BACKGROUND:Psychiatric research is increasingly embracing a paradigm shift from categorical diagnoses to neurobiologically meaningful dimensions that cross current diagnostic boundaries. This transposition calls for redefining endophenotypes to accommodate transdiagnostic vulnerabilities. We sought to identify shared and disorder-specific neurocognitive endophenotypes for schizophrenia, bipolar I disorder (BD-I) and a broad psychosis/BD-I phenotype in a mega-analysis of twin/sibling data. STUDY DESIGN:We performed genetic model fitting to intelligence (IQ) and computerised neurocognitive data derived from 1050 twins/siblings from three research centres in the UK, Denmark and the Netherlands, affected (n = 257) or unaffected (n = 793) by schizophrenia, other primary psychoses and BD-I. We examined the endophenotypic status of IQ, spatial working memory (SWM), visual recognition, sustained attention/rapid visual processing (RVP), mental flexibility, and spatial planning/problem solving (all validated as endophenotypes for schizophrenia in previous studies) in relation to schizophrenia, BD-I and the broad phenotype. STUDY RESULTS:After covarying for age, gender, education and research centre, IQ and SWM emerged as transdiagnostic endophenotypes, showing statistically significant heritabilities (h2 67-75% and 28-30%, respectively), phenotypic correlations (rph |0.14|-|0.25|) and genetic correlations (rg |0.18|-|0.42|) with all diagnostic phenotypes. Additionally, all remaining cognitive domains received validation as endophenotypes for the broad phenotype, and all, but RVP, for schizophrenia. CONCLUSIONS:IQ and SWM tap into transdiagnostic elements of the genetic vulnerabilities to psychosis and BD-I. Our findings add to emergent evidence which spurs cautious optimism that a psychiatric nosology based on aetiology rather than phenotypical classifications may be feasible in the future, enabling biotyping and novel approaches to treatment.

Ketogenic interventions have garnered attention for their potential benefits in individuals with psychiatric and neurocognitive disorders. This review analyzed findings from studies investigating the impact of ketogenic interventions on clinical outcomes in individuals with serious mental illness (SMI) and neurocognitive disorders. A comprehensive search was conducted to identify studies reporting on psychopathology or cognitive performance in individuals with schizophrenia spectrum, major mood, mild cognitive impairment (MCI), or major neurocognitive disorders/dementia treated with a ketogenic intervention. Changes in body composition, metabolic parameters, adherence, and safety were also assessed. Evidence was organized by population and outcome of interest, and supplemented by a quantitative meta-analysis. Seventy-three studies (SMI k = 31; neurocognitive disorders k = 42) were included, with treatment durations ranging from single-dose interventions up to 12 years. Evidence in SMI was largely limited to case reports and single-arm trials reporting symptom remission, reductions in positive and negative symptoms, and mood improvements. Controlled trials in neurocognitive disorders provided more substantiated evidence amenable to meta-analysis. Ketogenic interventions improved cognitive performance (SMD 0.24, 95% CI [0.06, 0.43], p = 0.01, n = 587, k = 14, I² = 61%) and reduced body weight (MD − 3.13 kg, 95% CI [−5.91, −0.35], p = 0.03, n = 80, k = 3, I² = 6%) in this population. Gastrointestinal symptoms were the most frequently reported adverse event. While the evidence for ketogenic interventions differs by population, promising findings emerge. In neurocognitive disorders, controlled trial data support modest cognitive and metabolic benefits. In SMI, preliminary evidence highlights the evolving nature of this field and the need for more rigorous investigation, including RCTs, to establish clinical safety and efficacy.

Importance:Observational studies have reported associations between pregnancy vitamin D levels and offspring cognition, but no randomized clinical trial (RCT) has investigated the effect of high-dose vitamin D3 supplementation in pregnancy on offspring cognition into middle childhood. Objective:To assess whether high-dose vitamin D3 supplementation during pregnancy is associated with improved offspring cognition at age 10 years. Design, Setting, and Participants:This is a post hoc secondary analysis of the blinded, placebo-controlled Copenhagen Prospective Studies on Asthma in Childhood 2010 RCT conducted from March 4, 2009, to November 17, 2010. The cohort included 700 mother-child pairs from Denmark, of whom 623 were randomized. Exclusion criteria were vitamin D intake above 600 IU/d; endocrine, kidney, or heart disease; and insufficient Danish language proficiency. Cognitive assessments were conducted for the offspring at age 10 years, excluding those born at less than 28 weeks' gestation and with birth weight less than 1500 g. Participants were unblinded at 3 years of age, while investigators remained unaware of group assignments. The 10-year visits were conducted from February 11, 2019, to December 13, 2021. Statistical analyses were conducted from February to June 2025. Intervention:High-dose (2800 IU/d) or standard-dose (400 IU/d) vitamin D3 from pregnancy week 24 to 1 week post partum. Main Outcome and Measures:The primary outcome was cognitive functioning across 11 functions assessed at age 10 years using a comprehensive neuropsychological test battery as part of the Copenhagen Prospective Study on Neuro-Psychiatric Development (COPSYCH). Results:The vitamin D3 RCT and the COPSYCH visit were completed by 498 children (mean [SD] age, 10.3 [0.4] years; 258 boys [51.8%]): 247 prenatally exposed to high-dose vitamin D3 and 251 prenatally exposed to standard-dose vitamin D3. Covariate-adjusted analyses of standardized scores (mean [SD], 0 [1]; higher values indicating better performance) showed positive associations of high-dose vitamin D3 with verbal memory (β = 0.17 SD; 95% CI, 0.03-0.32 SD; P = .02), visual memory (β = 0.24 SD; 95% CI, 0.06-0.42 SD; P = .01), and flexibility or set shift (β = 0.19 SD; 95% CI, 0.01-0.37 SD; P = .04); however, high-dose vitamin D3 was no longer associated with flexibility or set shift after multiple test correction. Conclusion and Relevance:This post hoc analysis of an RCT suggests that high-dose vitamin D3 supplementation in pregnancy is positively associated with visual memory, verbal memory, and flexibility or set shift among offspring measured at age 10 years. These findings strengthen evidence on the association of prenatal vitamin D exposure with childhood cognition. Trial Registration:ClinicalTrials.gov Identifier: NCT00856947.

Emotional processing deficits are increasingly recognized as a salient feature of psychotic disorders, and emerging evidence suggests that impairments in facial emotion processing may serve as additive predictive markers for individuals at ultra-high risk (UHR) for psychosis, highlighting the importance of such deficits for early identification and intervention strategies. In this study we examined whether automated coding of facial features from brief video recordings (45 seconds) could discriminate 108 individuals at ultra-high risk for psychosis (UHR) from 65 matched healthy controls (HC). We assessed the alignment between automated coding of facial expressivity as measured by granulated muscle activity, and clinician-rated facial emotional expressivity by experienced clinicians. In addition, we explored associations with social skills and clinical symptoms. A random forest classifier with repeated nested cross-validation significantly classified UHR-individuals from HC with above chance accuracy (63%; p = 0.009, sensitivity=0.76, specificity=0.40). Automated coding of Presence, Intensity, and Variation of specific facial features correlated strongly with clinician-rated facial expressivity with moderate to large effect sizes (all corrected p < 0.001). Moreover, facial feature metrics were associated with attenuated psychotic symptoms and negative symptoms, supporting the clinical validity of automated facial expressivity coding from brief video recordings of UHR-individuals.

In observational studies, an unhealthy dietary pattern during pregnancy is associated with an increased likelihood of offspring ADHD. We investigated whether such associations may be partly attributable to genetic confounding. Polygenic scores (PGSs) for a healthy dietary pattern were calculated for mother, father, and child trios in the COPSAC2010 cohort. Diagnoses and trait scores of ADHD were assessed in the children at age 10. Using trio models, we tested whether the association between maternal genetic liability to a healthy dietary pattern and offspring ADHD could be accounted for by genetic confounding. In COPSAC2010 trio models (N-trio=437), a maternal healthy dietary pattern PGS was associated with reduced ADHD trait score after adjustment for child and paternal dietary pattern PGS, suggesting indirect genetic effects consistent with causal effects from maternal diet. However, this was not replicated in MoBa (N-trio=41 580) or ALSPAC (N-trio=1 211), where direct genetic effect estimates implied an important role for genetic confounding. Collectively, these genetic results indicate a potential pathway by which genetic confounding can inflate observed associations between maternal dietary pattern in pregnancy and offspring ADHD, and do not provide any robust evidence consistent with a causal pathway between the two. These findings should be interpreted in the light of both the limited predictive power of the dietary pattern PGS, which accounted for only a small proportion of pregnancy diet variance, and the multi-faceted nature of diet as an exposure.

Purpose Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are the two most prevalent neurodevelopmental disorders, characterized by early-onset impairments across multiple developmental domains, including language, motor coordination, cognition and behavioral regulation. Despite the early signs, diagnoses are often delayed, limiting opportunities for timely interventions. Evidence suggest that deviations in these domains may be predictive of later ADHD and ASD. However, findings have been inconsistent, and further clarification is needed to improve early identification. Methods This prospective study followed 590 children from the COPSAC2010 birth cohort to examine associations between neurodevelopmental measurements from birth to age 3 years and later clinical diagnoses and traits manifestations of ADHD and ASD at age 10. Early life neurodevelopment data included motor milestones, language production measured at age 12 and 24 months, cognitive functioning and behavioral/emotional observations at 36 months, as well as a general development questionnaire at 3 years. Associations were analyzed using logistic and linear regression analyses adjusted for demographic and perinatal covariates. Results We found that lower word production, shorter sentence, lower cognitive functioning and more behavioral/emotional problems in early life were significantly associated with increased risk of ADHD and elevated ADHD and ASD traits at age 10. Conclusion Deficits in language, cognitive functioning and more behavioral and emotional problems in early life could serve as risk indicators for later neurodevelopmental disorders. Recognizing these risk indicators could inform timely detection and improve developmental outcomes.

Background:Self-disorders, or anomalous disturbances in the basic sense of self, have been described in psychosis-risk states and may contribute to social cognitive impairment and functioning. This study examined self-disorder severity and associations with social cognition and functioning across individuals at clinical high risk for psychosis (CHR-P), autism spectrum disorder (ASD), and controls. ASD was included due to overlapping difficulties in social cognition/functioning with CHR-P. We hypothesized a graded pattern of self-disorders (CHR-P > ASD > controls) and stronger associations between self-disorders and social cognition in CHR-P. Methods:We included 39 CHR-P, 39 ASD, and 30 controls (mean age ≈24 years; 51% female). Self-disorders were assessed with the Inventory of Psychotic-Like Anomalous Self-Experiences (IPASE). Social cognitive domains included social cognitive bias and theory of mind alongside measures of social functioning. Analyses of covariance and bootstrapped regression models with IPASE as predictor were used, adjusting for age, sex, and IQ. Multiple comparisons were Benjamini-Hochberg corrected. Results:Self-disorders followed a graded distribution (CHR-P > ASD > controls) across all IPASE subscores. Both clinical groups showed elevated social cognitive bias and reduced social functioning compared to controls. Self-disorders were associated with social cognitive bias in ASD (B = 0.392, 95%CI 0.236-0.544, p < 0.001), but not in CHR P. Group differences in associations between self-disorders and social cognition/functioning did not survive correction for multiple comparisons. Conclusion:Self-disorders showed a graded distribution across groups but was only associated with social cognitive deficits in ASD. Findings suggest that shared symptom profiles may reflect divergent experiential processes across groups. Further research is needed to clarify clinical implications and generalizability.

The gut microbiome has been associated with brain health. The neuromodulatory effects of microbial-derived metabolites is supported by experimental evidence, and alterations of gut microbiota have been associated with the pathophysiology of certain neuropsychiatric disorders. Research on the gut microbiome’s role in attention-deficit/hyperactivity disorder (ADHD) have been predominantly cross-sectional and seldomly within the neonatal period, missing its potential impact on critical periods shaping long-term neurodevelopmental outcomes. This study addresses how initial colonization and timing of specific gut bacteria, and their metabolic byproducts, may influence the risk of future ADHD. Using the highly-phenotyped COPSAC2010 birth cohort, we show that a higher level of Bifidobacterium in the child’s one-week gut microbiome, after extensively adjusting for genetic and early-life factors, is associated with ADHD at age 10. Our analyses also reveal that the tryptophan-derived metabolite indole-3-lactic acid (ILA) in the neonatal dried blood spot (DBS) mediates the relationship between Bifidobacterium and ADHD risk. The association between neonatal DBS ILA and ADHD was replicated in two independent cohorts. Bifidobacterium is known to promote healthy neurodevelopmental outcomes; however, these findings suggest that the initial temporal colonization pattern of Bifidobacterium may be particularly important for neurodevelopment. In particular, elevated Bifidobacterium-derived metabolite ILA levels may have adverse consequences on the child’s neurodevelopment during the first week of life. This suggests that by promoting a suitable temporal colonization pattern for Bifidobacterium and its production of ILA in the newborn may represent potential strategies for clinical interventions for supporting adequate neurodevelopment, and mitigating the risk of future ADHD.

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.

Fish oil-derived omega-3 fatty acids (ꙍ-3 FA), particularly docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are critical for early brain development, but evidence of causal effects from supplementation during pregnancy is limited. In the prospective COPSAC2010 cohort of 700 mother-child pairs, we investigated whether i) maternal DHA + EPA blood concentrations in mid-pregnancy and ii) fish oil supplementation in a randomized trial in late pregnancy influence neurodevelopmental outcomes at age 10. Maternal blood DHA + EPA concentrations were measured at 24 weeks gestation, followed by randomization to 2.4 g daily fish oil (37% DHA, 55% EPA) or placebo until one-week postpartum. Psychopathology was assessed in the children at age 10 using the Kiddie Schedule for Affective Disorders and Schizophrenia -Present and Lifetime version and parental-rated questionnaires Statistical analyses included logistic and linear regression models. Higher maternal DHA + EPA concentrations were associated with reduced ADHD risk (OR 0.71, p = 0.03) and ADHD symptom load (β = -1.14, p < 0.001) in unadjusted analyses but not after confounder adjustment (OR 0.82, p = 0.24; β = -0.49, p = 0.21). Similar trends were observed for autistic traits (β = -1.96, [-1.11; -0.24] p = 0.01), but not significant after confounder adjustment. Fish oil supplementation showed no significant reduction in ADHD (OR 0.79, p = 0.37) or ASD risk (OR 0.56, p = 0.42). A secondary analysis suggested a protective effect for ADHD Predominantly Inattentive Presentation, although it did not hold significance after correction for multiple testing (OR 0.41; p = 0.03; FDRp=0.12). Thus, potential effects on inattentive ADHD symptoms should be explored in future studies.

Neurodevelopmental disorders (NDD) are characterized by impairments in brain development that affect motor and cognitive systems. Early identification of NDD risk factors is crucial for prevention. Metabolomic profiling holds promise for early detection but remains underexplored in longitudinal studies. Here, we map the longitudinal metabolomic profiles in 3212 samples covering 683 metabolites from 581 mother-child pairs at six timepoints in the Danish COPSAC2010 cohort to assess childhood NDD risk over a 10-years follow-up period. Cross-validated sPLS models identify metabolic biomarkers and patterns associated with NDD, with maternal gestational week 24 metabolic profile showing the best prediction. Metabolite trajectories prior 18-month of age are linked to NDD risk. Quinolinate is consistently associated with NDD across timepoints and mediated the effect of maternal inflammation on NDD. In the single metabolite analysis, no metabolites remained significant after multiple testing correction. In this work, we provide valuable insights into the role of the longitudinal metabolome in neurodevelopment.

INTRODUCTION:Auditory Verbal Hallucinations (AVH) are among the most frequent and severe symptoms in schizophrenia and related psychotic disorders. Virtual Reality (VR)-assisted interventions have emerged, demonstrating promising potential in reducing AVH severity. This treatment approach may be challenged with regards to feasibility, particularly when therapeutically managing the anxiety-related reactions associated with AVH. This pilot study evaluates the feasibility and acceptability of augmenting VR-assisted therapy with real-time biofeedback to address these challenges. The integration of biofeedback enables continuous adaptation of therapy based on physiological responses while allowing participants to train self-regulation of these parameters. METHODS:Neuro-VR is a randomized clinical pilot trial utilizing a mixed-methods design. Thirty participants with schizophrenia spectrum disorders and AVH will be randomized to either eight sessions of VR-assisted therapy or eight sessions of VR-assisted therapy augmented with real-time biofeedback. Assessments will be conducted at baseline and post-treatment. Outcome measures include both clinical metrics, electroencephalogram recordings, and qualitative interviews to evaluate feasibility, acceptability, and potential treatment effects of the combined approach. DISCUSSION:This study will explore whether integrating biofeedback into VR-assisted therapy enhances personalization, supports emotion regulation, and improves tolerability. The findings will provide preliminary evidence on the utility of physiological markers to guide VR-based interventions for AVH and inform the development of individualized, effective treatments for patients with schizophrenia. TRIAL REGISTRATION:ClinicalTrials.gov NCT06628323.

Importance:Revealing neurobiological markers of antipsychotic nonresponse in psychosis may aid outcome prediction and inform novel treatment targets. Objective:To examine differences in neurometabolites in antipsychotic nonresponsive compared to antipsychotic-responsive psychosis using individual participant data and meta-analysis. Data Sources:Web of Science was searched for studies published between January 1, 1980, and November 1, 2025. Authors of 21 eligible studies identified before August 2024 were invited to contribute individual participant data. Study Selection:Eighteen studies examining neurometabolites by treatment response in psychosis contributed individual participant data for the mega-analysis. These studies plus a further 5 studies were included in the meta-analyses of standardized mean differences and variability. Data Extraction and Synthesis:Individual participant data were analyzed using linear mixed models with study as a random effect. Subgroup analyses examined prospective designs and treatment-resistant samples. Published group means and standard deviations were extracted for meta-analyses. Main Outcomes and Measures:Group differences in glutamate, glutamate plus glutamine, choline, myo-inositol, N-acetylaspartate, γ-aminobutyric acid, and glutathione in the medial frontal cortex, dorsolateral prefrontal cortex, thalamus, and basal ganglia. Results:The mega-analysis included 1189 participants from 18 studies; of these, 476 were treatment nonresponders (mean [SD] age, 33.0 [12.5] years; 340 male), 427 were treatment responders (mean [SD] age, 30.3 [11.5] years; 299 male), and 286 were healthy control individuals (mean [SD] age, 31.0 [12.5] years; 170 male). Compared with the antipsychotic response group, nonresponders showed elevations in medial frontal glutamate (Glass Δ = 0.21; P = .02), glutamate plus glutamine (Glass Δ = 0.29; P = .002), choline (Glass Δ = 0.22; P = .03), and myo-inositol (Glass Δ = 0.35; P = .001); similar elevations were observed relative to control individuals. Elevated medial frontal glutamate plus glutamine in antipsychotic nonresponders compared with responders was also observed prospectively in first-episode psychosis (Glass Δ = 0.41; P = .002), whereas myo-inositol elevations were greatest in individuals meeting criteria for treatment-resistance (Glass Δ = 0.64; P = .001). The meta-analysis of 23 studies (1844 participants) also showed elevated medial frontal choline and myo-inositol in antipsychotic nonresponse compared with response. Conclusions and Relevance:These findings provide evidence of an association between antipsychotic nonresponse in psychosis with elevations in medial frontal glutamate, choline, and myo-inositol. The presence of elevations in these markers supports the continued investigation of glutamate-acting and inflammatory pathway-associated interventions for psychosis and schizophrenia.

Importance Observational studies have reported associations between pregnancy vitamin D levels and offspring cognition, but no randomized clinical trial (RCT) has investigated the effect of high-dose vitamin D 3 supplementation in pregnancy on offspring cognition into middle childhood. Objective To assess whether high-dose vitamin D 3 supplementation during pregnancy is associated with improved offspring cognition at age 10 years. Design, Setting, and Participants This is a post hoc secondary analysis of the blinded, placebo-controlled Copenhagen Prospective Studies on Asthma in Childhood 2010 RCT conducted from March 4, 2009, to November 17, 2010. The cohort included 700 mother-child pairs from Denmark, of whom 623 were randomized. Exclusion criteria were vitamin D intake above 600 IU/d; endocrine, kidney, or heart disease; and insufficient Danish language proficiency. Cognitive assessments were conducted for the offspring at age 10 years, excluding those born at less than 28 weeks’ gestation and with birth weight less than 1500 g. Participants were unblinded at 3 years of age, while investigators remained unaware of group assignments. The 10-year visits were conducted from February 11, 2019, to December 13, 2021. Statistical analyses were conducted from February to June 2025. Intervention High-dose (2800 IU/d) or standard-dose (400 IU/d) vitamin D 3 from pregnancy week 24 to 1 week post partum. Main Outcome and Measures The primary outcome was cognitive functioning across 11 functions assessed at age 10 years using a comprehensive neuropsychological test battery as part of the Copenhagen Prospective Study on Neuro-Psychiatric Development (COPSYCH). Results The vitamin D 3 RCT and the COPSYCH visit were completed by 498 children (mean [SD] age, 10.3 [0.4] years; 258 boys [51.8%]): 247 prenatally exposed to high-dose vitamin D 3 and 251 prenatally exposed to standard-dose vitamin D 3 . Covariate-adjusted analyses of standardized scores (mean [SD], 0 [1]; higher values indicating better performance) showed positive associations of high-dose vitamin D 3 with verbal memory (β = 0.17 SD; 95% CI, 0.03-0.32 SD; P = .02), visual memory (β = 0.24 SD; 95% CI, 0.06-0.42 SD; P = .01), and flexibility or set shift (β = 0.19 SD; 95% CI, 0.01-0.37 SD; P = .04); however, high-dose vitamin D 3 was no longer associated with flexibility or set shift after multiple test correction. Conclusion and Relevance This post hoc analysis of an RCT suggests that high-dose vitamin D 3 supplementation in pregnancy is positively associated with visual memory, verbal memory, and flexibility or set shift among offspring measured at age 10 years. These findings strengthen evidence on the association of prenatal vitamin D exposure with childhood cognition. Trial Registration ClinicalTrials.gov Identifier: NCT00856947

AIM:Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder associated with long-term adverse outcomes, yet diagnosis often occurs years after symptoms first emerge. Because ADHD involves impairments across multiple developmental domains, early deviations in language, cognition, motor development and behavioural regulation may indicate later risk before core ADHD symptoms can be reliably assessed. However, previous studies have often relied on questionnaires or registry data rather than objective early-life assessments combined with later clinical ADHD diagnosis and genetic risk. METHODS:We studied 590 children from the prospective COPSAC2010 birth cohort to examine associations between neurodevelopmental measures from birth to age 3 and clinical ADHD diagnosis and trait manifestations at age 10. Associations were analysed using adjusted logistic and linear regression models, and ADHD polygenic risk scores were examined in relation to early neurodevelopment and later ADHD outcomes. RESULTS:ADHD at age 10 was associated with lower word production (OR 0.69 [0.48; 0.95] 0.028), shorter sentence length (OR 0.71 [0.56; 0.88] 0.003), reduced cognitive functioning (OR 0.96 [0.93; 0.99] 0.025) and more behavioural/emotional problems (OR 1.05 [1.00; 1.09] 0.034) in early life. CONCLUSION:Early language, cognitive and behavioural/emotional difficulties may serve as indicators of later ADHD and support earlier identification of vulnerable children.

QuestionDo neurometabolite levels differ according to antipsychotic response in psychosis?FindingsThis mega-analysis of individual-level data in 1189 participants found elevated medial frontal glutamate, choline, and myo-inositol in individuals showing antipsychotic nonresponse compared to antipsychotic responders and healthy control individuals. The elevations in medial frontal choline and myo-inositol associated with nonresponse were also evident in meta-analysis.MeaningAntipsychotic nonresponse in psychosis was associated with elevations in markers of glutamatergic and neuroinflammatory pathways in this study, supporting further investigation of interventions targeting these mechanisms. This mega-analysis assesses differences in neurometabolites in antipsychotic nonresponsive compared to antipsychotic-responsive psychosis using individual participant data and meta-analysis. ImportanceRevealing neurobiological markers of antipsychotic nonresponse in psychosis may aid outcome prediction and inform novel treatment targets.ObjectiveTo examine differences in neurometabolites in antipsychotic nonresponsive compared to antipsychotic-responsive psychosis using individual participant data and meta-analysis.Data SourcesWeb of Science was searched for studies published between January 1, 1980, and November 1, 2025. Authors of 21 eligible studies identified before August 2024 were invited to contribute individual participant data.Study SelectionEighteen studies examining neurometabolites by treatment response in psychosis contributed individual participant data for the mega-analysis. These studies plus a further 5 studies were included in the meta-analyses of standardized mean differences and variability.Data Extraction and SynthesisIndividual participant data were analyzed using linear mixed models with study as a random effect. Subgroup analyses examined prospective designs and treatment-resistant samples. Published group means and standard deviations were extracted for meta-analyses.Main Outcomes and MeasuresGroup differences in glutamate, glutamate plus glutamine, choline, myo-inositol, N-acetylaspartate, gamma-aminobutyric acid, and glutathione in the medial frontal cortex, dorsolateral prefrontal cortex, thalamus, and basal ganglia.ResultsThe mega-analysis included 1189 participants from 18 studies; of these, 476 were treatment nonresponders (mean [SD] age, 33.0 [12.5] years; 340 male), 427 were treatment responders (mean [SD] age, 30.3 [11.5] years; 299 male), and 286 were healthy control individuals (mean [SD] age, 31.0 [12.5] years; 170 male). Compared with the antipsychotic response group, nonresponders showed elevations in medial frontal glutamate (Glass Delta = 0.21; P = .02), glutamate plus glutamine (Glass Delta = 0.29; P = .002), choline (Glass Delta = 0.22; P = .03), and myo-inositol (Glass Delta = 0.35; P = .001); similar elevations were observed relative to control individuals. Elevated medial frontal glutamate plus glutamine in antipsychotic nonresponders compared with responders was also observed prospectively in first-episode psychosis (Glass Delta = 0.41; P = .002), whereas myo-inositol elevations were greatest in individuals meeting criteria for treatment-resistance (Glass Delta = 0.64; P = .001). The meta-analysis of 23 studies (1844 participants) also showed elevated medial frontal choline and myo-inositol in antipsychotic nonresponse compared with response.Conclusions and RelevanceThese findings provide evidence of an association between antipsychotic nonresponse in psychosis with elevations in medial frontal glutamate, choline, and myo-inositol. The presence of elevations in these markers supports the continued investigation of glutamate-acting and inflammatory pathway-associated interventions for psychosis and schizophrenia.

BACKGROUND:Inflammation in pregnancy induced by chronic disease, infection, or environmental exposures has been associated with neurodevelopmental conditions in observational study designs. OBJECTIVE:To investigate causal effects of pregnancy inflammation on offspring neurodevelopment in the Norwegian Mother, Father and Child Cohort Study (MoBa) using a genetically informed design. METHODS:In pre-registered analyses, we tested potential causal effects of increased C-reactive protein (CRP), interleukin-6 (IL-6), and glycoprotein acetyls (GlycA) in pregnancy on neurodevelopmental outcomes using trio polygenic score (PGS) and intergenerational Mendelian randomization (MR) analyses. PGS and MR genetic instruments were used to predict neurodevelopmental outcomes in the MoBa cohort, which included mother-reported neurodevelopmental traits registered from age 3 to 8 years and diagnoses of ADHD and autism. In both the trio PGS and intergenerational MR analyses, simultaneous inclusion of mothers', fathers', and children's genotypes allowed for effects consistent with the hypothesized causal pathway (maternal inflammation) to be estimated independent of familial confounding factors. RESULTS:Validation analyses of genetic instruments only showed strong predictive value for CRP. Trio PGS in 41,531 complete trios did not reveal maternal indirect effects of genetic liability to higher CRP on offspring neurodevelopmental outcomes. The results of the trio MR also failed to support a causal link between maternal inflammation, proxied by higher CRP, during pregnancy and offspring neurodevelopment. CONCLUSION:This study provided no evidence consistent with causal effects of higher CRP in pregnancy on offspring neurodevelopment. This may imply that observational links are driven by genetic confounding, though other factors - such as selective participation in MoBa - cannot be ruled out as alternative explanations for our null findings.

Resting-state functional magnetic resonance imaging (rs-fMRI) has offered insights into the neural mechanisms underlying psychosis, particularly when associated with clinically relevant features. 102 individuals at ultra-high risk for psychosis (UHR) and 105 matched healthy controls (HC) aged 18–40 underwent clinical and cognitive assessments and rs-fMRI at baseline. Using a recently developed prediction-based extension of the network-based statistics (NBS-predict), incorporating nested cross-validation, we tested the predictive power of functional connectivity estimated from rs-fMRI data, investigating diagnostic classification and prediction of level of functioning, estimated IQ, and UHR-symptoms. Hyper-connectivity predicted group with a classification accuracy of 0.58, p = 0.043, and hypo-connectivity predicted group with a classification accuracy of 0.59, p = 0.018. Hyper-connectivity in UHR-individuals was observed primarily in interhemispheric and cortico-thalamic connections, within networks that predicted poorer levels of functioning across groups. Hypo-connectivity in UHR-individuals was observed mainly in thalamic connections with posterior cingulate cortex, frontal medial, and precuneus, within networks that predicted higher level of functioning across groups. Post hoc analyses identified a significant groupwise interaction effect on the association between functional connectivity and level of functioning (ρ = 0.34, p < 0.001), with main nodes in the frontal medial regions connected across hemispheres. Within-group, no connections predicted level of functioning or UHR-symptoms. Whole-brain functional connectivity predicted UHR-status in hyper- and hypo-connected networks, with thalamus as a central integrative hub across networks. Connections that predicted level of functioning across groups were equivalent to the connections predicting UHR-status, hence capturing a neural correlate to a key clinical component of the UHR-status.

BACKGROUND:People with schizophrenia-spectrum or bipolar disorder frequently have physical comorbidities, but the epidemiology of developing multiple physical conditions is unclear. We hypothesised that this group experiences an earlier accumulation of physical multimorbidity affecting multiple systems. Our aim was to estimate the relative and absolute incidence of physical multimorbidity in people with and without severe mental illness. METHODS:We did a cohort study using statewide hospital registries in Queensland, Australia, between Jan 1, 2000, and Dec 31, 2023. Individuals with a recorded diagnosis of schizophrenia-spectrum or bipolar disorder were age-matched and sex-matched (1:4) to individuals without these disorders. The study outcome was systemic physical multimorbidity, defined as the cumulative number of systems affected by chronic physical disease. We measured the relative incidence of developing systemic physical multimorbidity in at least one to at least five systems using Fine-Gray adjusted subdistribution hazard ratios (HRs); absolute differences were measured using differences in the cumulative incidence function at 20 years. Additional age-stratified and sex-stratified analyses were undertaken. This study featured no lived experience involvement. FINDINGS:A total of 178 665 individuals were included in the analysed sample: 30 189 people with schizophrenia-spectrum or bipolar disorder (11 940 females and 18 249 males; median age 32 years [IQR 24-42]) were compared with 148 476 hospital comparators in the control group (61 365 females and 87 111 males; median age 33 years [IQR 24-44]). Ethnicity data were not available. Relative incidence was higher in the disorder group with adjusted subdistribution HRs of 1·85 (95% CI 1·81-1·88) for at least one affected system, 2·25 (2·19-2·32) for at least two affected systems, 2·65 (2·56-2·74) for at least three affected systems, 2·93 (2·81-3·05) for at least four affected systems, and 3·16 (3·01-3·30) for at least five affected systems. At 20 years, absolute cumulative incidence differences were 9·79 additional cases per 100 persons (95% CI 9·06-10·53) for at least one affected system, 18·43 additional cases (17·58-19·28) for at least two affected systems, 18·57 additional cases (17·73-19·42) for at least three affected systems, 15·71 additional cases (14·92-16·51) for at least four affected systems, and 11·66 additional cases (10·95-12·37) for at least five affected systems. Elevated adjusted subdistribution HRs were consistently observed for younger strata, with the highest observed in females younger than 25 years with at least five affected systems (adjusted subdistribution HR 9·24 [95% CI 7·30-11·71]). INTERPRETATION:People with schizophrenia-spectrum or bipolar disorder experience increased relative and absolute incidence of systemic physical multimorbidity spanning multiple systems, compared with individuals without these disorders. The largest differences were observed among younger cohorts, emphasising the need for early prevention. FUNDING:None.

Abstract Persistent negative symptoms (PNS), defined as negative symptoms of at least moderate severity that endure over time and are not attributable to other psychopathological dimensions such as depression or parkinsonism, have been associated with poor functional outcomes in schizophrenia, in both chronic stages and in the early phases of the disorder. This post-hoc analysis of a large cohort of schizophrenia spectrum disorder patients within their first 7 years of illness, enrolled in the European Long-acting Antipsychotics in Schizophrenia Trial (EULAST), aimed to: 1) confirm prior findings about the prevalence and clinical impact of unconfounded persistent negative symptoms (PNS) on dropout rates and psychosocial functioning after 12 and 18 months of treatment; and 2) explore the prevalence of enduring negative symptoms (E-NS), defined as persistent negative symptoms either confounded or unconfounded by depression or parkinsonism, and their influence on functional outcome. At week 0, 60.6% of patients exhibited at least one negative symptom of moderate severity. Among them, 42.8% met criteria for unconfounded negative symptoms. After 1 year, the frequency of PNS and E-NS was 7.9% and 15%, respectively, with a prospective consistency around 32%. PNS subjects had similar levels of functioning at week 0 (d = −0.179, p = 0.194), but worse functioning after 12 (d = −0.697, p = 0.028) and 18 (d = -0.676, p = 0.024) months of treatment, as compared to those with negative symptoms of similar severity at baseline that did not persist (non-persistent negative symptoms, N-PNS). No difference among groups was observed in drop-out rates. The comparison between the E-NS and N-PNS groups revealed the same functional outcome differences observed in the PNS versus N-PNS comparison. Our findings confirm that long-term persistence of negative symptoms, both primary and secondary, contributes to poor functional outcome. Future research should focus on identifying predictors of symptom persistence to guide the development of targeted interventions aimed at improving long-term functional outcomes in this patient population.