Schizophrenia Research

Schizophrenia spectrum disorders (SSD) have been linked to immune dysregulation and altered intestinal barrier function, although findings across studies remain inconsistent. The present study investigated circulating markers of intestinal permeability and immune activation in individuals with early-stage SSD and healthy controls and examined their associations with clinical outcomes. Serum concentrations of intestinal fatty acid-binding protein (iFABP), zonulin, soluble CD14 (sCD14), bactericidal/permeability-increasing protein (BPI), and lipopolysaccharide-binding protein (LBP) were measured in 36 patients with SSD at baseline and one-year follow-up and in 36 matched healthy controls. Linear mixed-effects models adjusted for age, sex, and body mass index (BMI) were used to evaluate group differences and longitudinal changes. No biomarker differences between patients and controls, and no longitudinal changes within patients, remained statistically significant after correction for multiple testing. Similarly, biomarker concentrations were not associated with symptom severity, global functioning, or neutrophil-to-lymphocyte ratio (NLR). Exploratory analyses identified a robust positive association between BMI and zonulin concentrations and additional associations among iFABP, LBP, and sCD14. Exploratory mixed-effects models identified a negative non-significant association between iFABP and sCD14 after adjustment for age, sex, and BMI. Overall, the findings do not support a generalized alteration of gut permeability or immune activation markers in SSD. Instead, they suggest that variation in gut-related biomarkers may be more strongly influenced by metabolic and individual factors than by diagnosis or current symptom severity.

Background: Predictive-processing accounts propose altered prediction-error signaling in psychosis. However, event-related potential (ERP) findings in first-episode psychosis (FEP) are inconsistent and focused predominantly on mismatch negativity (MMN). Examining anticipatory and later post-stimulus ERP responses alongside MMN within a single passive paradigm may broaden the assessment of predictive processing in FEP. Methods: 34 participants with non-affective FEP and 34 healthy controls (HC) underwent EEG during a passive auditory pattern-based paradigm. Mean amplitudes of contingent negative variation (CNV), MMN, and post-imperative negative variation (PINV) were quantified at five frontocentral electrodes. Exploratory analyses examined N1 and P2 mean amplitudes. Mixed models tested group, electrode, and group-by- electrode effects adjusting for age, sex and years of education. Regressions examined ERP associations with psychotic-like experiences, neurocognition, and social cognition across groups, and with symptoms, functioning, and antipsychotic dose within FEP. Results: FEP participants reported more psychotic-like experiences and showed poorer global and social cognition than HC (all p-FDR [≤] .042). Standardized adjusted FEP-HC differences at FCz were nonsignificant for CNV ({beta} = -0.46), MMN ({beta} = -0.30), and PINV ({beta} = -0.10; all p-FDR [≥] .265). Exploratory analyses identified lower P2 amplitude in FEP at FCz ({beta} = -0.73; p-FDR = .019) and in the averaged frontocentral ROI ({beta} = -0.64; p-FDR = .027). No ERP-phenotype associations survived FDR correction. Conclusions: Despite phenotypic differences between FEP and HC, no significant differences emerged in the primary ERP indices of predictive processing examined. The exploratory P2 finding and its possible relationship to predictive processing and frontal dysfunction in FEP warrant further investigation.

Background and Hypothesis: Although psychotic disorders are characterized by widespread cortical thinning, translating these findings into individualized biomarkers remains challenging. Regional Vulnerability Index (RVI) and Neuroscore are candidate individual-level biomarkers that quantify the similarity between an individual's structural brain pattern and generic psychosis-associated alterations. This study investigated cortical thickness (CT)-based RVI and Neuroscore, along with mean CT deviation from healthy individuals, across the psychosis spectrum. Study Design: Using structural 3T MRI data from 289 participants (clinical high risk for psychosis [CHR], n=39; first episode psychosis [FEP], n=44, chronic psychosis [CP], n=86; healthy controls [HC], n=120), RVI, Neuroscore, and mean CT deviation (z) scores were computed from region-wise CT measures quantified using FreeSurfer v7.2. Group differences and associations with symptoms were evaluated. Study Results: RVI and Neuroscore were significantly higher, and mean CT z-scores lower, in FEP and CP compared with CHR and HC, with moderate-to-large effect sizes (|Cohen's d| = 0.55-1.15). No differences were observed between FEP and CP or CHR and HC. Indices were not associated with psychosis-spectrum symptom severity in the CHR, FEP, or CP groups. RVI (r = -0.561, p < .001) and Neuroscore (r = -0.997, p < .001) were strongly negatively correlated with the mean CT z-score. Conclusions: CT-based RVI and Neuroscore appear to index established disease status but not risk status, while showing substantial overlap with mean CT deviation. These findings highlight the need to further refine these biomarkers through data-driven and multimodal approaches to improve their utility for risk and prognostic prediction.

Importance: Anhedonia, social withdrawal and executive deficits represent transdiagnostic symptoms in depression, schizophrenia and addition, yet transdiagnostic brain volumetric alterations and their contribution to these symptom domains have not been systematically characterized. Objective: To determine common and disorder-specific gray matter deficits in patients with schizophrenia (SZ), major depression disorder (MDD) and alcohol use disorder (AUD) compared to heathy controls. Data Sources: A comprehensive literature search using three databases including PubMed, Web of Science and PsycInfo (between January 2000 to March 2024) as well as searches on review articles. Study Selection: Studies had to be published in English, reporting whole-brain results, comparing patients and healthy controls. Data Extraction and Synthesis: This meta-analysis adhered to the PRISMA guidelines and was pre-registered (https://osf.io/s57uq) prior to data analysis. Data was independently extracted and verified by 3 contributors, and statistical brain maps were generated using Seed-based d Mapping with Permutation of Subject Images (SDM-PSI) random-effects model. 147 VBM studies encompassing 90 Schizophrenia, 44 MDD and 13 AUD studies were finally included. Main Outcomes and Measures: Statistical maps of common and disorder-specific gray matter deficits in patients versus healthy controls are presented. Statistical inference utilized permutation tests, with threshold at p < .0025 and cluster extent of 10 voxels. Heterogeneity was evaluated using the I2 statistic and publication bias using Eggers regression test. Results: Capitalizing on a coordinate-based meta-analysis involving n=13,041 participants, we found shared GMV alterations in the ventromedial prefrontal cortex, ventral anterior cingulate cortex, insula, superior temporal gyrus. On the network level, we found robust functional interactions of the identified shared regions with the cortical midline structures as well as social and theory of mind-related behavioral functions. Subsequent characterization analyses highlighted the involvement of dopaminergic and serotonergic neurotransmitters as well as associated genetic annotations. Conclusions and Relevance: Overall, the present meta-analysis found common as well as separate GMV abnormalities in schizophrenia, major depressive disorder and alcohol use disorder suggesting a common neurostructural substrate and treatment target for social withdrawal and anhedonia across these disorders. Keywords: alcohol-use disorder, depression, meta-analysis, schizophrenia, voxel-based morphometry

Background Psychiatric diagnoses and psychotropic medication use among children, adolescents, and young adults have increased in high-income countries, with concerns about geographic variation. We described national trends and geographic variation in Denmark from 2010 to 2025 and developed an interactive online tool to explore these patterns. Methods We conducted a nationwide, descriptive, repeated cross-sectional register-based study of all Danish residents aged 0-24 years in 2010-2025 (n=2,930,744), using the Danish National Patient Registry and the Danish National Prescription Registry. We estimated annual incidence, prevalence, and, for selected diagnoses, lifetime prevalence, by age and sex, and age- and sex-standardised rates across regions, health councils, and municipalities. We assessed geographic variation using deviations from national means, coefficients of variation, Gini coefficients, and funnel plots. Findings Psychiatric diagnoses and psychotropic medication use increased from 2010 to 2025. The annual prevalence of attention-deficit hyperactivity disorder (ADHD) increased from 0.41 to 2.3 per 100 individuals, autism spectrum disorders from 0.20 to 1.2, and melatonin use from 0.14 to 3.0. ADHD and autism spectrum disorders were more prevalent among boys and anxiety disorders among girls. Sertraline use was also more prevalent among girls. Geographic variation was observed across diagnoses and psychotropic medications at regional, health council, and municipal levels. For example, lifetime prevalence of autism ranged from 1.3 to 5.9 per 100 across municipalities, and in 2025 regional coefficients of variation ranged from 0.11 (sertraline) to 0.41 (atomoxetine). Results can be explored in the interactive online tool (https://bupstat.sdu.dk/?lang=en). Interpretation Psychiatric diagnoses and psychotropic medication use increased among Danish children, adolescents, and young adults, with marked geographic variation. Descriptive data cannot establish the causes of this variation, but the findings identify areas for further review and support continued monitoring. Funding Best for Us project (www.bedstforos.dk), funded by the Novo Nordisk Foundation (NNF24SA0093635) and the Obel Family Foundation (69348).

Brain-imaging models predicting psychiatric outcomes are rarely tested where they would be used. Clinical high risk for psychosis is a demanding test case because services differ in whom they recruit and how they record transition. We re-estimated a published structural magnetic resonance imaging (MRI) risk model and applied it unchanged to four independent cohorts (685 participants, 106 transitions). Discrimination was weak (area under the curve, 0.56) and near chance in the two cohorts not previously used to evaluate the model (0.53 and 0.56). Predicted risks did not transfer (calibration slope, 0.17). Exploratory performance landscapes, which map local discrimination across participant characteristics, showed that discrimination varied with negative-symptom severity, also in external cohorts, whereas apparent age- and brain-age-related variation depended on single cohorts; no global test survived multiple-testing correction. Reporting where a model works, not only its average accuracy, can reveal when one diagnostic label hides several prediction problems.

Abstract Background: Glycosylated RNAs (GlycoRNAs) participate in immune recognition and intercellular communication, but their relationship with brain cell-type transcriptional signatures in major depressive disorder (MDD) remains unclear. We examined GlycoRNA-related transcriptional coupling with microglial and other cellular signatures in the dorsolateral prefrontal cortex (DLPFC). Method: Postmortem DLPFC transcriptomic data from 22 controls and 26 MDD patients (GSE102556) were analyzed. GlycoRNA-related pathway enrichment was quantified using gene set variation analysis (GSVA), whereas microglial, neuronal, astrocytic, and oligodendrocytic signatures were derived using single-sample gene set enrichment analysis (ssGSEA). Pearson correlations, linear regression, and generalized estimating equations (GEE) evaluated cell-type-specific associations and diagnostic interactions. Exploratory GEE results underwent false discovery rate (FDR) correction. Results: No differentially expressed genes survived FDR correction, and GlycoRNA-related and cell-type signatures did not differ significantly between groups. In controls, GlycoRNA enrichment was positively associated with the microglial signature (beta = 0.447, FDR-adjusted P = 0.006), with significantly weaker associations for neurons, astrocytes, and oligodendrocytes (all FDR-adjusted P < 0.05). The two-way GlycoRNA x is_microglia interaction was nominally significant (beta = 0.210, P = 0.048), confirming that GlycoRNA transcriptional coupling is substantially stronger for microglia than for the other three cell types combined. The microglial association was numerically attenuated in MDD (beta difference = -0.273, P = 0.167), but diagnostic interactions were nonsignificant. Conclusions: GlycoRNA pathway transcriptional enrichment exhibits preferential microglial association in control DLPFC. Its possible attenuation in MDD remains to be validated. keyword: Major depressive disorder; GlycoRNA; microglia; dorsolateral prefrontal cortex; generalized estimating equation; ssGSEA; bioinformatics

Background: Although sleep disorders are generally associated with cognitive decline, definitions of sleep conditions and cognitive function vary greatly across studies. Therefore, we evaluated associations between consensus definitions of sleep and cognitive outcomes across multiple studies. Methods: Consensus sleep measures were ascertained at baseline visits in three cohort studies (HCHS/SOL, MESA and ARIC, N=11,563): short and long sleep ([&le;]6hours and [&ge;]9hours), insomnia (Women's Health Initiative Insomnia Rating Scale [&ge;]10 or [&ge;]6 for 3 questions), daytime sleepiness (Epworth Sleepiness [&ge;]11) and obstructive sleep apnea (OSA, Apnea-Hypopnea Index [&ge;]15). Cognitive measures were ascertained at baseline and follow-up visits in each study and used to calculate harmonized outcomes: global cognitive function (GCF) at baseline, change in GCF between baseline and follow-up, poor GCF at baseline ([&ge;]1SD below the median), and incident poor GCF at follow-up. Study-specific analyses were adjusted for age, sex, center, education, race/ethnicity, APOE4 and language of cognitive assessments as needed. Results were meta-analyzed across studies. Results: Long sleep was consistently associated with lower baseline GCF ({beta}=-0.19, SE=0.03, p=3.78x10-14, FDR p=7.56x10-13, p-heterogeneity=0.78) and increased odds of poor baseline GCF (OR=1.77, 95% CI=1.49-2.09, p=2.96x10-11, FDR p=2.96x10-10, p-heterogeneity=0.22) across cohorts. Insomnia was also suggestively associated with lower baseline GCF ({beta}=-0.051, SE=0.02, p=0.01, FDR p=0.07, p-heterogeneity=0.005) and increased odds of poor baseline GCF (OR=1.22, 95% CI=1.06-1.41, p=6.76x10-3, FDR p=0.05, p-heterogeneity=0.03). Sleep measures were not associated with change in cognitive function. Discussion: Associations of long sleep and insomnia with harmonized cross-sectional GCF across three large, multiethnic cohorts suggest that cognitive function may be associated with distinct sleep phenotypes.

Background: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental condition, and co-occurring autistic traits may shape its phenotypic expression. Although creativity has been discussed as a relative strength in ADHD, it remains unclear whether autistic traits are associated with different dimensions of creativity in adults with ADHD and whether large-scale brain networks contribute to these associations. Methods: We compared divergent thinking (DT) and real-life creativity between 65 adults with ADHD and 73 neurotypical controls. We used subgroup comparisons, partial correlation analyses, and multiple regression models to determine the effects of autistic traits (ATs) on creativity dimensions within the ADHD cohort. Guided by prior creativity-network research, we analyzed resting-state functional connectivity (FC) of the Default Mode Network (DMN) and Frontoparietal Network (FPN) to uncover the neural mechanisms. Results: The ADHD cohort demonstrated significantly higher scores on both DT (ps = 0.002-0.009) and real-life creativity measures (ps = 0.011-0.017) compared to the neurotypical control group. Importantly, increased ATs within the ADHD group were associated with a dissociated creativity profile, showing positive associations with DT but negative associations with real-life creativity. At the neural level, stronger right DMN FPN connectivity mediated positive associations between ATs and DT performance (ps = 0.007-0.018), but mediated a negative association between ATs and self-reported imagination (p = 0.029). Conclusions: In individuals with ADHD, co-occurring ATs exert a paradoxical effect on creativity, enhancing DT while compromising real-life creative achievement. In this subgroup with ADHD and elevated ATs, interventions should capitalize on ATs-associated ideational strengths while circumventing translational barriers, to enhance real-world creative outcomes.

Abstract Background: Insomnia is highly prevalent in major depressive disorder (MDD), yet the clinical and biological significance of dysfunctional beliefs and attitudes about sleep (DBAS) in MDD remains poorly understood. We examined whether distinct DBAS dimensions are associated with insomnia severity, depressive phenotypes, and neuroimmune-metabolic-oxidative (NIMETOX) biomarkers. Methods: DBAS-30 dimensions, clinical phenotypes, and NIMETOX biomarkers were assessed in 87 hospitalized patients with MDD and 31 healthy controls. Principal component analysis (PCA) was used to ascertain DBAS cognitive dimensions, and associations were examined using multivariable analyses. Results: Compared with controls, MDD patients showed lower scores on "perceived consequences of insomnia," "sleep-related worry and helplessness," and "medication-related beliefs," but higher "causal attributions to aging or biochemical imbalance" scores. A composite DBAS score reflecting these 4 MDD-associated cognitive dimensions was constructed, labeled DBAS dimensional index (DBAS-DI). This score was lower in MDD and inversely associated with Insomnia Severity Index (ISI) scores, overall MDD severity, physiosomatic symptoms, current suicidal ideation, and recurrence of illness. DBAS-DI and the expectations domain jointly explained 35.4% of the variance in ISI scores, with inverse and positive associations, respectively. The DBAS-DI score was inversely associated with indices of the acute-phase inflammatory response, oxidative stress, fecal branched-chain short-chain fatty acids (SCFAs) and positively associated with serum antioxidant capacity and protective SCFAs, such as acetate, propionate, and butyrate. Conclusions: DBAS abnormalities in MDD extend beyond insomnia-related cognitions and are associated with illness severity, suicidality, recurrence, and NIMETOX alterations. These findings suggest that dysfunctional sleep-related cognitions are embedded within broader immune-oxidative and gut microbial-metabolic processes that may contribute to the insomnia-depression interface.

Objective: Amphetamine (AMP) and its derivates are commonly prescribed for the management of attention-deficit/hyperactivity disorder (ADHD). This study aimed to 1) quantify AMP's transfer into human milk in lactating women receiving therapeutic doses and 2) contextualize infant exposure. Methods: Milk samples and dyad health histories of thirteen lactating women treated with varying doses of either mixed AMP, dextroamphetamine, or lisdexamfetamine were released for this study from the InfantRisk Human Milk Biorepository. Milk drug concentrations were quantified by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) and used to calculate standard relative infant dose (RIDmat) and RID standardized to the defined daily dose (RIDDDD) of 15 mg AMP base. Results: Average milk concentrations (Cavg) of AMP base ranged from 23.3 to 297.0 ng/mL and increased linearly (R^2 = 0.92) with maternal daily dose. The RIDmat ranged 3.6-10.8% and RIDDDD ranged 1.4-21.8%. The fitted regression line crossed the 10% RIDDDD threshold at 1.17x DDD, with the upper 95% prediction limit crossing at 0.84x DDD. No adverse event reported by the mother-infant dyads were attributed to AMP exposure, notably including absence of reduced milk supply. Conclusions:The levels of AMP observed in human milk followed a dose predictable manner. The average patient was predicted to remain below the 10% RID DDD safety threshold at total daily doses at or below approximately 28 mg of mixed AMP salts or 59 mg of lisdexamfetamine. Ninety-five percent of patients were predicted to remain below the threshold at or below approximately 20 mg and 40 mg, respectively.

Background: Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) are widely used for EGFR-mutated non-small cell lung cancer (NSCLC) but have distinct toxicity profiles across generations. Aims: To investigate relationships between EGFR-TKI physicochemical, pharmacokinetic and pharmacological properties and drug-specific adverse drug reactions (ADRs) using national and global pharmacovigilance data. Methods: ADRs for erlotinib, afatinib and osimertinib were extracted from the UK MHRA Yellow Card scheme and WHO VigiAccess. Disproportionality analysis used reporting odds ratios (RORs). Signals were defined as ROR >2, lower 95% confidence interval >1 and >3 cases. Drug properties were curated from ChEMBL, emc, SmPC and EMA sources. Results: VigiAccess contained 88,662 individual case safety reports (163,619 ADRs) and Yellow Card contained 752 reports (1,814 ADRs). Four System Organ Class (SOC) signals were identified in VigiAccess and three in Yellow Card, with five additional Yellow Card Preferred Term signals. Eye disorders showed the strongest consistent association with erlotinib (VigiAccess ROR 4.33; Yellow Card ROR 4.18). Osimertinib was associated with pneumonitis (ROR 7.67) and pulmonary embolism (ROR 3.94). Afatinib showed psychiatric disorder signals in both databases (ROR 3.2-3.3) and diarrhoea (ROR 2.79). Neoplasm-related signals likely reflected confounding by indication. Conclusions: EGFR-TKIs demonstrate generation-specific pharmacovigilance profiles. Integration with drug properties supports mechanistic plausibility for several signals, while the atypical afatinib psychiatric association warrants further investigation. Findings are hypothesis-generating and require confirmation in controlled observational or mechanistic studies.

Background: Self-harm is a frequent and challenging occurrence in adult inpatient psychiatric units. The use of restrictive practice to manage self-harm incidents continues to be widespread within mental health environments despite increasing national and organisational guidance to minimise its use. Aim: The aim of this project was to introduce and evaluate a continuous quality improvement programme to progressively reduce incidents of self-harm and the use of restrictive practice. The project was set in a female acute mental health inpatient unit. The project sought to embed improvements in an inpatient unit interventions, procedures, and culture and staff mindset, and move towards a sustained collaborative and positive therapeutic and communication-based approach. Methods: A retrospective service evaluation design was employed to assess differences in the number of incidents of self-harm, enhanced observation, seclusion, restraint and rapid tranquillisation in the period following the introduction of a continuous whole-systems multimodal interventional initiative in 2019. Pre- and post-initiation data were compared (2017/18 compared to 2019/2025) to evaluate improvement and whether this had been sustained. Data were analysed using descriptive statistics, including frequencies, percentages, and means. Results: Self-harm incidents reduced between 2017/18 and 2019, with a downward trend sustained between 2019 and 2025 (136 to 72 incidents respectively between 2019 and 2025; 47% reduction). A sustained reduction in the use of restrictive practice was shown in all domains pre- and post-initiation (2017/18 compared to 2025). Clinical implications: No one approach will successfully reduce self-harm and the use of restrictive practice. Approaches employed have to be multi-faceted, multi-interdisciplinary, collaborative, and blend together to deliver improvement. Sustained progress requires commitment to an iterative process of continuous collaboration, improvement and adaptation.

Pharmacological treatments targeting core autistic features remain limited. In neurotypical adults, cannabidiol (CBD) alters mismatch negativity (MMN), an electrophysiological marker of automatic auditory deviance detection that has been associated with autistic traits. The effects of CBD on MMN, as measured using electroencephalography (EEG), in autistic children remain unknown. This secondary analysis of a pilot randomised, double-blind, placebo-controlled crossover trial examined the effects of 12 weeks of oral CBD oil on MMN during a duration-deviant auditory oddball task. We hypothesised that CBD would produce more negative MMN amplitudes and shorter peak latencies relative to placebo. Nineteen autistic children (6-12 years, 8 female) received CBD (dose) and placebo in randomised order, separated by an 8-week washout. Age-adjusted linear mixed-effects models tested Time (baseline, follow-up) x Treatment (CBD, placebo) effects on mean MMN amplitude and peak latency separately at Fz and FCz. Exploratory Spearman correlations examined baseline associations between MMN and Developmental Behaviour Checklist-2 (DBC-2) Social Relating scores. At FCz, latency decreased following CBD but increased following placebo but did not survive FDR correction (p = .029, pFDR = .058) and no other interactions were significant. Higher baseline DBC-2 Social Relating scores were associated with more negative MMN amplitude at FCz (rho = -.58, pFDR = .028) and Fz (rho = -.59, pFDR = .028). These findings provide tentative evidence that CBD may modulate MMN latency in autistic children. Larger trials should clarify CBDs effects on MMN and further examine the association between MMN amplitude and social-relating difficulties.

Deep brain stimulation (DBS) can be an effective treatment for severe obsessive-compulsive disorder (OCD), but response is variable, and objective, reliable predictors of who will respond positively are absent. In three individuals with OCD, we implanted intracranial electrodes across the cortico-striato-limbic network before DBS. Prefrontal gamma activity, most prominently in the orbitofrontal cortex (OFC), distinguished high- from low-symptom OCD states reproducibly across days. Acute stimulation of the ventral capsule/ventral striatum relieved OCD symptoms and, in one patient, significantly shifted this OFC gamma signal. Effective connectivity from therapeutic stimulation sites to these prefrontal regions defined three patient-specific OCD subnetworks; the baseline strength of the nucleus accumbens/ventral pallidum-OFC subnetwork predicted acute and long-term DBS response. Imaging-based modeling of current propagation in stimulation-activated ventral capsule to the OFC tracked acute response, suggesting that this prediction could be approximated from imaging alone. These findings outline a predictive, subnetwork-level framework for personalized DBS in OCD.

Objective: To determine whether plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are elevated in hospitalised patients with delirium relative to patients with dementia and primary psychiatric disorders (PPD). Methods and analysis: This was a cross-sectional observational study conducted at the Royal Melbourne Hospital, Melbourne, Australia, between April and October 2024, with comparator samples from a research biobank. In Phase 1 (Delirium Discovery Cohort), we measured plasma NfL and GFAP using the Single molecule array (Simoa) platform in hospitalised patients with delirium and compared them with dementia and PPD groups. Biomarker concentrations were the primary outcome and were compared using general linear models adjusted for age, sex, and estimated glomerular filtration rate, with bootstrapped confidence intervals. Discriminative performance was assessed as a secondary outcome using receiver operating characteristic (ROC) curve analysis. In Phase 2, we applied this threshold to independent dementia and PPD groups. Results: In Phase 1 (n =176), inpatients with delirium showed higher concentrations of both NfL and GFAP than patients with dementia ({beta} = 0.78; 95% CI [0.37, 1.20] and {beta} = 0.39 [0.07, 0.73] respectively) or PPD groups ({beta} = 1.17; [0.69, 1.66] and {beta} = 0.83 [0.51, 1.24] respectively). ROC curve analysis for differentiating delirium from dementia and PPD groups yielded an optimal NfL threshold of 24.1 pg/mL (AUC = 0.89, 96% sensitivity, 70% specificity). In comparison, GFAP showed lower accuracy (AUC = 0.85), and combining NfL with GFAP (AUC = 0.90) did not significantly improve performance. In Phase 2 (n = 154), the NfL threshold of > 24 pg/ml maintained strong performance (AUC = 0.95, 96% sensitivity, and 77% specificity). Conclusions: Plasma NfL shows promise as a biomarker for delirium in hospitalised patients, distinguishing it with high sensitivity from patients with dementia and PPD. Larger multicentre studies are needed to refine cut-offs, evaluate temporal dynamics, and determine integration into acute hospital delirium pathways.

Introduction: This study aimed to characterize the neurochemical profile of Alzheimer s disease (AD) continuum stages using proton magnetic resonance spectroscopy (1H-MRS) data for brain metabolites and macromolecules. We used Orthogonal Projection to Latent Structures Discriminant Analysis (OPLS-DA) to classify diagnostic groups and assess feature importance. Methods: Our dataset consisted of 7 T short-echo time 1H-MRS spectra of the posterior cingulate cortex/precuneus of individuals diagnosed with AD (n = 27) or Mild Cognitive Impairment (MCI, n = 27) and Healthy Controls (HC, n = 31). Classification used 100-round Monte Carlo cross-validation based on metabolite concentrations and macromolecular peak intensities. Variable importance in projection (VIP) was assessed across classification models to identify the most relevant neurochemical features. The resulting metabolite rankings were compared with previous literature to evaluate their biological plausibility. Results: Classification was strongest for AD versus HC (AUC=0.88) and lower for comparisons involving MCI. Metabolites contributing most strongly to classification included myo-inositol, ascorbate, and choline-containing compounds, consistent with previous studies on AD-related neurochemical alterations. In addition, specific macromolecular components were identified as relevant features, suggesting a potential contribution of MM signals to the characterization of AD-related neurochemistry. Discussion: These findings support the use of short-echo-time 1H-MRS as a complementary tool for characterizing neurochemical changes in the AD continuum, with potential applications in disease characterization and monitoring, warranting validation in larger cohorts.

Negative emotional bias, including reduced processing of positive information and negative interpretation of ambiguous stimuli, is a core feature of depression. Esketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist with rapid antidepressant effects in treatment-resistant depression (TRD), reduces depressive symptoms, but its effects on distinct components of emotional processing remain unclear. Fifty-three patients with TRD and 53 healthy controls performed an Emotional Facial Expression Morphing task. Patients were assessed at baseline, 24 hours after the first esketamine administration, and after 4 weeks of treatment. Statistical models examined detection thresholds for happy and sad faces, negative categorisation of neutral faces, and signal detection indices separating emotion-neutral discrimination sensitivity (d') from response criterion (c), indexing the evidence required to report the presence of an emotion. At baseline, patients required greater happy-face intensity for emotion detection and were more likely to categorise detected neutral faces as negative. They also showed a more conservative response criterion without group difference in discrimination sensitivity. Responders showed an early increase in d'; and, by week 4, less negative categorisation of neutral faces than non-responders. A lower baseline response criterion was associated with responder status and, in secondary continuous analyses, with greater subsequent MADRS improvement. These findings indicate that TRD involves abnormalities across detection-related, valence-related, and decisional aspects of facial-emotion processing that are differently associated with esketamine response: baseline response criterion emerged as a candidate prognostic marker, whereas negative categorisation of neutral faces tracked clinical response. Assessing these domains may inform clinical evaluation, pending independent replication.

Background Autism spectrum disorder (ASD) shows wide phenotypic variation, from adults without intellectual disability and with low support needs to minimally verbal children with intellectual disability and severe behavioral symptoms. Genetic studies of this heterogeneity have focused mainly on high-impact de novo variants and polygenic scores; here we investigate, at the molecular level, the role of common variants. Materials and methods We analyzed genotypic and phenotypic data from 9,332 individuals with ASD in the SPARK cohort. We considered 31 traits: six latent factors derived from the Social Communication Questionnaire and the Repetitive Behavior Scale-Revised, 22 co-occurring diagnoses, parent-reported IQ range, age at diagnosis, and age at first walking. We performed within-case genome-wide association studies (GWAS) and, for the 10 traits with evidence of SNP heritability, association analyses with genetically predicted gene and protein expression, splicing, and enhancer activity in brain and blood (xWAS). Nominated genes were tested for enrichment in biological processes, brain cell types, and developmental stages. xWAS-derived transcriptional signatures were compared with chemical perturbation signatures from CMap/LINCS L1000 to prioritize candidate drugs. Results GWAS identified seven genome-wide significant loci for five traits, including loci near GABRG3 and TENM2 associated with co-occurring sleep, feeding or toileting problems. xWAS identified seven gene-trait associations involving three phenotypes (FDR < 0.1), including CACNA1G with communication skills and NEGR1 with learning disability. GWAS and xWAS nominated different genes which however converged on synaptic transmission and gated channel activity, with preferential expression in neurons during later stages of brain development. PARP and p38 MAPK inhibitors were predicted to reverse the signatures of both social-communication and repetitive-behavior phenotypes, whereas several compound classes, including histone deacetylase inhibitors and mTOR inhibitors, were predicted to reverse the signatures of some phenotypes while mimicking those of others. Conclusion Combining within-case GWAS with xWAS nominates candidate genes mediating common-variant effects on ASD heterogeneity, provides biological insight, and suggests candidates for phenotypically stratified drug repositioning.

Abstract Autistic young adults experience substantial gaps in services supporting community living and participation. The Community Autism Peer Support (CAPS) program is a community-based intervention in which trained autistic peer specialists provide individualized support to autistic young adults pursuing self-determined goals related to community participation and independent living. We conducted a single-site, two-arm randomized controlled trial to evaluate the feasibility of implementing the CAPS program. Forty autistic adults aged 18 to 30 years were randomized to CAPS (n = 20) or services as usual alone (n = 20) and assessed at baseline, 3 months, and 12 months. Study findings showed that CAPS attracted autistic young adults with diverse demographic and diagnostic backgrounds, and most intervention participants remained engaged in services for extended periods. While the study was underpowered to detect statistical differences in outcomes because it was not a main focus of the research, a consistent pattern of results favored the CAPS condition across all outcomes. The largest positive signals were observed for overall and social quality of life, with additional favorable changes in internalized stigma, unmet needs, social functioning, loneliness, and positive autistic identity. Findings provide support for the feasibility and promise of an autistic-delivered peer specialist model focused on community living and participation. The consistent pattern of favorable changes supports continued development of CAPS as a person-centered approach to addressing outcomes important to autistic adults.