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Abstract Background Japan has one of the lowest COVID-19 death rates, while the annual suicide rate in 2020 has risen for the first time since 2007. This study aimed to identify high-risk populations and assess the impact of medical visits on suicide trends post-COVID-19 pandemic in Japan. Method This quasi-experimental study analyzed a population-based database from Hyogo Prefecture (2012–2022). Interrupted time-series analyses identified level and trend changes in monthly suicide rates per 1 million population during the exposure period (2020–2022) versus the control period (2012–2019). Regular visits to primary care and psychiatry stratified analysis. Results 2181 cases were analyzed, with two-thirds male and a median age of 54. Primary care physicians and psychiatric history were present in 69% and 40% of patients. The study found significant level changes in suicide rates overall (4.14, 95% CI: 1.70, 6.58) among individuals without regular primary care physician visits (2.83, 95% CI: 1.35, 4.32) and without psychiatric visits (2.85, 95% CI: 0.56, 5.14). In contrast, no significant changes were observed in individuals with regular primary care (0.99, 95% CI: -0.78, 2.76) or regular psychiatric visits (0.59, 95% CI: -0.98, 2.16). The trend changes were not significant in any of the groups. Conclusion This study suggests that a history of attending a medical institution may have prevented the rapid increase in suicides during the early stages of the COVID-19 pandemic.

Abstract Background Seizure threshold increases with age and the frequency of electroconvulsive therapy (ECT). Therefore, therapeutic seizures can be difficult to induce, even at maximum stimulus charge with available ECT devices. Such cases are known as difficult-to-induce-seizures electroconvulsive therapy cases (DECs). However, no clinical guidelines exist for DECs; thus, clinicians often face difficulties determining treatment strategies. This study aimed to obtain a consensus among clinical experts regarding the treatment of DECs. Methods We asked Japanese ECT experts to rate 14 approaches under six conditions of DECs on a 9-point Likert scale (1 = “disagree” to 9 = “agree”). Based on responses from 195 experts, the approaches were classified as first-line (95% confidence interval mean ≥ 6.5), second-line (mean, 3.5–6.5), or third-line strategies (mean

Abstract Aims High mobility group box‐1 (HMGB1) is one of the damage‐associated molecular patterns produced by stress and induces inflammatory responses mediated by receptors of advanced glycation end‐products (RAGE) on the cell surface. Meanwhile, soluble RAGE (sRAGE) exhibits an anti‐inflammatory effect by capturing HMGB1. Animal models have shown upregulation of HMGB1 and RAGE in the brain or blood, suggesting the involvement of these proteins in depression pathophysiology. However, there have been no reports using blood from depressed patients, nor ones focusing on HMGB1 and sRAGE changes associated with treatment and their relationship to depressive symptoms. Methods Serum HMGB1 and sRAGE concentrations were measured by enzyme‐linked immunosorbent assay in a group of patients with severe major depressive disorder (MDD) (11 males and 14 females) who required treatment with electroconvulsive therapy (ECT), and also in a group of 25 age‐ and gender‐matched healthy subjects. HMGB1 and sRAGE concentrations were also measured before and after a course of ECT. Depressive symptoms were assessed using the Hamilton Rating Scale for Depression (HAMD). Results There was no significant difference in HMGB1 and sRAGE concentrations in the MDD group compared to healthy subjects. Although ECT significantly improved depressive symptoms, there was no significant change in HMGB1 and sRAGE concentrations before and after treatment. There was also no significant correlation between HMGB1 and sRAGE concentrations and the HAMD total score or subitem scores. Conclusion There were no changes in HMGB1 and sRAGE in the peripheral blood of severely depressed patients, and concentrations had no relationship with symptoms or ECT.

Abstract Aim Thrombospondin‐1 (TSP‐1) is an astrocyte‐derived synaptogenesis‐related factor. It was previously reported to be increased by chronic treatment of electroconvulsive seizure, a model of electroconvulsive therapy (ECT), in rat hippocampus. The aim of this study was to examine whether serum levels of TSP‐1 are associated with depression and ECT. Methods Serum TSP‐1 levels of major depressive disorder (MDD) patients (n = 36) and age‐ and gender‐matched healthy controls (n = 36) were measured by TSP‐1 ELISA. MDD patients were diagnosed according to the Diagnostics and Statistical Manual of Mental Disorders‐IV‐TR and underwent ECT. MDD patients were also analyzed for serum TSP‐1 levels pre‐ and post‐ECT. Evaluation of symptoms was obtained using the Hamilton Rating Scale for Depression. Results Serum TSP‐1 levels showed significant decreases specific to female MDD patients. However, TSP‐1 did not change pre‐ and post‐ECT, did not correlate with symptoms, nor was not affected by the dose of antidepressants. Conclusion Serum TSP‐1 is a possible female‐specific factor that reflects depressive trait, but not state.

Abstract Background Astrocytes have been implicated in the pathophysiology of mood disorders and in the mechanism of the pharmacological effects of antidepressant drugs by the production of neurotrophic/growth factors. Previous studies have identified astrocyte‐expressed Gαi/o‐coupled lysophosphatidic acid receptor 1 (LPAR1), as being involved in antidepressant‐induced production of glial cell line‐derived neurotrophic factor (GDNF) and matrix metalloproteinase‐9 (MMP‐9) activation, an important step in the production of GNDF. However, the precise mechanism of MMP‐9 activation by antidepressants has yet to be identified, in particular the intracellular signaling pathway between LPAR1/Gαi/o and MMP‐9. Methods and Results Treatment of rat C6 astroglial cells (C6 cells) with amitriptyline increased Src family tyrosine kinase phosphorylation in a time and concentration‐dependent manner. Amitriptyline‐induced GDNF mRNA expression was blocked by Src family tyrosine kinase inhibitors. In addition, inhibiting Src family tyrosine kinase blocked amitriptyline‐induced zymographic MMP‐9 activation in C6 cells. The amitriptyline‐induced zymographic MMP‐9 activity was completely blocked by selective inhibition of Gαi/o protein and LPAR1. Furthermore, the amitriptyline‐induced Src family tyrosine kinase phosphorylation was blocked by LPAR1, but not MMP‐9 inhibition, indicating that Src family tyrosine kinase involvement is downstream of LPAR1. Conclusions The current findings suggest that the pharmacological effect of antidepressant such as amitriptyline is mediated through an intracellular signaling pathway via the LPAR1/Gαi/o/Src family tyrosine kinase, which leads to MMP‐9 activation and GDNF production.