Impact of the Japanese Government's 'General Principles of Suicide Prevention Policy' on youth suicide from 2007 to 2022.

BACKGROUND: The Japanese Government programme 'General Principles of Suicide Prevention Policy' (GPSPP) contributed to decreasing suicide mortality rates (SMRs) before the COVID-19 pandemic, but they increased after the pandemic. AIMS: To identify risk factors for youth suicide and the impact of GPSPP on youth suicide. METHOD: Annual suicide numbers during 2007-2022 were obtained from government databases. SMRs of student and non-student youths were analysed with a linear mixed-effects model. Interrupted time-series analysis was conducted to investigate temporal relations between three GPSPP periods and SMRs with 52 suicide motives among high school, special vocational school and university students. Multiple regression analysis was conducted to investigate the influence of grade repetition on university student SMRs. RESULTS: Non-student youth SMRs were higher than student SMRs. School-related (worrying about the future/underachievement), health-related (mainly mental illness) and family-related (conflict with parent and severe verbal reprimands) motives were major motives for student SMRs. During the first GPSPP period (2007-2012), no student SMRs decreased. During the second period (2012-2017), university and special vocational school student SMRs increased, but high school student SMRs were unchanged. In contrast, during the third period (2017-2022), with the exception of male special vocational school students, all SMRs increased. Unexpectedly, long-term grade repetition was negatively associated with health-related SMRs. CONCLUSIONS: These findings suggest that GPSPP-supported programmes in schools partially contributed to student suicide prevention. To suppress increasing student SMRs, social/life support specialists should participate in in-school support services to bolster the social standing and lives of students who repeat grades or experience setbacks.

Suicidal Mortality and Motives Among Middle-School, High-School, and University Students.

Importance: The suicide mortality rate per 100 000 population (SMRP) consistently decreased before the COVID-19 pandemic outbreak in Japan and then unexpectedly increased during the pandemic. However, the underlying mechanisms remain poorly understood. Objective: To identify trends in and factors associated with suicidal mortality and motives among students in Japan from 2007 to 2022. Design, Setting, and Participants: In this cross-sectional study, data on SMRPs among Japanese middle-school, high-school, and university students were obtained from the government suicide database Suicide Statistics of the National Police Agency. Main Outcomes and Measures: Age-dependent and temporal fluctuations in annual SMRPs, disaggregated by suicidal motive (7 categories and 52 subcategories), sex, and school, were analyzed using linear mixed-effect and joinpoint regression models, respectively. Results: Total suicide numbers from 2007 to 2022 were as follows: 760 male middle-school students, 635 female middle-school students, 2376 male high-school students, 1566 female high-school students, 5179 male university students, and 1880 female university students. The mean (SD) student populations from 2007 to 2022 were as follows: 1 752 737 (81 334) male middle-school students, 1 675 572 (78 824) female middle-school students, 1 648 274 (67 520) male high-school students, 1 614 828 (60 032) female high-school students, 1 652 689 (32 724) male university students, and 1 229 142 (57 484) female university students. Among male students, the leading motives were school-related factors (underachievement and worrying about the future), followed by family-related and health-related motives. Among female students, school-related and family-related motives decreased, but health-related motives showed an age-dependent increase. The SMRPs of middle-school male students and female students were almost equal (mean [SD], 2.7 [1.0] vs 2.4 [1.4]), but the age-dependent increase in SMRPs among male students was pronounced (mean [SD], high-school vs university male students, 9.1 [2.4] vs 19.6 [3.0]; high-school vs university female students, 6.1 [2.4] vs 9.6 [1.8]). However, the incidence of suicide among high-school students associated with health-related motives was greater in female students. The majority of suicides associated with major impactable suicidal motives (school-related, health-related, and family-related motives) began increasing before the pandemic. Changes in SMRP associated with interpersonal relationships, such as conflict with classmates or parents, were not significant, but the rates increased greatly during the pandemic. Conclusions and Relevance: School-related, health-related, and family-related problems were major motives, whereas the impacts of health-related and family-related motives increased and decreased with age, respectively. Notably, most SMRPs associated with major impactable motives (underachievement, conflict with a parent or classmate, and mental illnesses) had already begun increasing in the late 2010s, indicating that recent increasing SMRPs among school-aged individuals were associated with pandemic-related factors and other factors affecting this generation before the pandemic. It may be inappropriate to uniformly apply research findings based on school-aged individuals to school-based suicide prevention programs for students in middle school, high school, and university.

Analyzing the changing relationship between personal consumption and suicide mortality during COVID-19 pandemic in Japan, using governmental and personal consumption transaction databases.

During the early stages of the ongoing COVID-19 pandemic, suicides did not increase in most countries/regions. Japan, however, was an exception to this, reporting increased numbers of female suicides with no changes in male suicide. To explore the trends of increasing suicides, the fluctuations of personal consumption (as an indicator of lifestyle) and standardized suicide death rate (SDR) disaggregated by age, sex, and prefecture, were determined using a linear mixed-effect model. Additionally, fixed effects of personal consumption on SDR during the pandemic were also analyzed using hierarchical linear regression models with robust standard errors. During the first wave of the pandemic, SDR for both sexes decreased slightly but increased during the second half of 2020. SDR of females younger than 70 years old and males younger than 40 years old continued to increase throughout 2021, whereas SDR for other ages of both sexes did not increase. Personal consumption expenditures on out-of-home recreations (travel agencies, pubs, and hotels) and internet/mobile communication expenses decreased, but expenditures on home-based recreations (contents distribution) increased during the pandemic. Increased expenditures on internet/mobile communication were related to increasing SDR of both sexes. Increasing expenditures on content distributions were related to increasing females' SDR without affecting that of males. Decreasing expenditures on pubs were related to increasing SDR of both sexes in the non-metropolitan region. These findings suggest that transformed individual lifestyles, extended time at home with a decreased outing for contact with others, contributed to the progression of isolation as a risk of suicide. Unexpectedly, increasing compensatory contact with others using internet/mobile communication enhanced isolation resulting in increased suicide risk.

Bidirectional Causality between Spreading COVID-19 and Individual Mobilisation with Consumption Motives across Prefectural Borders in Japan.

A combination of pharmaceutical and non-pharmaceutical interventions as well as social restrictions has been recommended to prevent the spread of coronavirus disease 2019 (COVID-19). Therefore, social contact surveys play an essential role as the basis for more effective measures. This study attempts to explore the fundamental basis of the expansion of COVID-19. Temporal bidirectional causalities between the numbers of newly confirmed COVID-19 cases (NCCC) and individual mobilisations with consumption motives across prefecture borders in three metropolitan regions in Japan were analysed using vector autoregression models. Mobilisation with consumption in pubs from Kanto to Tokai contributed to the spread of COVID-19 in both regions. Meanwhile, causal mobilisation with consumption motives in Kansai also contributed to the expansion of COVID-19; however, the pattern was dependent on the industrial characteristics of each prefecture in Kansai. Furthermore, the number of pub visitors in Kanto immediately decreased when NCCC increased in Kanto. In contrast, the causal mobilisations for the expansion of COVID-19 in the Tokai and Kansai regions were unaffected by the increasing NCCC. These findings partially proved the validity of the conventional governmental measures to suppress pub visitors across prefectural borders. Nevertheless, the individual causal mobilisations with consumption motives that contributed to the increasing COVID-19 cases are not identical nationwide, and thus, regional characteristics should be considered when devising preventive strategies.

Exploring characteristics of increased suicide during the COVID-19 pandemic in Japan using provisional governmental data.

Background: The Japanese age-standardised death rate of suicide (SDR) had decreased during 2009-2019, but increased in 2020-2021, during the COVID-19 pandemic. Methods: This study aimed to explain the trend change in the SDR during the pandemic, disaggregated by prefecture, gender, suicide method and household, as compared to predicted SDR derived from pre-pandemic data, using linear mixed-effect and hierarchical linear regression models with robust standard error analyses. Findings: The SDR was lower during March-June 2020 (during the first wave of the pandemic), but higher during July-December 2020 than the predicted SDR. In 2021, males' SDR was nearly equal to the predicted SDR, whereas females' SDR in the metropolitan-region (17.5%: 95% confidence interval: 13.9-21.2%) and non-metropolitan-region (24.7%: 95% confidence interval: 22.8-26.7%) continued to be higher than the predicted SDR. These gender- and region-dependent temporal fluctuations of SDR were synchronised with those of SDRs caused by hanging, at home and single-person-households. Additionally, the rising number of infected patients with the SARS-CoV-2 and polymerase chain reaction (PCR) diagnostic examinations were positively (ß = 0.024) and negatively (ß =-0.002) related to the SDR during the pandemic, respectively. Interpretation: Japanese suicide statistics have previously established that the predominant method and place of suicide were by hanging and at the individual's home, respectively. The present findings suggest that transformed lifestyles during the pandemic, increasing time spent at home, enhanced the suicide risk of Japanese people by hanging and at home. Funding: Regional Suicide Countermeasures Emergency Enhancement Fund of Mie Prefecture (2021-40).

Impact of 5-HT7 receptor inverse agonism of lurasidone on monoaminergic tripartite synaptic transmission and pathophysiology of lower risk of weight gain.

A part of atypical antipsychotics exert mood-stabilising effects via modulation of various monoamine receptors and intracellular signalling. Recent pharmacodynamic studies suggested that tripartite-synaptic transmission can be involved in pathophysiology of mood-disorders, schizophrenia, their associated cognitive impairments, and several adverse-reactions to atypical antipsychotics. Therefore, to explore mechanisms underlying antidepressive mood-stabilising and antipsychotic effects of lurasidone, we determined concentration-dependent effects of acute and subchronic lurasidone administrations on astroglial L-glutamate release, and expression of connexin43, ERK, AKT, adenosine monophosphate activated protein kinase (AMPK), 5-HT1A (5-HT1AR) and 5-HT7 (5-HT7R) receptors in cultured astrocytes using ultra-high-pressure liquid-chromatography with mass-spectrometry and capillary-immunoblotting systems. Therapeutically-relevant lurasidone concentration suppressed astroglial L-glutamate release through activated connexin43-containing hemichannel by decreasing connexin43 expression in plasma-membrane. Subchronic lurasidone administration downregulated 5-HT1AR and 5-HT7R in astroglial plasma-membrane concentration-dependently. Subchronic lurasidone administration attenuated ERK and AMPK signallings concentration-dependently without affecting AKT signalling. These results suggest that effects of subchronic lurasidone administration on astroglial L-glutamate release, 5-HT receptor, and intracellular signalling are similar to vortioxetine and different from mood-stabilising atypical antipsychotics, clozapine. Therefore, inhibitory effects of subchronic lurasidone administration on astroglial L-glutamate release through activated connexin43-containing hemichannel probably contribute to pathophysiology of antidepressive mood-stabilising effects of lurasidone. Furthermore, inhibitory effects of subchronic lurasidone administration on ERK and AMPK activities (without affecting AKT activity) induced by downregulation of 5-HT7R could result in clinical advantages of lurasidone, lower risk of weight gain.

Determining What Changed Japanese Suicide Mortality in 2020 Using Governmental Database.

The pandemic of 2019 novel coronavirus disease (COVID-19) caused both COVID-19-related health hazards and the deterioration of socioeconomic and sociopsychological status due to governmental restrictions. There were concerns that suicide mortality would increase during the COVID-19 pandemic; however, a recent study reported that suicide mortality did not increase in 21 countries during the early pandemic period. In Japan, suicide mortality was reduced from 2009 to 2019, but both the annual number of suicide victims and the national suicide mortality rates in 2020 increased compared to that in 2019. To clarify the discrepancy of suicide mortality between the first and second half of 2020 in Japan, the present study determines annual and monthly suicide mortality disaggregated by prefectures, gender, age, means, motive, and household factors during the COVID-19 pandemic and pre-pandemic periods using a linear mixed-effects model. Furthermore, the relationship between suicide mortality and COVID-19 data (the infection rate, mortality, and duration of the pandemic) was analysed using hierarchal linear regression with a robust standard error. The average of monthly suicide mortality of both males and females in all 47 prefectures decreased during the first stay-home order (April-May) (females: from 10.1-10.2 to 7.8-7.9; males: from 24.0-24.9 to 21.6 per 100,000 people), but increased after the end of the first stay-home order (July-December) (females: from 7.5-9.5 to 10.3-14.5; males: from 19.9-23.0 to 21.1-26.7 per 100,000 people). Increasing COVID-19-infected patients and victims indicated a tendency of suppression, but the prolongation of the pandemic indicated a tendency of increasing female suicide mortality without affecting that of males. Contrary to the national pattern, in metropolitan regions, decreasing suicide mortality during the first stay-home order was not observed. Decreasing suicide mortality during the first stay-home order was not observed in populations younger than 30 years old, whereas increasing suicide mortality of populations younger than 30 years old after the end of the first stay-home order was predominant. A decrease in suicide mortality of one-person household residents during the first stay-home order was not observed. The hanging suicide mortality of males and females was decreased and increased during and after the end of the first stay-home orders, respectively; however, there was no decrease in metropolitan regions. These results suggest that the suicide mortality in 2020 of females, younger populations, urban residents, and one-person household residents increased compared to those of males, the elderly, rural residents, and multiple-person household residents. Therefore, the unexpected drastic fluctuations of suicide mortality during the COVID-19 pandemic in Japan were probably composed of complicated reasons among various identified factors in this study, and other unknown factors.

Distinct Effects of Escitalopram and Vortioxetine on Astroglial L-Glutamate Release Associated with Connexin43.

It has been established that enhancement of serotonergic transmission contributes to improvement of major depression; however, several post-mortem studies and experimental depression rodent models suggest that functional abnormalities of astrocytes play important roles in the pathomechanisms/pathophysiology of mood disorders. Direct effects of serotonin (5-HT) transporter inhibiting antidepressants on astroglial transmission systems has never been assessed in this context. Therefore, to explore the effects of antidepressants on transmission associated with astrocytes, the present study determined the effects of the selective 5-HT transporter inhibitor, escitalopram, and the 5-HT partial agonist reuptake inhibitor, vortioxetine, on astroglial L-glutamate release through activated hemichannels, and the expression of connexin43 (Cx43), type 1A (5-HT1AR) and type 7 (5-HT7R) 5-HT receptor subtypes, and extracellular signal-regulated kinase (ERK) in astrocytes using primary cultured rat cortical astrocytes in a 5-HT-free environment. Both escitalopram and 5-HT1AR antagonist (WAY100635) did not affect basal astroglial L-glutamate release or L-glutamate release through activated hemichannels. Subchronic (for seven days) administrations of vortioxetine and the 5-HT7R inverse agonist (SB269970) suppressed both basal L-glutamate release and L-glutamate release through activated hemichannels, whereas 5-HT1AR agonist (BP554) inhibited L-glutamate release through activated hemichannels, but did not affect basal L-glutamate release. In particular, WAY100635 did not affect the inhibitory effects of vortioxetine on L-glutamate release. Subchronic administration of vortioxetine, BP554 and SB269970 downregulated 5-HT1AR, 5-HT7R and phosphorylated ERK in the plasma membrane fraction, but escitalopram and WAY100635 did not affect them. Subchronic administration of SB269970 decreased Cx43 expression in the plasma membrane but did not affect the cytosol; however, subchronic administration of BP554 increased Cx43 expression in the cytosol but did not affect the plasma membrane. Subchronic vortioxetine administration increased Cx43 expression in the cytosol and decreased it in the plasma membrane. WAY100635 prevented an increased Cx43 expression in the cytosol induced by vortioxetine without affecting the reduced Cx43 expression in the plasma membrane. These results suggest that 5-HT1AR downregulation probably increases Cx43 synthesis, but 5-HT7R downregulation suppresses Cx43 trafficking to the plasma membrane. These results also suggest that the subchronic administration of therapeutic-relevant concentrations of vortioxetine inhibits both astroglial L-glutamate and Cx43 expression in the plasma membrane via 5-HT7R downregulation but enhances Cx43 synthesis in the cytosol via 5-HT1AR downregulation. This combination of the downregulation of 5-HT1AR, 5-HT7R and Cx43 in the astroglial plasma membrane induced by subchronic vortioxetine administration suggest that astrocytes is possibly involved in the pathophysiology of depression.

Effects of Financial Expenditure of Prefectures/Municipalities on Regional Suicide Mortality in Japan.

In Japan, suicide mortality has been improving from 2009; however, suicide remains one of the leading causes of death. Although previous studies identified solid relationships between governmental financial support for social welfare systems and suicide mortality, little attention is paid to how specific regional policies, designed according to regional cultural, economic, and social welfare situations, affect suicide mortality. Therefore, the present study analyses the relationships between the regional governmental expenditure of six major divisions and suicide mortality across the 47 prefectures in Japan from 2009 to 2018 using fixed-effect analysis of hierarchal linear regression with robust standard error. The expenditure in "public health", "police", "ambulance/fire services", "welfare" and "education" is associated with reduction in suicide mortality, at least in some statistical indicators, whereas expenditure of "public works" indicated the influence of increasing suicide mortality or had no effect. Welfare expenditure was the most predominantly effective among the six major divisions of regional governmental expenditure. In the welfare subdivisions, expenditure of "child welfare" and "social welfare" was effective in a reduction in suicide mortality, but expenditure of "elderly welfare" surprisingly contributed to increasing suicide mortality. Child welfare expenditure negatively impacted suicide mortality in wide-ranging generations of both males and females; the positive effects of elderly welfare expenditure reached were limited as working-age populations increased, but unexpectedly did not affect the suicide mortality of elderly populations. The relatively increasing expenditure of elderly welfare with the relatively decreasing child welfare are unavoidable due to the Japanese social issues associated with a declining birth rate and ageing population. Furthermore, the budget of that regional government that can modify its expenditure structure by making its own policies is limited since most regional governmental expenditure is composed of essential expenditure for maintaining and operating regional social welfare systems. Although severe social situations in Japan are still unoptimised, the present results suggest that scientific-evidence-based redistributions of welfare expenditure in regional governments can at least partially improve Japanese society and welfare systems.

Chronic Administrations of Guanfacine on Mesocortical Catecholaminergic and Thalamocortical Glutamatergic Transmissions.

It has been established that the selective α2A adrenoceptor agonist guanfacine reduces hyperactivity and improves cognitive impairment in patients with attention-deficit/hyperactivity disorder (ADHD). The major mechanisms of guanfacine are considered to involve the activation of the postsynaptic α2A adrenoceptor of glutamatergic pyramidal neurons in the frontal cortex, but the effects of chronic guanfacine administration on catecholaminergic and glutamatergic transmissions associated with the orbitofrontal cortex (OFC) are yet to be clarified. The actions of guanfacine on catecholaminergic transmission, the effects of acutely local and systemically chronic (for 7 days) administrations of guanfacine on catecholamine release in pathways from the locus coeruleus (LC) to OFC, the ventral tegmental area (VTA) and reticular thalamic-nucleus (RTN), from VTA to OFC, from RTN to the mediodorsal thalamic-nucleus (MDTN), and from MDTN to OFC were determined using multi-probe microdialysis with ultra-high performance liquid chromatography. Additionally, the effects of chronic guanfacine administration on the expression of the α2A adrenoceptor in the plasma membrane fraction of OFC, VTA and LC were examined using a capillary immunoblotting system. The acute local administration of therapeutically relevant concentrations of guanfacine into the LC decreased norepinephrine release in the OFC, VTA and RTN without affecting dopamine release in the OFC. Systemically, chronic administration of therapeutically relevant doses of guanfacine for 14 days increased the basal release of norepinephrine in the OFC, VTA, RTN, and dopamine release in the OFC via the downregulation of the α2A adrenoceptor in the LC, OFC and VTA. Furthermore, systemically, chronic guanfacine administration did not affect intrathalamic GABAergic transmission, but it phasically enhanced thalamocortical glutamatergic transmission. The present study demonstrated the dual actions of guanfacine on catecholaminergic transmission-acute attenuation of noradrenergic transmission and chronic enhancement of noradrenergic transmission and thalamocortical glutamatergic transmission. These dual actions of guanfacine probably contribute to the clinical effects of guanfacine against ADHD.

Brivaracetam prevents astroglial l-glutamate release associated with hemichannel through modulation of synaptic vesicle protein.

The antiepileptic/anticonvulsive action of brivaracetam is considered to occur via modulation of synaptic vesicle protein 2A (SV2A); however, the pharmacological mechanisms of action have not been fully characterised. To explore the antiepileptic/anticonvulsive mechanism of brivaracetam associated with SV2A modulation, this study determined concentration-dependent effects of brivaracetam on astroglial L-glutamate release associated with connexin43 (Cx43), tumour-necrosis factor-α (TNFα) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/glutamate receptor of rat primary cultured astrocytes using ultra-high-performance liquid chromatography. Furthermore, interaction among TNFα, elevated extracellular K+ and brivaracetam on expression of SV2A and Cx43 was determined using capillary immunoblotting. TNFα and elevated extracellular K+ predominantly enhanced astroglial L-glutamate release associated with respective AMPA/glutamate receptor and hemichannel. These effects were enhanced by a synergistic effect of TNFα and elevated extracellular K+ in combination. The activation of astroglial L-glutamate release, and expression of SV2A and Cx43 in the plasma membrane was suppressed by subchronic brivaracetam administration but were unaffected by acute administration. These results suggest that migration of SV2A to the astroglial plasma membrane by hyperexcitability activates astroglial glutamatergic transmission, perhaps via hemichannel activation. Subchronic brivaracetam administration suppressed TNFα-induced activation of AMPA/glutamate receptor and hemichannel via inhibition of ectopic SV2A. These findings suggest that combined inhibition of vesicular and ectopic SV2A functions contribute to the antiepileptic/anticonvulsive mechanism of brivaracetam action.

Current Limitations and Candidate Potential of 5-HT7 Receptor Antagonism in Psychiatric Pharmacotherapy.

Several mood-stabilizing atypical antipsychotics and antidepressants weakly block serotonin (5-HT) receptor type-7 (5-HT7R); however, the contributions of 5-HT7R antagonism to clinical efficacy and pathophysiology are yet to be clarified. A novel mood-stabilizing antipsychotic agent, lurasidone exhibits predominant binding affinity to 5-HT7R when compared with other monoamine receptors. To date, we have failed to discover the superior clinical efficacy of lurasidone on schizophrenia, mood, or anxiety disorders when compared with conventional mood-stabilizing atypical antipsychotics; however, numerous preclinical findings have indicated the possible potential of 5-HT7R antagonism against several neuropsychiatric disorders, as well as the generation of novel therapeutic options that could not be expected with conventional atypical antipsychotics. Traditional experimental techniques, electrophysiology, and microdialysis have demonstrated that the effects of 5-HT receptor type-1A (5-HT1AR) and 5-HT7R on neurotransmission are in contrast, but the effect of 5-HT1AR is more predominant than that of 5-HT7R, resulting in an insufficient understanding of the 5-HT7R function in the field of psychopharmacology. Accumulating knowledge regarding the pharmacodynamic profiles of 5-HT7R suggests that 5-HT7R is one of the key players in the establishment and remodeling of neural development and cytoarchitecture during the early developmental stage to the mature brain, and dysfunction or modulation of 5-HT7R is linked to the pathogenesis/pathophysiology of neuropsychiatric and neurodevelopmental disorders. In this review, to explore candidate novel applications for the treatment of several neuropsychiatric disorders, including mood disorders, schizophrenia, and other cognitive disturbance disorders, we discuss perspectives of psychopharmacology regarding the effects of 5-HT7R antagonism on transmission and intracellular signaling systems, based on preclinical findings.

Efficacy of Psychiatric Treatment to Treat a Specific Phobia of Intravitreal Injections in a Patient with Neovascular Age-Related Macular Degeneration.

Intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) is essential for the treatment of macular diseases such as wet age-related macular degeneration and macular edema. Although continued treatment is needed to maintain good vision, some patients cannot continue such injections for various reasons, including specific phobias. Here, we report a case of a patient with a specific phobia of intravitreal injections who could resume treatment after undergoing combined drug and cognitive-behavioral therapy (CBT). A 74-year-old Japanese man diagnosed with retinal angiomatous proliferation by fluorescein angiography and indocyanine green angiography was treated with intravitreal anti-VEGF injection. However, at 8 months after the first treatment, he became difficult to treat because of a phobia of injections. He was treated with photodynamic therapy, but his macular edema did not improve. After a psychiatric consultation, he was diagnosed with a specific phobia of intravitreal injections. Combined drug and CBT enabled him to resume receiving intravitreal injections. This case demonstrates that a specific phobia of intravitreal injections may benefit from combined drug and CBT. In this regard, some patients with high anxiety and fear of intravitreal injections should be referred to a psychiatrist at an early stage.

Candidate Strategies for Development of a Rapid-Acting Antidepressant Class That Does Not Result in Neuropsychiatric Adverse Effects: Prevention of Ketamine-Induced Neuropsychiatric Adverse Reactions.

Non-competitive N-methyl-D-aspartate/glutamate receptor (NMDAR) antagonism has been considered to play important roles in the pathophysiology of schizophrenia. In spite of severe neuropsychiatric adverse effects, esketamine (racemic enantiomer of ketamine) has been approved for the treatment of conventional monoaminergic antidepressant-resistant depression. Furthermore, ketamine improves anhedonia, suicidal ideation and bipolar depression, for which conventional monoaminergic antidepressants are not fully effective. Therefore, ketamine has been accepted, with rigorous restrictions, in psychiatry as a new class of antidepressant. Notably, the dosage of ketamine for antidepressive action is comparable to the dose that can generate schizophrenia-like psychotic symptoms. Furthermore, the psychotropic effects of ketamine precede the antidepressant effects. The maintenance of the antidepressive efficacy of ketamine often requires repeated administration; however, repeated ketamine intake leads to abuse and is consistently associated with long-lasting memory-associated deficits. According to the dissociative anaesthetic feature of ketamine, it exerts broad acute influences on cognition/perception. To evaluate the therapeutic validation of ketamine across clinical contexts, including its advantages and disadvantages, psychiatry should systematically assess the safety and efficacy of either short- and long-term ketamine treatments, in terms of both acute and chronic outcomes. Here, we describe the clinical evidence of NMDAR antagonists, and then the temporal mechanisms of schizophrenia-like and antidepressant-like effects of the NMDAR antagonist, ketamine. The underlying pharmacological rodent studies will also be discussed.

A Working Hypothesis Regarding Identical Pathomechanisms between Clinical Efficacy and Adverse Reaction of Clozapine via the Activation of Connexin43.

Clozapine (CLZ) is an approved antipsychotic agent for the medication of treatment-resistant schizophrenia but is also well known as one of the most toxic antipsychotics. Recently, the World Health Organization's (WHO) global database (VigiBase) reported the relative lethality of severe adverse reactions of CLZ. Agranulocytosis is the most famous adverse CLZ reaction but is of lesser lethality compared with the other adverse drug reactions of CLZ. Unexpectedly, VigiBase indicated that the prevalence and relative lethality of pneumonia, cardiotoxicity, and seizures associated with CLZ were more serious than that of agranulocytosis. Therefore, haematological monitoring in CLZ patients monitoring system provided success in the prevention of lethal adverse events from CLZ-induced agranulocytosis. Hereafter, psychiatrists must amend the CLZ patients monitoring system to protect patients with treatment-resistant schizophrenia from severe adverse CLZ reactions, such as pneumonia, cardiotoxicity, and seizures, according to the clinical evidence and pathophysiology. In this review, we discuss the mechanisms of clinical efficacy and the adverse reactions of CLZ based on the accumulating pharmacodynamic findings of CLZ, including tripartite synaptic transmission, and we propose suggestions for amending the monitoring and medication of adverse CLZ reactions associated with pneumonia, cardiotoxicity, and seizures.

Analysing regional unemployment rates, GDP per capita and financial support for regional suicide prevention programme on suicide mortality in Japan using governmental statistical data.

OBJECTIVES: To explore the mechanisms of reduced suicide mortality in Japan, which decreased from 25.7 to 16.5 per 100 000 people following the comprehensive suicide prevention programme from 2009 to 2018, the present study determined the relationship between regional suicide mortality, socioeconomic data (GDP per capita, unemployment rates) and financial support for regional suicide prevention programmes. DESIGN AND SETTING: Stepwise multiple regression analysis was used to determine the effects of regional GDP per capita, unemployment rates and implementation amount of financial support for regional suicide prevention programmes (Emergency Fund to Enhance Community-Based Suicide Countermeasures-EFECBSC) on age and gender disaggregated suicide mortalities in Japan between 2009 and 2018. Data on each prefecture's complete unemployment rates, GDP per capita and implementation amount of EFECBSC sub-divisions were derived from an official Japanese governmental database. RESULTS: Both prefectural enlightenment and intervention model programmes were found to lead to a decrease in male suicide mortality, but were less effective in reducing female suicide mortality. Municipal enlightenment and intervention model programmes were also less effective in reducing suicide mortality. Municipal development programmes for listener and leader led to a greater decrease in suicide mortality for both men and women compared with such programmes at the prefectural level. Contrary to our expectations, reduced complete unemployment rate only reduced suicide mortality in the older male population without affecting female suicide mortality. CONCLUSION: The study findings suggest an inverse relationship between financial support and suicide mortality in Japan. Furthermore, independent factors in the reduction of suicide mortality rates provide important information for planning evidence-based and cost-effective regional suicide prevention programmes.

Pathomechanism of nocturnal paroxysmal dystonia in autosomal dominant sleep-related hypermotor epilepsy with S284L-mutant α4 subunit of nicotinic ACh receptor.

To study the pathomechanism and pathophysiology of nocturnal paroxysmal dystonia of autosomal dominant sleep-related hypermotor epilepsy (ADSHE), this study determined functional abnormalities in thalamic hyperdirect pathway from reticular thalamic nucleus (RTN), motor thalamic nuclei (MoTN), subthalamic nucleus (STN) to substantia nigra pars reticulata (SNr) of transgenic rats (S286L-TG) bearing S286 L missense mutation of rat Chrna4 gene, which corresponds to the S284 L mutation in the human CHRNA4 gene. The activation of α4ß2-nAChR in the RTN increased GABA release in MoTN resulting in reduced glutamatergic transmission in thalamic hyperdirect pathway of wild-type. Contrary to wild-type, activation of S286L-mutant α4ß2-nAChR (loss-of-function) in the RTN relatively enhanced glutamatergic transmission in thalamic hyperdirect pathway of S286L-TG via impaired GABAergic inhibition in intra-thalamic (RTN-MoTN) pathway. These functional abnormalities in glutamatergic transmission in hyperdirect pathway contribute to the pathomechanism of electrophysiologically negative nocturnal paroxysmal dystonia of S286L-TG. Therapeutic-relevant concentration of zonisamide (ZNS) inhibited the glutamatergic transmission in the hyperdirect pathway via activation of group II metabotropic glutamate receptor (II-mGluR) in MoTN and STN. The present results suggest that S286L-mutant α4ß2-nAChR induces GABAergic disinhibition in intra-thalamic (RTN-MoTN) pathway and hyperactivation of glutamatergic transmission in thalamic hyperdirect pathway (MoTN-STN-SNr), possibly contributing to the pathomechanism of nocturnal paroxysmal dystonia of ADSHE patients with S284L mutant CHRNA4. Inhibition of glutamatergic transmission in thalamic hyperdirect pathway induced by ZNS via activation of II-mGluR may be involved, at least partially, in ZNS-sensitive nocturnal paroxysmal dystonia of ADSHE patients with S284L mutation.

Activation of Astroglial Connexin is Involved in Concentration-Dependent Double-Edged Sword Clinical Action of Clozapine.

Clozapine (CLZ) is a gold-standard antipsychotic against treatment-refractory schizophrenia, but is one of the most toxic antipsychotic agents. Pharmacological mechanisms of the double-edged sword clinical action of CLZ remain to be clarified. To explore the mechanisms of CLZ, the present study determined the astroglial transmission associated with connexin43 (Cx43), which is the most principal expression in astrocytes and myocardial cells, and expression of Cx43 in primary cultured astrocytes. Both acute and subchronic administrations of CLZ concentration-dependently increased Cx43-associated astroglial release of l-glutamate and d-serine, whereas therapeutic-relevant concentration of CLZ acutely did not affect but subchronically increased astroglial release. In contrast, after the subchronic administration of therapeutic-relevant concentration of valproate (VPA), acute administration of therapeutic-relevant concentration of CLZ drastically increased Cx43-associated astroglial releases. VPA increased Cx43 expression in cytosol fraction without affecting plasma membrane fraction, whereas CLZ increased Cx43 expression in both fractions. Acute administration of therapeutic-relevant concentration of CLZ drastically increased Cx43 expression in the plasma membrane fraction of astrocytes subchronically treated with VPA. The present findings suggest that CLZ-induced the activation of Cx43-associated channel activity and transported Cx43 to plasma membrane, probably contribute to the double-edged sword clinical action of CLZ, such as improvement of cognitive dysfunction and CLZ-induced myocarditis.

Pathogenesis and pathophysiology of autosomal dominant sleep-related hypermotor epilepsy with S284L-mutant α4 subunit of nicotinic ACh receptor.

BACKGROUND AND PURPOSE: The mechanisms causing spontaneous epileptic seizures, including carbamazepine-resistant/zonisamide -sensitive seizures and comorbidity in autosomal dominant sleep-related hypermotor epilepsy (ADSHE) are unclear. This study investigated functional abnormalities in thalamocortical transmission in transgenic rats bearing rat S286L-mutant Chrna4 (S286L-TG) of α4 subunit of the nicotinic ACh receptor (nAChR) that corresponds to the human S284L-mutant CHRNA4. EXPERIMENTAL APPROACH: Effects of carbamazepine and zonisamide on epileptic discharges of S286L-TG rat were measured using telemetry electrocorticogram. Transmission abnormalities of L-glutamate and GABA in thalamocortical pathway of S286L-TG rats were investigated using multiprobe microdialysis and ultra-high-performance liquid-chromatography. KEY RESULTS: Epileptic discharges in S286L-TG rats were reduced by zonisamide but not by carbamazepine, similar to that of S284L-ADSHE patients. Carbamazepine unaffected functional abnormality in transmission of S286L-TG rats. However, zonisamide was able to compensate for the attenuated S286L-mutant nAChR induced GABA release in frontal-cortex, without affecting attenuated thalamocortical glutamatergic transmission. Excitatory effects of S286L-mutant nAChR on thalamocortical transmission were attenuated compared with those of wild-type nAChR. Loss-of-function of S286L-nAChR enhanced transmission in thalamocortical motor pathway by predominantly attenuating GABAergic transmission. However, it attenuated transmission in thalamocortical cognitive pathway by reducing inhibitory GABAergic and excitatory glutamatergic transmission. CONCLUSION AND IMPLICATIONS: Our results suggest that functional abnormalities of S286L-nAChR are associated with intra-frontal and thalamocortical transmission, possibly contributing to the pathogenesis of ADSHE-seizure and comorbidity of S284L-ADSHE. Selective compensation of impaired GABAergic transmission by zonisamide (but not by carbamazepine) in frontal cortex may be involved, at least partially, in carbamazepine-resistant ADSHE-seizure of S284L-ADSHE patients.