Neuropsychopharmacology Reports最新文献

Aim: Clinical practice guidelines have improved the quality and standardization of psychiatric care; however, their long-term implementation in real-world settings remains limited. The Effectiveness of the Guidelines for Dissemination and Education (EGUIDE) project was established to promote sustained evidence-based practice through a multilayered educational program for psychiatrists in Japan.

Methods: This multicenter observational study longitudinally tracked psychiatrists' self-rated clinical behavior (CB) scores related to guideline adherence for up to 8 years after initial EGUIDE participation. CB was assessed using a validated questionnaire covering general guideline use (CB-G), schizophrenia (CB-S), and major depressive disorder (CB-D), with a comprehensive index (CB-C) representing the mean of all domains. Data were analyzed using the Kruskal-Wallis test, the Mann-Whitney U test, and the Bonferroni correction (two-tailed p < 0.05).

Results: A total of 1562 psychiatrists (mean age, 32.7 ± 7.1 years) were included. All CB indices (CB-C, CB-G, CB-S, and CB-D) significantly improved post training compared with the baseline (H = 831.2-984.0; all p < 10^-72), with small-to-moderate effect sizes (r = 0.09-0.29). These improvements were maintained throughout the 8-year follow-up, with no significant decline, and several domains showed small but continued increases between 3 and 7 years post training.

Conclusion: The EGUIDE program achieved long-term, sustained improvements in psychiatrists' guideline-adherent clinical behaviors through an integrated system combining education, supervision, feedback, and follow-up. This autonomous, cyclical framework represents a high-impact model for continuous quality improvement and may be adaptable to other medical specialties.

We previously performed data-driven classification based on large-scale neuroimaging datasets to identify a potential novel subtype of psychiatric disorders characterized by the pronounced enlarged ventricles and cognitive impairment (EVCI) in one cohort. However, these findings have yet to be validated across independent cohorts. Herein, we investigated the availability of cognitive data in other cohorts in the Cognitive Genetics Collaborative Research Organization (COCORO) project to assess the presence of cognitive impairment (CI). Subsequently, we compared the prevalence of CI, lateral ventricular volume, and demographic and clinical characteristics between individuals with EVCI and those with EV but without CI (EV-nonCI). Cognitive data were available for 27 individuals with EVCI from the other 8 cohorts. Among the 27 individuals in the EV group, 5 (18.5%) exhibited EVCI, all of whom were diagnosed with schizophrenia. Three individuals (60%) in the EVCI group were male. Compared with the EV-non-CI group, the EVCI group presented significantly lower current intellectual quotient (IQ) scores (p = 5.8 × 10^-4), but there was no significant difference in premorbid IQ (p = 0.56). Furthermore, there was no significant difference in the Z scores for lateral ventricular volume between the groups (p = 0.26). This study validated the existence of the EVCI subgroup in independent cohorts, thus supporting our previous findings.

Background: Imbalances between excitatory and inhibitory (E/I) neurotransmitters in the brain may contribute to the pathophysiology of bipolar disorder (BD). Proton magnetic resonance spectroscopy (¹H-MRS) measures glutamatergic neurometabolites and gamma-aminobutyric acid (GABA) as indices of E/I neurotransmission. Previous meta-analyses reported higher glutamatergic neurometabolite levels in the medial prefrontal cortex of BD, but findings on GABA levels in the anterior cingulate cortex (ACC) of BD patients remain inconsistent.

Methods: We conducted a cross-sectional study using ¹H-MRS to compare GABA and glutamate plus glutamine (Glx) levels in the dorsal ACC (dACC) of 27 patients with BD and 27 age- and sex-matched healthy controls (HCs). We used the ¹H-MRS (3 T MRI, MEGAPRESS, 256 averages, TR = 1500 ms, TE = 68 ms). Clinical symptoms were evaluated using standardized rating scales. Statistical analyses were conducted to assess group differences in neurometabolite levels and to explore the associations between these neurometabolite levels and clinical symptom severity within the BD group.

Results: No significant differences in dACC GABA levels, Glx levels, or Glx/GABA ratio were observed between the BD and HC groups. There were no significant differences within the BD group based on BD subtype (I or II) or clinical phase (depression or euthymic). Patients with lithium treatment had higher GABA levels compared to those without.

Discussion: Our results suggest that GABAergic function in the dACC may not play a pivotal role in the pathophysiology of BD. Given possible GABAergic dysregulation in BD, further research using alternative methodologies is warranted to elucidate the pathological basis.

Aim: As part of a post-marketing commitment, this study evaluated the incidences of intracranial hemorrhage and serious (intracranial or gastrointestinal) hemorrhage requiring hospitalization in Japanese patients with depression prescribed vortioxetine or selective serotonin reuptake inhibitors (SSRIs).

Methods: This real-world, retrospective cohort study used data from the JMDC claims database. Patients with depression who received an initial prescription for vortioxetine or SSRIs (index date) between November 2019 and November 2022, with an observation period of 6 months before (look-back period) and up to 360 days after (follow-up period) the index date were included. The primary analysis estimated the incidence of intracranial hemorrhage, while the secondary analysis estimated the incidence of serious hemorrhage requiring hospitalization. A multivariate model incorporating age, sex, antithrombotic and nonsteroidal anti-inflammatory drug prescriptions, and hypertension as covariates was used to calculate adjusted hazard ratios (aHRs). A propensity score incorporating 21 additional covariates assessed the robustness of the primary analysis (sensitivity analysis).

Results: Overall, 147 777 patients were included; 22 827 were prescribed vortioxetine (exposure) and 124 950 were prescribed SSRIs (control). The incidence of intracranial hemorrhage was 1.5 per 10 000 person-years in the exposure group and 3.2 per 10 000 person-years in the control group (aHR: 0.5, 95% confidence interval [CI]: 0.1-1.9). The incidence of serious hemorrhage requiring hospitalization was 27.4 per 10 000 person-years in the exposure group and 31.4 per 10 000 person-years in the control group (aHR: 0.8, 95% CI: 0.6-1.2). The incidence of intracranial hemorrhage in the exposure group versus the control group in the sensitivity analysis was similar to the primary analysis (aHR: 0.4, 95% CI: 0.1-1.9).

Conclusion: The incidence of intracranial hemorrhage and serious hemorrhage requiring hospitalization was low in Japanese patients with depression prescribed vortioxetine, and comparable with that observed in patients prescribed SSRIs.

Trial registration: ClinicalTrials.gov: NCT05932407.

Background: In our previous study, the minor T allele of the rs7858836 C/T single-nucleotide polymorphism (SNP) in the ASTN2 gene, which encodes astrotactin 2, was associated with reduced fentanyl requirements after laparoscopic-assisted colectomy and after mandibular osteotomy. In this study, we investigated the effects of this SNP on pain-related phenotypes in patients who underwent laparoscopic gynecologic surgery (LGS).

Methods: We studied 333 Japanese women, 21-69 years, who underwent LGS at Juntendo University Hospital between 2017 and 2019. We evaluated associations between SNP genotypes and postoperative pain-related phenotypes, including fentanyl requirements, rescue analgesic requirements, and the average pain scores on an 11-point Numeric Rating Scale (NRS) during the 24-h postoperative period. Patients with the TT or CT genotype were compared with those with the CC genotype using the Mann-Whitney test or χ² test. Values of p < 0.05 were considered statistically significant.

Results: The minor T allele frequency was 34.1%. Patients with the CT or TT genotype reported significantly lower average NRS pain scores (median, 1.6 vs. 2.0; p = 0.031) and required fewer rescue analgesics (5.5% vs. 15.0%; p = 0.003) compared to those with the CC genotype. Postoperative fentanyl requirements did not differ between the two groups (p = 0.940).

Conclusion: The minor T allele of the rs7858836 SNP was significantly associated with lower postoperative pain intensity, albeit only slightly, and decreased the need for rescue analgesics under comparable fentanyl dosing conditions, potentially reflecting lower pain sensitivity. However, the magnitude of the effect was less than our previous findings.

Aim: Altered brain energy metabolism related to neural hyperexcitation, which leads to increased lactate levels in the brain and cerebrospinal fluid (CSF), has been implicated in several neuropsychiatric disorders. This study aimed to investigate CSF levels of lactate and related metabolites in Japanese individuals with schizophrenia and major depressive disorder (MDD), using samples from the National Center for Neurology and Psychiatry biobank.

Methods: CSF levels of lactate, pyruvate, and glucose were measured in 27 patients with schizophrenia, 26 patients with MDD, and 27 age-matched non-psychiatric controls. Analyses were conducted by diagnostic groups and demographic variables.

Results: CSF lactate levels were significantly higher in individuals with schizophrenia and MDD compared with controls. CSF glucose levels were significantly elevated in individuals with MDD compared with controls. Pyruvate levels showed no significant group differences. Across all individuals, CSF lactate, pyruvate, and glucose levels were positively correlated. Lactate and glucose levels showed positive correlations with age. No significant associations were found between the three metabolites' levels and medication dosages, except for an effect of imipramine on glucose levels.

Conclusion: This study confirmed elevated CSF lactate levels in Japanese individuals with schizophrenia and MDD, consistent with findings in other populations. The elevation of CSF lactate is unlikely to reflect medication effects and instead may represent an underlying pathophysiology associated with altered brain energy metabolism in the brain.

Non-suicidal self-injury (NSSI) is a prevalent phenomenon among adolescents and poses significant public health concerns. Research has identified various functions of NSSI. However, public perceptions of these functions remain unclear. This cross-sectional study explored public understanding of the functions of NSSI and examined the relations between these perceptions and demographic factors of gender and age group. A nationwide online survey was conducted with 2000 Japanese adults (mean age 44.6 years, SD = 14.3) to assess their agreement with 20 statements about NSSI functions using a six-point scale. After conducting an exploratory factor analysis of the functions of NSSI, the study performed a two-factor analysis of variance with the factor scores for each function as the dependent variable and gender and age group as the independent variables. The exploratory factor analysis revealed a four-factor structure: (1) negative emotion regulation, (2) interpersonal effect, (3) avoidance of obligations, and (4) positive mood improvement. A series of two-way analyses of variance revealed gender and age differences, with women and younger individuals being more likely to endorse emotion regulation functions, and middle-aged and older adults more likely to support avoidance functions. Regarding interpersonal relationship factors, no statistically significant results were observed for either gender or age group. The findings suggest the importance of understanding public perceptions of NSSI functions for targeted psychological education and awareness. Future research should directly compare public perceptions with the perceptions of those who engaged in NSSI, considering other demographic factors.

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.

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).