Association depressive symptoms with memory function and social capital before and during COVID-19 in community-dwelling older adults in rural Japan: A retrospective study with a longitudinal data.

OBJECTIVES: This study aimed to investigate the impact of memory function and social capital on depressive symptoms during the COVID-19 pandemic among older adults in rural Japan. METHODS: A retrospective study with longitudinal data was conducted during COVID-19 from May 2021 to November 2021 (T2) in Kurogawa, Japan. The candidate population for this study was 145 with the following requirements: (1) older individuals aged 65 years or above who were registered in the Kurogawa study, and (2) those with previous data (from November 2016 to February 2020; T1 as pre-pandemic). Memory function was assessed using the Wechsler Memory Scale-Revised Logical Memory II delayed recall part A (LM II-DR). Depressive symptoms were assessed using the Japanese version of the 15-item Geriatric Depression Scale (GDS-15). Social capital was evaluated through civic participation, social cohesion, and reciprocity. Fear of the COVID-19 infection (FCV-19S) was evaluated. RESULTS: The final analysis included 96 participants (mean age = 81.0 years, SD = 4.8) Multivariate analysis for GDS-15 score by Mixed Model Repeated Measures (MMRM) revealed significant associations between LM II-DR (ß = -0.13, 95% CI: -0.21-0.05, p = 0.002) and FCV-19S during COVID-19 (ß = 0.08, 95% CI: 0.01-0.15, p = 0.02) with GDS-15 score. However, civic participation, social cohesion and reciprocity were not associated with GDS-15 score. CONCLUSIONS: Among older adults in rural Japan, memory function and fear of the COVID-19 infection were significantly associated with depressive symptoms in MMRM analysis. However, social capital was not associated with depressive symptoms. This highlights the need to address memory function and fear of the COVID-19 infection in interventions for older adults during crises like the COVID-19 pandemic.

Association Between Antidiabetic Drugs and Delirium: A Study Based on the Adverse Drug Event Reporting Database in Japan.

BACKGROUND AND OBJECTIVE: Several associations between diabetes mellitus and delirium have been reported; however, they have been inconsistent, and evidence on the effects of antidiabetic medications on delirium is also limited. This study aimed to investigate whether the use of antidiabetic drugs is a risk factor for delirium development. METHODS: Using the Japanese Adverse Event Reporting Database, we analyzed 662,899 reports between 2004 and 2022. Reporting odds ratios (RORs) and 95% confidence intervals (CIs) for delirium associated with diabetes and using each antidiabetic medication were calculated after adjusting for potential confounders. RESULTS: Overall, 8892 of the reports analyzed were associated with delirium. A comparison of the incidence of delirium between patients with and without diabetes showed no significant difference, with 1.34% in patients without diabetes and 1.37% in those with diabetes. In each antidiabetic medication, signals for delirium were detected for sulfonylurea (crude ROR, 1.35; 95% CI 1.21-1.51) and insulin (crude ROR, 1.28; 95% CI 1.13-1.44). These results were maintained even after adjusting for factors with potential confounders (sulfonylurea: adjusted ROR, 1.75; 95% CI 1.54-2.00, insulin: adjusted ROR, 1.35; 95% CI 1.20-1.54). CONCLUSIONS: Our results suggest no association between diabetes and delirium; however, using sulfonylurea and insulin may be associated with delirium development. Nonetheless, these findings should be validated in future studies.

Evaluation of the delirium preventive effect of dual orexin receptor antagonist (DORA) in critically ill adult patients requiring ventilation with tracheal intubation at an advanced emergency center: A single-center, retrospective, observational study.

OBJECTIVE: ICU delirium reportedly contributes to increased mortality attributed to underlying diseases, long-term cognitive decline, and increased healthcare costs. Dual orexin receptor antagonists (DORAs), suvorexant and lemborexant, have been suggested for preventing ICU delirium. Although ventilator management is a risk factor for delirium, no study has examined the efficacy of suvorexant and lemborexant in preventing delirium in critically ill patients requiring ventilation. Thus, we retrospectively evaluated the efficacy of DORA in preventing delirium in critically ill adult patients requiring ventilatory management in the emergency room. METHOD: This retrospective study included patients aged ≥18 years who were admitted to the emergency room and received ventilator support between January 2015 and April 2022. The HR (95% CI) for delirium development in patients taking DORA was estimated using a Cox proportional hazards model, which was adjusted for the patient background and concomitant medications. HRs were calculated for patients taking suvorexant and those taking lemborexant using a stratified analysis. RESULTS: Of the 297 patients included in the study, 67 were in the DORA group; 50 were on suvorexant and 17 were on lemborexant. The DORA group had a lower incidence of delirium than the control group (p < 0.0001). The risk of delirium was lower in the DORA group compared the control group (HR, 0.22; 95% CI 0.12-0.40).The risk of developing delirium was lower with suvorexant (HR 0.22; 95% CI 0.11-0.41) and lemborexant (HR 0.25; 95% CI 0.08-0.81). CONCLUSION: DORA is a promising drug that could have the potential to prevent delirium, and its efficacy in preventing delirium should be tested in randomized controlled trials in the future.

Risk of delirium with antiepileptic drug use: a study based on the Japanese Adverse Drug Event Report database.

BACKGROUND: Antiepileptic drugs may cause delirium, and the risk may vary with each drug. However, related studies have provided inconsistent results. AIM: The aim of this study was to investigate whether the use of antiepileptic drugs is a risk factor for delirium development. METHOD: Using the Japanese Adverse Drug Event Report database, we analysed 573,316 reports pertaining to the period from 2004 to 2020. Reporting odds ratios and 95% confidence intervals of delirium associated with use of antiepileptic drugs were calculated after adjusting for potential confounders. Furthermore, for each antiepileptic drug, we performed an analysis stratified based on older age and benzodiazepine receptor agonist usage. RESULTS: There were 27,439 reports of antiepileptic drug-related adverse events. Of these, 191 reports were associated with antiepileptic drugs and delirium (crude reporting odds ratio [cROR], 1.66; 95% confidence interval [CI], 1.43-1.93). The use of lacosamide (adjusted reporting odds ratio [aROR], 2.44; 95% CI, 1.24-4.80), lamotrigine (aROR, 1.54; 95% CI, 1.05-2.26), levetiracetam (aROR, 1.91; 95% CI, 1.35-2.71), and valproic acid (aROR, 1.49; 95% CI, 1.16-1.91) was related to a significantly higher reporting odds ratio for delirium, even after adjustment for possible confounding factors. However, when used in combination with benzodiazepine receptor agonists, none of the antiepileptic drugs were found to be associated with delirium. CONCLUSION: Our study's findings suggest that antiepileptic drug usage may be associated with delirium development.

Effects of anti-ulcer drugs on delirium in trauma patients.

OBJECTIVE: Histamine-2 receptor antagonists (H2RAs) may induce a higher risk of developing delirium than proton pump inhibitors (PPIs), but current evidence is insufficient. Therefore, this study aimed to investigate whether anti-ulcer drugs increase delirium risk. METHOD: Data were obtained from the medical records of patients admitted to a hospital due to trauma. We compared the incidence of delirium in patients who received H2RAs and PPIs with that in patients who received no anti-ulcer drugs. RESULTS: A total of 150, 158, and 238 patients received H2RAs, PPIs, and no anti-ulcer drugs, respectively. Delirium incidence was significantly higher in patients who received H2RAs (34.0%) and PPIs (44.9%) than in those who did not receive anti-ulcer drugs (22.3%). Even after adjustment for possible confounding factors, the association between H2RAs and delirium remained (adjusted OR 1.78; 95% CI 1.04-3.05), but that between PPIs and delirium was attenuated (adjusted OR 1.25; 95% CI 0.71-2.23). CONCLUSIONS: Our results show that H2RAs are associated with delirium risk. We replicated findings of a previous data-driven study. Clinicians need to consider the effect of delirium in anti-ulcer drug selection.

Serum oxytocin correlated with later logical memory in older Japanese women: A 7-year follow-up study.

Objectives: This study aimed to investigate the longitudinal relationship between serum oxytocin and logical memory among older adults in rural Japan and clarify sex differences in this relationship. Measurements: The first survey was conducted from October 2009 to March 2011 (Time 1) and the second from November 2016 to September 2017 (Time 2). The final analysis for Time 1 included 385 participants (median age 75 years, interquartile range [IQR] 70-81 years) and that for Time 2 included 76 participants (median age 80 years, IQR 76-83 years). We assessed cognition, logical memory, and living conditions, and measured serum oxytocin levels. Logical memory was evaluated using the Wechsler Memory Scale-Revised Logical Memory II delayed recall part A (LM II-DR). Serum oxytocin was measured using the enzyme immunoassay method. Results: The median (IQR) oxytocin level among men (n = 20) was 34 (16-78) pg/mL at Time 1 and 53 (28-140) pg/mL at Time 2. The median (IQR) oxytocin level among women (n = 56) was 117 (35-412) pg/mL at Time 1 and 76 (32-145) pg/mL at Time 2. The median oxytocin level among women at Time 2 was significantly lower than that at Time 1 (p = 0.004). The multivariate analysis showed that for women, LM II-DR score at Time 2 was positively associated with oxytocin level at Time 1 (p = 0.042) and negatively associated with age (p = 0.02). Conclusions: Our study suggests that maintaining high oxytocin levels in older women may prevent age-related decline in logical memory.

Evaluation of Suvorexant and Lemborexant for the Prevention of Delirium in Adult Critically Ill Patients at an Advanced Critical Care Center: A Single-Center, Retrospective, Observational Study.

Objective: There is limited evidence for the efficacy of the novel dual orexin receptor antagonists (DORAs) suvorexant and lemborexant in preventing delirium. We examined the efficacy of DORAs in preventing delirium in critically ill patients at an advanced emergency and critical care center.Methods: In this retrospective observational study, patients 18 years of age or older admitted to the emergency center between July 2018 and November 2021 with hospitalization duration of at least 72 h were included. Kaplan-Meier curves were plotted and log rank tests were performed to compare between patients with and without DORA treatment. Cox regression analyses adjusting for factors associated with delirium risk were also performed.Results: Of the 633 enrolled patients, 82 were treated with suvorexant and 41 with lemborexant. Cox regression analysis showed that, without adjustment, the hazard ratios (95% CIs) for the development of delirium were 0.56 (0.36-0.86) for patients treated with suvorexant and 0.26 (0.11-0.62) for those treated with lemborexant. After adjustment for delirium risk factors, the hazard ratios (95% CIs) remained low at 0.34 (0.20-0.58) for suvorexant and 0.21 (0.08-0.52) for lemborexant.Conclusions: Both suvorexant and lemborexant may be effective in preventing delirium in critically ill adult patients in an advanced critical care center.

Association of orexin receptor antagonists with falls during hospitalization.

WHAT IS KNOWN AND OBJECTIVE: The use of hypnotics, especially benzodiazepines (BZs), increases the risk of falls. Regarding the association of orexin receptor antagonists with fall risk, consistent results have not been obtained for suvorexant, and studies of lemborexant have not been reported. Therefore, this study investigated whether orexin receptor antagonists, including lemborexant, increase the risk of falls. METHODS: Data were obtained from the medical records of patients hospitalized at Saga University Hospital in Japan between July 2020 and April 2021. Patients were retrospectively divided into the fall and non-fall groups, and the groups were compared for medication usage. RESULTS AND DISCUSSION: The fall and non-fall groups included 132 and 6857 patients respectively. A significantly higher proportion of patients in the fall group used hypnotics (40.2% vs. 21.7%; p < 0.0001). Hypnotics remained significantly associated with a higher risk of falls after adjusting for confounders (adjusted odds ratio [OR] = 1.67, 95% confidence interval [CI] = 1.13-2.48, p = 0.01). In particular, the use of benzodiazepines was associated with a significantly higher risk of falls (adjusted OR = 2.08, 95% CI = 1.38-3.15, p = 0.0005). Meanwhile, suvorexant use was not linked to the risk of falls, and lemborexant use was associated with a significantly lower risk of falls (adjusted OR = 0.27, 95% CI = 0.09-0.84, p = 0.02). WHAT IS NEW AND CONCLUSION: The use of hypnotics is a risk factor for falls, but orexin receptor antagonists may represent a safe option for patients requiring hypnotics. Our results provide evidence supporting the safety of these drugs.

Delirium risk of histamine-2 receptor antagonists and proton pump inhibitors: A study based on the adverse drug event reporting database in Japan.

OBJECTIVE: Although histamine-2 receptor antagonists (H2RAs) have been shown to be more likely to cause delirium than proton pump inhibitors (PPIs), these results were not adjusted for potential confounding factors. Accordingly, we investigated whether H2RAs and PPIs are risk factors for delirium, even when adjusting for other risk factors by analyzing adverse drug event reports compiled in the post-marketing stages of drugs provided by the Japanese regulatory authorities. METHOD: We analyzed 577,431 reports in the Japanese Adverse Drug Event Report database from April 2004 to July 2020. RESULTS: Of all reports analyzed, 2532 described delirium, and 574,899 described other adverse events. Delirium was associated with H2RAs (crude reporting odds ratio, ROR, 4.17; 95% CI, 3.34-5.22) but not PPIs (crude ROR 0.62; 95% CI 0.43-0.90). Even with adjustment for age, sex, history of dementia or depression, and concomitant drugs reported as risk factors for delirium, the use of H2RAs showed a significantly higher adjusted ROR than that of PPIs (H2RAs: adjusted ROR 3.99; 95% CI 3.18-5.01 and PPIs: adjusted ROR 0.58; 95%CI 0.40-0.84). CONCLUSIONS: These results suggest that, from a cognitive perspective, PPIs may be preferable to H2RAs for patients with or at risk for delirium.

Deep Vein Thrombosis after Lithium Toxicity: A Report of Two Cases and Literature Review.

Lithium administration can reportedly cause toxicity, including lithium-associated thrombosis; however, not all reported cases of this adverse effect have been attributable to lithium overdoses. We report here two cases of deep vein thrombosis that occurred in association with lithium toxicity. Lithium overdose was deemed to be the cause in only one of these cases; a patient in whom deep vein thrombosis occurred 11 days after identification of lithium toxicity. In the other patient, the deep vein thrombosis occurred 15 days after diagnosis of lithium toxicity; this patient was not considered to have been overdosed. Both patients had other risk factors in addition to receiving lithium. We recommend monitoring D-dimer concentrations to facilitate early detection of deep vein thrombosis in patients with lithium toxicity.

ProBDNF induces sustained elevation of intracellular Ca2+ possibly mediated by TRPM7 channels in rodent microglial cells.

Microglia are intrinsic immune cells that release factors including pro- and anti-inflammatory cytokines, nitric oxide (NO) and neurotrophins following activation in the brain. Elevation of intracellular Ca2+ concentration ([Ca2+ ]i) is important for microglial functions, such as the release of cytokines or NO from activated microglia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin well known for its roles in the activation of microglia. Interestingly, proBDNF, the precursor form of mature BDNF, and mature BDNF elicit opposing neuronal responses in the brain. Mature BDNF induces sustained intracellular Ca2+ elevation through the upregulation of the surface expression of TRPC3 channels in rodent microglial cells. In addition, TRPC3 channels are important for the BDNF-induced suppression of NO production in activated microglia. In this study, we observed that proBDNF and mature BDNF have opposite effects on the relative expression of surface p75 neurotrophin receptor (p75NTR ) in rodent microglial cells. ProBDNF induces a sustained elevation of [Ca2+ ]i through binding to the p75NTR , which is possibly mediated by Rac 1 activation and TRPM7 channels in rodent microglial cells. Flow cytometry showed that proBDNF increased the relative surface expression of TRPM7. Although proBDNF did not affect either mRNA expression of pro- and anti-inflammatory cytokines or the phagocytic activity, proBDNF potentiates the generation of NO induced by IFN-γ and TRPM7 channels could be involved in the proBDNF-induced potentiation of IFN-γ-mediated production of NO. We show direct evidence that rodent microglial cells are able to respond to proBDNF, which might be important for the regulation of inflammatory responses in the brain.

Effect of memantine, an anti-Alzheimer's drug, on rodent microglial cells in vitro.

The pathophysiology of Alzheimer's disease (AD) is related to neuroinflammatory responses mediated by microglia. Memantine, an antagonist of N-methyl-D-aspartate (NMDA) receptors used as an anti-Alzheimer's drug, protects from neuronal death accompanied by suppression of proliferation and activation of microglial cells in animal models of AD. However, it remains to be tested whether memantine can directly affect microglial cell function. In this study, we examined whether pretreatment with memantine affects intracellular NO and Ca2+ mobilization using DAF-2 and Fura-2 imaging, respectively, and tested the effects of memantine on phagocytic activity by human ß-Amyloid (1-42) phagocytosis assay in rodent microglial cells. Pretreatment with memantine did not affect production of NO or intracellular Ca2+ elevation induced by TNF in rodent microglial cells. Pretreatment with memantine also did not affect the mRNA expression of pro-inflammatory (TNF, IL-1ß, IL-6 and CD45) or anti-inflammatory (IL-10, TGF-ß and arginase) phenotypes in rodent microglial cells. In addition, pretreatment with memantine did not affect the amount of human ß-Amyloid (1-42) phagocytosed by rodent microglial cells. Moreover, we observed that pretreatment with memantine did not affect 11 major proteins, which mainly function in the phagocytosis and degradation of ß-Amyloid (1-42), including TREM2, DAP12 and neprilysin in rodent microglial cells. To the best of our knowledge, this is the first report to suggest that memantine does not directly modulate intracellular NO and Ca2+ mobilization or phagocytic activity in rodent microglial cells. Considering the neuroinflammation hypothesis of AD, the results might be important to understand the effect of memantine in the brain.

Serum Oxytocin Levels and Logical Memory in Older People in Rural Japan.

OBJECTIVE: The present study aimed to investigate the relationship between serum oxytocin (OT) and logical memory among older people in rural Japan. METHODS: This was a cross-sectional study using a survey conducted from October 2009 through March 2011. Most of the study was conducted as part of a national prevalence survey of dementia in Japan. The final sample comprised 385 community-dwelling people aged 65 years or older living in rural Japan. The mean age and standard deviation were 75.7 ± 6.76 years (144 men, mean age 75.0 ± 6.48 years; 241 women, mean age 76.2 ± 6.91 years). The participants underwent screening examinations for a prevalence survey of dementia. The screening examinations were the Mini-Mental State Examination, Clinical Dementia Rating, and "logical memory A" from the Wechsler Memory Scale-Revised (WMSR). We used the WMSR Logical Memory II delayed recall score (LM II-DR) to assess logical memory. Levels of serum OT were obtained using the enzyme immunoassay method. RESULTS: Serum OT levels were significantly higher among women than men. The present study revealed that serum OT levels were positively associated with LM II-DR in older women living in rural Japan in multiple linear regression analyses. CONCLUSIONS: The present results suggested a positive correlation between OT and logical memory in older women living in rural Japan.

Donepezil suppresses intracellular Ca2+ mobilization through the PI3K pathway in rodent microglia.

BACKGROUND: Microglia are resident innate immune cells which release many factors including proinflammatory cytokines or nitric oxide (NO) when they are activated in response to immunological stimuli. Pathophysiology of Alzheimer's disease (AD) is related to the inflammatory responses mediated by microglia. Intracellular Ca2+ signaling is important for microglial functions such as release of NO and cytokines. In addition, alteration of intracellular Ca2+ signaling underlies the pathophysiology of AD, while it remains unclear how donepezil, an acetylcholinesterase inhibitor, affects intracellular Ca2+ mobilization in microglial cells. METHODS: We examined whether pretreatment with donepezil affects the intracellular Ca2+ mobilization using fura-2 imaging and tested the effects of donepezil on phagocytic activity by phagocytosis assay in rodent microglial cells. RESULTS: In this study, we observed that pretreatment with donepezil suppressed the TNFα-induced sustained intracellular Ca2+ elevation in both rat HAPI and mouse primary microglial cells. On the other hand, pretreatment with donepezil did not suppress the mRNA expression of both TNFR1 and TNFR2 in rodent microglia we used. Pretreatment with acetylcholine but not donepezil suppressed the TNFα-induced intracellular Ca2+ elevation through the nicotinic α7 receptors. In addition, sigma 1 receptors were not involved in the donepezil-induced suppression of the TNFα-mediated intracellular Ca2+ elevation. Pretreatment with donepezil suppressed the TNFα-induced intracellular Ca2+ elevation through the PI3K pathway in rodent microglial cells. Using DAF-2 imaging, we also found that pretreatment with donepezil suppressed the production of NO induced by TNFα treatment and the PI3K pathway could be important for the donepezil-induced suppression of NO production in rodent microglial cells. Finally, phagocytosis assay showed that pretreatment with donepezil promoted phagocytic activity of rodent microglial cells through the PI3K but not MAPK/ERK pathway. CONCLUSIONS: These suggest that donepezil could directly modulate the microglial function through the PI3K pathway in the rodent brain, which might be important to understand the effect of donepezil in the brain.

Microglial CD206 Gene Has Potential as a State Marker of Bipolar Disorder.

The pathophysiology of bipolar disorder, especially the underlying mechanisms of the bipolarity between manic and depressive states, has yet to be clarified. Microglia, immune cells in the brain, play important roles in the process of brain inflammation, and recent positron emission tomography studies have indicated microglial overactivation in the brain of patients with bipolar disorder. We have recently developed a technique to induced microglia-like (iMG) cells from peripheral blood (monocytes). We introduce a novel translational approach focusing on bipolar disorder using this iMG technique. We hypothesize that immunological conditional changes in microglia may contribute to the shift between manic and depressive states, and thus we herein analyzed gene profiling patterns of iMG cells from three patients with rapid cycling bipolar disorder during both manic and depressive states, respectively. We revealed that the gene profiling patterns are different between manic and depressive states. The profiling pattern of case 1 showed that M1 microglia is dominant in the manic state compared to the depressive state. However, the patterns of cases 2 and 3 were not consistent with the pattern of case 1. CD206, a mannose receptor known as a typical M2 marker, was significantly downregulated in the manic state among all three patients. This is the first report to indicate the importance of shifting microglial M1/M2 characteristics, especially the CD206 gene expression pattern between depressive and manic states. Further translational studies are needed to dig up the microglial roles in the underlying biological mechanisms of bipolar disorder.