Neuropsychopharmacology Reports最新文献

Objective: Multiple sclerosis (MS) is characterized by chronic neuroinflammation and oxidative stress. Vitamin D is believed to exert immunomodulatory and antioxidant effects, yet its impact on specific inflammatory proteins such as CHI3L1 (YKL-40) in MS remains unclear. This study evaluated whether 8-week vitamin D3 supplementation affects serum CHI3L1 levels, oxidative stress markers, and antioxidant enzyme activities in patients with MS.

Methods: In this single-arm pre-post clinical trial, 35 patients with MS (aged 30-56 years) received oral vitamin D3 supplementation (50 000 IU/week) for 8 weeks. Serum 25(OH)D and CHI3L1 levels were determined using commercial enzyme-linked immunosorbent assay (ELISA) kits. oxidative stress markers were measured pre- and post-intervention using commercial colorimetric kits. Statistical analysis was performed using paired t-tests or Wilcoxon signed-rank tests.

Results: Vitamin D3 supplementation significantly increased serum 25(OH)D levels (20.80 ± 8.6 to 39.11 ± 12.26 ng/mL; p < 0.001). CHI3L1 concentration decreased by 21.7% (33.28 ± 8.9 to 26.05 ± 9.1 ng/mL; p < 0.001). oxidative stress was reduced, evidenced by lower TOS (1.55 ± 0.50 to 0.59 ± 0.23 mmol H₂O₂ equiv./L; p < 0.001) and MDA (0.08 ± 0.03 to 0.05 ± 0.026 nmol/mL; p < 0.001). Antioxidant capacity improved, as demonstrated by elevated TAC (0.622 ± 0.138 to 0.797 ± 0.15 mmol Fe²⁺/L; p < 0.001) and increased activities of SOD (10.5%; p < 0.001), CAT (19.5%; p < 0.001), and GPx (35.6%; p < 0.05). Significant inverse correlations were observed between serum 25(OH)D and CHI3L1 (r = -0.999, p < 0.001), TOS (r = -0.456, p = 0.0058), and MDA (r = -0.577, p < 0.001).

Conclusion: Vitamin D3 supplementation was associated with reductions in CHI3L1 and oxidative stress markers, while suggesting enhancement of antioxidant capacity. This observed biomarker changes support vitamin D3 as a potential adjunct therapy targeting interconnected pathological pathways in MS.

Aims: This study aimed to investigate whether multi-timepoint DNA methylation levels at the SLC6A4 gene during early adolescence are associated with psychopathological and behavioral clusters, SLC6A4 encodes the serotonin transporter, which regulates the concentration of serotonin in the synaptic cleft. The clusters were previously identified by deep learning analysis of self- and parental-report questionnaires from participants in the Tokyo Teen Cohort (TTC) study in Japan.

Methods: We extracted genomic DNA from saliva samples of a subset of TTC participants (N = 122) at ages 11, 13, and 15. DNA methylation levels at the functional CpG sites within the SLC6A4 promoter were measured using bisulfite pyrosequencing. Five psychopathological and behavioral clusters were applied from the previous study: minimal problems, persistent or worsening internalizing problems, subjective problems overlooked by caregivers, persistent externalizing problems, and chronic severe problems across symptoms. Linear mixed-effects models were applied to assess the associations between DNA methylation levels and psycho-behavioral clusters.

Results: Males exhibited significantly lower mean methylation levels compared to females across all time points. Males classified as persistent externalizing problems showed notably lower methylation levels than those classified as minimal problems.

Conclusions: DNA methylation levels in the SLC6A4 could potentially serve as epigenetic signatures for male adolescents exhibiting externalizing behavioral problems. To our knowledge, this is the first study to track SLC6A4 methylation at three developmental time points across early to mid-adolescence. Further epigenetic research is warranted to understand the role of environmental and genetic factors in the manifestation of adolescent behavioral problems.

Aim: The regulation of new psychoactive and dangerous abused substances is very important for the prevention of drug abuse. A simple and effective evaluation method using laboratory animals is needed to regulate designated drugs with high accuracy and speed.

Methods: In the present study, we used the typical κ-opioid receptor agonist U50,488H and the typical 5-HT_2A/2C receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), which have a similar mechanism of action to hallucinogenic drugs, in a conditioned place aversion (CPA) test in mice. In addition, because hallucinogenic drugs can cause emotional abnormalities during hallucinations, we performed a marble-burying test in mice.

Results: In the CPA test, both κ-opioid receptor and 5-HT_2A/2C receptor agonists produced significant aversive effects and abnormal behavior. These aversive effects and abnormal behavior were probably due in part to the hallucinogenic effects of these drugs.

Conclusion: Therefore, these tests using mice may be useful for evaluating hallucinogenic effects. We hope that these simple and rapid evaluation methods will be used to identify designated drugs.

Objective: The 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.

Methods: We 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.

Results: For 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.

Conclusion: The 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 registration: The protocol for the EGUIDE Project is registered with the University Hospital Medical Information Network Registry (UMIN000022645).

Aim: This 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.

Methods: We 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.

Results: In 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.

Discussion: This 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.

Aim: Orexin-A (OXA) is a neuropeptide that regulates arousal, behavior, and sleep-wake rhythms. While altered OXA levels have been observed in schizophrenia, longitudinal data are limited. This study examined the relationship between changes in serum OXA levels and physical activity, sleep, and psychiatric symptoms in patients with chronic schizophrenia.

Methods: Seventeen long-term inpatients with schizophrenia underwent assessments at baseline (T1) and again after 6 months (T2). Serum OXA levels, sleep and activity parameters derived from actigraphy, and psychiatric symptoms (evaluated with the Positive and Negative Syndrome Scale [PANSS]) were collected at both time points. Spearman's correlations were used to analyze associations between the T2-T1 change in serum OXA (ΔOXA) and the corresponding Δ values of each sleep, activity, and PANSS measure, to explore longitudinal associations among these variables.

Results: ΔOXA was positively correlated with Δ step count (ρ = 0.53, p = 0.03) and negatively correlated with Δ time in bed (ρ = -0.50, p = 0.04). No significant associations were found with PANSS scores, other sleep parameters, pharmacotherapy, or body mass index.

Conclusion: In this preliminary longitudinal sample, increases in serum OXA were linked to greater daytime activity and reduced time in bed, suggesting that orexinergic signaling may modulate behavioral regulation in schizophrenia beyond its established role in sleep-wake control. Larger studies, with adjustment for multiple comparisons, are warranted to evaluate OXA as a candidate biomarker or therapeutic target.

Background and aims: Preclinical 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.

Methods: In 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).

Results: There 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).

Conclusion: These 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 registration: ClinicalTrials.gov identifier: NCT03879759.

Aim: The relationship between mental illness and criminal behavior is a critical social issue that remains under debate. This study aimed to investigate differences in cortical gray matter (GM) volume between mentally ill individuals institutionalized in a residence for the execution of security measures (REMS) following a violent offense-and deemed not criminally responsible due to their psychiatric condition-and a control group of healthy non-offenders, using voxel-based morphometry (VBM) analyses.

Method: We recruited 13 male violent offenders with psychotic disorders institutionalized in REMS and 13 healthy controls. Psychiatric symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS), and psychopathy traits with the Psychopathy Checklist-Revised (PCL-R). High-resolution structural Magnetic Resonance scans were acquired on a 3T scanner. VBM analyses were used to identify GM volume differences between groups, and correlation analyses were performed to assess associations between brain structure and clinical measures.

Results: The experimental group showed wide variability in symptom severity and psychopathy traits. VBM analyses revealed GM volume reductions in bilateral insular cortex, in left superior temporal gyrus (STG) and right fusiform gyrus (FG) of the experimental group. GM volume in the left STG-insula cluster significantly correlated with BPRS scores. No significant associations were found with PCL-R scores.

Conclusion: These findings highlight structural brain alterations associated with psychotic symptomatology and should serve as a starting point for future research exploring the neural changes associated of pathological social behavior in mentally ill persons who committed violent crimes.

Purpose: Suicide attempt by overdose medication of benzodiazepine is common. In Japan, governmental restrictions on benzodiazepine multidrug use started as of 2012, resulting in a decrease in benzodiazepine prescriptions and multidrug use. This study aimed to examine whether suicide attempts due to overdose medication of psychotropic drugs decreased after this regulation.

Methods: We retrospectively obtained information from clinical records for 4183 and 4140 patients admitted to the intensive care unit of the Advanced Emergency Medical Center at Teikyo University Hospital, Tokyo, during the 2-year period from April 2013 to March 2015 (immediately after the introduction of the regulation: Period 1) and from April 2018 to March 2020 (after the enhancement of the regulations: Period 2), respectively. The proportion of patients who attempted suicide, that of overmedication with prescribed psychotropic drugs, and their clinical characteristics were compared between the two periods.

Results: The proportion of patients with suicide attempts by psychotropic overdose medication in Period 1 was 4.1%, whereas it decreased significantly to 2.8% in Period 2 (p = 0.004). The mean (standard deviation) diazepam-equivalent daily prescription for those overdosing was 32.0 (33.3) mg in Period 1, compared to 25.6 (30.0) mg in Period 2, a significant decrease (p = 0.01). The mean number of concomitant benzodiazepines also decreased significantly from 2.8 (1.4) to 2.0 (1.0) (p = 0.0002).

Conclusions: Our results suggest that the governmental regulation to control multidrug use of benzodiazepine prescriptions in Japan reduced the number and doses of benzodiazepines prescribed and decreased suicide attempts by overdose medication of prescribed psychotropic drugs.

Background: Atypical antipsychotics (AAs) are commonly used in the treatment of schizophrenia and are often preferred as first-line therapy over typical antipsychotics (TAs) due to their lower risk of extrapyramidal side effects. Both groups are efficacious in treating symptoms of schizophrenia, but increasing research has highlighted AAs as being associated with a risk of developing dyslipidaemia. Existing research has pointed to the need for more data focusing on the effects of individual AAs on dyslipidaemia in this population.

Methods: The scoping review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping reviews (PRISMA-ScR) checklist. The thematic analysis was used to synthesize data from 12 studies selected through structured searches across six databases. Inclusion criteria focused on primary studies between 2015 and 2025 involving adult patients with schizophrenia (18-65 years) treated with AAs and reporting on lipid abnormalities. The themes were identified via Braun and Clarke's six-step framework.

Results: Clozapine and olanzapine were most strongly associated with increased LDL, total cholesterol, and triglycerides, and reduced HDL. Aripiprazole and lurasidone showed minimal impact. Identified biomarkers included asprosin, IGFBP-2, MIF, and white blood cell counts. Pharmacogenetic markers such as APOA1 gene polymorphisms and specific SNPs were also linked to lipid profile variability. Anthropometric indicators like waist-to-hip ratio were correlated with dyslipidaemic risk.

Conclusion: The review shows significant associations between specific AAs and lipid abnormalities, particularly with clozapine and olanzapine. Biomarkers and genetic polymorphisms offer promising avenues for monitoring and personalized treatment. Evidence for certain AAs, such as amisulpride, paliperidone, and ziprasidone, remains sparse, highlighting the need for further targeted research. These findings support informed prescribing and the development of predictive tools to mitigate metabolic risks in the treatment of schizophrenia.