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Bipolar disorder is a chronic disorder characterized by fluctuations in mood state and energy and recurrent episodes of mania/hypomania and depression. Bipolar disorder may be regarded as a neuro-progressive disorder in which repeated mood episodes may lead to cognitive decline and dementia development. In the current review, we employed genome-wide association studies to comprehensively investigate the genetic variants associated with bipolar disorder and dementia. Thirty-nine published manuscripts were identified: 20 on bipolar disorder and 19 on dementia. The results showed that the genes CACNA1C, GABBR2, SCN2A, CTSH, MSRA, and SH3PXD2A were overlapping between patients with bipolar disorder and dementia. In conclusion, the genes CACNA1C, GABBR2, SCN2A, CTSH, MSRA, and SH3PXD2A may be associated with the neuro-progression of bipolar disorder to dementia. Further genetic studies are needed to comprehensively clarify the role of genes in cognitive decline and the development of dementia in patients with bipolar disorder.

Abstract Bright light exposure (BL) induces neurogenesis in the rat hippocampal dentate gyrus (DG). We had previously conducted a randomized controlled trial (RCT) in which a 4-week period of BL in healthy participants resulted in increased volume of the left DG-head. This study aimed to investigate the effects of BL on the DG in patients with mood disorders. A 4-week RCT was conducted in which patients with mood disorders were randomly assigned to either a BL group (10,000 lx) or dim light exposure group (DL group; 50 lx). All patients underwent clinical assessment and magnetic resonance imaging at baseline and after the intervention. The study registration number is UMIN000019220. Our final sample included 24 patients (BL group, n = 12; DL group, n = 12). A significant effect of time and group was detected in the volumes of the left DG-head (F (1, 22) = 11.6, partial η2 = 0.35, p = 0.003) and left DG-total (left DG-total = left DG-head + left DG-body; [F (1, 22) = 6.5, partial η2 = 0.23, p = 0.02]). Additionally, the BL group demonstrated a significant increase in the volume of the left DG-head (95% CI: −5.4 to −1.6, d = 1.2, p = 0.002) and left DG-total (95% CI: −6.3 to −1.5, d = 1.06, p = 0.005) as well as a positive correlation between the percentage change in the volume of the left DG-total and the percentage change in the scores of the mood visual analog scale (r = 0.58, p = 0.04). In conclusion, our study results suggest that compared to DL, BL leads to a significantly greater increase in the left DG volume in patients with mood disorders. This increase in the left DG volume may be associated with mood improvement in the patients.

Abstract Background Benzodiazepines, such as flunitrazepam, may be at risk of disinhibition, leading to aggressiveness, impulsivity, self‐harm, and possibly suicide attempts, whereas ramelteon may be far from disinhibition. Case Presentation In a 43‐year‐old female with primary insomnia, flunitrazepam alone did not induce any type of disinhibition, but the addition of ramelteon to flunitrazepam brought about disinhibition, leading to aggressiveness and finally to her suicide attempt. Her disinhibition rapidly subsided as soon as ramelteon alone was discontinued. Conclusion These findings suggest that a suicide attempt may occur during ramelteon and flunitrazepam combination in a susceptible patient.

Parental nurturing attitudes influence children and are linked to the establishment of self-esteem. Females who have experienced poor maternal care during their childhood may have low self-esteem, and this factor may significantly augment the likelihood of depression. Particularly, childhood maltreatment among individuals with bipolar disorder is associated with unfavorable clinical features, such as a heightened risk of severe manic, depressive, or psychotic symptoms, as well as suicide attempts. Here, we report a case of a woman with bipolar disorder who had self-reported low self-esteem due to poor maternal care, which subsequently improved via an existential approach. This existential approach confers meaning to the lives of every individual, even in the face of adversity. Our findings suggest that the existential approach may enable the discovery of more positive life values during times of hardship and could improve self-reported low self-esteem due to poor maternal and change the way of life in patients with bipolar disorder.

Abstract Background Although clozapine is the optimal drug for patients with treatment-resistant schizophrenia, the drug has harmful adverse effects such as leukopenia. Adenine and cepharanthine are known to be effective for radiation- or drug-induced leukopenia. Furthermore, ninjin-yoei-to, a Chinese herbal medicine, augments the production of granulocyte-macrophage colony-stimulating factor. Thus, these drugs may be useful for clozapine-induced leukopenia. Case presentation A 21 years-old woman with schizophrenia was hospitalized for initiation of clozapine treatment. Despite concomitant use of adenine, cepharanthine, and lithium carbonate having activities of increasing leukocytes, a decrease in leukocyte counts occurred after the initiation of clozapine. Additional administration of ninjin-yoei-to increased leukocyte counts, which prevented the development of leukopenia. Conclusions This is the first case that concomitant use of adenine, cepharanthin, and ninjin-yoei-to exhibited the effectiveness of reversing the decrease in leukocytes caused by clozapine. Monitoring leukocyte counts and preventing leukopenia are essential for successful treatment with clozapine for refractory schizophrenia. These medicines may be a potential option for preventing clozapine-induced leukopenia.

BackgroundSince our previous investigation on the effects of trace lithium, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA) on deliberate self-harm and suicide attempts in 2018, to our knowledge, no replication study has been conducted on this topic.Subjects and methodsWe increased 37 new patients and totally 234 patients were re-analyzed to further investigate the association of suicide-related behaviors with levels of trace lithium, EPA, DHA, and AA in a different way to avoid multicollinearity.ResultsHigher lithium levels were significantly associated with fewer suicide attempts and deliberate self-harm, higher EPA levels were significantly associated with fewer deliberate self-harm, and higher AA levels were significantly associated with more deliberate self-harm.DiscussionAlthough the sample size was only slightly larger than the previous study, the present results were clearly different from the previous ones due to the use of different statistical analyses to avoid multicollinearity.ConclusionThe present findings suggest that naturally absorbed lithium may protect against suicide and deliberate self-harm, while naturally absorbed EPA may protect against deliberate self-harm. However, naturally absorbed AA may be a risk factor for deliberate self-harm.

During sickness absence, it appears necessary for psychiatric patients suffering from depression or bipolar disorder to undergo a psychiatric rehabilitation called the rework program that aids in work restoration and maintenance. However, few studies have investigated the effects of such a program and predictors of work restoration and maintenance in the participants. Here, we aimed to investigate the effects of a rework program as well as to examine whether cognitive function and mental state at the end of the rework program predict the probability of work restoration and maintenance and whether the frequency of rework program participation predicts successful work restoration and maintenance. The rework program included both patients absent from work and unemployed patients. Patients completed assessments including Trail Making Test Type B (TMT-B), the Wisconsin Card Sorting Test, and the Social Adaptation Self-Evaluation Scale just before graduating from the rework program. Simultaneously, their depressive state was assessed using the Hamilton Depression Rating scale. The patients were divided into the job group, comprising 94 patients who were able to restore their work or get a new job, and the non-job group, comprising 34 patients who were not able to do so. We found that the program was more effective in patients absent from work than in unemployed patients, TMT-B could predict work restoration and maintenance, and the frequency of rework program participation could predict work restoration but not work maintenance. Based on the findings, we propose “Yamashita’s criterion” where a TMT-B completion time of 70 s is the cut-off point for work restoration. The present findings may provide useful evidence that could aid in the further development of rework program(s).

Abstract Background Recently, we showed that 4-week mindfulness-based intervention (MBI) followed by 4-week existential approach (EXMIND) was as effective for developing self-compassion as 8-week MBI. This study aims to identify the predictors to EXMIND. Methods Of the 63 participants who completed the EXMIND group, 60 participants had baseline, 4-week, and 8-week total scores of the Self-Compassion Scale (SCS). Of the participants, 49 were female and 11 were male, with a mean age of 48.4 years. We investigated the participants’ intervention response patterns, then used analysis of variance to compared those patterns by age, gender, and the baseline scores of the Temperament Evaluation of Memphis, Pisa and San Diego Auto-questionnaire, the Temperament and Character Inventory, Mini-Mental State Examination, the Japanese Adult Reading Test, Young Mania Rating Scale, Hamilton Rating Scale for Depression, the Parental Bonding Instrument, and the Purpose in Life Test. In addition, multivariate logistic regression analysis was performed to identify any response pattern predictors. Results Participants were divided into 4 groups based on response patterns in the changes of total SCS scores of the EXMIND group. The first group consisted of 15 participants who responded positively to MBI, but negatively to the existential approach (A group). The second group consisted of 23 participants who responded negatively to MBI, but positively to the existential approach (B group). The third group consisted of 20 participants who responded positively to both MBI and the existential approach (C group). The fourth group consisted of only 2 participants who responded negatively to both MBI and the existential approach (D group). Participants who responded positively to both MBI and the existential approach (C group) reported more maternal overprotectiveness than the other participants (groups A, B, and D). Conclusions The present findings suggest that maternal overprotection may predict consistent improvement of self-compassion during EXMIND therapy.

The catalyst layer (CL) being the site of electrochemical reactions, is the core subunit of the membrane electrode assembly (MEA) in polymer electrolyte fuel cells (PEFCs). Thus, the porous structure of the CL has a significant influence on oxygen transfer resistance and affects the charge/discharge performance. In this study, the three-dimensional (3D) porous structure of the catalyst layer is reconstructed based on the deep convolutional generative adversarial network (DCGAN) deep learning method, utilizing focused ion beam scanning electron microscopy (FIB-SEM) microstructure graphs as training data. Each set of spatial-continuous microstructure graphs, generated by DCGAN with interpolation in latent space, is applied to build a unique 3D microstructure of the CL without the use of real FIB-SEM data. Meanwhile, distinct interpolation conditions in the DCGAN are discussed to optimize the ultimate structure by approaching the structural information to real data, including that of porosity, particle size distribution, and tortuosity. Moreover, the comparison of real and generated structural data reveal that the data generated by DCGAN shows an adjacency relationship with real data, indicating its potential applicability in the field of electrochemical simulation with reduced situational costs.

Abstract Background Most studies have reported that suicide mortality rates are negatively associated with lithium levels in tap water; however, a few studies showed either no association or a positive association. Thus, the association between suicide mortality and lithium levels in tap water remains controversial. To clarify the association, our study evaluated the association between lithium levels in tap water and suicide mortality rates in Miyazaki Prefecture of Japan, after adjusting for confounding factors. Methods We measured lithium levels in tap water across the 26 municipalities of Miyazaki Prefecture in Japan. We examined the standardized mortality ratio (SMR) for suicide in each municipality and used the data as the average suicide SMRs over 5 years (2009–2013). Weighted least-squares regression analysis, adjusted for the size of each municipality’s population, was used to investigate the association between lithium levels in tap water and suicide SMRs. In addition to a crude model, in an adjusted model, potential confounding factors (proportion of elderly people, proportion of one-person households, annual marriage rate, annual mean income, unemployment rate, the density of medical doctors per 100,000 people, annual total rainfall, and proportion of people with a college education or higher) were added as covariates. Results We showed that male and female suicide SMRs were not associated with lithium levels in tap water in Miyazaki Prefecture. After adjusting for confounders, male suicide SMRs were significantly and positively associated with the proportion of elderly people in the population and annual total rainfall, and female suicide SMRs were associated with the proportion of elderly people in the population. Conclusions No association between lithium levels in tap water and suicide mortality rates was found in Miyazaki Prefecture.

Existential psychotherapy is rooted in the European tradition of existential philosophy. Existential philosophers include Husserl and Heidegger, who were German, and Camus, Sartre, de Beauvoir, and Merleau-Ponty, who were French. Their works contain existentially ultimate themes such as death, freedom, meaninglessness, and isolation. Based on their knowledge of existential philosophy, Binswanger, Frankl, and Boss developed the earlier existential psychotherapies such as Dasein-analysis and Logotherapy, while May, Laing, Yalom, May, and Wong started later existential psychotherapies in the British and American culture. Focusing on patients with advanced cancer and/or terminal care, we found nine types of existential psychotherapies which were investigated using randomized controlled trials (RCTs): Meaning-Centered Group Psychotherapy (MCGP), Individual Meaning-Centered Psychotherapy (IMCP), Meaning-Making intervention (MMi), Meaning of Life Intervention, Managing Cancer and Living Meaningfully (CALM), Hope Intervention, Cognitive and Existential Intervention, Dignity Therapy, and Life-Review Interviews, from 19 relevant RCTs. All deal with death, meaninglessness, isolation, and freedom. Particularly, MCGP, IMCP, MMi, Meaning of Life intervention, and CALM emphasize finding and/or making meaning in the individual's life. The effects on existential or spiritual well-being were confirmed in MCGP, IMCP, Meaning of Life intervention, and Life-Review intervention although the number of studies were very few. In the other interventions, there were heterogenous findings and again the number of studies was very small. Further studies are required to investigate the effects of existential psychotherapy on patients with advanced cancer.

Abstract Objectives Although many antidepressants are available, they are not always used appropriately. For appropriate use of antidepressants, the old concept of a linear dose–response relationship, in which the dose is linearly increased to achieve a sufficient antidepressant effect, should be reconsidered. Furthermore, there is ongoing debate on the safe and appropriate use of antidepressants in patients with bipolar depression. Antidepressants may be used under certain conditions in patients with bipolar depression. These neglected—but not negligible—aspects of antidepressants have been discussed herein. Methods A narrative qualitative review Results Dose–response relationships of antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are not linear. They may be bell‐shaped, with efficacy initially increasing with an increase in dose but decreasing when the dose is increased beyond a certain point. Despite using international diagnostic criteria, uncertainty remains on whether operationally diagnosed depression is latent bipolar I depression, latent bipolar II depression, or true depression. Furthermore, operationally diagnosed bipolar II depression may be latent bipolar I depression, true bipolar II depression, or depression with false hypomanic episodes. Manic/hypomanic switches are most likely to occur in patients receiving tricyclic antidepressants, followed by those receiving serotonin and noradrenaline reuptake inhibitors and SSRIs, in that order. Also, these switches are most likely to occur in patients with bipolar I depression, followed by those with bipolar II depression and true depression, in that order. Conclusions Considering the diagnostic subtype of bipolar depression and antidepressant properties may help to determine the optimal treatment strategy.

Several predictors for work restoration and maintenance of restoration have been examined among employees with mood and/or anxiety disorders, but whether frequency of participation in a return-to-work (RTW) program can predict successful work restoration and maintenance remains unclear. In the present study, we attempted to investigate the hypothesis that the frequency of RTW program participation can predict successful work restoration and maintenance. Among seventy-seven patients attending an RTW program, the frequency of participation was positively associated with work restoration but not with maintenance. The result was in partial agreement (restoration) and partial disagreement (maintenance of restoration) with our hypothesis. Thus, the present study suggests that the frequency of participation in an RTW program can predict successful work restoration but not maintenance.

Abstract Objectives Bright light therapy (BLT) was reported as an effective adjunctive treatment option for bipolar disorder. Previous meta‐analytic study showed that augmentation treatment with light therapy significantly decreased the severity of bipolar depression. However, most of included studies were case–control studies and several of them focused on BLT that was provided in combination with sleep deprivation therapy. Methods In this meta‐analysis, we used several electronic databases to search the studies and included only randomized controlled trial (RCT) studies to compare BLT with control experimental groups for treating bipolar depression with pharmacological treatment to clarify the adjunctive efficacy of BLT. We searched the databases of EMBASE, MEDLINE, Scopus, The Cochrane Central Register of Controlled Trials, the Cumulative Index to Nursing and Allied Health Literature, and Clinicaltrials.gov for studies published in English until September 19, 2019. Two researchers conducted the literature screening, data extraction, and methodological quality assessment independently. The main outcome was the response rate and remission rate. We used the Review Manager 5.3 Software for the meta‐analysis. Results Four trials with a total of 190 participants (intervention: 94, control: 96) with bipolar depression were evaluated to gauge the effects of light therapy. The meta‐analysis showed risk ratios of 1.78 (95% CI 1.24–2.56, p = .002; I2 = 17%) demonstrating a significant effect of light therapy in the response rate of bipolar disorder. The meta‐analysis shows risk ratios of 2.03 (95% CI 0.48–8.59, p = .34; I2 = 67%) demonstrating no significant effect of light therapy in the remission rate of patients with bipolar disorder. None of the articles reported any serious adverse effects. Manic switch rate was 1.1% in the light therapy group and 1.2% in the control group. Conclusions Bright light therapy is an effective treatment for reducing depression symptoms among patients with bipolar depression.

Background In pharmacological doses, lithium successfully treats bipolar disorder and it can reduce violent crimes committed by individuals with this disorder. Aims To investigate whether naturally occurring lithium in drinking water lowers rates of violent crime in the general population. Method We examined lithium levels in the drinking water of the 274 municipalities of Kyushu Island in Japan and compared these with the crime rates in each municipality. Results We found that lithium levels were significantly and inversely associated with crime rates in 2009. Conclusions Our findings suggest that even very low levels of lithium in drinking water may play a role in reducing crime rates in the general population.

ObjectivesRecently, a 4-week mindfulness-based intervention followed by a 4-week existential approach was found to be as effective for increasing self-compassion as an 8-week mindfulness-based intervention. The purpose of the present study was to identify the factors that predicted change in self-compassion during the 8-week mindfulness-based intervention.MethodsFifty-seven of the 61 completers of the 8-week mindfulness-based intervention provided baseline, 4-week, and 8-week self-compassion scale scores. The mean age of the 47 females and 10 males was 49.6 years. Pearson’s correlation coefficients were generated on the associations between the change of total self-compassion scale scores from baseline to 8 weeks with age; gender; and the baseline scores on the Temperament Evaluation of Memphis, Pisa and San Diego Auto-questionnaire, Temperament and Character Inventory (TCI), Mini-Mental State Examination, Japanese Adult Reading Test, Young Mania Rating Scale, Hamilton Rating Scale for Depression, Parental Bonding Instrument, and purpose in life (PIL). Multiple regression analysis was performed to identify the predictors of the change in total self-compassion scale scores.ResultsNovelty seeking (TCI) was significantly and negatively associated with the change in total self-compassion scale scores, whereas the PIL scores were significantly and positively associated with the change in total self-compassion scale scores. Novelty seeking was not significantly associated with baseline, 4-week, or 8-week total self-compassion scale scores, whereas the PIL scores were significantly and positively associated with baseline, 4-week, and 8-week total self-compassion scale scores. The limitation of the present study was a relatively small number of subjects which deterred a more sophisticated analysis of the pathways involved.ConclusionsThe present findings suggest that more PIL and less novelty seeking predict improvements in self-compassion during mindfulness-based interventions, although novelty seeking might substantially predict the improvement but self-compassion scale and PIL might somewhat conceptually overlap.

BackgroundAccumulating evidence has shown that valproate has the greatest teratogenic potential for increasing the risk of major congenital malformations, such as neural tube defects, cleft palate, and neurodevelopmental disability. Although valproate is a pharmacological option for acute mania and is used as a stabilization drug for patients with bipolar disorder, some global guidelines state that valproate should not be used for girls or women of childbearing age with bipolar disorder. We investigated patterns in psychiatrists' prescription of valproate for bipolar female patients of childbearing age in Japan.MethodsFrom March to May 2018, we conducted a questionnaire survey among psychiatrists from all prefectures in Japan on psychiatric practice as it relates to major depression and bipolar disorder throughout women's life. The questionnaire had two parts: (1) assessment of participating psychiatrists' backgrounds and attitudes toward patients and (2) their patterns of prescription of psychotropics for female patients with mood disorders across generations and periods of pregnancy. Each question item had four response options: “not at all,” “rarely,” “sometimes,” and “frequently.” We examined patterns of prescription for childbearing-aged women (late adolescence/young adulthood aged 18–24 years, childbearing-age, older adults aged 25–49 years) and pregnant women.ResultsIn total, 571 psychiatrists (427 males, 123 females, and 21 unknowns) responded appropriately to the questionnaire, including 320 who examined at least one or more late adolescence/young adulthood bipolar women. Approximately 70% of psychiatrists answered that they frequently or sometimes prescribed valproate for bipolar women of childbearing age [late adolescence/young adulthood: not at all, n = 23 (7.5%); rarely, n = 69 (22.5%); sometimes, n =116 (37.8%); and frequently, n = 99 (32.2%); childbearing-age, older adults: not at all, n = 13 (2.7%); rarely, n = 67 (13.8%); sometimes, n = 185 (38.1%); and frequently, n = 220 (45.4%)]. The proportion of general hospital psychiatrists who answered “not at all” or “rarely” to the frequency of their valproate prescriptions was higher than that of psychiatrists working in other medical facilities (χ2(3) = 18.2, p < 0.001).ConclusionMost psychiatrists frequently or sometimes prescribe valproate for women of childbearing age in Japan.

Abstract Background Given the reported inverse association between light and depressive mood, ambient light may also be associated with some of the brain regions in healthy subjects. The present study aims to investigate the effects of ambient light on glucose metabolism in the brain. We used the data of 28 healthy participants of the no intervention group from our previous randomized controlled trial and analyzed the association between ambient light and [18F]-FDG uptake in the brain. Results A whole brain analysis revealed a cluster of [18F]-FDG uptake that was significantly and inversely associated with log-transformed ambient light in the left culmen of the left cerebellum vermis. After adjustment for age, gender and serum melatonin levels, there remained a significant cluster of [18F]-FDG uptake with log-transformed ambient light in the left cerebellar vermis. Conclusions The present findings suggest that the uptake of [18F]-FDG is significantly and inversely associated with ambient light in the left cerebellar vermis in healthy subjects. The cerebellar vermis may be involved in mood suppression which may be alleviated by light exposure where glucose uptake and metabolism in this area are decreased. Trial Registration This study is a secondary analysis of the previous randomized study which was registered as UMIN000007537. Retrospectively registered (March 20th, 2012).

Objectives: Mindfulness is a method of training the regulation of attention with non-judgmental acceptance that is linked to beneficial effects on health. The existential approach supports the uniqueness of each individual and helps to provide meaning to their lives. In this randomized controlled trial, we examined whether mindfulness-based intervention (MBI) and the existential approach could be combined sequentially and whether they operated antagonistically or cooperatively.Methods: One hundred thirty-seven participants aged 20 years or older without any severe mental disorders were randomly assigned (1:1), via an envelope method, to receive either 8-week MBI (N = 68) or 4-week MBI followed by 4-week existential approach (EXMIND) (N = 69). Participants were first allocated to a waiting-list group and subsequently randomized to the MBI group or EXMIND group. The primary outcome was self-compassion scale (SCS) total scores at 0, 4, and 8 weeks during intervention or waiting. The analyses were performed by linear mixed models for both primary and secondary outcomes following the intention-to-treat principle.Results: Both MBI and EXMIND groups had significantly increased SCS total scores compared to those of the waiting group, with mean SCS total scores of 2.3 (SD 3.0) in the MBI group and 2.1 (2.9) in the EXMIND group versus 0.3 (2.2) in the waiting group.Conclusions: Our findings suggest that MBI followed by existential approach are not antagonistic and may have cooperative effects, suggesting that EXMIND may be a useful treatment.

Major depression, because of its recurring and life-threatening nature, is one of the top 10 diseases for global disease burden. Major depression is still diagnosed on the basis of clinical symptoms in patients. The search for specific biological markers is of great importance to advance the method of diagnosis for depression. We examined the methylation profile of 2 CpG islands (I and IV) at the promoters of the brain-derived neurotrophic factor (BDNF) gene, which is well known to be involved in the pathophysiology of depression. We analyzed genomic DNA from peripheral blood of 20 Japanese patients with major depression and 18 healthy controls to identify an appropriate epigenetic biomarker to aid in the establishment of an objective system for the diagnosis of depression. Methylation rates at each CpG unit was measured using a MassArray® system (SEQUENOM), and 2-dimensional hierarchical clustering analyses were undertaken to determine the validity of these methylation profiles as a diagnostic biomarker. Analyses of the dendrogram from methylation profiles of CpG I, but not IV, demonstrated that classification of healthy controls and patients at the first branch completely matched the clinical diagnosis. Despite the small number of subjects, our results indicate that classification based on the DNA methylation profiles of CpG I of the BDNF gene may be a valuable diagnostic biomarker for major depression.