 control subjects). We did not detect any significant genetic association of these SNPs with schizophrenia in this cohort. However, we observed a significant association of SNP02 (rs2276939) in the male patients with schizophrenia (allelic P = 0.003, genotypic P = 0.008). A haplotype analysis revealed that haplotypes consisting of SNP02-SNP03 (rs10014424)-SNP04 (rs6854536) also showed a significant association in the male patients with schizophrenia (P = 0.018). These associations remained significant even after correction for multiple testing. The present findings suggest that the H2AFZ gene may be a susceptibility factor in male subjects with schizophrenia, and that modification of the H2AFZ signaling pathway warrants further study in terms of the pathophysiology of schizophrenia.

Erratum to: Association study of H2AFZ with schizophrenia in a Japanese case-control sample.

Table 1 contains several errors as originally published. Table 1 should read as follows; the corrected values are shown in italics.

Treatment readiness and prognosis for problematic smartphone use: Evaluation of the Stages of Change, Readiness, and Treatment Eagerness Scale (SOCRATES) and log data.

Aim: While moderate smartphone use contributes to information gathering and relationship building, excessive smartphone use, also referred to as problematic smartphone use (PSU), has raised concerns because of its addictive nature and associated health consequences. This study aimed to investigate the relationship between treatment readiness and prognosis in individuals with PSU and to assess the predictive ability of smartphone log data in evaluating treatment readiness. Methods: A sample of 47 patients with PSU participated in this study. Treatment readiness was assessed using the Stages of Change, Readiness, and Treatment Eagerness Scale (SOCRATES), and log data were collected using a smartphone log application. Results: The results showed a significant correlation between baseline SOCRATES scores and the difference in Global Assessment of Functioning scores between baseline and 6 months (Spearman's ρ = 0.640, P-value = .001), suggesting that treatment readiness may explain part of the treatment outcomes (Pearson's r 2 = 0.379, P-value = 0.032). In addition, baseline log data, including the log acquisition rate, showed a positive correlation with treatment readiness (Spearman's ρ = 0.328, P-value = 0.045). Conclusion: These findings provide valuable insights into the relationship between treatment readiness and clinical outcomes in patients with PSU, and suggest the potential of log data as objective indicators of treatment motivation.

Explicit and implicit effects of gaming content on social media on the behavior of young adults.

Excessive gameplay can have negative effects on both mental and physical health, especially among young people. Nowadays, social media platforms are bombarding users with gaming-related content daily. Understanding the effect of this content on people's behavior is essential to gain insight into problematic gaming habits. However, this issue is yet to be studied extensively. In this study, we examined how gaming-related content on social media affects young adults explicitly and implicitly. We studied 25 healthy young adults (average age 21.5 ± 2.2) who played online games casually and asked them to report their gaming desire. We also conducted an implicit association test (IAT) to measure their implicit attitudes toward gaming-related content. We also investigated the relationship between these measures and various psychological factors, such as personality traits, self-efficacy, impulsiveness, and cognitive flexibility. The results revealed that participants had a higher explicit gaming desire when exposed to gaming-related cues on social media than neutral cues. They also had a robust positive implicit attitude toward gaming-related content on social media. Explicit gaming desire was positively correlated with neuroticism levels. Furthermore, the IAT effect was negatively correlated with self-efficacy and cognitive flexibility levels. However, there were no significant correlations between explicit gaming desire/IAT effect and impulsiveness levels. These findings suggest that gaming-related content on social media can affect young adults' behavior both explicitly and implicitly, highlighting the need for further research to prevent gaming addiction in vulnerable individuals.

Neural responses to gaming content on social media in young adults.

Excessive gaming can impair both mental and physical health, drawing widespread public and clinical attention, especially among young generations. People are now more exposed to gaming-related content on social media than before, and this exposure may have a significant impact on their behavior. However, the neural mechanisms underlying this effect remain unexplored. Using functional magnetic resonance imaging (fMRI), this study aimed to investigate the neural activity induced by gaming-related content on social media among young adults casually playing online games. While being assessed by fMRI, the participants watched gaming-related videos and neutral (nongaming) videos on social media. The gaming-related cues significantly activated several brain areas, including the medial prefrontal cortex, posterior cingulate cortex, hippocampus, thalamus, superior/middle temporal gyrus, precuneus and occipital regions, compared with the neutral cues. Additionally, the participants' gaming desire levels positively correlated with a gaming-related cue-induced activation in the left orbitofrontal cortex and the right superior temporal gyrus. These findings extend previous studies on gaming cues and provide useful information to elucidate the effects of gaming-related content on social media in young adults. Continued research using real-world gaming cues may help improve our understanding of promoting gaming habits and provide support to individuals vulnerable to gaming addiction.

[Genetics of schizophrenia].

Many studies have reported that genetic variants play a major role in the pathogenesis of schizophrenia. In the past five years, the genetics knowledge base of schizophrenia has advanced considerably. These advances have mostly been through genome-wide association studies (GWAS) and copy number variations (CNVs) studies. Moreover, exome sequencing by using the next-generation DNA sequencers is launched in recent years. In the next few years, the high-throughput sequencing is likely to play an important role. These findings have produced new hypotheses about etiology of schizophrenia and they can indicate future research strategies. Therefore, it is expected that further studies will yield deeper insights.

Hyperfocus symptom and internet addiction in individuals with attention-deficit/hyperactivity disorder trait.

Background: Hyperfocus symptom is the intense concentration on a certain object. It is a common but often overlooked symptom in those with attention-deficit/hyperactivity disorder (ADHD). Hyperfocus disrupts attention control and results in a focus on inappropriate behaviors. It allows individuals to focus on internet use and make them use internet excessively. This excessive internet use can lead to an addiction. This study investigated the status of IA and hyperfocus, the mediation effect of hyperfocus in relation to IA, and the relationship between ADHD subtypes and hyperfocus in those with ADHD symptoms. Methods: This web-based cross-sectional study included 3,500 Japanese adults who completed internet-based questionnaires, which included the Adult ADHD Self-Report Scale (ASRS), Internet Addiction Test (IAT), and Hyperfocus Scale (HFS) to assess ADHD symptoms, internet dependence, and hyperfocus symptoms, respectively. The mediating role of HFS in the relationship between ASRS and IAT was assessed by mediation analysis. To analyze the relationship between hyperfocus symptoms and ADHD subtypes, we compared the correlation of HFS with the Inattention and Hyperactive Scores of ASRS. Results: ADHD traits were associated with higher IAT scores (p < 0.001) and higher HFS scores (p < 0.001). Mediation analysis and bootstrap testing showed that HFS significantly mediated the association between ASRS and IAT. Analyses of ADHD subtypes demonstrated that HFS was significantly correlated with the Inattention (R = 0.597, p < 0.001) and Hyperactive (R = 0.523, p < 0.001) Scores. The correlation between HFS and the Inattention Score was significantly higher than that between HFS and the Hyperactive Score (p < 0.001). Conclusion: Our findings suggest that hyperfocus may play an important role in addictive behavior in ADHD as a manifestation of attentional control malfunction.

Association study of Nogo-related genes with schizophrenia in a Japanese case-control sample.

Many studies have suggested that myelin dysfunction may be causally involved in the pathogenesis of schizophrenia. Nogo (RTN4), myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMG) all bind to the common receptor, Nogo-66 receptor 1 (RTN4R). We examined 68 single nucleotide polymorphisms (SNPs) (51 with genotyping and 17 with imputation analysis) from these four genes for genetic association with schizophrenia, using a 2,120 case-control sample from the Japanese population. Allelic tests showed nominally significant association of two RTN4 SNPs (P = 0.047 and 0.037 for rs11894868 and rs2968804, respectively) and two MAG SNPs (P = 0.034 and 0.029 for rs7249617 and rs16970218, respectively) with schizophrenia. The MAG SNP rs7249617 also showed nominal significance in a genotypic test (P = 0.017). In haplotype analysis, the MAG haplotype block including rs7249617 and rs16970218 showed nominal significance (P = 0.008). These associations did not remain significant after correction for multiple testing, possibly due to their small genetic effect. In the imputation analysis of RTN4, the untyped SNP rs2972090 showed nominally significant association (P = 0.032) and several imputed SNPs showed marginal associations. Moreover, in silico analysis (PolyPhen) of a missense variant (rs11677099: Asp357Val), which is in strong linkage disequilibrium with rs11894868, predicted a deleterious effect on Nogo protein function. Despite a failure to detect robust associations in this Japanese cohort, our nominally positive signals, taken together with previously reported biological and genetic findings, add further support to the "disturbed myelin system theory of schizophrenia" across different populations.

Factors affecting mental illness and social stress in hospital workers treating COVID-19: Paradoxical distress during pandemic era.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has affected all countries in the world. Hospital workers are at high risk of mental illness, such as anxiety and depression. Furthermore, they also face many social stresses, such as deterioration of human relations and income reduction. Apart from mental illness, these social stresses can reduce motivation and lead to voluntary absenteeism, which contribute to a collapse of medical systems. Thus, for maintaining medical systems, it is crucial to clarify risk factors for both mental illness and increased social stress among hospital workers. However, little attention has been paid to factors affecting social stress, and thus, we aimed to address this gap. METHODS: In this cross-sectional survey of 588 hospital workers, the levels of anxiety, depression, and social stress were assessed using the 7-item Generalized Anxiety Disorder scale (GAD-7), 9-item Patient Health Questionnaire (PHQ-9), and Tokyo Metropolitan Distress Scale for Pandemic (TMDP). Multiple regression analyses were conducted to identify the demographic variables affecting these problems. RESULTS: Older age and female sex were common risk factors for anxiety, depression, and social stress. Moreover, occupational exposure to COVID-19 and hospital staff other than doctors/fewer non-work days were risk factors for increased anxiety and depression, respectively. Furthermore, living with families/others was a risk factor for increased social stress during this pandemic. CONCLUSION: Our findings could be useful for developing policies and practices to minimize the risk of mental illness and increased social stress among hospital workers, highlighting that attention should be paid to social factors, such as an individual's household situation.

Association studies of WD repeat domain 3 and chitobiosyldiphosphodolichol beta-mannosyltransferase genes with schizophrenia in a Japanese population.

Schizophrenia and schizophrenia-like symptoms induced by the dopamine agonists and N-methyl-D aspartate type glutamate receptor antagonists occur only after the adolescent period. Similarly, animal models of schizophrenia by these drugs are also induced after the critical period around postnatal week three. Based upon the development-dependent onsets of these psychotomimetic effects, by using a DNA microarray technique, we identified the WD repeat domain 3 (WDR3) and chitobiosyldiphosphodolichol beta-mannosyltransferase (ALG1) genes as novel candidates for schizophrenia-related molecules, whose mRNAs were up-regulated in the adult (postnatal week seven), but not in the infant (postnatal week one) rats by an indirect dopamine agonist, and phencyclidine, an antagonist of the NMDA receptor. WDR3 and other related proteins are the nuclear proteins presumably involved in various cellular activities, such as cell cycle progression, signal transduction, apoptosis, and gene regulation. ALG1 is presumed to be involved in the regulation of the protein N-glycosylation. To further elucidate the molecular pathophysiology of schizophrenia, we have evaluated the genetic association of WDR3 and ALG1 in schizophrenia. We examined 21 single nucleotide polymorphisms [SNPs; W1 (rs1812607)-W16 (rs6656360), A1 (rs8053916)-A10 (rs9673733)] from these genes using the Japanese case-control sample (1,808 schizophrenics and 2,170 matched controls). No significant genetic associations of these SNPs were identified. However, we detected a significant association of W4 (rs319471) in the female schizophrenics (allelic P = 0.003, genotypic P = 0.008). Based on a haplotype analysis, the observed haplotypes consisting of W4 (rs319471)-W5 (rs379058) also displayed a significant association in the female schizophrenics (P = 0.016). Even after correction for multiple testing, these associations remained significant. Our findings suggest that the WDR3 gene may likely be a sensitive factor in female patients with schizophrenia, and that modification of the WDR3 signaling pathway warrants further investigation as to the pathophysiology of schizophrenia.

A distinctive abnormality of diffusion tensor imaging parameters in the fornix of patients with bipolar II disorder.

Diffusion tensor imaging (DTI) studies have revealed a changed integrity in the white matter of bipolar disorder. However, only a few investigations have examined bipolar II disorder (BP-II). A cross-sectional study was conducted to compare thirty-eight patients with BP-II (mean age = 38.26 years, F/M = 19/19) with thirty-eight age- and gender-matched healthy controls (mean age = 34.45 years, F/M = 18/20). Tract Based Spatial Statistics (TBSS) analysis of the fractional anisotropy (FA) was done with age, gender and education years as covariates, then a complementary atlas-based region-of-interest (ROI) analysis including the axial diffusivity (AD) and radial diffusivity (RD) was conducted to obtain further information. The patients with BP-II showed a significant decrease in FA in the corpus callosum (commissure fibers), fornix (association fibers) and right anterior corona radiata (projection fibers) compared to the controls. Moreover, a significant increase in the RD was observed in all of the fibers of the BP-II patients, while the AD significantly increased only in the fornix of the patients. Thus, in addition to the abnormal integrity of the commissure and projection fibers, the present study suggested an involvement of the limbic association fibers in the pathophysiology of BP-II induced by a distinctive neuropathology.

Acute confusional state after designer tryptamine abuse.

A 23-year-old Japanese woman was brought to the emergency department about 6.5 h after taking liquid and later a half tablet purchased on the street. About 4.5 h prior to presentation, she displayed excited and disorganized behavior. On examination, she was not alert or oriented, with a Glasgow Coma Scale score of 13, did not answer any questions from doctors while smirking and looking around restlessly, and sometimes exhibited echolalia, imitating the speech of doctors. She was given intravenous infusion of fluid for 8 h, then discharged. Gas chromatography-mass spectrometry of urine revealed 5-methoxy-diisopropyltryptamine, 5-methoxy-N-methyltryptamine and an unidentified tryptamine. Identifying chemical products based solely on information of users is insufficient, and urinalysis is necessary in cases potentially involving designer drugs.