A Marked Effect of Electroconvulsive Stimulation on Behavioral Aberration of Mice with Neuron-Specific Mitochondrial DNA Defects

We developed transgenic (Tg) mice modeling an autosomally inherited mitochondrial disease, chronic progressive external ophthalmoplegia, patients with which sometimes have comorbid mood disorders. The mutant animals exhibited bipolar disorder-like phenotypes, such as a distorted day–night rhythm and a robust activity change with a period of 4–5 days, and the behavioral abnormalities were improved by lithium. In this study, we tested the effect of electroconvulsive stimulation (ECS) on the behavioral abnormalities of the model. Electroconvulsive therapy, which has long been used in clinical practice, provides fast-acting relief to depressive patients and drug-resistant patients. We performed long-term recordings of wheel-running activity of Tg and non-Tg mice. While recording, we administrated a train of ECS to mice, six times over two weeks or three times over a week. The treatment ameliorated the distorted day–night rhythm within three times of ECS, but it had no effect on the activity change with a period of 4–5 days in the female mice. To study the mechanism of the action, we investigated whether ECS could alter the circadian phase but found no influence on the circadian clock system. The potent and fast-acting efficacy of ECS in the mutant mice supports the predictive validity of the mice as a model of bipolar disorder. This model will be useful in developing a safe and effective alternative to lithium or electroconvulsive therapy

Mood Stabilizers and Antipsychotics for Acute Mania: Systematic Review and Meta-Analysis of Augmentation Therapy vs Monotherapy From the Perspective of Time to the Onset of Treatment Effects

Background: Existing meta-analytic evidence on bipolar mania treatment has revealed that augmentation therapy (AUG) with antipsychotics and mood stabilizers is more effective than monotherapy. However, the speed of the onset of treatment effects and subsequent changes in risk/benefit are unclear. Methods: We searched the Cochrane CENTRAL, MEDLINE, and EMBASE databases until January 2021. Our primary outcomes were response and tolerability. We set 3 time points: 1, 3, and 6 weeks after randomization. Results: Seventeen studies compared AUG therapy and MS monotherapy (comparison 1), and 8 studies compared AUG therapy and antipsychotics monotherapy (comparison 2). In comparison 1, AUG therapy resulted in significantly more responses than monotherapy, with an odds ratio of 1.45 (95% confidence interval [CI]: 1.17 to 1.80) at 3 weeks and 1.59 (95% CI: 1.28 to 1.99) at 6 weeks. Significant improvement was observed in the first week with a standardized mean difference of −0.25 (95% CI: −0.38 to −0.12). In comparison 2, AUG therapy was significantly more effective than monotherapy, with an odds ratio of 1.73 (95% CI: 1.25 to 2.40) at 3 weeks and 1.74 (95% CI: 1.11 to 2.73) at 6 weeks. Significant improvement was observed in the first week with an standardized mean difference of −0.23 (95% CI: −0.39 to −0.07). Regarding tolerability, there was no significant difference between AUG therapy and monotherapy at 3 and 6 weeks in both comparisons. Conclusions: Early AUG therapy should be considered, as it has shown efficacy from weeks 1 to 6, although attention to side effects is necessary for acute mania treatment

Cyclotraxin-B, the First Highly Potent and Selective TrkB Inhibitor, Has Anxiolytic Properties in Mice

In the last decades, few mechanistically novel therapeutic agents have been developed to treat mental and neurodegenerative disorders. Numerous studies suggest that targeting BDNF and its TrkB receptor could be a promising therapeutic strategy for the treatment of brain disorders. However, the development of potent small ligands for the TrkB receptor has proven to be difficult. By using a peptidomimetic approach, we developed a highly potent and selective TrkB inhibitor, cyclotraxin-B, capable of altering TrkB-dependent molecular and physiological processes such as synaptic plasticity, neuronal differentiation and BDNF-induced neurotoxicity. Cyclotraxin-B allosterically alters the conformation of TrkB, which leads to the inhibition of both BDNF-dependent and -independent (basal) activities. Finally, systemic administration of cyclotraxin-B to mice results in TrkB inhibition in the brain with specific anxiolytic-like behavioral effects and no antidepressant-like activity. This study demonstrates that cyclotraxin-B might not only be a powerful tool to investigate the role of BDNF and TrkB in physiology and pathology, but also represents a lead compound for the development of new therapeutic strategies to treat brain disorders

An Association Analysis between Mitochondrial DNA A10398G Polymorphism and Temperament in Japanese Young Adults

The mitochondrial (mt) DNA C5178A and A10398G polymorphisms have been reported to be associated with mental disorders such as bipolar disorder. However, the effects of these polymorphisms on temperament in healthy people are poorly understood. Evaluating healthy subjects can have the advantage of providing new strategies for maintaining psychological health and preventing mental illness. We examined the association between mtDNA polymorphisms and temperament in Japanese students. There was no significant difference in examined temperament when analysed by genotypes, 5178–10398 haplotypes, or sex. The subgroup analysis based on sex indicated that there was an interactive effect of the mtDNA A10398G polymorphism and sex on anxiety and obsession. This finding is preliminary and cannot exclude the possibility of false-positive due to small sample size (144 subjects) and multiple statistical testing. Further studies involving a larger sample size or other ethnic groups are necessary to confirm that mtDNA A10398G polymorphism can be a genetic factor for temperament

Defining Hypo-Methylated Regions of Stem Cell-Specific Promoters in Human iPS Cells Derived from Extra-Embryonic Amnions and Lung Fibroblasts

BACKGROUND: Human induced pluripotent stem (iPS) cells are currently used as powerful resources in regenerative medicine. During very early developmental stages, DNA methylation decreases to an overall low level at the blastocyst stage, from which embryonic stem cells are derived. Therefore, pluripotent stem cells, such as ES and iPS cells, are considered to have hypo-methylated status compared to differentiated cells. However, epigenetic mechanisms of "stemness" remain unknown in iPS cells derived from extra-embryonic and embryonic cells. METHODOLOGY/PRINCIPAL FINDINGS: We examined genome-wide DNA methylation (24,949 CpG sites covering 1,3862 genes, mostly selected from promoter regions) with six human iPS cell lines derived from human amniotic cells and fetal lung fibroblasts as well as two human ES cell lines, and eight human differentiated cell lines using Illumina's Infinium HumanMethylation27. A considerable fraction (807 sites) exhibited a distinct difference in the methylation level between the iPS/ES cells and differentiated cells, with 87.6% hyper-methylation seen in iPS/ES cells. However, a limited fraction of CpG sites with hypo-methylation was found in promoters of genes encoding transcription factors. Thus, a group of genes becomes active through a decrease of methylation in their promoters. Twenty-three genes including SOX15, SALL4, TDGF1, PPP1R16B and SOX10 as well as POU5F1 were defined as genes with hypo-methylated SS-DMR (Stem cell-Specific Differentially Methylated Region) and highly expression in iPS/ES cells. CONCLUSIONS/SIGNIFICANCE: We show that DNA methylation profile of human amniotic iPS cells as well as fibroblast iPS cells, and defined the SS-DMRs. Knowledge of epigenetic information across iPS cells derived from different cell types can be used as a signature for "stemness" and may allow us to screen for optimum iPS/ES cells and to validate and monitor iPS/ES cell derivatives for human therapeutic applications

Low- and Medium-Dispersion Spectropolarimetry of Nova V475 Sct (Nova Scuti 2003): Discovery of an Asymmetric High-Velocity Wind in a Moderately Fast Nova

We present low-resolution ($R\sim 90$) and medium-resolution ($R\sim 2500$) spectropolarimetry of Nova V475 Sct with the HBS instrument, mounted on the 0.91-m telescope at the Okayama Astrophysical Observatory, and with FOCAS, mounted on the 8.2-m Subaru telescope. We estimated the interstellar polarization toward the nova from the steady continuum polarization components and H$\alpha$ line emission components. After subtracting the interstellar polarization component from the observations, we found that the H$\alpha$ emission seen on 2003 October 7 was clearly polarized. In the polarized flux spectrum, the H$\alpha$ emission had a distinct red wing extending to $\sim +4900$ km s$^{-1}$ and a shoulder around $+3500$ km s$^{-1}$, showing a constant position angle of linear polarization \theta_{\rm *}\simeq 155\arcdeg\pm 15\arcdeg. This suggests that the nova had an asymmetric outflow with a velocity of $v_{\rm wind}\simeq 3500$ km s$^{-1}$ or more, which is six times higher than the expansion velocity of the ionized shell at the same epoch. Such a high-velocity component has not previously been reported for a nova in the `moderately fast' speed class. Our observations suggest the occurrence of violent mass-loss activity in the nova binary system even during the common-envelope phase. The position angle of the polarization in the H$\alpha$ wing is in good agreement with that of the continuum polarization found on 2003 September 26 ($p_{\rm *}\simeq 0.4$--0.6 %), which disappeared within the following 2 d. The uniformity of the PA between the continuum polarization and the wing polarization on October 7 suggests that the axis of the circumstellar asymmetry remained nearly constant during the period of our observations.Comment: 27 pages, 7 figures, accepted for publication in A

Double-Blind, Placebo-Controlled Study of Lurasidone Monotherapy for the Treatment of Bipolar I Depression

Aim:Previous studies conducted primarily in the USA and Europe have demonstrated the efficacy and safety of lurasidone 20-120 mg/day for the treatment of bipolar I depression. The aim of the current study was to evaluate the efficacy and safety of lurasidone monotherapy for the treatment of bipolar I depression among patients from diverse ethnic backgrounds, including those from Japan. Methods:Patients were randomly assigned to double‐blind treatment for 6 weeks with lurasidone, 20-60 mg/day (n = 184) or 80-120 mg/day (n = 169), or placebo (n = 172). The primary end‐point was change from baseline to Week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS). Results:Lurasidone treatment significantly reduced mean MADRS total scores from baseline to Week 6 for the 20-60‐mg/day group (−13.6; adjusted P = 0.007; effect size = 0.33), but not for the 80-120‐mg/day group (−12.6; adjusted P = 0.057; effect size = 0.22) compared with placebo (−10.6). Treatment with lurasidone 20-60 mg/day also improved MADRS response rates, functional impairment, and anxiety symptoms. The most common adverse events associated with lurasidone were akathisia and nausea. Lurasidone treatments were associated with minimal changes in weight, lipids, and measures of glycemic control. Conclusion: Monotherapy with once daily doses of lurasidone 20-60 mg, but not 80-120 mg, significantly reduced depressive symptoms and improved functioning in patients with bipolar I depression. Results overall were consistent with previous studies, suggesting that lurasidone 20-60 mg/day is effective and safe in diverse ethnic populations, including Japanese

Brain metabolism in bipolar patients measured by Magnetic resonance spectroscopy

科学研究費補助金研究成果報告書研究種目: 基盤研究(C)研究期間: 1995～1997課題番号: 07671065研究代表者: 山田 尚登（滋賀医科大学・医学部・助教授）研究分担者: 加藤 忠史（滋賀医科大学・医学部・助手）研究分担者: 塩入 俊樹（滋賀医科大学・医学部・助手）研究分担者: 村下 淳（滋賀医科大学・医学部・助手