Temporal Fluctuations of Suicide Mortality in Japan from 2009 to 2023 Using Government Databases.

In Japan, suicide mortalities consistently decreased before the COVID-19 pandemic (from 2009 to 2019) but, conversely, increased after the pandemic outbreak from 2020 to 2022. To provide up-to-date suicide statistics in Japan, this study determined the temporal fluctuations of standardized suicide mortalities (SMRs), disaggregated by sex and age, by joinpoint regression analysis using the government suicide database, named the "Basic Data on Suicide in Region". From January 2009 to December 2023, three temporal fluctuation patterns of SMRs pertaining to working age and older adults were detected, such as attenuations of decreasing trends before the COVID-19 pandemic (from around the mid-2010s), a sharply increasing trend that coincided with the pandemic outbreak, and gradually decreased during the pandemic, but no changes at the end of the COVID-19 pandemic. In particular, the SMRs of working-age females sharply increased concurrently with the pandemic outbreak, whereas those of males did not change. However, before the pandemic, decreasing trends of the SMRs of working-age males diminished in the mid-2010s, but those of females consistently decreased. The SMRs of working-age males indicated non-significant but sharply increasing trends in early 2022, a trend that was not observed for females. In contrast to working-age adults, the SMRs of adolescents already began to increase in the mid-2010s and also indicated consistently increasing trends between the periods during and after the pandemic. These results suggest, contrary to our expectations, that the impacts of both the outbreak and end of the COVID-19 pandemic were limited regarding the increase in SMRs from 2020. Therefore, when revising suicide prevention programs in the post-COVID-19 era, it should be noted that focusing on pandemic-associated factors alone is not sufficient.

Impacts of Working Hours, Wages, and Regular Employment Opportunity on Suicide Mortalities of Employed and Unemployed Individuals before and during the COVID-19 Pandemic in Japan.

Standardized suicide mortality rates per 100,000 population (SMRs) in Japan consistently decreased from 2009-2019, but these decreasing trends were reversed to increase in 2020. To clarify the mechanisms of recent increasing suicide in Japan, temporal fluctuations of SMRs disaggregated by sex and employment status (employed and unemployed individuals) and labor indices such as working hours, wages, and regular employment opportunity index (REO) from January 2012 to June 2023 were analyzed using interrupted time-series analysis. Additionally, temporal causalities from labor indices to SMRs were analyzed using vector autoregressive and non-linear auto-regressive distributed lag analyses. Decreasing trends among employed SMRs of both sexes were attenuated after the enactment of the "Work Style Reform Program" in 2018, but male SMRs were unaffected by the COVID-19 pandemic. However, female employed SMRs sharply increased, synchronized with the "Work Style Reform Act" and the COVID-19 pandemic outbreak (the COVID-19 impact was greater than the "Work Style Reform Act"). Additionally, unemployed SMRs of both sexes sharply increased with the revision and scale-down of countermeasures against economic deterioration caused by COVID-19 ("revision of economic supportive countermeasures against economic deterioration caused by COVID-19"). Unexpectedly, after enacting the "Work Style Reform Act", wages decreased due to possibly decreasing working hours. Increasing REO, which consistently increased, was a protective factor for male suicides, but unemployed SMRs were not affected by any labor indices. It has been established that controlling a heavy workload plays an important role in suppressing the deterioration of physical and mental conditions, including suicide; however, this study suggested that, at least within appropriate ranges of working hours, decreasing working hours due to excessive management probably contributes to increasing suicides of some vulnerable individuals via de-creasing their wages. Although governmental welfare and economic support measures had to be revised according to rapidly changing situations during the COVID-19 pandemic, this study also suggested that temporal gaps among a part of revisions of several welfare and economic support measures were unexpectedly involved in drastically/sharply increasing suicides of unemployed individuals in 2022.

Age-Dependent Activation of Purinergic Transmission Contributes to the Development of Epileptogenesis in ADSHE Model Rats.

To explore the developmental processes of epileptogenesis/ictogenesis, this study determined age-dependent functional abnormalities associated with purinergic transmission in a genetic rat model (S286L-TG) of autosomal-dominant sleep-related hypermotor epilepsy (ADSHE). The age-dependent fluctuations in the release of ATP and L-glutamate in the orbitofrontal cortex (OFC) were determined using microdialysis and ultra-high-performance liquid chromatography with mass spectrometry (UHPLC-MS). ATP release from cultured astrocytes was also determined using UHPLC-MS. The expressions of P2X7 receptor (P2X7R), connexin 43, phosphorylated-Akt and phosphorylated-Erk were determined using capillary immunoblotting. No functional abnormalities associated with purinergic transmission could be detected in the OFC of 4-week-old S286L-TG and cultured S286L-TG astrocytes. However, P2X7R expression, as well as basal and P2X7R agonist-induced ATP releases, was enhanced in S286L-TG OFC in the critical ADSHE seizure onset period (7-week-old). Long-term exposure to a modest level of P2X7R agonist, which could not increase astroglial ATP release, for 14 d increased the expressions of P2X7R and connexin 43 and the signaling of Akt and Erk in astrocytes, and it enhanced the sensitivity of P2X7R to its agonists. Akt but not Erk increased P2X7R expression, whereas both Akt and Erk increased connexin 43 expression. Functional abnormalities, enhanced ATP release and P2X7R expression were already seen before the onset of ADSHE seizure in S286L-TG. Additionally, long-term exposure to the P2X7R agonist mimicked the functional abnormalities associated with purinergic transmission in astrocytes, similar to those in S286L-TG OFC. Therefore, these results suggest that long-term modestly enhanced purinergic transmission and/or activated P2X7R are, at least partially, involved in the development of the epileptogenesis of ADSHE, rather than that of ictogenesis.

Age-Dependent Activation of Pannexin1 Function Contributes to the Development of Epileptogenesis in Autosomal Dominant Sleep-related Hypermotor Epilepsy Model Rats.

To explore the processes of epileptogenesis/ictogenesis, this study determined the age-dependent development of the functional abnormalities in astroglial transmission associated with pannexin1-hemichannel using a genetic rat model of autosomal dominant sleep-related hypermotor epilepsy (ADSHE) named 'S286L-TG'. Pannexin1 expression in the plasma membrane of primary cultured cortical astrocytes and the orbitofrontal cortex (OFC), which is an ADSHE focus region, were determined using capillary immunoblotting. Astroglial D-serine releases induced by artificial high-frequency oscillation (HFO)-evoked stimulation, the removal of extracellular Ca2+, and the P2X7 receptor agonist (BzATP) were determined using ultra-high performance liquid chromatography (UHPLC). The expressions of pannexin1 in the plasma membrane fraction of the OFC in S286L-TG at four weeks old were almost equivalent when compared to the wild type. The pannexin1 expression in the OFC of the wild type non-statistically decreased age-dependently, whereas that in S286L-TG significantly increased age-dependently, resulting in relatively increasing pannexin1 expression from the 7- (at the onset of interictal discharge) and 10-week-old (after the ADSHE seizure onset) S286L-TG compared to the wild type. However, no functional abnormalities of astroglial pannexin1 expression or D-serine release through the pannexin1-hemichannels from the cultured astrocytes of S286L-TG could be detected. Acutely HFO-evoked stimulation, such as physiological ripple burst (200 Hz) and epileptogenic fast ripple burst (500 Hz), frequency-dependently increased both pannexin1 expression in the astroglial plasma membrane and astroglial D-serine release. Neither the selective inhibitors of pannexin1-hemichannel (10PANX) nor connexin43-hemichannel (Gap19) affected astroglial D-serine release during the resting stage, whereas HFO-evoked D-serine release was suppressed by both inhibitors. The inhibitory effect of 10PANX on the ripple burst-evoked D-serine release was more predominant than that of Gap19, whereas fast ripple burst-evoked D-serine release was predominantly suppressed by Gap19 rather than 10PANX. Astroglial D-serine release induced by acute exposure to BzATP was suppressed by 10PANX but not by Gap19. These results suggest that physiological ripple burst during the sleep spindle plays important roles in the organization of some components of cognition in healthy individuals, but conversely, it contributes to the initial development of epileptogenesis/ictogenesis in individuals who have ADSHE vulnerability via activation of the astroglial excitatory transmission associated with pannexin1-hemichannels.

Risk factors of postoperative coronal malalignment following long-segment spinal fusion surgery in which multilevel lateral lumbar interbody fusion was used for degenerative lumbar kyphoscoliosis.

OBJECTIVE: In patients with adult spinal deformity, especially degenerative lumbar kyphoscoliosis (DLKS), preoperative sagittal malalignment and coronal malalignment (CM) often coexist. Lateral lumbar interbody fusion (LLIF) has recently been widely chosen for DLKS treatment due to its minimal invasiveness and excellent sagittal alignment correction. However, postoperative CM may remain or occur due to an oblique takeoff phenomenon following multilevel LLIF, resulting in poor clinical outcomes. The authors investigated the risk factors for postoperative CM after long-segment fusion corrective surgery in which multilevel LLIF was used in patients with DLKS. METHODS: Fifty-four consecutive patients with DLKS, main Cobb angle ≥ 20°, and lumbar lordosis ≤ 20° who underwent corrective spinal fusion surgery, including extreme lateral interbody fusion at ≥ 3 segments, were included at the authors' institute between April 2014 and October 2019. Patients who underwent suitable 3-column osteotomy, classified as grade 3-6 per the Scoliosis Research Society-Schwab criteria, were excluded. Patients were divided into CM and non-CM groups based on postoperative CM evaluated using standard standing-position radiographs obtained 2 years postoperatively. CM was defined as an absolute C7-CSVL (deviation of C7 plumb line off central sacral vertical line; calculated by defining the convex side of the CSVL as positive numerical values) value of ≥ 3.0 cm. Patient demographics and preoperative sagittal alignment parameters were evaluated. The following variables were measured to assess coronal alignment: main Cobb angle; preoperative C7-CSVL; amount of lateral listhesis; L4, L5, and sacral coronal tilt angles; coronal vertebral deformity angles; and coronal spine rigidity. RESULTS: Regarding risk factors for postoperative CM, patient characteristics, preoperative sagittal parameters, and coronal parameters did not significantly differ between the 2 groups, except for preoperative C7-CSVL (p = 0.016). Multivariate logistic regression analysis revealed that preoperative C7-CSVL (+1 cm; OR 1.23, 95% CI 1.05-1.50; p = 0.007) was a significant predictor of postoperative CM. Receiver operating characteristic curve analysis demonstrated that the cutoff value for preoperative C7-CSVL was +0.3 cm, the sensitivity was 85.7%, the specificity was 60.6%, and the area under the curve was 0.70. CONCLUSIONS: In corrective fusion surgery for DLKS in which multilevel LLIF was used, the occurrence of postoperative CM was associated with preoperative C7-CSVL. According to the C7-CSVL, which was evaluated by defining the convex side of the CSVL as positive numerical values and the concave side as negative numerical values, the CM group had a significantly higher value of preoperative C7-CSVL than did the non-CM group. Alternative corrective fusion methods, other than multiple LLIFs, may be considered in DLKS cases with a C7-CSVL of +0.3 cm or greater.

Outcomes and Vertebral Osteophytes and Bulging Intervertebral Discs Occupancy as a Decision-Making Tool for Surgical Success in Patients Undergoing Microendoscopic Foraminotomy for Lumbar Foraminal Stenosis.

OBJECTIVE: The objective of this study was to determine the long-term outcomes of microendoscopic foraminotomy in treating lumbar foraminal stenosis and identify the optimal extent of decompression that yields improved results and fewer complications. METHODS: A retrospective cohort study reviewed the medical records of 95 consecutive patients who underwent microendoscopic foraminotomy for lumbar foraminal stenosis. Clinical outcomes were assessed using the Japanese Orthopaedic Association scoring system and visual analog scale for low back and leg pain. Surgical success was determined by meeting significant improvement thresholds for back and leg pain at 2 years postoperatively. Multiple regression analysis identified factors associated with improved pain scores. Receiver operating characteristic curve analysis determined the cut-off values for successful surgeries. RESULTS: Significant improvements were observed in Japanese Orthopaedic Association and visual analog scale scores for back and leg pain 2 years postoperatively compared with preoperative scores (P < 0.0001) and sustained over a ≥5-year follow-up period. Reoperation rates were low and did not significantly increase over time. Multiple regression analysis identified occupancy of the vertebral osteophytes and bulging intervertebral discs (O/D complex) as surgical success predictors. A 45.0% O/D complex occupancy cutoff value was determined, displaying high sensitivity and specificity for predicting surgical success. CONCLUSIONS: This study provides evidence supporting the long-term efficacy of microendoscopic foraminotomy for lumbar foraminal stenosis and predicting surgical success. The 45.0% O/D complex occupancy cut-off value can guide patient selection and outcome prediction. These insights contribute to informed surgical decision-making and underscore the importance of evaluating the O/D complex in preoperative planning and predicting outcomes.

Trends in Suicidal Mortality and Motives among Working-Ages Individuals in Japan during 2007-2022.

Suicides in Japan consistently decreased from 2009-2019, but increased during the COVID-19 pandemic. To identify causes of increasing suicides, age-dependent and temporal fluctuations of suicide mortality rate per 100,000 (SMRP) in working-age generations (20-59 years) disaggregated by suicidal motives (7-categories; 52-subcategories) and sex from 2007 to 2022, were analyzed by analysis of variance and joinpoint regression, respectively, using the government suicide database "Suicide Statistics". The SMRP of 20-29 year-old males and 20-49 year-old females began to increase in the late 2010s. SMRPs of these high-risk groups for suicides caused by depression (the leading suicidal motive for all groups) began increasing in the late 2010s. Economic-related, employment-related, and romance-related problems contributed to the increasing SMRPs in 20-29 males in the late 2010s. Romance-related and family-related problems contributed to the increasing SMRPs of 20-29 females in the late 2010s. Increasing SMRPs caused by child-raising stress in 20-39 year-old females from the late 2010s was a remarkable finding. In contrast, SMRPs of 30-59 year-old males consistently decreased until 2021; however, in these groups, SMRPs for suicides caused by various motives sharply increased in 2022. The consistent increase in SMRPs of high-risk groups from the late 2010s to the pandemic suggest recent socioeconomic and psychosocial problems in Japan possibly contributed to the increasing SMRPs in these high-risk groups independently of pandemic-associated factors, whereas the SMRPs of males of 30-59 years were probably associated with the ending of the pandemic rather than pandemic-associated factors.

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.

Impacts of Complete Unemployment Rates Disaggregated by Reason and Duration on Suicide Mortality from 2009-2022 in Japan.

In Japan, suicides had consistently decreased before the COVID-19 pandemic (from 2009-2019), but conversely increased after the pandemic outbreak (from 2020-2022). To identify the features of fluctuations of suicides in Japan, the standardized suicide mortality rates per 100,000 population (SMRP) disaggregated by gender (males/females) and age (10-year cohorts) from 2009-2022 were analyzed using interrupted time-series and joinpoint regression analyses. Temporal causalities from unemployment rate (CUR) disaggregated by unemployment duration and reasons for seeking work to SMRP were analyzed using vector autoregressive modelling with Granger causality analysis. SMRP fluctuations from 2009-2022 were composed of three patterns, such as positive discontinuity (increasing) synchronized with the pandemic outbreak, attenuations of decreasing trends before the pandemic, turning from decreasing before the pandemic to increasing/unchanging after the pandemic outbreak. Dismissal CUR positively related to SMRP of working-age generations, whereas voluntary CUR negatively related to SMRP of younger population (<30 years), which turned to persistently increasing before the pandemic (approximately 2016-2017). CUR shorter than 3 months positively related to SMRP of working-age females, which displayed promptly increasing synchronization with the pandemic outbreak. CUR longer than 12 months positively related to SMRP of working-age males, which contributed to persistently increasing SMRPs during the pandemic. These results suggest that increasing SMRP during 2020-2022 in Japan has been probably at-tributed to interactions among the pandemic-related factors, continuous vulnerabilities from before the pandemic and newly developing risk factors for suicides during the pandemic. Unexpectedly, increasing SMRPs of working-age males in 2022 suggest that either prolongation of the pandemic or the ending of the pandemic might positively affect suicides in Japan.

Unique Characteristics of New Bone Formation Induced by Lateral Lumbar Interbody Fusion Procedure.

Introduction: Despite the absence of bone grafting in the area outside the cage, lateral bridging callus outside cages (LBC) formation is often observed here following extreme lateral interbody fusion (XLIF) conversely to conventional methods of transforaminal lumbar interbody fusion and posterior lumbar interbody fusion. The LBC, which may increase stabilization and decrease nonunion rate in treated segments, has rarely been described. This study aimed to identify the incidence and associated factors of LBC following XLIF. Methods: We enrolled 136 consecutive patients [56 males, 80 females; mean age 69.6 (42-85) years] who underwent lumbar fusion surgery using XLIF, including L4/5 level with posterior fixation at a single institution between February 2013 and February 2018. One year postoperatively, the treated L4/5 segments were divided into the LBC formation and non-formation groups. Potential influential factors, such as age, sex, body mass index, bone density, height of cages, cage material (titanium or polyetheretherketone [PEEK]), presence or absence of diffuse idiopathic skeletal hyperostosis (DISH), and radiological parameters, were evaluated. Multivariate logistic regression analysis was performed for factors significantly different from the univariate analysis. Results: The incidence of LBC formation was 58.8%. Multivariate logistic regression analysis showed that the length of osteophytes [+1 mm; odds ratio, 1.29; 95% confidence interval, 1.17-1.45; p<0.0001] was significant LBC formation predictive factors. Receiver operating characteristic curve analysis demonstrated that the cut-off value for osteophyte length was 14 mm, the sensitivity was 58.8%, the specificity was 84.4%, and the area under the ROC curve for this model was 0.79. Conclusions: The incidence of LBC formation was 58.8% in L4/5 levels one year after the XLIF procedure. We demonstrated that the length of the osteophyte was significantly associated with LBC formation.

A Novel Gliotransmitter, L-ß-Aminoisobutyric Acid, Contributes to Pathophysiology of Clinical Efficacies and Adverse Reactions of Clozapine.

Clozapine is listed as one of the most effective antipsychotics and has been approved for treating treatment-resistant schizophrenia (TRS); however, several type A and B adverse reactions, including weight gain, metabolic complications, cardiotoxicity, convulsions, and discontinuation syndromes, exist. The critical mechanisms of clinical efficacy for schizophrenia, TRS, and adverse reactions of clozapine have not been elucidated. Recently, the GABA isomer L-ß-aminoisobutyric acid (L-BAIBA), a protective myokine in the peripheral organs, was identified as a candidate novel transmission modulator in the central nervous system (CNS). L-BAIBA activates adenosine monophosphate-activated protein kinase (AMPK) signalling in both the peripheral organs and CNS. Activated AMPK signalling in peripheral organs is an established major target for treating insulin-resistant diabetes, whereas activated AMPK signalling in the hypothalamus contributes to the pathophysiology of weight gain and metabolic disturbances. Clozapine increases L-BAIBA synthesis in the hypothalamus. In addition, the various functions of L-BAIBA in the CNS have recently been elucidated, including as an activator of GABA-B and group-III metabotropic glutamate (III-mGlu) receptors. Considering the expressions of GABA-B and III-mGlu receptors (localised in the presynaptic regions), the activation of GABA-B and III-mGlu receptors can explain the distinct therapeutic advantages of clozapine in schizophrenia or TRS associated with N-methyl-D-aspartate (NMDA) receptor disturbance compared with other atypical antipsychotics via the inhibition of the persistent tonic hyperactivation of thalamocortical glutamatergic transmission in the prefrontal cortex. L-BAIBA has also been identified as a gliotransmitter, and a detailed exploration of the function of L-BAIBA in tripartite synaptic transmission can further elucidate the pathophysiology of effectiveness for treating TRS and/or specific adverse reactions of clozapine.

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.

Enhanced L-ß-Aminoisobutyric Acid Is Involved in the Pathophysiology of Effectiveness for Treatment-Resistant Schizophrenia and Adverse Reactions of Clozapine.

Clozapine is an effective antipsychotic for the treatment of antipsychotic-resistant schizophrenia; however, specific types of A/B adverse effects and clozapine-discontinuation syndromes are also well known. To date, both the critical mechanisms of clinical actions (effective for antipsychotic-resistant schizophrenia) and the adverse effects of clozapine remain to be elucidated. Recently, we demonstrated that clozapine increased the synthesis of L-ß-aminoisobutyric acid (L-BAIBA) in the hypothalamus. L-BAIBA is an activator of the adenosine monophosphate-activated protein kinase (AMPK), glycine receptor, GABAA receptor, and GABAB receptor (GABAB-R). These targets of L-BAIBA overlap as potential targets other than the monoamine receptors of clozapine. However, the direct binding of clozapine to these aminoacidic transmitter/modulator receptors remains to be clarified. Therefore, to explore the contribution of increased L-BAIBA on the clinical action of clozapine, this study determined the effects of clozapine and L-BAIBA on tripartite synaptic transmission, including GABAB-R and the group-III metabotropic glutamate receptor (III-mGluR) using cultured astrocytes, as well as on the thalamocortical hyper-glutamatergic transmission induced by impaired glutamate/NMDA receptors using microdialysis. Clozapine increased astroglial L-BAIBA synthesis in time/concentration-dependent manners. Increased L-BAIBA synthesis was observed until 3 days after clozapine discontinuation. Clozapine did not directly bind III-mGluR or GABAB-R, whereas L-BAIBA activated these receptors in the astrocytes. Local administration of MK801 into the reticular thalamic nucleus (RTN) increased L-glutamate release in the medial frontal cortex (mPFC) (MK801-evoked L-glutamate release). Local administration of L-BAIBA into the mPFC suppressed MK801-evoked L-glutamate release. These actions of L-BAIBA were inhibited by antagonists of III-mGluR and GABAB-R, similar to clozapine. These in vitro and in vivo analyses suggest that increased frontal L-BAIBA signaling likely plays an important role in the pharmacological actions of clozapine, such as improving the effectiveness of treating treatment-resistant schizophrenia and several clozapine discontinuation syndromes via the activation of III-mGluR and GABAB-R in the mPFC.

A Candidate Gliotransmitter, L-ß-Aminoisobutyrate, Contributes to Weight Gain and Metabolic Complication Induced by Atypical Antipsychotics.

Lurasidone and quetiapine are effective atypical mood-stabilizing antipsychotics, but lurasidone and quetiapine are listed as lower-risk and high-risk for weight gain/metabolic complications, respectively. The pathophysiology of the discrepancy of metabolic adverse reactions between these antipsychotics remains to be clarified. The GABA isomer, ß-aminoisobutyric acid (BAIBA) enantiomer, was recently re-discovered as myokine via an AMP-activated protein kinase activator (AMPK) enhancer and inhibitory gliotransmitter. Notably, activation of AMPK in peripheral organs improves, but in the hypothalamus, it aggravates metabolic disturbances. Therefore, we determined effects of chronic administration of lurasidone and quetiapine on intracellular and extracellular levels of the BAIBA enantiomer. L-BAIBA is a major BAIBA enantiomer in the hypothalamus and astrocytes, whereas L-BAIBA only accounted for about 5% of total plasma BAIBA enantiomers. Chronic lurasidone administration did not affect body weight but decreased the L-BAIBA level in hypothalamus and cultured astrocytes, whereas chronic quetiapine administration increased body weight and the L-BAIBA level in hypothalamus and astrocytes. Contrary, neither lurasidone nor quetiapine affected total plasma levels of the BAIBA enantiomer since D-BAIBA levels were not affected by these antipsychotics. These results suggest that activation of intracellular L-BAIBA signaling is, at least partially, involved in the pathophysiology of metabolic adverse reaction of quetiapine. Furthermore, this study also demonstrated that lurasidone and quetiapine suppressed and enhanced astroglial L-BAIBA release induced by ripple-burst stimulation (which physiologically contributes to cognitive memory integration during sleep), respectively. Therefore, L-BAIBA probably contributes to the pathophysiology of not only metabolic adverse reactions, but also a part of clinical action of lurasidone or quetiapine.

Opposing effects of clozapine and brexpiprazole on ß-aminoisobutyric acid: Pathophysiology of antipsychotics-induced weight gain.

Clozapine is one of the most effective antipsychotics and has the highest risk of weight gain and metabolic complications; however, the detailed pathophysiology of its clinical action and adverse reactions remains to be clarified. Therefore, the present study determined the chronic effects of clozapine (high risk of weight gain) and brexpiprazole (relatively low risk of weight gain) on intracellular and extracellular levels of ß-aminoisobutyric acid (BAIBA) enantiomers, which are endogenous activators of AMP-activated protein kinase (AMPK). L-BAIBA is the dominant BAIBA enantiomer in the rat hypothalamus and cultured astrocytes, whereas L-BAIBA accounts for only approximately 5% of the total plasma BAIBA enantiomers. L-BAIBA displayed GABAB receptor agonistic action in the extracellular space and was released through activated astroglial hemichannels, whereas in the intracellular space, L-BAIBA activated AMPK signalling. Chronic administration of the effective doses of clozapine increased intracellular and extracellular levels of L-BAIBA in the hypothalamus and cultured astrocytes, whereas that of brexpiprazole decreased them. These results suggest that enhancing hypothalamic AMPK signalling by increasing intracellular L-BAIBA levels is, at least partially, involved in the pathophysiology of clozapine-induced weight gain and metabolic complications.

Therapeutic Potential and Limitation of Serotonin Type 7 Receptor Modulation.

Although a number of mood-stabilising atypical antipsychotics and antidepressants modulate serotonin type 7 receptor (5-HT7), the detailed contributions of 5-HT7 function to clinical efficacy and pathophysiology have not been fully understood. The mood-stabilising antipsychotic agent, lurasidone, and the serotonin partial agonist reuptake inhibitor, vortioxetine, exhibit higher binding affinity to 5-HT7 than other conventional antipsychotics and antidepressants. To date, the initially expected rapid onset of antidepressant effects-in comparison with conventional antidepressants or mood-stabilising antipsychotics-due to 5-HT7 inhibition has not been observed with lurasidone and vortioxetine; however, several clinical studies suggest that 5-HT7 inhibition likely contributes to quality of life of patients with schizophrenia and mood disorders via the improvement of cognition. Furthermore, recent preclinical studies reported that 5-HT7 inhibition might mitigate antipsychotic-induced weight gain and metabolic complication by blocking other monoamine receptors. Further preclinical studies for the development of 5-HT7 modulation against neurodevelopmental disorders and neurodegenerative diseases have been ongoing. To date, various findings from various preclinical studies indicate the possibility that 5-HT7 modifications can provide two independent strategies. The first is that 5-HT7 inhibition ameliorates the dysfunction of inter-neuronal transmission in mature networks. The other is that activation of 5-HT7 can improve transmission dysfunction due to microstructure abnormality in the neurotransmission network-which could be unaffected by conventional therapeutic agents-via modulating intracellular signalling during the neurodevelopmental stage or via loss of neural networks with aging. This review attempts to describe the current and novel clinical applications of 5-HT7 modulation based on preclinical findings.