Psychiatry and Clinical Neurosciences最新文献

Aims: Mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD), are highly heritable and linked to fronto-limbic circuit dysfunction. This longitudinal fMRI study examined whether baseline responses of the amygdala, anterior cingulate cortex (ACC), and ventrolateral prefrontal cortex (vlPFC) evoked by facial emotional expressions predicted first-onset or recurrence of mood episodes over 7 years in monozygotic twins.

Methods: The sample comprised 68 unaffected twins (UT) without a history of mood disorders but varying familial risk, and 62 affected twins (AT) in remission from MDD or BD. At baseline, participants underwent functional Magnetic Resonance Imaging (fMRI) of fearful and happy face processing and completed behavioral measures of emotional processing, which were repeated at follow-up.

Results: Lower baseline activation of the bilateral amygdala (left hazard ratio, HR = 1.69, 95% CI 1.15-2.45; right HR = 1.80, 95% CI 1.23-2.25), dorsal ACC (HR = 1.27, 95% CI 1.02-1.57), and right anterior vlPFC (HR = 2.28, 95% CI 1.56-3.26) by fearful (vs. happy) faces was associated with higher risk of first-onset mood episodes in the UT group. In the AT group, baseline fronto-limbic emotional activations were not associated with recurrence risk. Behaviorally, the UT group that later developed a mood episode showed slower recognition of happy faces and greater avoidance of subliminal fearful faces compared with the UT group that remained well.

Conclusion: Dysfunctional fronto-limbic processing of facial emotions indicates increased propensity to develop a mood disorder, but is not associated with increased risk for recurrence of mood episodes. This dissociation suggests that distinct neural mechanisms underlie the first-onset versus the recurrence of mood disorders.

Aim: To examine the implementation of evidence-based psychotherapy across international healthcare contexts and identify barriers to clinical delivery.

Methods: We conducted an international, cross-sectional, web-based survey of psychiatrists from October 2024 to March 2025. The questionnaire assessed familiarity with 10 evidence-based psychotherapy modalities, frequency of use, delivery confidence, perceived barriers, and clinical workload. Responses from 16 countries were analyzed across five geographic regions using chi-squared tests and effect sizes.

Results: Among 424 respondents, 201 (47.4%) demonstrated low composite familiarity with evidence-based psychotherapies. Cognitive behavior therapy maintained moderate familiarity across regions, while other modalities remained largely unfamiliar. Japan exhibited the most constrained practice environment, with 48.3% reporting consultations under 10 min compared to 15.1% in other regions, and 30.0% seeing 40 or more patients daily. Major time constraints were reported by 63.3% of Japanese psychiatrists, significantly higher than other regions (P = 0.015). Frequent use of evidence-based psychotherapy was lowest in Japan (20.0%) and highest in the Middle East (60.0%). Despite these challenges, 77.4% of all respondents rated these approaches as highly important. Respondents identified improved postgraduate training (54.0%), continuing education access (38.2%), and enhanced supervision (36.0%) as priorities.

Conclusion: Implementation varies across healthcare contexts, with Japan exemplifying system-level constraints where brief consultations and high patient volumes override practitioner knowledge and motivation. While psychiatrists value evidence-based approaches and seek to implement them, organizational barriers ultimately determine actual practice patterns. Findings indicate that training initiatives without concurrent structural reforms cannot bridge implementation gaps. Effective integration requires alignment of education, healthcare delivery structures, and payment systems.

Clinical trial registration: Not applicable.

Background: Alzheimer's disease (AD) shows distinct trajectories of cognitive decline based on age of onset, highlighting the need for reliable functional biomarkers.

Aim: This study aims to evaluate whether functional connectivity density (FCD) can serve as a functional biomarker linking tau pathology to cognition, either directly or as a mediator.

Methods: We included 52 cognitively unimpaired controls, 54 late-onset AD (LOAD), and 44 young-onset AD (YOAD) patients who underwent amyloid and [F18]Florzolotau PET, resting-state functional magnetic resonance imaging (MRI), and two cognitive tests. Voxel-wise FCD analyses compared patient groups with controls. Direct associations between FCD and cognition were assessed, and mediation analyses tested whether FCD mediated tau-related cognitive effects.

Results: In YOAD, reduced precuneus short-range FCD was directly associated with poorer cross-sectional cognitive performance, without mediating or moderating longitudinal decline. In LOAD, higher left anterior cingulate FCD covaried with tau burden and fully mediated its relationship with cognition and the rate of decline.

Discussion: Our results reveal distinct FCD signatures in YOAD and LOAD that mirror their differential functional responses to tau pathology. In YOAD, reduced precuneus FCD appears to serve as a state marker of cognitive impairment, whereas in LOAD, elevated anterior cingulate FCD suggests compensatory network recruitment consistent with a functional reserve model. These findings underscore FCD's promise as a subtype-specific biomarker for tracking AD progression.

Aim: Schizophrenia is associated with subtle brain structural alterations, but separating disease from medication effects is challenging. Antipsychotic dopamine D2 receptor (D2R) antagonism has been associated with striatal volume increases, but effects of partial D2R agonism by newer antipsychotics are largely unexplored. This study aimed to compare short-term brain changes associated with either D2R antagonism or partial D2R agonism using normative modeling. Secondarily, the study aimed to explore long-term effects following naturalistic treatment.

Methods: Antipsychotic-naïve patients with first-episode psychosis received 6 weeks of monotherapy with either amisulpride (D2R antagonist) (N = 41) or aripiprazole (partial D2R agonist) (N = 45). All patients underwent structural magnetic resonance imaging before and after 6 weeks of treatment. A subset was re-scanned at 6 months, 1 year, and 2 years of naturalistic treatment. A pretrained normative model was applied to 186 subcortical and cortical regions. We used Wilcoxon signed-rank tests to identify longitudinal structural deviations.

Results: Amisulpride and aripiprazole were associated with striatal volume increases after 6 weeks. No cortical effects were observed with amisulpride. Thinning of the temporal lobe was observed with aripiprazole. After 6 months, and 1 and 2 years, the striatal changes abated but cortical thinning in the frontal lobes emerged.

Conclusions: Both partial D2R agonism and D2R antagonism appear linked to striatal volume increases; however, changes appear transient. Conversely, frontal thinning occurs over time and appears less closely linked to antipsychotic treatment. Interpreting structural brain changes in patients with psychosis require consideration of short-term pharmacological effects as well as factors related to illness progression.

Background and objectives: Emerging evidence suggests that sexual behaviors play a critical but understudied role in neurological and psychiatric health. The causal and biological mechanisms linking age at first sexual intercourse (AFS) and lifetime number of sexual partners (LNSP) to brain disorders remain unknown. This study aims to determine whether sexual behavior influences neurological and psychiatric disorders through biological mechanisms, integrating observational and genetic evidence to uncover causal pathways.

Methods: Utilizing data from the UK Biobank, the relationships of AFS and LNSP with neurological and psychiatric disorders, brain structure, and inflammation indicators were examined with Cox proportional hazards and linear regression model and further examined the potential causality, genetic correlation, and shared genetics by Mendelian randomization, linkage disequilibrium score regression, multi-trait analysis of genome-wide association studies, transcriptome-wide association studies, and functional enrichment analysis.

Results: In this large-scale study of 394,395 participants with a median follow-up of 14.7 years, earlier AFS and higher LNSP were associated with increased risks of stroke, major depressive disorder, anxiety disorders, and bipolar disorder. These behavioral traits were also linked to alterations in gray/white matter and inflammatory markers. Mendelian randomization and linkage disequilibrium score regression analyses confirmed causal relationships and shared heritability with brain disorders, multi-trait analysis of genome-wide association studies and transcriptome-wide association studies, revealing overlapping genetic influences in blood and neural tissues. Functional enrichment analysis demonstrated shared biological pathways including immunity.

Conclusions: This study provides robust evidence linking sexual behavior traits to neurological and psychiatric disorders through large-scale longitudinal analyses, causal genetic methods, and multi-omics integration.

Aim: Attention-deficit/hyperactivity disorder (ADHD) is associated with dysregulation of dopamine and norepinephrine neurotransmission. Extended-release methylphenidate (MPH), a first-line treatment for ADHD, modulates these systems. However, its specific effects on the dopamine transporter (DAT) and norepinephrine transporter (NET) are inadequately characterized. This study evaluated the effects of MPH on DAT and NET binding in adults with ADHD and examined the relationship between transporter binding and cognitive improvement.

Methods: This longitudinal dual-tracer positron emission tomography (PET) study used [¹⁸F]-FEPE2I for DAT imaging and (S,S)-[¹⁸F]- FMeNER-D2 for NET imaging. PET imaging and cognitive assessments were conducted on 21 adults with ADHD before MPH treatment, and 12 of these participants were reevaluated after achieving treatment stabilization.

Results: MPH treatment significantly decreased DAT binding in the caudate and putamen and NET binding in the thalamus and pons. Improvements in attention and multitasking abilities were observed. Baseline NET binding in the pons was higher in individuals with ADHD than in controls, and higher baseline DAT binding in the putamen predicted improvement in sustained attention. However, changes in DAT and NET binding did not correlate with cognitive improvement. Blood concentration analysis revealed that even at MPH blood levels that resulted in high DAT occupancy in the striatum, NET occupancy in the thalamus remained moderate.

Conclusions: MPH simultaneously reduced DAT and NET binding in ADHD, enhanced dopamine and norepinephrine transmission, and improved cognitive function. The differential occupancy of DAT and NET suggests distinct contributions to the therapeutic effects of MPH.

Aim: To evaluate the efficacy and safety of oral zuranolone for 14 days, compared with placebo, in Japanese patients with major depressive disorder (MDD).

Methods: This multicenter, Phase 3 study was conducted in two parts (70 sites; Japan) including a randomized, double-blind, placebo-controlled, parallel-group part presented herein. Participants aged 18-75 years with the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score ≥ 22 were randomized (1:1) ratio to receive either zuranolone (30 mg once daily) or placebo for 14 days with follow-up on Days 3, 8, and 15 and then weekly for 6 weeks (57 days) thereafter. The primary endpoint was change from baseline in the HAMD-17 total score at Day 15.

Results: Overall, 412 participants were randomized to receive either zuranolone 30 mg (n = 207) or placebo (n = 205). The difference in the least-squares mean (95% confidence interval [CI]) change from baseline in the HAMD-17 total score between groups (-1.20; 95% CI: -2.32, -0.08; P = 0.0365) was statistically significant on Day 15. A significant improvement in the HAMD-17 total score was observed with zuranolone 30 mg during the early treatment period on Days 3 and 8 compared with placebo; however, no significant differences were observed between the groups at later time points, from Day 22 to Day 57. The frequency of adverse events was higher in the zuranolone group (55.1%) than in the placebo group (40.7%); however, no serious adverse events were reported.

Conclusion: Zuranolone improved depressive symptoms on Day 15, compared with placebo, in Japanese patients with MDD. No new safety signals were observed.

Clinical trial registration: jRCT2031210577.

Aim: Artificial Intelligence (AI)-based prediction models of treatment response promise to revolutionize psychiatric care by enabling personalized treatment, but very few have been thoroughly tested in different samples or compared to current clinical standards. Here we present models predicting antipsychotic response and assess their clinical utility in a robust methodological framework.

Methods: Machine learning models were trained and cross-validated on clinical and sociodemographic data from 594 individuals with established schizophrenia (NCT00014001) and 323 individuals with first episode psychosis (NCT03510325). Models predicted four measures of antipsychotic response at 3 months after baseline. Clinical utility was assessed using decision curve and calibration curve analyses. Model performance was tested in a reduced feature space and across sex, ethnicity, antipsychotic, and symptom change subgroups to investigate model fairness.

Results: Models predicting total symptom severity (r = 0.4-0.68) and symptomatic remission (BAC = 62.4%-69%) performed well in both samples and externally validated successfully in the opposing cohort (r = 0.4-0.5, BAC = 63.5%-65.7%). Performance remained significant when the models were reduced to 8-9 key variables (r = 0.53 for total symptom severity, BAC = 65.3% for symptomatic remission). Models predicting symptomatic remission had a net benefit across risk thresholds of 0.5-0.9 and were moderately well-calibrated (ECE = 0.16-0.18). Model performance different across sex, ethnicity and medication subgroups.

Conclusions: We present a robust framework for training and assessing the clinical utility of prediction models in psychiatry. Our models generalize across different psychosis populations and show promising calibration and net benefit. However, performance disparities across demographic and treatment subgroups highlight the need for more diverse clinical samples to ensure equitable prediction.