牧之段 学

Dendritic spine abnormalities are believed to be one of the critical etiologies of autism spectrum disorder (ASD). Over the past decade, the importance of microglia in brain development, particularly in synaptic elimination, has become evident. Thus, microglial abnormalities may lead to synaptic dysfunction, which may underlie the pathogenesis of ASD. Several human studies have demonstrated aberrant microglial activation in the brains of individuals with ASD, and studies in animal models of ASD have also shown a relationship between microglial dysfunction and synaptic abnormalities. However, there are very few methods available to directly assess whether phagocytosis by human microglia is abnormal. Microglia are tissue-resident macrophages with phenotypic similarities to monocyte-derived macrophages, both of which consistently exhibit pathological phenotypes in individuals with ASD. Therefore, in this study, we examined the phagocytosis capacity of human macrophages derived from peripheral blood monocytes. These macrophages were polarized into two types: those induced by granulocyte-macrophage colony-stimulating factor (GM-CSF MΦ, traditionally referred to as "M1 MΦ") and those induced by macrophage colony-stimulating factor (M-CSF MΦ, traditionally referred to as "M2 MΦ"). Synaptosomes purified from human induced pluripotent stem cell-derived neuron were used to assess phagocytosis capacity. Our results revealed that M-CSF MΦ exhibited higher phagocytosis capacity compared to GM-CSF MΦ, whereas ASD-M-CSF MΦ showed a marked impairment in phagocytosis. Additionally, we found a positive correlation between phagocytosis capacity and cluster of differentiation 209 expression. This research contributes to a deeper understanding of the pathobiology of ASD and offers new insights into potential therapeutic targets for the disorder.

AIM: Autism spectrum disorder (ASD) is a neurodevelopmental condition that markedly impairs the physical, emotional, and social domains of health-related quality of life (HRQOL). Children with ASD typically report lower HRQOL than their neurotypical peers. This study investigated the impact of self-esteem and depressive symptoms on HRQOL in children with ASD and explored the discrepancies between parent-reported and self-reported HRQOL. METHODS: This study involved 94 participants, comprising 50 children with ASD and 44 typically developed. HRQOL was measured using the J-KIDSCREEN-52 (self-reported and parent-reported). Self-esteem, depressive symptoms, and social support were assessed using the Rosenberg Self-Esteem Scale, the Depression Self-Rating Scale for Children, and the Multidimensional Scale of Perceived Social Support, respectively. Discrepancies between parent-reported and self-reported HRQOL were examined. Multiple regression analyses were performed to determine the influence of depressive symptoms and self-esteem on HRQOL. RESULTS: Children with ASD showed markedly lower HRQOL than their neurotypical peers. Discrepancies between parent-reported and self-reported HRQOL revealed differing perspectives. Higher depressive symptoms were strongly correlated with poorer HRQOL. Conversely, higher self-esteem was linked to better HRQOL, notably in terms of self-perception. Social support also markedly influenced HRQOL. CONCLUSION: This study underscores the necessity of addressing depressive symptoms, self-esteem, and social support as interventions to enhance HRQOL in children with ASD. The differences between parent-reported and self-reported HRQOL highlight the need to incorporate both views into clinical assessments for comprehensive and effective interventions. Future research should explore these dynamics longitudinally and across diverse populations to refine the intervention strategies.

Objective: To provide proof-of-concept (PoC), dose-range finding, and safety data for BI 1358894, a TRPC4/5 ion channel inhibitor, in patients with borderline personality disorder (BPD). Methods: This was a phase 2, multinational, randomized, double-blind, placebo controlled trial. Patients were randomized to oral placebo or BI 1358894 (5 mg, 25 mg, 75 mg, or 125 mg) once daily in a 2.5:1:1:1:2 ratio for 12 weeks. The primary end point was change from baseline in the Zanarini Rating Scale for BPD (ZAN BPD) total score at Week 10. Secondary end points included ≥30% ZAN-BPD reduction response from baseline at Week 10, change from baseline at Week 10 in the Difficulties in Emotion Regulation Scale-16 item total, State-Trait Anxiety Inventory-State Anxiety total, Patient Health Questionnaire-9 total, Clinical Global Impressions-Severity, and Patient Global Impression-Severity scores. Results: Of 655 enrolled patients, 390 were randomized and 323 (82.8%) completed the trial. For primary and secondary end points, no differences were observed between treatment and placebo; therefore, PoC was not established. The proportion of patients with adverse events (AEs, BI 1358894 overall vs placebo: 77.9% vs 75.0%) and serious AEs (SAEs; 10.3% vs 8.6%) was comparable between treatments. The proportion of patients with an SAE of suicidal ideation was 4.2% (BI 1358894 overall) and 6.3% (placebo). Conclusions: Although the primary end point was not met, BI 1358894 was well tolerated with no increase in self harm or suicidality. More targeted populations, alternative outcome assessments, and additional measures to minimize placebo effects should be considered for future trials. Trial Registration: ClinicalTrials.gov identifier: NCT04566601.

Individuals with autism spectrum disorder (ASD) are more likely to experience adverse childhood experiences (ACEs) compared with typically developing (TD) individuals, which predisposes them to an elevated risk of mental health issues. This review elucidates the profound impact of ACEs on individuals with ASD by synthesizing findings from a plethora of epidemiologic and biological studies, encompassing genetics, epigenetics, and neuroimaging. Despite the limited number of studies explicitly focusing on this intersection, the extant literature consistently demonstrates that ASD individuals are disproportionately affected by ACEs, leading to significant deterioration in mental health and brain function. Furthermore, the nature and extent of the effects of ACEs appear to diverge between ASD and TD populations, underscoring the necessity for tailored clinical and research approaches. Understanding these complex and intertwined interactions is imperative for advancing both clinical practice and research, with the goal of mitigating the adverse outcomes associated with ACEs in ASD individuals.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder. Some children with ASD show enhanced cortisol response to stress. BTBR T+ Itpr3tf/J (BTBR) mice, an ASD model, display behavior consistent with the three diagnostic categories of ASD and exhibit an exaggerated response to stress in adulthood. However, it remains unclear how basal corticosterone levels change and how the hypothalamic-pituitary-adrenal axis responds to stress during the early life stages in BTBR mice. In this study, we found that basal corticosterone levels showed characteristic changes, peaking at weaning during postnatal development in both BTBR and control C57BL/6J (B6J) mice. Furthermore, we observed higher corticosterone and corticotropin-releasing hormone levels in BTBR mice than in B6J mice following acute stress exposure during weaning; however, adrenocorticotropic hormone levels were lower in BTBR mice. Glucocorticoid receptor mRNA expression levels in the hippocampus and lateral septum after stress were higher in BTBR mice than in B6J mice. This study documented changes in corticosterone levels at baseline during postnatal development in mice and showed that BTBR mice exhibited disrupted stress responses at weaning.

BACKGROUND: Alzheimer's disease (AD) is associated with impairments in not only memory but also visuospatial cognitive function. Despite its adverse effects on the quality of life, patients with early-stage AD are often neglected. Emerging evidence suggests that patients with AD exhibit increased vulnerability of myelin, a crucial component for neuronal conduction and survival. To test our hypothesis that myelin damage was associated with cognitive deficits in AD, we examined correlations of myelin integrity, quantified by T1-weighted/T2-weighted (T1w/T2w) ratios, with visuospatial cognitive abilities and compared them between patients with AD and cognitively normal (CN) individuals. METHODS: Fifty-seven patients with AD and 22 CN subjects were enrolled in this study. To assess subjects' visuo-constructive abilities, we employed the Rey-Osterrieth Complex Figure Copy Test (ROCFT-c) paired with analysis of T1- and T2-weighted magnetic resonance imaging brain images. Voxel-based associations between T1w/T2w ratios and ROCFT-c scores in the AD group were assessed, controlling for age and handedness (voxel threshold uncorrected P < 0.001, cluster threshold uncorrected P < 0.05). Additionally, we compared the T1w/T2w ratios of these identified brain regions between the AD and CN groups. RESULTS: The voxel-based analysis demonstrated positive correlations between T1w/T2w ratios and ROCFT-c scores in the right middle temporal gyrus and right praecuneus in patients with AD who exhibited significantly lower T1w/T2w ratios in the right middle temporal gyrus (P = 0.038) and a trend toward lower T1w/T2w ratios in the right praecuneus (P = 0.055). CONCLUSIONS: Our results demonstrated a strong association between reduced myelin integrity in the right middle temporal gyrus and right praecuneus and visuospatial cognitive dysfunction in patients with AD. These findings are believed to shed light on the neural basis of visuospatial processing in patients with AD, underlining the necessity for developing objective biomarkers for assessing patients' visuospatial cognitive function.

Abstract Aberrant salience processing has been proposed as a pathophysiological mechanism underlying psychiatric symptoms in patients with schizophrenia. The gaze trajectories of individuals with schizophrenia have been reported to be abnormal when viewing an image, suggesting anomalous visual salience as one possible pathophysiological mechanism associated with psychiatric diseases. This study was designed to determine whether visual salience is affected in individuals with schizophrenia, and whether this abnormality is unique to patients with schizophrenia. We examined the gaze behaviors of 1012 participants recruited from seven institutes (550 healthy individuals and 238, 41, 50 and 133 individuals with schizophrenia, bipolar disorder, major depressive disorder and autism spectrum disorder, respectively) when they looked at stationary images as they liked, i.e., free-viewing condition. We used an established computational model of salience maps derived from low-level visual features to measure the degree to which the gaze trajectories of individuals were guided by visual salience. The analysis revealed that the saliency at the gaze of individuals with schizophrenia were higher than healthy individuals, suggesting that patients’ gazes were guided more by low-level image salience. Among the low-level image features, orientation salience was most affected. Furthermore, a general linear model analysis of the data for the four psychiatric disorders revealed a significant effect of disease. This abnormal salience processing depended on the disease and was strongest in patients with schizophrenia, followed by patients with bipolar disorder, major depressive disorder, and autism spectrum disorder, suggesting a link between abnormalities in salience processing and strength/frequency for psychosis of these disorders.

AIM: Adverse childhood experiences are potentially traumatic events with long-lasting effects on the health and well-being of patients with autism spectrum disorder (ASD). It is important to clarify which types of long-lasting autism-related symptoms are influenced by childhood experiences to design future intervention studies. However, few studies have examined the association between childhood experiences and autistic symptoms in large samples of adults with ASD and individuals with typical development (TD). In this study, we evaluate the effects of adverse childhood experiences on multiple ASD phenotypes among both individuals with ASD and those with TD. METHOD: We combined questionnaire evaluations; Childhood Abuse and Trauma Scale, the Japanese version of the Autism-Spectrum Quotient, Conners' Adult ADHD Rating Scale, the Japanese version of the Impact of Event Scale-Revised, and the Japanese version of the Adolescent/Adult Sensory Profile. RESULTS: Individuals with ASD and those with TD (n = 205 and 104, respectively) were included. There were significant correlations between the extent of adverse childhood experiences and severity of attention-deficit/hyperactivity disorder symptoms, posttraumatic stress disorder symptoms, and hypersensitivity in both participants with ASD and those with TD. By contrast, ASD core symptoms showed no significant correlation with adverse childhood experiences in either group. These results remained consistent after adjusting for age, sex, and the estimated intelligence quotient. CONCLUSION: These findings suggest the need for a detailed disentanglement of ASD-related core and peripheral symptoms of adverse childhood experiences, which may help to appropriately set outcomes for future early interventions for the childhood experiences of individuals with ASD.

Background Social isolation during critical periods of development is associated with alterations in behavior and neuronal circuitry. This study aimed to investigate the immediate and developmental effects of social isolation on firing properties, neuronal activity-regulated pentraxin (NARP) and parvalbumin (PV) expression in the prefrontal cortex (PFC), social behavior in juvenile socially isolated mice, and the biological relevance of NARP expression in autism spectrum disorder (ASD). Methods Mice were subjected to social isolation during postnatal days 21–35 (P21–P35) and were compared with group-housed control mice. Firing properties in the PFC pyramidal neurons were altered in P35 socially isolated mice, which might be associated with alterations in NARP and PV expression. Results In adulthood, mice that underwent juvenile social isolation exhibited difficulty distinguishing between novel and familiar mice during a social memory task, while maintaining similar levels of social interaction as the control mice. Furthermore, a marked decrease in NARP expression in lymphoblastoid cell lines derived from adolescent humans with ASD as compared to typically developing (TD) humans was found. Conclusion Our study highlights the role of electrophysiological properties, as well as NARP and PV expression in the PFC in mediating the developmental consequences of social isolation on behavior.

Background Schizophrenia is a complex mental disorder characterized by significant cognitive and neurobiological alterations. Impairments in cognitive function and eye movement have been known to be promising biomarkers for schizophrenia. However, cognitive assessment methods require specialized expertise. To date, data on simplified measurement tools for assessing both cognitive function and eye movement in patients with schizophrenia are lacking. Objective This study aims to assess the efficacy of a novel tablet-based platform combining cognitive and eye movement measures for classifying schizophrenia. Methods Forty-four patients with schizophrenia, 67 healthy controls, and 41 patients with other psychiatric diagnoses participated in this study from 10 sites across Japan. A free-viewing eye movement task and 2 cognitive assessment tools (Codebreaker task from the THINC-integrated tool and the CognitiveFunctionTest app) were used for conducting assessments in a 12.9-inch iPad Pro. We performed comparative group and logistic regression analyses for evaluating the diagnostic efficacy of the 3 measures of interest. Results Cognitive and eye movement measures differed significantly between patients with schizophrenia and healthy controls (all 3 measures; P&lt;.001). The Codebreaker task showed the highest classification effectiveness in distinguishing schizophrenia with an area under the receiver operating characteristic curve of 0.90. Combining cognitive and eye movement measures further improved accuracy with a maximum area under the receiver operating characteristic curve of 0.94. Cognitive measures were more effective in differentiating patients with schizophrenia from healthy controls, whereas eye movement measures better differentiated schizophrenia from other psychiatric conditions. Conclusions This multisite study demonstrates the feasibility and effectiveness of a tablet-based app for assessing cognitive functioning and eye movements in patients with schizophrenia. Our results suggest the potential of tablet-based assessments of cognitive function and eye movement as simple and accessible evaluation tools, which may be useful for future clinical implementation.

BACKGROUND: To examine whether the "Effectiveness of Guideline for Dissemination and Education in psychiatric treatment (EGIUDE)" project affects the rate of prescriptions of hypnotic medication and the type of hypnotic medications prescribed among psychiatrists, for schizophrenia and major depressive disorder in Japan. METHODS: The EGUIDE project is a nationwide prospective study of evidence-based clinical guidelines for schizophrenia and major depressive disorder in Japan. From 2016 to 2021, clinical and prescribing data from patients discharged from hospitals participating in the EGUIDE project were used to examine hypnotic medication prescriptions The prescribing rate of hypnotics and the prescribing rate of each type of hypnotic (benzodiazepine receptor agonist, nonbenzodiazepine receptor agonist, melatonin receptor agonist, and orexin receptor antagonist) were compared among patients who had been prescribed medication by psychiatrists participating in the EGUIDE project and patients who had been prescribed medication by nonparticipating psychiatrists. Multivariate logistic regression analysis was performed to examine the effect of the EGUIDE project on the prescription of hypnotic medications. RESULTS: A total of 12,161 patients with schizophrenia and 6,167 patients with major depressive disorder were included. Psychiatrists participating in the EGUIDE project significantly reduced the rate of prescribing hypnotic medication and benzodiazepine receptor agonists for both schizophrenia (P < 0.001) and major depressive disorder (P < 0.001) patients. CONCLUSION: This is the first study to investigate the educational effects of guidelines for the treatment of psychiatric disorders on psychiatrists in terms of prescribing hypnotic medications to patients. The EGUIDE project may play an important role in reducing hypnotic medication prescription rates, particularly with respect to benzodiazepine receptor agonists. The results suggest that the EGUIDE project may result in improved therapeutic behavior.

AIM: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is thought to involve a variety of neurophysiological characteristics. Event-related potentials (ERPs) reflect cognitive functions in the brain's cognitive processing. In this study, we investigated differences in P300 and N100 of ERPs between ASD and typically developing groups and focused on the relationship between the components of ERPs and measures of autistic traits and sensory processing characteristics. METHODS: ERPs were measured in 96 subjects in the ASD group and 62 subjects in the age- and sex-adjusted typically developing group. Correlations between each component and the scores of the Autism-Spectrum Quotient Japanese version (AQ-J) and the Adolescent and Adult Sensory Profile (AASP) were also evaluated. RESULTS: The ASD group showed a significant decrease in the amplitude of N100 at C3. Furthermore, a negative correlation was found between lower amplitude at C3 of N100 and low registered sensory scores in both groups. CONCLUSION: Our findings imply that the N100 amplitude at C3 could be a potential indicator for examining the neurophysiological traits of ASD; however, these results should be interpreted with caution due to their preliminary nature. These tentative insights into sensory processing anomalies may be discernible in specific subsets of the ASD population, providing a foundation for future investigative pathways.

BACKGROUND: A growing body of evidence suggests that immune dysfunction and inflammation in the peripheral tissues as well as the central nervous system are associated with the neurodevelopmental deficits observed in autism spectrum disorder (ASD). Elevated expression of pro-inflammatory cytokines in the plasma, serum, and peripheral blood mononuclear cells of ASD has been reported. These cytokine expression levels are associated with the severity of behavioral impairments and symptoms in ASD. In a prior study, our group reported that tumor necrosis factor-α (TNF-α) expression in granulocyte-macrophage colony-stimulating factor-induced macrophages (GM-CSF MΦ) and the TNF-α expression ratio in GM-CSF MΦ/M-CSF MΦ (macrophage colony-stimulating factor-induced macrophages) was markedly higher in individuals with ASD than in typically developed (TD) individuals. However, the mechanisms of how the macrophages and the highly expressed cytokines affect neurons remain to be addressed. METHODS: To elucidate the effect of macrophages on human neurons, we used a co-culture system of control human-induced pluripotent stem cell-derived neurons and differentiated macrophages obtained from the peripheral blood mononuclear cells of five TD individuals and five individuals with ASD. All participants were male and ethnically Japanese. RESULTS: Our results of co-culture experiments showed that GM-CSF MΦ affect the dendritic outgrowth of neurons through the secretion of pro-inflammatory cytokines, interleukin-1α and TNF-α. Macrophages derived from individuals with ASD exerted more severe effects than those derived from TD individuals. LIMITATIONS: The main limitations of our study were the small sample size with a gender bias toward males, the use of artificially polarized macrophages, and the inability to directly observe the interaction between neurons and macrophages from the same individuals. CONCLUSIONS: Our co-culture system revealed the non-cell autonomous adverse effects of GM-CSF MΦ in individuals with ASD on neurons, mediated by interleukin-1α and TNF-α. These results may support the immune dysfunction hypothesis of ASD, providing new insights into its pathology.

Microglia and brain-derived neurotrophic factor (BDNF) are essential for the neuroplasticity that characterizes critical developmental periods. The experience-dependent development of social behaviors-associated with the medial prefrontal cortex (mPFC)-has a critical period during the juvenile period in mice. However, whether microglia and BDNF affect social development remains unclear. Herein, we aimed to elucidate the effects of microglia-derived BDNF on social behaviors and mPFC development. Mice that underwent social isolation during p21-p35 had increased Bdnf in the microglia accompanied by reduced adulthood sociability. Additionally, transgenic mice overexpressing microglial Bdnf-regulated using doxycycline at different time points-underwent behavioral, electrophysiological, and gene expression analyses. In these mice, long-term overexpression of microglial BDNF impaired sociability and excessive mPFC inhibitory neuronal circuit activity. However, administering doxycycline to normalize BDNF from p21 normalized sociability and electrophysiological function in the mPFC, whereas normalizing BDNF from later ages (p45-p50) did not normalize electrophysiological abnormalities in the mPFC, despite the improved sociability. To evaluate the possible role of BDNF in human sociability, we analyzed the relationship between adverse childhood experiences and BDNF expression in human macrophages, a possible proxy for microglia. Results show that adverse childhood experiences positively correlated with BDNF expression in M2 but not M1 macrophages. In summary, our study demonstrated the influence of microglial BDNF on the development of experience-dependent social behaviors in mice, emphasizing its specific impact on the maturation of mPFC function, particularly during the juvenile period. Furthermore, our results propose a translational implication by suggesting a potential link between BDNF secretion from macrophages and childhood experiences in humans.

AIM: Functional neuroimaging studies have suggested that prefrontal cortex dysfunction occurs in individuals with autism spectrum disorder (ASD). Near-infrared spectroscopy (NIRS) is a noninvasive optical tool used to investigate oxygenation and hemodynamic responses in the cerebral cortex by measuring changes in oxygenated hemoglobin. Previous studies using NIRS have suggested that male children with ASD exhibit reduced hemodynamic responses in the dorsolateral prefrontal cortex; however, only a few studies examined this response in adults with ASD. METHODS: We examined the characteristics of prefrontal hemodynamic responses in 114 adults with ASD and 84 typically developing controls. Relative concentrations of oxygenated hemoglobin were measured with frontal probes every 0.1 s during the Stroop color-word task, using 24-channel NIRS. RESULTS: Our findings demonstrated that the oxygenated hemoglobin changes in the ASD group were significantly smaller than those in the control group at channels 19, 20, 23, and 24- located over the orbitofrontal cortex and frontal pole (p <0.05 for all three channels). The differences in oxygenated hemoglobin changes at Ch 20 were significantly correlated with the Autism-Spectrum Quotient Japanese version (AQ-J) total score and attention switching score, which is a symptom cluster of AQ-J (p = 0.043 and p = 0.009, respectively). CONCLUSION: Adults with ASD have reduced prefrontal hemodynamic responses as measured using near-infrared spectroscopy and the reduced activity of the frontal pole in particular is related to reduced attentional function.

BACKGROUND: Social isolation during critical periods of development is associated with alterations in behavior and neuronal circuitry. This study aimed to investigate the immediate and developmental effects of social isolation on firing properties, neuronal activity-regulated pentraxin (NARP) and parvalbumin (PV) expression in the prefrontal cortex (PFC), social behavior in juvenile socially isolated mice, and the biological relevance of NARP expression in autism spectrum disorder (ASD). METHODS: Mice were subjected to social isolation during postnatal days 21-35 (P21-P35) and were compared with group-housed control mice. Firing properties in the PFC pyramidal neurons were altered in P35 socially isolated mice, which might be associated with alterations in NARP and PV expression. RESULTS: In adulthood, mice that underwent juvenile social isolation exhibited difficulty distinguishing between novel and familiar mice during a social memory task, while maintaining similar levels of social interaction as the control mice. Furthermore, a marked decrease in NARP expression in lymphoblastoid cell lines derived from adolescent humans with ASD as compared to typically developing (TD) humans was found. CONCLUSION: Our study highlights the role of electrophysiological properties, as well as NARP and PV expression in the PFC in mediating the developmental consequences of social isolation on behavior.

Autism spectrum disorder (ASD) is a heterogeneous disorder characterized by impaired social communication and restricted repetitive behaviors, however the biological mechanisms remain unclear. Although trace elements play essential roles in the living body, it is unclear how alterations of trace elements in ASD are involved in pathogenesis. Here we analyzed the plasma metallome and identified the alterations of 11 elements in individuals with ASD. The copper decrease was negatively correlated with ASD symptom scores. A copper-deficient mouse model reflecting the condition showed ASD-like behaviors and impaired oligodendrocyte development. In copper-deficient mice, mechanistic target of rapamycin (mTOR) signaling was reduced, and its activation by agonist improved social impairment and oligodendrocyte developmental defects. Supporting these results, white matter volumes were negatively correlated with social symptoms in individuals with ASD. Our results demonstrate that copper-deficiency contributes to ASD by causing oligodendrocytes impairment via mTOR signaling. Our findings indicate that the effects of copper-deficiency and mTOR imbalance are relevant to the pathogenesis of ASD and are potential therapeutic targets.

高齢者は,身体疾患や喪失体験などから自己の身体に対する不安が高まり,身体愁訴を訴えることが少なくない.なかには身体症状を,それを十分に説明しうる身体的疾患や検査結果がないにもかかわらず,執拗に訴え続ける患者もおり,「身体症状症」と診断される.今回筆者らは,長らく身体症状症と診断されていたが,レビー小体型認知症(DLB)と診断を改め,ドネペジル(donepezil)の投与により身体愁訴が改善した高齢男性の一例を経験した.DLBは病初期において,中核症状が目立たない一方で,さまざまな精神神経症状が先行することもあり,その診断に難渋することも多い.本症例では,「執拗な身体症状の訴え」が問題の中心にあったため,背景のDLBには注意が向けられていなかった.高齢者の身体愁訴を診るときには,背景にDLBが存在する可能性に留意することが重要である.(著者抄録)

子どもにとっては現実と空想の境界が曖昧であり,幻覚や妄想が見られることは多く報告されている。なかでも自閉スペクトラム症(ASD;Autism Spectrum Disorder)では精神病症状をきたしやすく,治療方針の観点からも統合失調症との鑑別は重要である。その幻覚妄想症状の性質や発症様式から両疾患の鑑別は一見簡単な様に見えるが,若年ではもともと言動にまとまりが得られにくいことや,その臨床像に類似点をもつため鑑別に苦慮する症例が散見される。Kannerによる早期幼児自閉症の記載以来,両疾患の異同について活発に議論が行われるも未だに一貫した見解は得られず,両疾患の併存を念頭に置いた治療方針の検討を重要視する専門家の声も多い。両疾患の病態解明が期待される中,近年は米国国立精神衛生研究所による生物学的観点から精神疾患を再分類するRDoC(Research Domain Criteria)が試みられており,その一環で遺伝子研究や脳画像研究がめざましく発展している。これらの研究からASDと統合失調症の類似点及び相違点が多数報告されており,その病態を生物学的観点から評価する試みが常に行われている。本稿ではASDに伴う精神病症状について心理学的な考察に加え,脳機能・脳構造学的な側面からみたその機序や臨床上の意義を検討したうえで,治療や介入における留意点を述べる。(著者抄録)

AIM: Recent advances in natural language processing models are expected to provide diagnostic assistance in psychiatry from history of present illness (HPI). However, existing studies have been limited, with the target diseases including only major diseases, small sample sizes, or no comparison with diagnoses made by psychiatrists to ensure accuracy. Therefore, we formulated an accurate diagnostic model that covers all psychiatric disorders. METHODS: HPIs and diagnoses were extracted from discharge summaries of 2642 cases at the Nara Medical University Hospital, Japan, from May 21, 2007, to May 31, 2021. The diagnoses were classified into 11 classes according to the code from ICD-10 Chapter V. Using UTH-BERT pre-trained on the electronic medical records of the University of Tokyo Hospital, Japan, we predicted the main diagnoses at discharge based on HPIs and compared the concordance rate with the results of psychiatrists. The psychiatrists were divided into two groups: semi-Designated with 3-4 years of experience and Residents with only 2 months of experience. RESULTS: The model's match rate was 74.3%, compared to 71.5% for the semi-Designated psychiatrists and 69.4% for the Residents. If the cases were limited to those correctly answered by the semi-Designated group, the model and the Residents performed at 84.9% and 83.3%, respectively. CONCLUSION: We demonstrated that the model matched the diagnosis predicted from the HPI with a high probability to the principal diagnosis at discharge. Hence, the model can provide diagnostic suggestions in actual clinical practice. This article is protected by copyright. All rights reserved.

OBJECTIVE: Genetic and environmental factors contribute to the development of Attention Deficit/Hyperactivity Disorder (ADHD). Perinatal inflammation is one of the promising environmental risk factors for ADHD, but the relationship between the genetic risk for ADHD and perinatal inflammation requires further examination. METHODS: A possible gene-environmental interaction between perinatal inflammation and ADHD polygenic risk score (ADHD-PRS) on ADHD symptoms was investigated in children aged 8-9 from the Hamamatsu Birth Cohort for Mothers and Children (N = 531). Perinatal inflammation was evaluated by the level of concentration of three cytokines assayed in umbilical cord blood. The genetic risk for ADHD was assessed by calculating ADHD-PRS for each individual using a previously collected genome-wide association study of ADHD. RESULTS: Perinatal inflammation (β [SE], 0.263 [0.017]; P < 0.001), ADHD-PRS (β [SE], 0.116[0.042]; P = 0.006), and an interaction between the two (β [SE], 0.031[0.011]; P = 0.010) were associated with ADHD symptoms. The association between perinatal inflammation and ADHD symptoms measured by ADHD-PRS was evident only in the two higher genetic risk groups (β [SE], 0.623[0.122]; P < 0.001 for the medium-high risk group; β [SE], 0.664[0.152]; P < 0.001 for the high-risk group). CONCLUSION: Inflammation in the perinatal period both directly elevated ADHD symptoms and magnified the impact of genetic vulnerability on ADHD risk particularly among children aged 8-9 with genetically higher risk for ADHD.

BACKGROUND: Polypharmacy of additional psychotropics alongside the main treatment drug (antipsychotics in schizophrenia and antidepressants in major depressive disorder) is common in Japan. Our goal is to align psychotropic prescription in Japan with international standards, while reducing the differences between facilities. To achieve this goal, we aimed to compare prescriptions at the time of hospital admission and discharge. METHODS: Data on prescriptions at admission and discharge from 2016 to 2020 were collected. We divided the patients into four groups: (1) mono_mono group, monotherapy of the main drug at admission and discharge; (2) mono_poly group, monotherapy at admission and polypharmacy at discharge; (3) poly_poly group, polypharmacy at admission and discharge; and (4) poly_mono group, polypharmacy at admission and monotherapy at discharge. We compared the changes in dosage and number of psychotropics among the four groups. RESULTS: For both schizophrenia and major depressive disorder, the patients who received monotherapy with the main drug at admission were likely to receive main drug monotherapy at discharge and vice versa. For schizophrenia, the polypharmacy was prescribed more often in the mono_poly group than that in the mono_mono group. The prescription was not changed at all for more than 10% of the patients. CONCLUSIONS: It is critical to avoid a polypharmacy regimen to ensure that guideline-compliant treatment is provided. We expect higher rates of monotherapy with the main drug after the EGUIDE lectures. TRIAL REGISTRATION: The study protocol was registered in the University Hospital Medical Information Network Registry (UMIN000022645).

BACKGROUND: Although several guidelines recommend monotherapy with antipsychotics for the treatment of schizophrenia, patients who receive long-acting injectable antipsychotics (LAIs) are frequently treated with oral antipsychotics (OAPs). In the present study, we investigated the detailed use of psychotropic medications among patients throughout Japan with schizophrenia who received LAIs or OAPs. METHODS: The present study used data from the project for the Effectiveness of Guidelines for Dissemination and Education in psychiatric treatment from 94 facilities in Japan. The LAI group included patients who received any LAI, and the non-LAI group included patients who took only OAP medications at discharge. The participants of this study were 2518 schizophrenia patients (263 in the LAI group and 2255 in the non-LAI group) who received inpatient treatment and had prescription information at discharge between 2016 and 2020. RESULTS: This study revealed significantly higher rates of polypharmacy antipsychotics, number of antipsychotics, and chlorpromazine equivalents in the LAI group than in the non-LAI group. In contrast, the LAI group showed lower rate of concomitant use of hypnotic and/or antianxiety medication than the non-LAI group. CONCLUSIONS: Presenting these real-world clinical results, we want to encourage clinicians to keep monotherapy in mind for the treatment of schizophrenia, especially by reducing concomitant use of antipsychotics in the LAI group and reducing hypnotic and/or antianxiety medication in the non-LAI group.

Sensory over-responsivity (SOR) causes social and daily distress in individuals with autism spectrum disorder (ASD). Compared to typically developed (TD) individuals, ASD individuals are at higher risk of adverse childhood experiences (ACEs), which induce abnormal neuronal development. However, whether or how ACEs are associated with abnormal neural development and SOR in ASD remains to be determined. Forty-five individuals with ASD and 43 TD individuals underwent T1-weighted and neurite orientation dispersion and density imaging; the axonal and dendritic densities were defined as the neurite density index (NDI). Voxel-based analyses were performed to explore the brain regions associated with SOR. The relationships between severity of ACEs and SOR, and NDI in the brain regions were examined. ASD individuals showed a significantly positive association between SOR severity and NDI in the right superior temporal gyrus (STG), which was not found in TD individuals. Severity of ACEs correlated significantly with that of SOR and NDI in the right STG in ASD; ASD individuals having severe SOR showed significantly higher NDI in the right STG than those with mild SOR and TD individuals. In individuals with ASD, NDI in the right STG, but not ACEs, could predict the severity of SOR, which was not shown in TD subjects. Our findings suggest that severe ACEs are involved in excessive neurite density in the right STG in ASD. ACE-associated excessive neurite density in the right STG is critical for SOR in ASD, which may be a therapeutic target in the future.

AIM: Eye movements and cognitive functions are significantly impaired in schizophrenia. We aimed to develop promising clinical diagnostic markers that fit practical digital health applications in psychiatry using eye movement and cognitive function data from 1254 healthy individuals and 336 patients with schizophrenia. METHODS: Multivariate analyses using logistic regression were performed to confirm net performance of eye movements and cognitive functions scored using the Wechsler Adult Intelligence Scale Third Edition and Wechsler Memory Scale-Revised. We then examined the discrimination performance of pairs containing an eye movement and a cognitive function measure to search the pairs that would be effective in practical application for the discrimination according to the diagnostic criterion between the groups. RESULTS: The multivariate analyses confirmed that eye movements and cognitive functions were effective modalities for discriminating between patients with schizophrenia and healthy controls. The discriminant analyses of the pairs demonstrated that seven eye movement measures and seven scores from cognitive function tests showed high discrimination performance when paired with one measure from the other modality. Moreover, seven pairs of digit-symbol-coding or symbol-search and eye movement measures had high and robust discrimination performance. CONCLUSION: Seven pairs of an eye movement and a cognitive function measure were effective, robust, and less time-consuming in assisting clinical diagnosis by categorizing healthy individuals or patients with schizophrenia. Our findings may help develop an objective auxiliary diagnosis method working even on portable devices, which facilitates the consistency of diagnosis, earlier intervention, and shared decision-making. This article is protected by copyright. All rights reserved.

AIM: Treatment guidelines are designed to assist patients and health care providers and are used as tools for making treatment decisions in clinical situations. The treatment guidelines of the Japanese Society of Mood Disorders establish treatment recommendations for each severity of depression. The individual fitness score (IFS) was developed as a simple and objective indicator to assess whether individual patients are practicing treatment by the recommendations of the depression treatment guidelines of the Japanese Society of Mood Disorders. METHODS: The EGUIDE project members determined the IFS through the modified Delphi method. In this article, the IFS was calculated based on the treatment of depressed patients treated and discharged between 2016 and 2020 at facilities participating in the EGUIDE project. In addition, we compared scores at admission and discharge. RESULTS: The study included 428 depressed patients (mild n = 22, moderate/severe n = 331, psychotic n = 75) at 57 facilities. The mean IFS scores by severity were statistically significantly higher at discharge than at admission with moderate/severe depression (mild 36.1 ± 34.2 vs. 41.6 ± 36.9, p = 0.49; moderate/severe 50.2 ± 33.6 vs. 55.7 ± 32.6, p = 2.1 × 10-3; psychotic 47.4 ± 32.9 versus 52.9 ± 36.0, p = 0.23). CONCLUSION: We developed the IFS based on the depression treatment guideline, which enables us to objectively determine how close the treatment is to the guideline at the time of evaluation in individual cases. Therefore, the IFS may influence guideline-oriented treatment behavior and lead to the equalization of depression treatment in Japan, including pharmacotherapy.

薬物依存症再発予防プログラムであるSMARPP(Serigaya Methamphetamine Relapse Prevention Program)参加群と不参加群の属性を比較検討した。さらに、SMARPP参加群の治療継続率や断薬率などのSMARPP導入効果を確認した。SMARPP導入前では2015年1月1日～2016年12月31日、SMARPP導入後では2017年1月1日～2020年12月31日を調査期間とし、当院を初診しDSM-5でアルコールを除く物質使用障害の診断基準を満たす者を対象とした。SMARPP導入後における参加群は59人、不参加群は152人、後参加群は13人であり、初診時年齢は参加群が38.5歳、不参加群が38.5歳、両群とも男女比は約3:1であった。最終観察時における治療継続群と治療中断群の初診時の属性について、初診時年齢、初回使用年齢、初回使用から初診までの年数のいずれにおいても両群に有意な差を認めなかった。薬物依存症患者の早期の治療中断が多いことが当院の課題であったが、SMARPP導入により治療継続率と断薬率の上昇がみられた。

AIM: We investigated the association of electroconvulsive therapy (ECT) with anxiolytic and sleep medication use in patients with major depressive disorder (MDD) and schizophrenia (SZ). METHODS: This nationwide observational study analyzed data from 3483 MDD inpatients and 6663 SZ inpatients. Patients with MDD and SZ were classified into those who underwent ECT during hospitalization and those who did not. A propensity score-matching method was performed to adjust for preadmission characteristics and clinical information, which were expected bias between the two groups. Rates of anxiolytic and sleep medication use at discharge were compared in the matched sample. RESULTS: 500 MDD patients were assigned to both groups. In the matched MDD sample, the rate of anxiolytic and sleep medication use at discharge was significantly lower in the ECT group than in the non-ECT group (64.9% vs. 75.8%, P = 1.7 × 10-4 ). In the ECT group, the rate of anxiolytic and sleep medication use at discharge was significantly lower than that prior to admission (64.9% vs. 73.2%, P = 1.2 × 10-14 ). 390 SZ patients were allocated. In the matched SZ sample, the ECT group was not significantly different from the non-ECT group in the rate of anxiolytics and sleep medications use at discharge (61.3% vs. 68.2%, P = 4.3 × 10-2 ). In the ECT group, the rate of anxiolytics and sleep medications use at discharge was significantly lower than that before admission (61.3% vs. 70.5%, P = 4.4 × 10-4 ), although this was not the primary outcome. CONCLUSION: Reduction of anxiolytic and sleep medication use may be considered positively when ECT is indicated for treatment of MDD.

BACKGROUND: Posttraumatic stress disorder (PTSD) can be a source of significant social and daily distress in autism spectrum disorder (ASD). Compared to typically developed (TD) individuals, people with ASD are at an increased risk of adverse childhood experiences (ACEs), which can result in abnormal neuronal development. However, whether or how ACEs influence abnormal neural development and PTSD symptoms in ASD has not been fully elucidated. METHODS: Thirty-nine TD individuals and 41 individuals with ASD underwent T1-weighted magnetic resonance imaging and neurite orientation dispersion and density imaging (NODDI), with axonal and dendritic densities assessed in terms of the orientation dispersion index and neurite density index (NDI), respectively. Voxel-based analyses were performed to explore the brain regions associated with PTSD symptoms, and the relationships between the severity of ACEs and PTSD symptoms and NODDI parameters in the extracted brain regions were examined. RESULTS: There was a significant positive association between PTSD symptom severity and NDI in the bilateral supplementary motor area; right superior frontal, left supramarginal, and right superior temporal gyrus; and right precuneus in the ASD group, but not in the TD group. ACE severity was significantly associated with NDI in the right superior frontal and left supramarginal gyrus and right precuneus in the ASD group. Moreover, NDI in the right precuneus mainly predicted the severity of PTSD symptoms in the ASD group, but not the TD group. CONCLUSION: These results suggest that ACE-associated higher neurite density is of clinical importance in the pathophysiology of PTSD symptoms in ASD.

OBJECT: Real-world data from wearable devices has the potential to understand mental health status in everyday life. We aimed to investigate the feasibility of estimating mental health status using a wrist-worn wearable device (Fitbit Sense) that measures movement using a 3D accelerometer and optical pulse photoplethysmography (PPG). METHODS: Participants were 110 patients with mental illnesses from different diagnostic groups. The study was undertaken between 1 October 2020 and 31 March 2021. Participants wore a Fitbit Sense on their wrist and also completed the State-Trait Anxiety Inventory (STAI), Positive and Negative Affect Schedule (PANAS), and EuroQol 5 dimensions 5-level (EQ-5D-5L) during the study period. To determine heart rate (HR) variability (HRV), we calculated the sdnn (standard deviation of the normal-to-normal interval), coefficient of variation of R-R intervals, and mean HR separately for each sleep stage and the daytime. The association between mental health status and HR and HRV was analyzed. RESULTS: The following significant correlations were found in the wake after sleep onset stage within 3 days of mental health status assessment: sdnn, HR and STAI scores, HR and PANAS scores, HR and EQ-5D-5L scores. The association between mental health status and HR and HRV was stronger the closer the temporal distance between mental health status assessment and HR measurement. CONCLUSION: A wrist-worn wearable device that measures PPG signals was feasible for use with patients with mental illness. Resting state HR and HRV could be used as an objective assessment of mental health status within a few days of measurement.

BACKGROUND: Several guidelines recommend monotherapy in pharmacotherapy for schizophrenia and major depressive disorder. The content of regular prescriptions has been reported in several studies, but not enough research has been conducted on the content of pharmacotherapy, including pro re nata (PRN) medications. The purpose of this study was to evaluate the content of pharmacotherapy, including PRN medications, and to clarify the relationship with regular prescriptions. METHODS: We used data from the "Effectiveness of Guidelines for Dissemination And Education in psychiatric treatment" (EGUIDE) project to investigate the presence or absence of PRN psychotropic medications at discharge for each drug category. We compared the PRN psychotropic prescription ratio at discharge by diagnosis for each drug category. The antipsychotic monotherapy ratio and no prescription ratio of other psychotropics for schizophrenia at discharge and the antidepressant monotherapy ratio and no prescription ratio of other psychotropics for major depressive disorder at discharge were calculated for each regular prescription, including PRN psychotropic medications, as quality indicators (QIs). Spearman's rank correlation test was performed for QI values of regular prescriptions and the QI ratio between regular prescriptions and prescriptions including PRN medications for each diagnosis. RESULTS: The PRN psychotropic prescription ratio at discharge was 28.7% for schizophrenia and 30.4% for major depressive disorder, with no significant differences by diagnosis. The prescription ratios of PRN antipsychotic medications and PRN antiparkinsonian medications were significantly higher for schizophrenia. The prescription ratios of PRN anxiolytic and hypnotic and PRN antidepressant medications were significantly higher for patients with major depressive disorder. For both schizophrenia and major depressive disorder, the QI was lower for discharge prescriptions, including PRN medications, than for regular prescriptions. QI values for regular prescriptions and the QI ratio were positively correlated. CONCLUSIONS: Considering PRN psychotropic medications, the monotherapy ratio and no prescription ratio of other psychotropics at discharge decreased in pharmacotherapy for schizophrenia and major depressive disorder. A higher ratio of monotherapy and no prescription of other psychotropics on regular prescriptions may result in less concomitant use of PRN psychotropic medications. Further studies are needed to optimize PRN psychotropic prescriptions.

AIMS: The Guidelines for the Pharmacotherapy of Schizophrenia were established to improve the quality of medical care, and the EGUIDE project was conducted to train clinicians on guideline usage. A quality indicator (QI) was established to measure the prevalence of the guidelines, and a survey was conducted, which revealed a gap between the guidelines and actual clinical practice (evidence-practice-gap). The purpose of this study was to develop an individual fitness score (IFS) formula that expresses the degree to which prescribers adhere to the Guidelines for Pharmacological Therapy of Schizophrenia in a simple manner, and to determine the validity of this formula from a survey of the prescriptions of the EGUIDE project participants'. METHODS: To establish appropriate scores, members discussed the proposed formula and then voted on them. The IFS formula developed was set up so that antipsychotic monotherapy would be given 100 points, with points deducted if concomitant or adjunctive antipsychotic medications were used, and a minimum score of 0. To validate this formula, prescriptions of hospitalized schizophrenic patients at admission and at discharge were scored and compared. RESULT: IFS points vary and ranged from 0 to100. The average pre-admission score for all subjects was 45.6, and the average score at discharge was 54, those were significantly higher during discharge. CONCLUSIONS: We developed an IFS formula, a tool to easily visualize the degree to which current prescriptions conform to the guidelines for the pharmacological treatment of schizophrenia.

Accumulating evidence indicates that social stress in the juvenile period affects hypothalamic-pituitary-adrenal (HPA) axis activity in adulthood. The biological mechanisms underlying this phenomenon remain unclear. We aimed to elucidate them by comparing adult mice that had experienced social isolation from postnatal day 21-35 (juvenile social isolation (JSI) group) with those reared normally (control group). JSI group mice showed an attenuated HPA response to acute swim stress, while the control group had a normal response to this stress. Activity levels of the paraventricular nucleus in both groups were comparable, as shown by c-Fos immunoreactivities and mRNA expression of c-Fos, Corticotropin-releasing factor (CRF), Glucocorticoid receptor, and Mineralocorticoid receptor. We found greater vascular coverage by tanycytic endfeet in the median eminence of the JSI group mice than in that of the control group mice under basal condition and after acute swim stress. Moreover, CRF content after acute swim stress was greater in the median eminence of the JSI group mice than in that of the control group mice. The attenuated HPA response to acute swim stress was specific to JSI group mice, but not to control group mice. Although a direct link awaits further experiments, tanycyte morphological changes in the median eminence could be related to the HPA response.

Background Cognitive impairment is common in people with mental disorders, leading to transdiagnostic classification based on cognitive characteristics. However, few studies have used this approach for intellectual abilities and functional outcomes. Aims The present study aimed to classify people with mental disorders based on intellectual abilities and functional outcomes in a data-driven manner. Method Seven hundred and forty-nine patients diagnosed with schizophrenia, bipolar disorder, major depression disorder or autism spectrum disorder and 1030 healthy control subjects were recruited from facilities in various regions of Japan. Two independent k-means cluster analyses were performed. First, intelligence variables (current estimated IQ, premorbid IQ, and IQ discrepancy) were included. Second, number of work hours per week was included instead of premorbid IQ. Results Four clusters were identified in the two analyses. These clusters were specifically characterised in terms of IQ discrepancy in the first cluster analysis, whereas the work variable was the most salient feature in the second cluster analysis. Distributions of clinical diagnoses in the two cluster analyses showed that all diagnoses were unevenly represented across the clusters. Conclusions Intellectual abilities and work outcomes are effective classifiers in transdiagnostic approaches. The results of our study also suggest the importance of diagnosis-specific strategies to support functional recovery in people with mental disorders.

BACKGROUND: Although clozapine is effective for treatment-resistant schizophrenia (TRS), the rate of clozapine prescription is still low. Although antipsychotic monotherapy is recommended in clinical practice guidelines, the rate of antipsychotic polypharmacy is still high. There is little evidence on whether a clozapine prescription influences changes in the rate of monotherapy and polypharmacy, including antipsychotics and other psychotropics. We therefore hypothesized that the rate of antipsychotic monotherapy in patients with TRS who were prescribed clozapine would be higher than that in patients with schizophrenia who were not prescribed clozapine. METHODS: We assessed 8306 patients with schizophrenia nationwide from 178 institutions in Japan from 2016 to 2019. We analyzed the psychotropic prescription data at discharge in patients diagnosed with TRS and with no description of TRS (ND-TRS) based on the diagnosis listed in the discharge summary. RESULTS: The rate of antipsychotic monotherapy in the TRS with clozapine group (91.3%) was significantly higher than that in the TRS without clozapine group (45.9%; p < 2.0 × 10 -16) and the ND-TRS without clozapine group (54.7%; p < 2.0 × 10 -16). The rate of antipsychotic monotherapy without any other concomitant psychotropics in the TRS with clozapine group (26.5%) was significantly higher than that in the TRS without clozapine group (12.6%; p = 1.1 × 10 -6) and the ND-TRS without clozapine group (17.0%; p = 5.9 × 10 -6). CONCLUSIONS: Clozapine prescription could be associated with a high rate of antipsychotic monotherapy. Patients will benefit from the correct diagnosis of TRS and thus from proper clozapine prescription.