Kazuhiko Yamamuro

Background: The Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE) project is a nationwide Japanese educational program promoting guideline‐concordant pharmacotherapy for schizophrenia and major depressive disorder (MDD). Psychiatrists' self‐reported clinical behavior (CB) scores after EGUIDE training are partially associated with objective quality indicators of specific practices. However, their association with comprehensive objective measures of overall guideline adherence remains unclear. Methods: This multicenter observational study included 1897 EGUIDE‐trained psychiatrists. CB was assessed online immediately after training. The Guideline Adherence Rate (GAR) was calculated for 5328 patients with schizophrenia and 3538 patients with MDD whose discharge records were linked to their psychiatrist's CB score. Associations were evaluated using unadjusted patient‐level Spearman correlations, without modeling clustering within psychiatrists or institutions. Sensitivity analyses aggregated the data to the psychiatrist‐year level, adjusted for institution type, psychiatrist experience, and patient age, and used generalized estimating equations (GEE) to correct the patient‐level inference for clustering. Results: CB scores showed positive but very weak correlations with GAR (schizophrenia, ρ = 0.09–0.14; MDD, ρ = 0.08–0.11; all p < 0.001). Squared coefficients (approximately 0.006–0.020) indicated that CB scores accounted for < 2% of the rank‐order variation in GAR. These associations remained statistically significant in psychiatrist‐year‐level, covariate‐adjusted, and clustering‐corrected (GEE) sensitivity analyses. Conclusions: Post‐training self‐reported CB scores were weakly associated with patient‐level GAR. Given the cross‐sectional, unadjusted analysis and the non‐independence of patients treated by the same psychiatrist, these findings do not establish CB as a reliable proxy for actual clinical practice. Trial Registration: University Hospital Medical Information Network Clinical Trials Registry, UMIN000022645

Early social experience is critical for the maturation of social behavior, and its disruption during juvenile development may confer long-term psychiatric vulnerability. Juvenile social isolation (j-SI) after weaning is widely used as a model of early social deprivation; however, its developmental and sex-specific effects on spontaneous social interaction remain unclear. We examined the behavioral consequences of post-weaning social isolation in male and female C57BL/6J mice ( Mus musculus ). Mice were individually housed from postnatal day (P)21, and spontaneous social interaction was assessed longitudinally at P35, P49, and P63 during prolonged cage-based sessions using an augmented reality-based behavioral monitoring system. Locomotor activity, inter-mouse distance, mean contact duration per initiated encounter, and interaction dynamics were quantified during the light and dark phases. Juvenile social isolation was associated with greater inter-mouse distance across most developmental stages and sex-phase combinations, whereas reductions in mean contact duration per initiated encounter varied by sex, developmental stage, and light/dark phase. Locomotor activity varied by developmental stage and sex, with late-emerging increases particularly evident during the dark phase in isolated mice. In contrast, lower interaction-partner switching in isolated males was detected only at the earliest stage (P35) during the light phase. An important design feature is that isolated mice were reunited at testing with cage mates from which they had been separated for more than two weeks and were therefore effectively unfamiliar, whereas group-housed mice were tested with continuously familiar cage mates; the reported effects therefore reflect social isolation together with its intrinsic reduction in social familiarity. These findings indicate that continued post-weaning social isolation is associated with persistent, sex-specific alterations in sociability and social interaction dynamics. Our results further suggest that juvenile social experience may shape the developmental maturation and temporal organization of social interaction across adolescence and early adulthood.

Background: Schizophrenia is characterized by positive symptoms, negative symptoms, and cognitive impairment and is primarily treated with antipsychotic medications. However, a subset of patients responds inadequately to treatment and is classified as having treatment‐resistant schizophrenia (TRS). The prevalence of TRS among patients with schizophrenia remains insufficiently characterized. This study aimed to determine the prevalence of TRS using nationwide data and standardized diagnostic criteria. Methods: This study included patients with schizophrenia who were discharged between 2016 and 2024 from 205 institutions participating in the Effectiveness of Guidelines for Dissemination and Education in Psychiatric Treatment (EGUIDE) project and authorized to prescribe clozapine. TRS was defined according to standardized diagnostic criteria used in Japan. The prevalence of TRS was calculated among patients who underwent a TRS examination by their treating psychiatrist. Results: Among 18 914 patients, 9870 (52.2%) underwent a TRS examination. Among these 9870 patients, 2819 were classified as having TRS, corresponding to a prevalence of 28.6%. Among the 2819 patients with TRS, 1307 were prescribed clozapine at discharge, corresponding to a clozapine treatment rate of 46.4%. Conclusions: This study had the largest sample size among single‐cohort studies investigating the prevalence of TRS. The prevalence of TRS was 28.6% among patients with schizophrenia who underwent a TRS examination and was nearly identical to the pooled prevalence reported in studies at low risk of bias in a previous meta‐analysis. These findings may provide important evidence regarding the prevalence of TRS in routine clinical practice.

Autistic traits are commonly assessed using self‐reported questionnaires, informant‐reported measures, and clinician‐administered diagnostic instruments; however, the convergence among these approaches and how they vary according to sex remain incompletely understood. We aimed to examine associations and discrepancies among self‐reported autistic traits (Autism‐Spectrum Quotient Japanese version [AQ‐J]), informant‐reported traits (Social Responsiveness Scale, Second Edition [SRS‐2]), and clinician‐rated autism trait intensity (Autism Diagnostic Observation Schedule, Second Edition [ADOS‐2], Module 4) in adults with autism spectrum disorder (ASD; n = 219) and typically developing (TD; n = 130) individuals. We also evaluated whether these patterns differed based on sex across measures. AQ‐J and SRS‐2 scores were higher in ASD than in TD participants. Questionnaire‐based measures showed minimal sex differences, whereas ADOS‐2 scores were higher in males within the ASD group. Repeated‐measures analyses revealed a significant measure‐by‐sex interaction ( p < 0.001, partial η ² = 0.036). This reflected significantly lower clinician‐rated trait intensity in females, despite non‐significant questionnaire‐based sex differences, with no overall sex difference in mean trait intensity. Self‐reported, informant‐reported, and clinician‐rated assessments capture overlapping but distinct aspects of the autism phenotype, and the pattern of sex differences depends on the measurement modality used.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication differences and restricted, repetitive behaviors. Convergent evidence implicates prefrontal cortex (PFC) circuit dysregulation and chronic neuroimmune activation in ASD. Despite increasing off-label use of guanfacine in children and adolescents with autism, its molecular and immunological rationale remains incompletely synthesized. Objective: To synthesize current evidence regarding the molecular, neurophysiological, and immunological mechanisms through which guanfacine may influence ASD-related neural and immune dysfunction. Methods: In this narrative review, we integrated evidence from pharmacology, systems neuroscience, immunology, and clinical studies to examine two converging mechanisms by which guanfacine may act in ASD and related conditions. Results: Guanfacine suppresses cAMP signaling through α2A-adrenoceptor activation, producing dual neuronal and immune effects. In PFC pyramidal neurons, reduced cAMP signaling promotes closure of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, strengthening network firing that supports working memory, attention, and emotion regulation. In parallel, activation of α2A-adrenoceptors on microglia and macrophages reduces production of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, and interleukin-6, while promoting anti-inflammatory phenotypes through nuclear factor kappa B suppression and peroxisome proliferator-activated receptor gamma activation. Evidence from human studies and ASD models indicates that α2A-adrenoceptor signaling, HCN channel function, and microglial reactivity are altered in autism and converge on synaptic refinement, dendritic spine stability, and PFC-dependent behavior. We further review clinical evidence for guanfacine in individuals with autism and in related conditions, including attention-deficit/hyperactivity disorder, post-traumatic stress disorder, traumatic brain injury, post-COVID cognitive impairment, delirium, and age-related cognitive decline. Conclusion: Collectively, the available evidence supports a mechanistic framework linking guanfacine, HCN channel modulation, and neuroimmune regulation, thereby bridging neuroinflammation and PFC function in ASD. The broader α2A–HCN–microglia axis may represent a promising therapeutic target for PFC- and neuroimmune-related features of ASD; however, adequately powered autism-specific randomized trials and biomarker-informed stratification strategies are needed to establish clinical efficacy and validate this framework.

Background: Alzheimer's disease (AD) is associated with memory impairment and social cognitive dysfunction, including facial emotion recognition (FER) deficits. Our previous diffusion tensor imaging (DTI) study linked poor recognition of negative facial emotions in patients with AD to increased mean diffusivity (MD) in the left uncinate fasciculus (UF). Whether FER deficits in AD reflect microstructural alterations in related grey matter regions remains unclear. Methods: In this cross‐sectional study, 74 patients with AD and 28 cognitively normal (CN) subjects underwent behavioural assessments using the Facial Emotion Selection Test (FEST). A subset of 67 AD patients and 23 CN patients underwent magnetic resonance imaging. DTI was used to assess the fractional anisotropy (FA) and MD of the bilateral UF, and neurite orientation dispersion and density imaging (NODDI) was used to evaluate the neurite density index (NDI) and orientation dispersion index (ODI) of the insula, amygdala and temporal lobe. Results: Patients with AD showed significantly lower FEST total, negative emotion, positive emotion and neutral expression scores. DTI revealed significantly lower FA and higher MD in the bilateral UF. In the AD group, higher bilateral UF MD was significantly associated with lower total FEST and negative emotional scores. NODDI analyses demonstrated significantly lower ODI in the insula, amygdala and temporal lobe in the AD group, whereas no significant between‐group differences were observed in the NDI. In the uncorrected analyses, ODI showed trend‐level positive associations with FEST performance; however, these associations did not remain significant after false discovery rate correction. Bilateral UF MD was negatively correlated with ODI in the insula and temporal lobes. Conclusions: FER is broadly impaired in AD and is associated with bilateral UF abnormalities and reduced ODI in the frontotemporal‐limbic regions. These findings suggest that social cognitive dysfunction in AD involves broader frontotemporal‐limbic network disruption than isolated white matter abnormalities.

Aim: Delirium, a serious neuropsychiatric hospitalization complication, is a manifestation of underlying neurocognitive vulnerability rather than an acute event. In Japan, a nationwide medical policy mandates early hospital‐wide delirium risk screening to evaluate predefined risk factors in inpatient populations. We aimed to identify demographic and clinical factors independently associated with referral‐based, consultation‐confirmed delirium. Methods: We conducted a retrospective observational study of consecutive hospitalized patients at Nara Medical University Hospital between June 2022 and November 2023, without exclusion criteria. Delirium risk factors were assessed within 3 days of admission using a standardized checklist based on national criteria. Delirium was diagnosed following specialist consultation according to the International Classification of Diseases, 10th Revision (ICD‐10), and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision criteria. Logistic regression analyses were performed to identify independent association with consultation‐confirmed delirium. Results: Among 20,980 patients (mean age, 67.1 ± 17.0 years; males, 55.0%), 209 (1.0%) were diagnosed with delirium following specialist consultation. Overall, 56.4% met at least one predefined risk criterion at admission. In multivariable analyses adjusted for age and sex, dementia (odds ratio [OR], 3.995; 95% confidence interval [CI], 2.647–6.029), history of delirium (OR, 3.649; 95% CI, 2.158–6.170), and heavy alcohol use (OR, 1.648; 95% CI, 1.002–2.710) were independently associated with consultation‐confirmed delirium. Conclusions: In this large cohort evaluated under a nationwide screening framework, consultation‐confirmed delirium was independently associated with baseline neurocognitive vulnerability (dementia and history of delirium) and heavy alcohol use, rather than chronological age alone, supporting vulnerability‐focused risk stratification in routine clinical practice.

Aim: This study aimed to describe the nationwide reach, longitudinal growth, and geographic dissemination of the Effectiveness of Guideline for Dissemination and Education in Psychiatric Treatment (EGUIDE) project in Japan from 2016 to 2024. Methods: The EGUIDE project is a nationwide, multicenter implementation initiative designed to promote the dissemination of clinical practice guidelines, specifically the Guidelines for Pharmacological Treatment of Schizophrenia and the Treatment Guidelines II: Major Depressive Disorder. The project provides educational lectures primarily for psychiatrists and other mental health professionals. We descriptively summarized the cumulative numbers of lectures delivered, participants enrolled, and participating institutions from 2016 to 2024. In addition, we calculated the proportion of hospitals with psychiatric departments that participated in each prefecture. Results: Between 2016 and 2024, a total of 194 guideline lectures on schizophrenia and major depressive disorder were conducted. The cumulative number of participants reached 4785 across 763 institutions, of which 592 were hospitals with psychiatric departments, corresponding to approximately 20% of all such hospitals nationwide. Participating hospitals were distributed across most prefectures in Japan, indicating broad geographic coverage. Conclusion: Over the 9‐year period, the EGUIDE project continuously delivered guideline lectures and steadily expanded its participant and institutional base. The nationwide distribution of participating institutions suggests that the project has established a broad implementation platform for psychiatric guideline dissemination in Japan. Continued efforts may further strengthen this dissemination network and support future evaluations of its impact on psychiatric practice.

Background: Educational interventions are widely used to promote guideline‐concordant psychiatric practice. However, it remains unclear whether participants' subjective satisfaction translates into actual changes in clinical behavior (CB). This study examined the association between subjective assessment (SA) scores of the EGUIDE training programs for schizophrenia and major depressive disorder (MDD) and CB. Methods: In this multicenter observational study, we analyzed data from psychiatrists who participated in the EGUIDE training program. SA scores were obtained immediately after training using standardized questionnaires assessing satisfaction with program content, knowledge, skills, and future clinical intentions. CB was evaluated using self‐report measures of guideline‐concordant practice in general, schizophrenia‐specific, and MDD‐specific domains. Associations between SA and CB scores were examined using Spearman's rank correlation coefficients. Results: A total of 1399 psychiatrists were included in the analysis. The comprehensive SA score showed a significant positive correlation with the comprehensive CB score ( r = 0.19, p < 0.001). Likewise, schizophrenia‐ and MDD‐specific SA scores were positively correlated with all CB domains, including general guideline use and disorder‐specific practices ( ρ = 0.14–0.19, all p < 0.001). Although effect sizes were small, the associations were consistent across disorders and clinical domains. Conclusions: Higher satisfaction with guideline‐based educational programs was associated with greater self‐reported guideline‐concordant CBs, suggesting that positive educational experiences may support improvements in psychiatric practice at the national level.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder shaped by genetic factors such as copy number variations (CNVs) and immunological factors such as maternal infection. However, most studies on the development of genetic ASD have focused on neurological aspects, and the role of immunity in genetic ASD remains unclear. Here, we demonstrate increased γδ T cells in the brains of 15q11-13 duplication ( 15q dup ) mice, which model a common CNV associated with ASD. Elevated CXCL16 in the brains of 15q dup mice promoted γδ T cell infiltration, specifically of Vγ6 ⁺ γδ T cells that produce IL-17A. Deletion of Vγ6 ⁺ γδ T cells throughout development or treatment with neutralizing antibodies against Vγ6 or IL-17A increased social behavior in 15q dup mice. These findings suggest that immune dysregulation contributes to social behavior deficits in 15q dup mice, consistent with observations in maternal immune activation models, and may represent a potential target for interventions for ASD-associated differences in social behavior.