Published papers

INTRODUCTION: Late-life mood disorders (LLMDs) may represent prodromal manifestations of neurodegenerative dementia; however, the neuropathological basis of LLMDs, including depression and bipolar disorder, remains unclear. We aimed to investigate the involvement of Alzheimer's disease (AD) and non-AD tau pathologies in LLMD participants. METHODS: Fifty-two LLMD participants and 47 age- and sex-matched healthy controls (HCs) underwent tau and amyloid beta (Aβ) positron emission tomography (PET) imaging using 18F-florzolotau and 11C-Pittsburgh compound B. Additionally, we conducted a clinicopathological correlation analysis in 208 autopsy cases, including various neurodegenerative diseases. RESULTS: LLMD participants were more likely to be tau PET and Aβ PET positive than HCs. The PET results were supported by the post mortem results that showed a higher likelihood of diverse tauopathies in patients with late-life mania or depression than those without. DISCUSSION: Our PET and autopsy assays suggest that AD and diverse non-AD tau pathologies might underlie the neuropathological basis of some LLMD cases. Highlights: Late-life mood disorders (LLMDs) may represent prodromal states of dementia. The neuropathological basis of LLMDs remains unclear. LLMD subjects were highly likely to be tau positron emission tomography (PET) positive. Brain bank data supported our PET results. Alzheimer's disease (AD) and diverse non-AD tau pathologies can contribute to LLMDs.

Background: Sunlight contains ultraviolet B (UVB) radiation that triggers the production of vitamin D by skin. Vitamin D has widespread effects on brain function in both developing and adult brains. However, many people live at latitudes (about > 40 N or S) that do not receive enough UVB in winter to produce vitamin D. This exploratory study investigated the association between the age of onset of bipolar I disorder and the threshold for UVB sufficient for vitamin D production in a large global sample. Methods: Data for 6972 patients with bipolar I disorder were obtained at 75 collection sites in 41 countries in both hemispheres. The best model to assess the relation between the threshold for UVB sufficient for vitamin D production and age of onset included 1 or more months below the threshold, family history of mood disorders, and birth cohort. All coefficients estimated at P ≤ 0.001. Results: The 6972 patients had an onset in 582 locations in 70 countries, with a mean age of onset of 25.6 years. Of the onset locations, 34.0% had at least 1 month below the threshold for UVB sufficient for vitamin D production. The age of onset at locations with 1 or more months of less than or equal to the threshold for UVB was 1.66 years younger. Conclusion: UVB and vitamin D may have an important influence on the development of bipolar disorder. Study limitations included a lack of data on patient vitamin D levels, lifestyles, or supplement use. More study of the impacts of UVB and vitamin D in bipolar disorder is needed to evaluate this supposition.

Background: Sunlight has profound impacts on physical and mental health, beyond vision, including effects on circadian rhythms, alertness, mood, and sleep. A family history of any mood disorders is strongly associated with psychiatric disorders including bipolar disorder. The purpose of this study was to evaluate the association between a family history of any mood disorder in patients with bipolar I disorder and solar insolation at varied international onset locations. Methods: Data for this analysis were available from 5842 patients with a diagnosis of bipolar I disorder obtained at 83 collection sites in both hemispheres. This included 4752 patients from 71 collection sites in the northern hemisphere and 1090 patients from 12 collection sites in the southern hemisphere. Patient data variables were obtained from records or interviews. Solar insolation data were obtained from The National Aeronautics and Space Administration (NASA) Power database for each onset location, and the ratio of the mean monthly minimum/mean monthly maximum solar insolation was calculated. Typically, the ratio is largest near the equator (little yearly change in solar insolation) and smallest near the poles (large yearly change in solar insolation). Results: A significant relationship was found between a family history of any mood disorder, the ratio of the mean monthly minimum/mean monthly maximum solar insolation, and gender. The odds of a family history of mood disorder increased as patient location nears the poles and decreased near the equator. Female gender also increased the odds of having a family history of a mood disorder. Conclusions: This study highlighted the association between family history, solar insolation, and gender in international patients with bipolar I disorder. Given the profound effects of sunlight on human health, the family of patients with bipolar disorder who live in the same location with the same solar insolation, and especially females, may be at increased risk for a mood disorder.

The COVID-19 pandemic has increased germ aversion, an aversive affective response to a high likelihood of pathogen transmission. While psychological factors are associated with chronic pain, the relationship between germ aversion and chronic pain remains unexplored. This study aimed to examine the relationship between germ aversion and new-onset and prognosis of chronic pain using longitudinal data collected during the COVID-19 pandemic. We conducted web-based surveys of full-time workers at baseline and after three months. Data were collected on demographic characteristics, psychological factors, and chronic pain. Germ aversion was assessed using a modified Perceived Vulnerability to Disease scale. We analyzed responses from 1265 panelists who completed the survey twice. The prevalence of chronic low back pain (CLBP) and chronic neck and shoulder pain (CNSP) was associated with sex, short sleep duration, psychological distress, loneliness, and germ aversion. Stratified analyses showed that germ aversion was a risk factor for CLBP at three months in both individuals with and without CLBP at baseline, and for CNSP at three months in those with CNSP at baseline, even after adjustment for confounders. In conclusion, this preliminary study suggests that high germ aversion is a risk factor for CLBP and CNSP in young and middle-aged workers.

Background/Objectives: Mindfulness-Based Cognitive Therapy (MBCT) is a well-documented treatment option for chronic pain. However, few studies have examined the emotional state experienced by participants with chronic pain during the sessions. This study aimed to assess the trajectory of mood experiences in an MBCT program and evaluate the effect on temporal mood state. Methods: The Temporary Mood Scale (TMS) was used to assess vigor, fatigue, anger-hostility, depression-dejection, tension-anxiety, and confusion before and after each MBCT session from July 2018 to May 2019. A total of 33 patients with chronic pain who attended the MBCT program were included in the study. A mixed-effect model was used to identify single-session and overall effects on each mood state. Pearson’s correlation analysis was used to examine the associations between changes in the six mood states and baseline conditions, including pain-related factors. Results: The mixed-effect model identified significant improvements in single-session effects on all mood states (p < 0.001). Significant overall effects were identified on vigor (p < 0.01), depression-dejection (p < 0.01), tension-anxiety (p < 0.001), and confusion (p < 0.05) states throughout the sessions. Moreover, participants with higher tension-anxiety at baseline showed significantly greater improvements in anger-hostility (p < 0.05), depression-dejection (p < 0.01), tension-anxiety (p < 0.05), and confusion (p < 0.01). Conclusions: Individual sessions and the overall MBCT program significantly improved the mood states of patients with chronic pain. Patients with higher tension-anxiety are likely to be effective treatment targets for MBCT programs.

Background: The coronavirus disease 2019 (COVID-19) pandemic has resulted in a total upending of our daily lives. While anxiety and depression were frequently reported among the general population, the pandemic’s impact on patients with mental health problems remains unknown. Methods: A cross-sectional questionnaire survey involving 1,166 patients was conducted at one psychiatric hospital and one mental health clinic. Results: Symptom deterioration was reported in 23% to 34% of the patients and 9% to 20% reported increase in drug dosage. No significant differences were reported in these items among diagnostic categories. Patients with F3 (mood disorders) reported more psychological stress during the pandemic’s beginning and during the emergency. Patients with F2 (schizophrenia, schizotypal, and delusional disorders) did online shopping and meetings less frequently, and reported poorer adherence of 3C’s, while mask management was stricter in patients with F4 (neurotic, stress-related, and somatoform disorders). Symptom deterioration was significantly associated with increase in drug dosage, new physical symptoms, anxiety unrelated to COVID-19, stress at the beginning of pandemic, stress during the ‘state of emergency’, poor adaptability to environmental change, daily life changes, decrease in sleeping time, and decrease in time spent outside. Conclusion: One third of patients reported symptom deterioration during the pandemic, which was associated with stress and daily life changes. Patients with good adaptability to environmental changes might resilient against symptom deterioration. Providing continuous support to help patients manage their daily life in this COVID-19 era may minimize the risk of symptom deterioration.

Objective: Corticosteroids can cause psychiatric symptoms known as corticosteroid-induced psychiatric disorders (CIPDs). Little is known regarding the relationship between intravenous pulse methylprednisolone (IVMP) and CIPDs. Therefore, we aimed to examine the relationship between corticosteroid use and CIPDs in this retrospective study. Methods: Patients who were prescribed corticosteroids during their hospitalization at a university hospital and referred to our consultation-liaison service were selected. Patients diagnosed with CIPDs according to the ICD-10 codes were included. The incidence rates were compared between patients receiving IVMP and those receiving any other corticosteroid treatment. The association between IVMP and CIPDs was examined by classifying patients with CIPD into three groups according to the use of IVMP and timing of CIPD onset. Results: Of the 14,585 patients who received corticosteroids, 85 were diagnosed with CIPDs, with an incidence rate of 0.6%. Among the 523 patients who received IVMP, the incidence rate of CIPDs was 6.1% (n = 32), which was significantly higher than that in patients receiving any other corticosteroid treatment. Among the patients with CIPDs, 12 (14.1%) developed CIPDs during IVMP, 19 (22.4%) developed CIPDs after IVMP, and 49 (57.6%) developed CIPDs without IVMP. There was no significant difference in the doses at the time of CIPD improvement among the three groups when we excluded one patient whose CIPD improved during IVMP. Conclusion: Patients receiving IVMP were more likely to develop CIPDs than those who did not receive IVMP. Furthermore, corticosteroid doses at the time of improvement of CIPDs were constant, regardless of IVMP use.

Background A key defining feature of delusions in psychiatric practice is their incorrigibility, reflecting marked cognitive inflexibility. Among cognitive biases in schizophrenia, belief inflexibility explains the maintenance of delusions, whereas the jumping-to-conclusions bias relates to delusion formation. However, belief inflexibility once a conclusion has been reached, which may more directly reflect the maintenance process following formation, has not yet been investigated. Methods Twenty-nine patients with schizophrenia (SZ) and twenty-eight healthy controls (HC) completed a modified beads task that separated phases reflecting cognitive processes involved in delusion formation (Phase 1) and maintenance (Phase 2). In Phase 1, following the classical beads task paradigm, beads were drawn one by one from one of two jars. After each draw, participants were asked whether they could state a conclusion about which jar was being used. Phase 1 ended once a conclusion was reached with sufficient confidence. In Phase 2, bead drawing continued, and participants judged whether to withdraw their Phase 1 conclusion. In some trials, subsequent bead colours contradicted the conclusion, favouring withdrawal. Results In Phase 1, the number of beads required to reach a conclusion did not differ significantly between groups. In Phase 2, however, SZ required significantly more beads to withdraw their prior conclusion, with this delayed withdrawal being particularly evident in those with delusion-predominant symptoms. Conclusions These findings are consistent with the notion that post-conclusion belief inflexibility contributes to the maintenance of delusions, providing empirical support for models of delusion maintenance distinct from those addressing delusion formation.

Background and Objective: Corticosteroids (CSs) are widely prescribed but can induce psychiatric adverse effects (depressive, manic, psychotic, and anxiety symptoms). This systematic review aimed to quantify the association between CS use and psychiatric symptoms and to explore potential moderators across clinical contexts. Methods: We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review and meta-analysis. MEDLINE and Embase were searched through 10 October, 2025, and 19 hand-searched records were also screened. We included observational studies in medical CS users and excluded sex steroids, neonatal exposure, prescription-only outcomes, purely objective outcomes, sleep/cognition/delirium-focused studies, CS deficiency, withdrawal, and studies confounded by co-medications; randomized controlled trials were excluded by design. Two reviewers screened studies, extracted data, and assessed risk of bias with the Newcastle-Ottawa Scale. Certainty of evidence for each pooled outcome was additionally evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Pairwise meta-analyses pooled standardized mean differences and odds ratios using random-effects models; I2 quantified heterogeneity. The acute phase was operationally defined as ≤ 8 weeks after CS initiation. An exploratory meta-regression across six studies (seven groups) examined dose, duration, cumulative dose, age, and sex. Results: Seventy-three studies (total N = 3,759,659) were included (22 cross-sectional, 31 cohort, 12 pre-post, 2 case-control, 2 registry, and 4 prospective patient-as-own-control investigations comparing outcomes during on-CS vs off-CS periods). Compared with non-users, CS use was associated with higher depressive symptom scores (standardized mean difference = 0.92, 95% confidence interval [CI] 0.40–1.45; p < 0.001; I2 = 89%; seven studies; n = 1403; eight groups). During the operationally defined acute phase (≤ 8 weeks after CS initiation), manic symptoms were more frequent than depressive symptoms (six studies; n = 1086; odds ratio = 2.42, 95% CI 1.48–3.97; p < 0.001; I2 = 0%). A single-arm meta-analysis estimated psychotic symptoms in 2.4% of CS users (95% CI 0.76–7.26; six studies; n = 1206). Anxiety showed no significant association with CS use (standardized mean difference = 0.13, 95% CI − 0.24 to 0.51; p = 0.26; I2 = 7%; three studies; n = 1251). Overall study quality (Newcastle-Ottawa Scale) was generally moderate to high, whereas certainty of evidence according to GRADE was generally low to very low across pooled outcomes. The exploratory meta-regression suggested that higher daily dose and older age were associated with greater depressive severity; by contrast, cumulative dose, treatment duration, and sex showed no significant associations, and these moderator findings remain exploratory. Conclusions: Corticosteroid use is associated with more severe depressive symptoms, and manic symptoms may predominate during acute treatment; psychotic reactions are uncommon. Dose and age may modulate depressive severity, but these moderator findings should be interpreted cautiously. Routine monitoring for mood and psychotic changes, especially early after initiation and in higher-dose or older patients, is warranted.

Background: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. Methods: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun’s electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). Results: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p < 0.01. Conclusion: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed.

Background: While the symptom of “I am already dead” is a hallmark of Cotard's syndrome, also known as nihilistic delusions, the symptom of “you are already dead” has been neglected. Case presentation: A woman aged in her 60s diagnosed with schizophrenia was admitted to our hospital for psychotic symptoms, including delusions of reference, delusions of guilt, auditory hallucinations, cenesthetic hallucinations, agitation, depression, suicidal ideation, and catatonia. During hospitalization, her cenesthetic hallucinations progressed to include nihilistic delusions. She described cenesthetic hallucinations along with various delusional descriptions, including the belief that various objects, such as spoons, irons, nails, rulers, bins, and coins, were inside her body and that her body was being burned or in danger of exploding. She also claimed an altered sense of her own body, that her body was larger than normal or reversed. Moreover, she reported nihilistic delusions that her face and body did not exist, that her heart was not functioning, and that she was going to die soon or was already dead. She occasionally refused to eat because of the feeling of being dead. Notably, during a severe episode, she claimed that a doctor in front of her was dead. Clozapine was effective in improving her symptoms. Ultimately, the patient regained her sense of being alive and acknowledged that the doctor was alive. Conclusion: We report the case of a patient presenting with nihilistic delusions regarding both self and others, along with prior cenesthetic hallucinations. Aberrant interoceptive processing could be a potential link between these two forms of nihilistic delusions.

Background: The rate of suicide attempts by patients with bipolar disorder is high. In addition to patient and country specific factors, environmental factors may contribute to suicidal behavior. Sunlight has multiple diverse impacts on human physiology and behavior. Solar insolation is defined as the electromagnetic energy from the sun striking a surface area on earth. We previously found that a large change in solar insolation between the minimum and maximum monthly values was associated with an increased risk of suicide attempts in patients with bipolar I disorder. Methods: The association between solar insolation and a history of suicide attempts in bipolar disorder was again investigated using an international database with 15% more data and more sites at diverse locations and countries. Results: Data were available from 5641 patients with bipolar I disorder living at a wide range of latitudes in 41 countries in both hemispheres. A large change in solar insolation between the minimum and maximum monthly values was associated with a history of suicide attempts in patients with bipolar I disorder, a replication of our prior analysis. The estimated model also associated state sponsored religion in the onset country, female gender, a history of alcohol or substance abuse, and being part of a younger birth cohort with a history of suicide attempts. Conclusions: A large change between the minimum and maximum monthly values of solar insolation was associated with a history of suicide attempts in bipolar I disorder, replicating our prior research. Physicians should be aware that daylight has wide ranging physiological and psychiatric impacts, and that living with large changes in solar insolation may be associated with an increased suicide risk.

Objective: Circadian rhythm disruption is commonly observed in bipolar disorder (BD). Daylight is the most powerful signal to entrain the human circadian clock system. This exploratory study investigated if solar insolation at the onset location was associated with the polarity of the first episode of BD I. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area of the Earth. Methods: Data from 7488 patients with BD I were collected at 75 sites in 42 countries. The first episode occurred at 591 onset locations in 67 countries at a wide range of latitudes in both hemispheres. Solar insolation values were obtained for every onset location, and the ratio of the minimum mean monthly insolation to the maximum mean monthly insolation was calculated. This ratio is largest near the equator (with little change in solar insolation over the year), and smallest near the poles (where winter insolation is very small compared to summer insolation). This ratio also applies to tropical locations which may have a cloudy wet and clear dry season, rather than winter and summer. Results: The larger the change in solar insolation throughout the year (smaller the ratio between the minimum monthly and maximum monthly values), the greater the likelihood the first episode polarity was depression. Other associated variables were being female and increasing percentage of gross domestic product spent on country health expenditures. (All coefficients: P ≤ 0.001). Conclusion: Increased awareness and research into circadian dysfunction throughout the course of BD is warranted.