ABSTRACTObjectiveThe Effectiveness Research on the Dissemination and Education of Psychiatric Clinical Practice Guidelines (EGUIDE Project) was launched in Japan to promote guideline‐adherent treatment for schizophrenia and major depressive disorder (MDD) through educational outreach programs. Although short‐term effects on participating physicians have been reported, the long‐term and facility‐wide effects remain unclear. This study evaluated whether guideline‐compliant treatment behaviors improved across institutions over time, indicating potential diffusion or spillover effects.MethodsWe conducted a prospective observational study involving 298 psychiatric facilities between 2016 and 2023. Discharge prescriptions and treatment data were collected for 19 623 patients with schizophrenia and 9805 patients with MDD. Adherence to the guidelines was assessed using 11 schizophrenia quality indicators (QI‐S) and seven MDD quality indicators (QI‐D). We performed logistic regression analyses, adjusting for age, sex, and facility type, with Bonferroni correction for multiple comparisons.ResultsFor schizophrenia, significant year‐on‐year improvements were observed in seven of the 11 QI‐S, including assessment of treatment‐resistant schizophrenia (TRS) diagnosis (from 42.2% to 62.5%), use of modified electroconvulsive therapy (mECT; from 6.1% to 11.8%), and nonprescription of anticholinergics (from 70.7% to 81.7%). For MDD, three of the seven QI‐D showed improvement, including assessment of severity diagnosis (from 51.2% to 77.0%) and use of mECT (from 12.8% to 26.6%). Notably, the implementation of cognitive behavioral therapy (CBT) decreased. These findings suggest long‐term behavioral changes across all facilities, extending even to nonparticipating clinicians.ConclusionThe presence of EGUIDE‐trained psychiatrists was associated with sustained improvements in guideline‐compliant treatments at the institutional level. These results imply not only individual educational benefits but also a diffusion of practice culture—that is, a spillover effect—leading to enhanced quality of psychiatric care. Continued educational efforts are essential to improving treatment practices at scale.Trial RegistrationThe protocol for the EGUIDE Project is registered with the University Hospital Medical Information Network Registry (UMIN000022645)

ABSTRACTBackground and AimsPreclinical studies have demonstrated that N‐acetylcysteine stabilizes levels of glutamate and glutathione and reduces alcohol‐seeking behaviors, indicating it as a potential pharmacotherapy for the management of alcohol use disorder. In this preliminary study, we examined brain metabolite levels and cognitive functioning in individuals with alcohol use disorder enrolled in a randomized controlled trial of N‐acetylcysteine versus placebo.MethodsIn this preliminary trial, 23 participants (average age = 49; 70% male) with moderate to severe alcohol use disorder (DSM‐5) were randomized to receive 2400 mg/day of N‐acetylcysteine (N = 9) or placebo (N = 14). At baseline and follow‐up (M = 19 days; SD = 3.73 days post‐baseline), participants underwent proton magnetic resonance spectroscopy (1H‐MRS) to assess levels of glutamate (Glu), glutathione (GSH) and total N‐acetylaspartate (tNAA) in the anterior cingulate cortex (ACC) and completed the Stroop Color and Word Test (SCWT; a measure of distractor interference and cognitive control) and the Trail Making Test (TMT; a measure of set shifting ability).ResultsThere were no significant differences between the N‐acetylcysteine or placebo groups in neurometabolite concentrations (GSH/Cr: p = 0.75, CI; −0.12–0.09, tNAAG/Cr: p = 0.797, CI; −0.10–0.13, Glu/Cr: p = 0.60, CI; −0.19–0.32), or cognitive scores (Stroop: p = 0.57, CI; −306.93–172.78, TMT: p = 0.166, CI; −6.62–36.77).ConclusionThese preliminary findings indicate that N‐acetylcysteine may not alter brain neurometabolite levels within the ACC or show improvements in certain domains of cognitive functioning measured by the SCWT and TMT, specifically resistance to distractor interference and set‐shifting ability respectively, in individuals with alcohol use disorder.Trial RegistrationClinicalTrials.gov identifier: NCT03879759

ABSTRACTIntroductionMajor depressive disorder (MDD) is a psychiatric disorder characterized by depressed mood and a loss of interest or pleasure. Treatment‐resistant depression (TRD) is clinically defined as the failure to achieve an adequate therapeutic response following trials of two or more antidepressant medications of sufficient dose and duration. The neuroinflammation hypothesis proposes that hypothalamic–pituitary–adrenal axis dysfunction and glucocorticoid resistance contribute to TRD pathophysiology, distinct from monoaminergic mechanisms. Human herpesvirus 6B (HHV‐6B) reactivation, triggered by stress, increases the risk of depression. Small protein encoded by the Intermediate stage Transcript of HHV‐6‐1 (SITH‐1), a latent HHV‐6B protein, may serve as a neuroinflammation biomarker. Previous studies showed elevated SITH‐1 antibody titers in depression patients compared to healthy controls. This study investigated the relationship between SITH‐1 antibody titers and clinical characteristics, particularly current symptoms and longitudinal depression trajectory, in patients with TRD.MethodsTwenty‐five patients with TRD and 18 healthy individuals were registered for the present study. Blood samples were collected from each participant, and clinical characteristics of TRD were assessed. The quantity of SITH‐1 was assessed by measuring antibody titers as SITH‐1 and calcium‐modulating ligand complex.ResultsSITH‐1 antibody titers were significantly elevated in the TRD group compared to healthy controls. Binary logistic regression analysis demonstrated that SITH‐1 antibody titers were significantly associated with TRD diagnosis, with the odds ratio for TRD of 15.7. Receiver Operating Characteristic analysis revealed that the optimal cutoff value for TRD classification was 2.07, yielding a sensitivity of 82.6% and a specificity of 94.4%. Multiple linear regression analysis demonstrated that the number of depressive episodes was significantly associated with SITH‐1 antibody titers, whereas 17‐item Hamilton Depression Rating Scale total scores showed no significant association.ConclusionThese findings suggest that SITH‐1 may reflect chronic neuroinflammatory processes and represent a promising novel biomarker for TRD.

ABSTRACTBackgroundPrimary polydipsia affects approximately 11%–20% of patients with chronic schizophrenia, and up to one‐third develop symptomatic hyponatremia. Rapid correction of hyponatremia can precipitate osmotic demyelination syndrome (ODS), involving demyelination in the central pons and extrapontine regions. ODS presenting with severe extrapyramidal symptoms (EPS) in schizophrenia has not been previously documented.Case PresentationA 34‐year‐old man with chronic schizophrenia, maintained on oral olanzapine and monthly flupentixol decanoate, developed polydipsia‐induced hyponatremia. His serum sodium was corrected at 9 mEq/L/day at a local hospital. Ten days later, he presented with fever, cough, dysarthria, dysphagia, and lead‐pipe rigidity. Laboratory tests revealed leukocytosis and rhabdomyolysis without delirium or autonomic instability. Dysarthria and dysphagia were consistent with pseudobulbar palsy. Brain MRI showed T2‐weighted and FLAIR hyperintensities in the bilateral basal ganglia and central pons, confirming ODS. The patient had a favorable clinical course with supportive treatment and regained independent mobility without the need for empirical immunotherapy.ConclusionsThis case highlights ODS as a rare but critical differential diagnosis for severe EPS in schizophrenia, particularly when presenting with lead‐pipe rigidity and pseudobulbar palsy. Greater awareness of this presentation can facilitate timely diagnosis and appropriate management, avoiding misattribution to antipsychotic‐induced side effects that may result in long‐term morbidity or mortality.

ABSTRACTAimThis study aimed to explore the relationship between self‐esteem and tumor necrotic factor‐alpha (TNF‐α) expression in individuals with autism spectrum disorder (ASD). Self‐esteem was assessed using the Contingencies of Self‐Worth (CSW) scale, with a focus on external and internal contingencies, and TNF‐α expression was measured, given its association with both ASD pathophysiology and self‐esteem in prior studies.MethodsWe enrolled 51 high‐functioning individuals with ASD and 34 typically developed (TD) individuals. Self‐esteem was assessed using the Japanese version of the CSW scale, which evaluates seven domains, and the Personal Sense of Power. TNF‐α expression in plasma was quantified via ELISA. Correlations of CSW scores and the Personal Sense of Power with TNF‐α levels were analyzed using multiple regression models adjusted for confounding factors such as age, sex, education level, and autistic symptoms.ResultsIn ASD individuals, TNF‐α expression was significantly negatively correlated with the external CSW domain of others' approval and showed a trend toward negative correlations with appearance and relationship harmony. These correlations were not observed in the TD individuals. Likewise, the Personal Sense of Power within family settings showed a trend toward positive correlations with TNF‐α expression in ASD individuals, but not in TD individuals.DiscussionThis study highlights the implication of TNF‐α levels in the self‐esteem of ASD individuals, particularly in interpersonal relationships. Lower TNF‐α expression was associated with higher self‐esteem in social contexts, independent of the severity of autistic symptoms. These findings suggest a biological link between inflammatory pathways and self‐esteem in ASD, contributing to a deeper understanding of the interplay between immune function and psychological well‐being in this population.

ABSTRACTBackgroundPatients' “pain attributions,” or their beliefs about chronic pain causes, critically affect pain experience and recovery, potentially modulating responses to analgesics and psychotropics. Since many pain‐mitigating drugs also impact psychological processes and brain functions underlying these attributions, such processes are relevant targets. The Chronic Pain Attribution Scale (CPAS) by Ashar et al. (2023) quantifies these beliefs. A Japanese version (CPAS‐J) is needed to assess this psychologically relevant construct in Japanese populations. This study aimed to develop and linguistically validate the CPAS‐J.MethodsThe CPAS‐J was developed following International Society for Pharmacoeconomics and Outcomes Research guidelines, with permission from the original author. The process included forward translation by eight bilingual medical experts, reconciliation by a pain research team, back‐translation by an independent translator, review by the original author, and a final consensus discussion to establish the definitive CPAS‐J.ResultsThe linguistic validation identified challenges in distinguishing “cause” from “trigger” in Japanese. To enhance comprehensibility, the team combined “kikkake” (initiating factor) and “gen'in” (broader cause/origin). The finalized CPAS‐J assesses perceived causes of pain.ConclusionsThe CPAS‐J was successfully developed through a rigorous process. This tool supports research on pain attributions in Japanese‐speaking populations and may improve our understanding of treatment responses by assessing a key psychological dimension of chronic pain that is linked to brain‐based processes.

ABSTRACTBackgroundOrganic psychosis associated with brain metastasis from cancer occasionally presents with psychiatric symptoms such as delusions or violent behavior. In these cases, however, psychotropics may not be sufficiently effective, and their continuous use may also be difficult due to side effects. Besides, regular oral administration of psychotropics becomes more difficult when medication refusal develops.Case PresentationA man in his 80s. At X‐1 years, lung cancer was found to have metastasized to the right frontal lobe, with no apparent psychiatric symptoms. At X years, however, the patient was hospitalized because of consciousness disturbance, and new brain metastases in the right parietal and occipital lobes were detected. Irritability, violent behaviors, and delusions became dominant and required physical restraint. Refusal to take oral medications was also noted. Blonanserin transdermal patch (40 mg/day) was started along with an intravenous drip of haloperidol, and he became mentally calm, although psychiatric symptoms persisted with fluctuations. His mental status was finally stabilized with blonanserin transdermal patch (80 mg/day) with no side effects, leading to hospital discharge on Day 53 after admission.ConclusionsBlonanserin transdermal patch may be effective for organic psychosis associated with brain metastasis. Because it can be used in cases where oral medication is difficult and has relatively few side effects, such as hypotension and extrapyramidal symptoms, it may be a helpful option for oncologists and liaison psychiatrists.

ABSTRACTBackgroundBenzodiazepine withdrawal delirium is a serious problem, and several candidates have been proposed to manage benzodiazepine withdrawal, such as valproic acid and carbamazepine, up to now. However, it is not always possible to use these candidates during the cancer perioperative period due to the risk of oversedation, and new candidates are being awaited.Case PresentationA woman in her late 80s was prescribed lorazepam 1.0 mg/day and brotizolam 0.25 mg/day for persistent anxiety and insomnia following the death of her husband and son. She had been receiving these medications for 3 years; however, they were ineffective, and she began consuming double the prescribed dose to manage her symptoms. Additionally, problematic drinking behavior was also acknowledged. Three months before the cancer surgery, the first author and her primary physician collaborated; lorazepam was gradually reduced to 0.5 mg/day, while yokukansan (5.0 g/day) and lemborexant (5.0 mg/day) were introduced instead. Her mental status stabilized, and surgery was performed as planned with no adverse effects. Postoperative and benzodiazepine withdrawal delirium were not observed.ConclusionThe combination of yokukansan and lemborexant may be an effective replacement for benzodiazepines in terms of their effects on 5‐hydroxytryptamine‐related mechanisms and regulation of the sleep cycle. During the cancer perioperative period, physicians may consider the gradual replacement or reduction of benzodiazepines with yokukansan and lemborexant before the surgery to avoid possible benzodiazepine‐related delirium.

ABSTRACTDepression is prevalent, yet conventional antidepressants often require time to produce therapeutic effects. Therefore, novel antidepressants with a more rapid onset of action are urgently needed. This study investigated the potential of δ opioid receptor (DOP) agonists as fast‐acting antidepressants, comparing their efficacy with that of existing treatments. We utilized the chronic social defeat stress (CSDS) model, which closely mimics clinical depressive symptoms, to evaluate the therapeutic effects of DOP agonists (SNC80, KNT‐127) and paroxetine, a selective serotonin reuptake inhibitor. Mice exposed to CSDS for 10 days showed social avoidance toward aggressor mice along with generalized depression and anxiety‐like behaviors. Both DOP agonists demonstrated dose‐dependent therapeutic effects at 1–10 mg/kg and showed improvements within 10–14 days of chronic administration. In contrast, paroxetine alleviated these symptoms after 28 days of treatment. These findings suggest that DOP agonists may offer a faster‐acting alternative to current antidepressant therapies.