Negative association between basal oxytocin and oxytocin changes after repetitive transcranial magnetic stimulation in patients with treatment-resistant depression.

Repetitive transcranial magnetic stimulation (rTMS) is a neuromodulator effective for treating depressive symptoms in patients with treatment-resistant depression (TRD). One of the multiple mechanisms for its antidepressant effects proposed is related to the hypothalamus. Oxytocin is a neuropeptide synthesized in the hypothalamus that affects human behavior and psychology, including social and affiliative behaviors, stress regulation, and fear and emotion processing. There have been no reports on the relationship between rTMS and oxytocin for the treatment of TRD. Therefore, we aimed to investigate changes in salivary oxytocin concentrations in patients with TRD before and after 6 weeks of rTMS treatment. A total of 28 patients with TRD who received rTMS at Saga University Hospital between August 2013 and August 2020 were included. Although rTMS treatment significantly improved 24-item Hamilton Depression Rating Scale scores, rTMS treatment did not change mean salivary oxytocin after 6 weeks of treatment in patients with TRD. Multiple regression analysis revealed that the change in salivary oxytocin levels after rTMS treatment was negatively associated with basal oxytocin levels before rTMS treatment, suggesting that rTMS treatment tends to decrease oxytocin levels in patients with depression with high basal oxytocin levels while increasing them in those with low basal levels. These findings suggest that rTMS treatment improved depressive symptoms through mechanisms other than the modulatory effect on oxytocin levels in patients with TRD, while there is room for further studies to confirm these findings using a larger patient sample size and/or a sham rTMS procedure.

Relationship between serum cortisol levels, stereotypies, and the presence of autism spectrum disorder in patients with severe intellectual disability.

Stereotypies are one of the diagnostic criteria for autism spectrum disorder (ASD) and are common to both ASD and intellectual disability (ID). Previous studies have been inconclusive, with some showing a positive correlation between stereotypies and cortisol, while others have shown a negative correlation. We hypothesised and investigated the presence of ASD as one of the variables involved in this discrepancy. We tested the following hypotheses on serum cortisol in a total of 84 hospitalised patients with severe ID and ASD with severe ID. Hypothesis (1) Higher levels of stereotypies are associated with higher levels of serum cortisol. Hypothesis (2) The presence of ASD will moderate the association between stereotypies and high serum cortisol levels. The results of the analysis supported hypotheses (1) and (2). We also found that in the population with ID, serum cortisol levels were significantly lower in the ASD group compared to the non-ASD group. The present findings that the association between stereotypies and serum cortisol levels in people with severe ID is moderated by the presence of ASD suggest that the stress response system may function differently in people with ID and ASD than in the general population.

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.

Salivary 3-methoxy-4-hydroxyphenylglycol and MRI-based volume change of the precuneus in community-dwelling elderly people.

BACKGROUND: The noradrenergic systems in the brain maintain cognitive functions including attention/concentration and establishment of long-term memory. In addition, hypofunction of noradrenergic systems is supposed to be involved in the pathophysiology of Alzheimer's disease. In this study, we tried to examine the possible associations of concentrations of basal salivary 3-methoxy-4-hydroxyphenylglycol (sMHPG), a major metabolite of noradrenaline, and brain volume changes during 4 years in elderly people living in a rural community. METHODS: The survey was conducted twice in Kurokawa-cho, Imari, Saga Prefecture, Japan, among people aged 65 years and older. We collected data from 226 residents. Measurements of sMHPG and brain MRIs were collected at Time 1 (2005-2007). Follow-up brain MRIs were taken at Time 2 (2009-2011). A total of 70 participants (18 men, mean age 71.9 ± 4.8 years; 52 women, mean age 72.0 ± 4.3 years) completed this survey. Concentrations of sMHPG at baseline were divided into two groups using the mean value (12.83 ng/ml). We compared the brain volumes between groups with higher and lower sMHPG concentrations over time using voxel-based morphometry implemented with statistical parametric mapping. RESULTS: In participants with higher sMHPG concentrations at baseline, brain volumes including right precuneus were significantly larger 4 years after baseline than those with lower sMHPG concentrations at baseline. No interaction between sMHPG concentration and MRI acquisition interval was found. CONCLUSION: Our results suggest that higher sMHPG concentrations in elderly people might be associated with maintenance of brain volume, especially in brain regions closely related to cognitive function.

Serum soluble triggering receptor expressed on myeloid cells-2 was not altered by rTMS in patients with treatment-resistant depression.

AIM: Repetitive transcranial magnetic stimulation (rTMS) is one of the most effective and minimally invasive treatments for treatment-resistant depression (TRD). However, the mechanism underlying the therapeutic effects of rTMS in patients with TRD remains unclear. In recent years, the pathogenesis of depression has been closely associated with chronic inflammation and microglia are believed to play an important role in chronic inflammation. Triggering receptor expressed on myeloid cells-2 (TREM2) plays an important role in microglial neuroinflammatory regulation. In this study, we investigated the changes in peripheral soluble TREM2 (sTREM2) before and after rTMS treatment in patients with TRD. METHODS: Twenty-six patients with TRD were enrolled in this frequency (10 Hz) rTMS study. Depressive symptoms, cognitive function, and serum sTREM2 concentrations were measured at baseline and the end of the 6-week rTMS treatment. RESULTS: This study showed that rTMS ameliorated depressive symptoms and partially improved cognitive dysfunction in TRD. However, rTMS treatment did not alter serum sTREM2 levels. CONCLUSIONS: This is the first sTREM2 study in patients with TRD who underwent rTMS treatment. These results suggest that serum sTREM2 may not be relevant for the mechanism underlying the therapeutic effect of rTMS in patients with TRD. Future studies should confirm the present findings using a larger patient sample and a sham rTMS procedure, as well as CSF sTREM2. Furthermore, a longitudinal study should be conducted to clarify the effects of rTMS on sTREM2 levels.

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.

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.

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.

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.

Development of an enzyme-linked immunosorbent assay for the quantification of O-Phosphoethanolamine in human plasma.

O-Phosphoethanolamine (PEA) is an endogenous substance that is attracting interest as a biomarker for depression, and thus there is a need to develop a simple analytical method that specifically measures PEA. Therefore, this study aimed to develop a simple and specific enzyme-linked immunosorbent assay (ELISA) for PEA. Anti-PEA antibody was obtained by immunizing mice with an antigen conjugated with mercaptosuccinyl bovine serum albumin using m-maleimidobenzoyl-N-hydroxysulfosuccinimide ester (MBS). In this assay, the PEA to be quantified is chemically modified by benzoyl chloride that is allowed to compete with a PEA-MBS-HRP conjugate for binding to a limited amount of an anti-PEA antibody, which was used to coat the wells of a microtiter plate. This ELISA shows a linear range of detection of 0.11-27 µM, and a limit of quantification of 0.144 µM. The anti-PEA antibody showed high affinity for benzoyl PEA. No detectable cross-reactivity was found with benzoyl 2-aminoethanol, O-phospho-l-tyrosine or benzoyl sphingosine-1-phosphate. The values of plasma PEA levels measured by this ELISA were comparable to those measured by HPLC, and a strong correlation was observed between the values determined by the two methods. The developed ELISA should provide a valuable new tool for the quantification of PEA in human plasma.

Association between cortisol and aging-related hippocampus volume changes in community-dwelling older adults: a 7-year follow-up study.

BACKGROUND: Identifying peripheral biomarkers related to modifiable risk factors to prevent dementia at an early stage will be extremely beneficial. We have been studying how older adults can maintain their mental health and continue to live in a familiar community. The aim of this study is to investigate the association between serum cortisol levels and brain volume among older adults in rural Japan. METHODS: This was a longitudinal study conducted in Kurokawa-cho, Imari, Saga Prefecture, Japan, among people aged 65 years and above, as reported previously. We conducted a survey twice. The first survey was conducted from October 2009 to March 2011 (Timepoint 1) and the second was conducted from November 2016 to September 2017 (Timepoint 2). Blood samples for serum cortisol levels analysis were collected from participants at Timepoint 1. Serum cortisol levels were measured using the enzyme-linked immunosorbent assay. The participants underwent brain MRI examinations, and Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) for cognitive function assessment at Timepoint 1 and Timepoint 2. We obtained 70 participants (16 men, mean age 72.69 ± 3.18 years; 54 women, mean age 72.69 ± 4.60 years, at Timepoint 1) for analysis. Correlation analysis was performed between serum cortisol levels at baseline (Timepoint 1) and brain volume (Timepoint 1, Timepoint 2, and Timepoint 1-Timepoint 2 difference) using voxel-based morphometry method. RESULTS: There was no significant difference in serum cortisol levels between men (72.32 ± 17.30 ng/ml) and women (76.60 ± 21.12 ng/ml) at baseline. Additionally, no effect of blood collection time on cortisol levels was observed in these participants. Small volume correction analysis at the cluster level by applying multiple comparison corrections (family-wise error; P < 0.05) showed a negative correlation between serum cortisol levels (Timepoint 1) and brain volume (Timepoint 2) within the region containing the left hippocampus. CONCLUSIONS: Serum cortisol levels may serve as a peripheral biomarker of age-related volume changes involving the hippocampus in older adults aged 65 years and above.

Changes in the metabolites of cerebrospinal fluid induced by rTMS in treatment-resistant depression: A pilot study.

Repetitive transcranial magnetic stimulation (rTMS) improves depressive symptoms in treatment-resistant depression (TRD). This study aimed to analyze changes in cerebrospinal fluid (CSF) metabolites in patients with TRD after rTMS. Five patients with TRD were enrolled in a high frequency (10-Hz) rTMS study. The concentration of 72 CSF metabolites were measured at baseline and at the end of the 6-week rTMS treatment. rTMS significantly increased CSF niacinamide, kynurenine, and creatinine levels and significantly decreased CSF cystine levels, but not the levels of the other 68 CSF metabolites. This is the first CSF metabolomics study on patients with TRD who underwent rTMS.

Is the Therapeutic Mechanism of Repetitive Transcranial Magnetic Stimulation in Cognitive Dysfunctions of Depression Related to the Neuroinflammatory Processes in Depression?

The lifetime prevalence of depression is reported to be >10%, and it is an important illness that causes various disabilities over a long period of life. Neuroinflammation process is often reported to be closely linked to the pathophysiology of depression. Approximately one-third of depression is known to be treatment-resistant depression (TRD), in which the symptoms are refractory to adequate treatment. Cognitive dysfunction is one of the most important symptoms of depression that impedes the rehabilitation of patients with depression. Repetitive transcranial magnetic stimulation (rTMS) is a minimally invasive and effective treatment for TRD and is also known to be effective in cognitive dysfunction in depression. Since the details of the therapeutic mechanism of rTMS are still unknown, we have been conducting studies to clarify the therapeutic mechanism of rTMS, especially focusing on cognitive dysfunction in depression. In the present review, we present our latest results and discuss them from the standpoint of the neuroinflammation hypothesis of depression, while citing relevant literature.

Neuroinflammation in Late-Onset Schizophrenia: Viewing from the Standpoint of the Microglia Hypothesis.

Schizophrenia develops mainly in adolescence, but late-onset schizophrenia (LOS) is not uncommon. According to the international consensus, schizophrenia which develops over 40 years old is called LOS and psychosis which develops over 60 years old is called very late-onset schizophrenia-like psychosis (VLOS). Compared to early-onset schizophrenia (EOS) that develops before the age of 40 years, LOS and VLOS are reported to be more common in women, and there are clinically clear differences such as less involvement of genetic factors than EOS. This review outlines the abnormalities of the neuroimmune system in the pathophysiology of LOS, especially focusing on the role of microglia.

Correlation between Post-Acute Electroconvulsive Therapy Alpha-Band Spectrum Power Increase and Improvement of Psychiatric Symptoms.

The results of quantitative electroencephalography (qEEG) studies on electroconvulsive therapy (ECT) have been inconsistent, and indicators of the efficacy of ECT have not been clearly identified. In this study, we examined whether qEEG could be used as an indicator of the effect of ECT by measuring it during the course of treatment. We analyzed qEEG data before and after acute-phase ECT in 18 patients with schizophrenia, mood disorders, and other psychiatric disorders. We processed the qEEG data and compared the spectral power between the data acquired before and after ECT. The spectral power increased significantly after ECT in the delta, theta, and alpha bands. There was a strong significant correlation between the increase in the spectral power of the alpha band after acute ECT and improvement in the Brief Psychiatric Rating Scale score. Our results suggest that an increase in the alpha-band spectral power may be useful as an objective indicator of the treatment effect of acute ECT.

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.

Association Between sTREM2, an Immune Biomarker of Microglial Activation, and Aging-Related Brain Volume Changes in Community-Dwelling Older Adults: A 7-Year Follow-Up Study.

BACKGROUND: This study aimed to investigate the association between serum levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a soluble form of an innate immune receptor expressed on the microglia, and brain volume in older adults. METHODS: The survey was conducted twice in Kurokawa-cho, Imari, Saga Prefecture, Japan, among people aged 65 years and older. We collected data from 596 residents. Serum sTREM2 level measurements, brain MRI, Mini-Mental State Examination (MMSE), and clinical dementia rating (CDR) were performed at Time 1 (2009-2011). Follow-up brain MRI, MMSE, and CDR were performed at Time 2 (2016-2017). The interval between Time 1 and Time 2 was approximately 7 years. Sixty-nine participants (16 men, mean age 72.69 ± 3.18 years; 53 women, mean age 72.68 ± 4.64 years) completed this study. We analyzed the correlation between serum sTREM2 levels (Time 1) and brain volume (Time 1, Time 2, and Time 1-Time 2 difference) using voxel-based morphometry implemented with Statistical Parametric Mapping. RESULTS: Participants in this study had lower MMSE and higher CDR scores 7 years after the baseline evaluation. However, analyses at the cluster level by applying multiple comparison corrections (family wise error; P < 0.05) showed no correlation between serum sTREM2 levels and volume of different brain regions, either cross-sectional or longitudinal. CONCLUSION: Serum sTREM2 level could not serve as an immune biomarker of aging-related volume changes in brain regions closely related to cognitive function in older adults aged 65 years and above.