Valproate, a Mood Stabilizer, Induces WFS1 Expression and Modulates Its Interaction with ER Stress Protein GRP94

Valproate is a standard treatment for bipolar disorder and a first-line mood stabilizer. The molecular mechanisms underlying its actions in bipolar disorder are unclear. It has been suggested that the action of valproate is linked to changes in gene expression and induction of endoplasmic reticulum (ER) stress-response proteins.Here we show that valproate modulates the ER stress response through the regulation of WFS1, an important component for mitigating ER stress. Therapeutic concentrations of valproate induce expression of WFS1 mRNA and activate the WFS1 promoter. In addition, WFS1 forms a complex with GRP94, an ER stress-response protein, in which valproate dose-dependently enhances its dissociation from GRP94.These results suggest that the therapeutic effects of valproate in bipolar disorder may be mediated by WFS1 expression and its dissociation from GRP94

CNVs in Three Psychiatric Disorders

BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25–0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD

Lack of association between XBP1 genotype and calcium signaling in the platelets of healthy subjects

Dysregulations of calcium (Ca) homeostasis may be involved in the pathophysiology of bipolar disorder. Enhanced Ca response to various agonists in peripheral blood cells is one of a few confirmed biological markers for bipolar disorder. Recently, a polymorphism of XBP1, a pivotal gene in the endoplasmic reticulum (ER) stress response, was shown to contribute to the genetic risk factor for bipolar disorder. Thus, in this study, we examined the relationship between the XBP1 gene polymorphism and the Ca signaling in the platelets of healthy controls. The present results suggest no significant difference in the basal Ca level or 5-HT-induced Ca mobilization among normal subjects with -116C/C, C/G and G/G genotypes. Further investigations are necessary to examine the relationship in the different peripheral blood cells and/or in larger samples from patients with bipolar disorder.http://www.sciencedirect.com/science/journal/0304394

Relationship between XBP1 genotype and personality traits assessed by TCI and NEO-FFI

There have been several researches on the role of personality in the pathophysiology of bipolar disorder. Recently, a polymorphism of XBP1, a pivotal gene in the endoplasmic reticulum (ER) stress response, was shown to contribute to the genetic risk factor for bipolar disorder. Therefore, in this study, we examined the relationship between the XBP1 gene polymorphism and the personality traits assessed by two self-rating scales, a shortened version of Temperament and Character Inventory (TCI) and NEO-Five Factor Inventory (NEO-FFI) in healthy subjects. The present results suggested that the XBP1 gene polymorphism was associated with the NEO-FFI score of neuroticism in female subjects. However, no significant differences in the other personality scale scores of both assessments were observed among normal subjects with -116C/C, C/G and G/G genotypes. Further investigations are necessary to examine the relationship in patients with bipolar disorder, or use full version of various self-rating personality assessments

Interactive effects of OXTR and GAD1 on envy-associated behaviors and neural responses.

Inequity aversion (negative feelings induced by outcome differences between the self and other) plays a key role in human social behaviors. The neurotransmitters oxytocin and GABA have been implicated in neural responses to inequity. However, it remains poorly understood not only how individual genetic factors related to oxytocin and GABA affect the neural mechanisms behind inequity aversion, but also how these genes interact. To address these issues, we examined relationships between genotypes, behavioral decisions and brain activities during the ultimatum game. We identified interactive effects between the polymorphisms of the oxytocin receptor gene (OXTR) and glutamate decarboxylase 1 gene for GABA synthesis (GAD1) on envy aversion (i.e., disadvantageous inequity aversion) and on envy-induced activity in the dorsal ACC (dACC). Thus, our integrated approach suggested interactive genetic effects between OXTR and GAD1 on envy aversion and the underlying neural substrates

Safety and real-world efficacy of lemborexant in the treatment of comorbid insomnia

Aim: To investigate the real-world effectiveness and safety of lemborexan for treating comorbid insomnia associated with other psychiatric disorders, and whether lemborexant helps reduce the dose of benzodiazepines (BZs). Methods: This retrospective observational study was conducted on outpatients and inpatients treated by physicians of Juntendo University Hospital Mental Clinic between April 2020 and December 2021. Results: Data of 649 patients who were treated with lemborexant were eventually enrolled. About 64.5% of patients were classified as the responder group. Response rates of ≥60% were recorded for most psychiatric disorders. Upon administration of lemborexant, diazepam-equivalent dose of BZs had been significantly reduced in participants (3.7 ± 8.2 vs. 2.9 ± 7.9, p < 0.001). The results of logistic regression analysis showed that outpatient (odds ratios: 2.310; 95% confidence interval [CI]: 1.32–4.05), shorter duration of BZ use (<1 year) (odds ratios: 1.512; 95% CI: 1.02–2.25), no adverse events (odds ratios: 10.369; 95% CI: 6.13–17.54), larger reduction of diazepam-equivalent dose of BZs upon introducing lemborexant prescription (odds ratios: 1.150; 95% CI: 1.04–1.27), and suvorexant was the replacement drug (odds ratios: 2.983; 95% CI: 1.44–6.19), which were significant predictors of good response. Conclusion: Although this is a retrospective and observational study with many limitations, our study results suggest that lemborexant is effective and safe