Progress in Neuro-Psychopharmacology and Biological Psychiatry

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.

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.

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).

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.

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.

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: 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 [&le;] .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 [&ge;] .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.

Exposure to armed conflict can leave persistent effects on mental health, yet its neurophysiological correlates remain poorly characterized, particularly in populations exposed to prolonged violence outside narrowly defined post traumatic stress disorder samples. Here we examined resting state electroencephalographic activity in 122 Colombian adults, including 74 participants exposed to armed conflict and 48 controls. Eyes closed EEG was analysed for 240 seconds per participant. We quantified absolute and relative spectral power across delta, theta, alpha and beta bands and regional functional connectivity using weighted phase lag index in theta, alpha and beta. Group comparisons were adjusted for age, education, sex and assessment year, with correction across 78 EEG contrasts. Median occipital and global alpha power was lower in exposed participants, although adjusted estimates were close to the null and confidence intervals were broad. Temporal theta relative power was lower in exposed participants at nominal significance, but this association did not survive Holm correction. No spectral power or regional connectivity contrast remained significant after multiple testing correction. Exploratory associations between EEG measures and MoCA performance were modest in participants with confirmed scores. These findings provide a systematic characterization of resting EEG after exposure to armed conflict in a population shaped by prolonged violence and displacement. They also indicate that large or widespread alterations in resting spectral power and connectivity were not detectable with the current sample and analytical framework, while defining candidate signals and methodological priorities for larger studies of conflict related brain health.

Study Objectives: Glucagon-like peptide-1 (GLP-1) receptor agonists raise resting heart rate. We asked whether, after semaglutide initiation, the increase is larger during rapid eye movement (REM) sleep than during non-rapid eye movement (NREM) sleep. Methods: In the Human Phenotype Project, an Israeli cohort of generally healthy adults aged 40 to 70 years, 96 of 494 self-reported semaglutide initiators had a home sleep study (WatchPAT; sleep stages estimated from peripheral arterial tone and actigraphy) before and at least three months after starting. Each was propensity-matched 1:1 to a never-user of GLP-1 drugs measured at the same visits. We estimated the initiators' change minus their controls' change (difference-in-differences). The REM minus NREM contrast was designated primary after an exploratory analysis. Results: Relative to controls (90 to 94 pairs), heart rate rose during nocturnal wake (+3.89 beats per minute [bpm], 95% confidence interval 2.35 to 5.44), NREM sleep (+4.82 bpm, 3.12 to 6.52) and REM sleep (+6.25 bpm, 4.42 to 7.91); the REM increase exceeded the NREM increase by 1.42 bpm (0.98 to 1.89). The excess persisted across matching designs and on a relative scale; the proportion of REM sleep did not change. Never-users with similar weight loss showed no REM sleep heart-rate rise (+0.40 bpm, -0.63 to 1.50). Heart-rate variability decreases disappeared after adjustment for heart rate. Conclusions: Semaglutide initiation was associated with higher heart rate throughout sleep, most during REM sleep, unexplained by weight loss. Clinic measurements may understate this effect. Confirmation with polysomnographic staging is needed.

BACKGROUND: One in three adolescents with a concussion history report experiencing long-lasting somatic, sleep, emotional, and/or cognitive disturbances (persisting symptoms after concussion (PSaC)). Cognitive difficulties, such as attentional problems, are common symptoms and can interfere with ongoing development. Clinically, psychiatric symptoms also present in youth with PSaC. A concussion causes diffuse functional and microstructural alterations to neural networks. To develop targeted treatments for PSaC (e.g., neurostimulation), we need to understand how and where structural alterations and neural dysfunction intersect to cause long-lasting symptoms. OBJECTIVES: 1) Identify functional and microstructural properties in intrinsic connectivity networks, as well as neuropsychological outcomes, that differentiate adolescents with concussion with PSaC from those who do not have PSaC. 2) Determine whether neural activity within intrinsic connectivity networks mediates the relationship between network microstructure and specific neuropsychological features in adolescents with concussion. METHODS: CAMBY is a prospective study of adolescents aged 12 to 18 years with a history of concussion. Participants are allocated based on recovery status (PSaC vs. No-PSaC (recovered controls)). Advanced structural (magnetic resonance imaging; MRI) and functional (magnetoencephalography; MEG) neuroimaging and neuropsychological measures will be collected one month or more after concussion. Microstructural and functional features will be computed within intrinsic connectivity networks, then compared between PSaC and recovered control groups and related to symptom domains and neuropsychological profiles. IMPACT: This will be the first study to integrate MRI, MEG, and neuropsychology in adolescents with PSaC to identify disrupted networks underlying PSaC. This observational study is a necessary step towards future clinical trials that accurately target promising therapeutic neurostimulation protocols.

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.

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.

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

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.

Objective To evaluate the association of early addiction consultation with withdrawal pharmacotherapy and complications in hospitalized patients with alcohol withdrawal. Methods Retrospective single-center cohort of adult hospitalizations with alcohol withdrawal (diagnosis code or CIWA-Ar [&ge;]10 within 24 hours) from July 2020 to January 2026. Exposure was an addiction consult service order within 24 hours of arrival, compared with no or later consultation. Primary outcomes were intensive care unit (ICU) transfer after the first 24 hours and delirium tremens or withdrawal seizure not present on admission. Process outcomes included phenobarbital and thiamine administration within 24 hours and benzodiazepine dose in the first 48 hours. Secondary outcomes included length of stay and 30-day death or return to hospital. Results Of 4,663 hospitalizations, 1,379 (29.6%) received early consultation. After adjustment, early consultation was associated with lower odds of ICU transfer (odds ratio [OR] 0.73; 95% CI 0.54-0.99) and fewer episodes of delirium tremens (risk difference -1.09 per 100; -1.45 to -0.73), with no significant difference in withdrawal seizure. Early consultation was associated with phenobarbital (OR 1.57; 1.32-1.86) and thiamine (OR 1.23; 1.07-1.41) within 24 hours, higher 48-hour lorazepam-equivalent dose (ratio of geometric means 1.44; 1.32-1.57), shorter stays (ratio 0.92; 0.88-0.97), and lower odds of 30-day death or return to hospital (OR 0.78; 0.66-0.91). Conclusions Early addiction consultation was associated with earlier, more intensive withdrawal pharmacotherapy, lower odds of ICU transfer, and fewer episodes of delirium tremens, although the complication associations were sensitive to cohort definition.

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.

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.

Brief assessments reduce clinician and patient burden and increase utilization. Recently, five core depression symptoms (low mood, poor concentration, low self-worth, loss of interest, low energy) have been shown to be particularly sensitive to treatment effects in adults. How these core depressive symptom domains perform for screening or diagnostic purposes in youth is unknown. To address this question, we extracted five analogous symptom items from four widely used symptom assessment tools for children and adolescents (Child Behavior Checklist [CBCL], Youth Self Report [YSR], Parent General Behavior Inventory [P-GBI], and Adolescent General Behavior Inventory [A-GBI]) to create 5-item short forms. We evaluated their psychometric properties and diagnostic utility in a large (N=1185), racially diverse sample (48% Black youth) across community and academic outpatient mental health settings, with diagnoses established through LEAD consensus. All short forms correlated highly with full-length measures (r=.74-.92) and demonstrated comparable inter-item correlations (r =.19-.46). The short forms did not differ meaningfully from the full measures in correlations with psychiatric diagnoses, demographics, or diagnostic interviews. Area under the curve (AUC) values for identifying depression and any mood disorder diagnosis (determined by semi-structured diagnostic interviews) were fair to good (AUC=0.60-0.79), which were not worse than full measures, except for the P-GBI. The CBCL-5, YSR-5, P-GBI-5, and A-GBI-5 may be useful brief depression assessments in youth. How these five symptom domains perform as outcome measures in treatment deserves study.

Background: Cervical spinal cord (CSC) compression and myelopathy are frequent, severe complications in mucopolysaccharidosis (MPS) types I and VI. Early detection is critical to prevent irreversible neurological deficits and preserve quality of life. This prospective study aimed to identify quantitative neuroimaging biomarkers of structural CSC damage and myelopathy in MPS I and VI. Methods: Structural and diffusion magnetic resonance imaging (MRI) of the CSC was analyzed in 17 MPS I patients, 3 MPS VI patients (19{+/-}7 years), and 19 case-matched healthy controls (20{+/-}7 years). CSC macrostructure (cross-sectional area, diameters) and microstructure (fractional anisotropy [FA], radial [RD], mean, axial diffusivities) were evaluated within and beyond the maximal compression areas. Results: MPS patients demonstrated reduced CSC cross-sectional area and anterior-posterior diameter at upper cervical levels, alongside widespread microstructural alterations (lower FA, higher RD) throughout the CSC versus controls (pFDR<0.05). Restricted foramen magnum space was associated with microstructural damage at lower cervical levels without overt macrostructural compression. Morphological and microstructural metrics were sensitive to CSC compression and myelopathy severity (pFDR<0.05). Lower CSC integrity correlated with more advanced growth retardation (p<0.001). Among patients receiving hematopoietic stem cell transplantation, earlier treatment correlated with preserved upper CSC morphology (p<0.05). Distinct neuroimaging phenotypes were observed across MPS genotypes (pFDR<0.05). Conclusions: CSC MRI provides candidate neuroimaging biomarkers for early detection and characterization of myelopathy in MPS I and VI. Structural damage extends beyond primary maximal compression areas, highlighting these markers for clinical monitoring and future therapeutic trials.