Decades of research have identified a strong association between heavy cannabis use and schizophrenia (SCZ), with evidence of correlated genetic factors. However, many studies on the genetic relationship between cannabis use and psychosis have lacked data on both phenotypes within the same individuals, creating challenges due to unmeasured confounding. We aimed to address this by using multimodal data from the All of Us Research Program, which contains genetic data as well as information on SCZ diagnosis and cannabis use.

We tested the association between cannabis use disorder (CUD) and SCZ polygenic scores (PGSs) with SCZ and heavy cannabis use. We tested models where both CUD and SCZ PGSs were included as joint predictors of heavy cannabis use and SCZ case status. We defined three sets of cases based on comorbidities: relaxed (assessing for only the primary condition), strict (excluding comorbidity), and dual-comorbidity.

CUD and SCZ polygenic liability were independently associated with heavy cannabis use; the SCZ PGS effect was very modest. In contrast, both SCZ and CUD PGSs were independently associated with SCZ, with independent significant effects of CUD PGS. Polygenic liability to CUD was associated with SCZ in individuals without a documented history of cannabis use, suggesting widespread pleiotropy.

These findings underscore the need for comprehensive models that integrate genetic risk factors for heavy cannabis use to advance our understanding of SCZ etiology.

People with severe mental illness (SMI) (schizophrenia-spectrum and bipolar disorders) experience a 15–20-year reduction in life expectancy. The role of social determinants, including that of social exclusion, in contributing to excess mortality in SMI remains underexplored.

Retrospective cohort study, comprising 8098 people with clinician-diagnosed SMI, matched to 581,209 population controls, followed for 5.7 years using person-level linked health/ census records. A social exclusion index was derived from census indicators: marital status, social isolation, economic inactivity, education, tenure, housing stability, and material assets.

Social exclusion was more common in SMI than in controls and strongly associated with higher mortality. Relative to the least socially excluded controls, adjusted hazard ratios (aHR) for mortality in SMI were: 16–44 years: aHR 7.58 (95% CI: 2.75–20.86) in the least socially excluded, increasing to 12.34 (7.92–19.24) in the most excluded; 45–64 years: 3.34 (1.98–5.64) [least excluded] increasing to 6.58 (5.32–8.14) [most excluded]; 65+ years: 2.71 (1.90–3.86) [least excluded], increasing to 3.07 (2.48–3.80)[most excluded]. Excess mortality among those with SMI was pronounced at younger ages if never married; by mid-life if living alone or economically inactive; and at 65+ years in those with SMI living alone, renting, or with no car ownership. Economic inactivity and lack of qualifications accounted for 16–35% of SMI mortality.

Social exclusion is an under-recognized contributor to premature mortality in SMI. Targeting social determinants through novel socially-focused interventions could improve survival in people with SMI.

The negative symptoms of psychosis are heterogeneous, which complicates efforts to understand their pathophysiology and develop effective treatments. Factor analytic studies of the Positive and Negative Syndrome Scale (PANSS) have reported two factorial negative symptom models, expressive deficit and social amotivation, albeit with different compositions. Although models derived from other assessment scales have been directly compared, no study has previously applied this approach to PANSS.

Our objectives were to (a) to establish which negative PANSS-derived factorial model provided the best fit to our data, (b) test its stability and (c) determine its clinical and demographic correlates.

A cohort of medication naive or minimally treated patients with first-episode schizophrenia (n = 446) were assessed using the PANSS scale before and 4 weeks after amisulpride treatment. Confirmatory factor analysis was performed to test five PANSS models. Hierarchical multiple regression was conducted to examine the associations between identified dimensions and clinical and demographic variables.

A nine-item PANSS model comprising social amotivation and expressive deficit dimensions outperformed the other models: comparative fit index = 0.98, goodness of fit index = 0.97, Tucker–Lewis index = 0.97, root mean square error of approximation = 0.06 (CI 90%: 0.04–0.08), Bayesian information criterion = 191.9, Akaike information criterion = 101.7. At baseline, the social amotivation dimension was associated with more severe depression whereas the expressive deficit dimension was associated with younger age. Both dimensions at baseline were associated with poor functioning, but expressive deficit to a lesser extent.

A nine-item PANSS model incorporating social amotivation and expressive deficit dimensions appeared to best reflect the underlying structure of negative symptoms in our sample.

To compare verbal memory encoding, storage, and retrieval in patients with schizophrenia (SZ), SZ plus substance use disorder (SZ+), and substance use disorder only (SUD), testing the hypothesis that SZ + group exhibits greater impairment across all processes.

A total of 294 male patients under treatment (SZ = 72, SZ+ = 72, SUD = 150) meeting DSM-5 criteria completed the Rey Auditory Verbal Learning Test (RAVLT). RAVLT measures assessed encoding, storage, and retrieval. ANCOVA/MANCOVA, controlling for premorbid IQ, were used to explore group differences.

Significant differences among groups were observed in all RAVLT measures (F(2,291) > 9.25, p < 0.001, ηp2 > 0.06) except retrieval. Post hoc analyses revealed that both SZ and SZ+ groups showed significant verbal memory impairments (learning trials and storage, interference, short and long-term recall and recognition) compared to the SUD group which performed within the normative range. The SZ and SZ+ groups showed altered values (Z ≥ −1.5) from the second learning trial onward and total learning, and the SZ+ group also for long-term recall and recognition.

This study confirms the existence of significant verbal memory deficits in both SZ and SZ+ groups compared to SUD. Verbal memory impairment appears as a central feature of SZ spectrum disorders, irrespective of SUD comorbidity. Exacerbated memory impairment in SZ+ compared to SZ on the RAVLT is subtle without reaching significant differences, although consideration of altered Z-scores suggests worse performance in SZ+ in encoding and consolidation processes. Further research should explore clinical variables and moderators of comorbidity effects in SZ.

Clinical progression during psychosis has been closely associated with grey matter abnormalities resulting from atypical brain development. However, the complex interplay between psychopathology and heterogeneous maturational trajectories challenges the identification of neuroanatomical features that anticipate symptomatic decline.

To investigate cortical volume longitudinal deviations in first-episode psychosis (FEP) using normative modelling, exploring their relationship with long-term cognitive and symptomatic outcomes, as well as their cytoarchitectural and neurobiological underpinnings.

We collected magnetic resonance imaging (MRI), cognitive and symptomatic data from 195 healthy controls and 357 drug-naïve or minimally medicated FEP individuals that were followed up 1, 3, 5 and 10 years following the first episode (1209 MRI scans and assessments in total). Using normative modelling, we derived subject-specific centile scores for cortical volume to investigate atypical deviations in FEP and their relationship to long-term cognitive and symptomatic deterioration. The resulting centile association maps were further characterised by examining their cytoarchitectural and neurobiological attributes using normative atlases.

FEP centiles demonstrated a widespread reduction at treatment initiation, with longitudinal analysis showing an increase during treatment time, indicating convergence towards normal maturation trajectories. Interestingly, this effect was reduced in highly medicated individuals. Additionally, we found that cognitive impairments experienced during early FEP stages worsened under long-term medication. Positive symptomatology was negatively associated with regional centiles, and individuals with higher centiles benefited most from treatment. Cytoarchitectural and neurobiological analyses revealed that regional centiles related to FEP, as well as to symptomatology, were associated with specific molecular features, such as regional serotonin and dopamine receptor densities.

Collectively, these findings underscore the potential use of centile-based normative modelling for a better understanding of how atypical cortical development contributes to the long-term clinical progression of neurodevelopmental conditions.

Shared genetic risk has been shown across psychiatric disorders. In particular, anorexia nervosa (AN), obsessive-compulsive disorder (OCD), and schizophrenia (SCZ) show shared genetic risk that matches clinical evidence of shared illness and cognitive phenotypes. Given this evidence, we leveraged a large US-based population-based study to determine genetic associations of disorder-specific and shared psychiatric, cognitive, and brain markers and explore whether the latter might be state versus trait markers in eating disorders.

We used data from the population-based Philadelphia Neurodevelopmental Cohort (N = 4,729) and conducted sex-stratified analyses to test for associations between genetic risk for three disorders (AN, OCD, and SCZ) and mental health phenotypes, neurocognitive traits, and cortical features in a non-clinical population. Exploratory analyses on cortical features were run on a subset with neuroimaging data (N = 626).

Genetic risk for AN was significantly associated with body image distortion (pFDR = 0.02), and body image distortion was significantly related to a reduction in grey matter volume (pFDR = 0.05).

Genetic risk for AN associates with AN trait in a non-clinical sample of youth, particularly in females. Whilst genetic risk was not associated with cognitive or cortical markers, the AN phenotype was associated with cortical markers.

How psychotic symptoms, depressive symptoms, cognitive deficits, and functional impairment may interact with one another in schizophrenia or bipolar disorder is unclear.

This study explored these interactions in a discovery sample of 339 Chinese, of whom 146 had first-episode schizophrenia and 193 had bipolar disorder. Psychotic symptoms were assessed using the Positive and Negative Symptom Scale; depressive symptoms, using the Hamilton Depression Rating Scale; cognitive deficits, using tests of processing speed, executive function, and logical memory; and functional impairment, using clinical assessments. Network models connecting the four types of variables were developed and compared between men and women and between disorders. Potential causal relationships among the variables were explored through directed acyclic graphing. The results in the discovery sample were compared to those obtained for a validation sample of 235 Chinese, of whom 138 had chronic schizophrenia and 97 had bipolar disorder.

In the discovery and validation cohorts, schizophrenia and bipolar disorder showed similar networks of associations, in which the central hubs included ‘disorganized’ symptoms, depressive symptoms, and deficits in processing speed during the digital symbol substitution test. Directed acyclic graphing suggested that disorganized symptoms were upstream drivers of cognitive impairment and functional decline, while core depressive symptoms (e.g. low mood) drove somatic and anxiety symptoms.

Our study advocates for transdiagnostic, network-informed strategies prioritizing the mitigation of disorganization and depressive symptoms to disrupt symptom cascades and improve functional outcomes in schizophrenia and bipolar disorder.

Sleep disorders are closely linked to the onset, progression and severity of psychiatric disorders, yet large-scale data from real-world inpatient settings remain limited. Evaluating the impact of chronic sleep disorders (CSD) in this context is essential for improving care.

We conducted an analysis of adult inpatients hospitalized from January 1, 2021, to December 31, 2023, using data from the Paris Psychiatry Hospital Group’s health data warehouse. Sleep disorders were identified via ICD-10 codes, hypnotic prescriptions, or mentions in medical record. CSD was defined using an Index of Length of Stays with Disorders (ILSD) >0.5, and no sleep disorders (NSD) with an ILSD of zero.

Among 13,913 psychiatric inpatients, 81% were classified as having CSD. Compared to NSD patients, those with CSD had a higher number of hospitalizations (1.84 vs 1.33, p<0.001) and increased use of seclusion (17.6% vs 13.3%, p<0.001) and physical restraint (6.6% vs 5.3%, p=0.003). Individuals with CSD were more frequently hospitalized than the NSD group for depressive disorders (15.6% vs13.1%, p<0.001), bipolar disorders (11.4% vs5.6%, p<0.001), personality disorders (5.3% vs4.3%, p=0.009), alcohol abuse (3.3% vs2.4%, p=0.005), other substance use disorders (2.9% vs2.2%, p=0.018), manic episode (2.0% vs0.9%, p<0.001), and anxiety disorders (1.4% vs0.9%, p=0.012). Hypnotics were prescribed in 50.5% of SD-related stays. The CSD group had more psychiatric and non-psychiatric comorbidities.

CSD are highly prevalent in psychiatric inpatients and associated with more severe clinical profiles, greater hospitalization burden, and increased restraint use. Targeted sleep management strategies may help improve outcomes and care.

The Virtual Reality Functional Capacity Assessment Tool (VRFCAT) is a performance-based measure developed to assess functional capacity through simulations of daily activities. This study examined its psychometric properties in a Spanish sample, including individuals with first-episode psychosis (FEP), schizophrenia, and healthy controls.

A total of 370 participants (99 FEP, 116 schizophrenia, and 155 controls) completed the VRFCAT in a multicenter study. Internal consistency (McDonald’s omega), discriminative validity (group comparisons and ROC curves), and convergent validity via correlations with cognitive performance and clinical symptoms were examined. Reference percentiles were calculated from the healthy control sample using quantile regression, stratified by age and education.

Item-level VRFCAT completion times showed acceptable to good internal consistency overall and in controls and schizophrenia samples, but poor in FEP. Differences in VRFCAT performance emerged (χ2 = 108.88, p < .001), with controls performing best, schizophrenia worst, and FEP in between. ROC analyses indicated good discriminative accuracy in distinguishing patients from controls (area under the curve [AUC] = 0.779, sensitivity = 80.0%, specificity = 64.2%); but limited discrimination between schizophrenia and FEP. Age and education, but not sex, significantly affected performance. VRFCAT showed small-to-moderate correlations with cognitive performance, and no significant associations with symptom severity.

The VRFCAT is a reliable and valid tool for assessing functional capacity in Spanish-speaking individuals with psychotic disorders. Its ecological validity, objectivity, psychometric properties, brief administration time, and ease of use support its potential use in clinical and research settings for evaluating functional recovery and treatment outcomes.

Structural abnormalities in cortical and subcortical brain regions are consistently observed in schizophrenia; however, substantial inter-individual variability complicates identifying clear neurobiological biomarkers. The Person-Based Similarity Index (PBSI) quantifies individual structural variability; however, its applicability across schizophrenia stages remains unclear. This study aimed to compare cortical and subcortical structural variability in recent-onset and chronic schizophrenia and explore associations with clinical measures.

Neuroimaging data from 41 patients with recent-onset schizophrenia, 32 with chronic schizophrenia, and 59 healthy controls were analysed. The PBSI scores were calculated for cortical thickness, surface area, cortical grey matter volume, and subcortical volumes. Group differences in PBSI scores were assessed using linear regression and analysis of variance. Correlations between the PBSI scores and clinical measures were also examined.

Both patients with recent-onset and chronic schizophrenia exhibited significantly lower PBSI scores than healthy controls, indicating greater morphometric heterogeneity. However, significant differences between the recent-onset and chronic patient groups were limited to subcortical and cortical thickness PBSI scores. Correlations between PBSI scores and clinical symptoms are sparse and primarily restricted to surface area variability and symptom severity in patients with recent-onset schizophrenia.

Patients with schizophrenia show marked structural brain heterogeneity compared with healthy controls, which is detectable even in the early stages of the illness. Although there were few differences in PBSI scores between the recent-onset and chronic schizophrenia groups and limited correlations between PBSI scores and clinical measures, the PBSI may still provide valuable insights into individual differences contributing to clinical heterogeneity in schizophrenia.

Subtle behavioral and cognitive symptoms precede schizophrenia (SCZ) and appear in individuals with elevated risk based on polygenic risk scores (SCZ-PRS) and family history of psychosis (SCZ-FH). However, most SCZ-PRS studies focus on European ancestry youth, limiting generalizability. Furthermore, it remains unclear whether SCZ-FH reflects common-variant polygenic risk or broader SCZ liability.

Using baseline data from the Adolescent Brain Cognitive Development (ABCD) study, we investigated associations of SCZ-FH and SCZ-PRS with cognitive, behavioral, and emotional measures from NIH-Toolbox, Child Behavior Checklist (CBCL), and Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS) for 9,636 children (mean age = 9.92 yrs, 47.4% female), specifically, 5,636 European, 2,093 African, and 1,477 Admixed American ancestry individuals.

SCZ-FH was associated with SCZ-PRS (b = 0.05, FDR-p = 0.02) and subthreshold psychotic symptoms (b = 0.46, FDR-p = 0.01) in European youth, higher CBCL scores (b range = 0.36–0.6, FDR-p < 0.001), and higher odds of multiple internalizing and externalizing disorders (OR = 1.10–1.22, FDR-p < 0.001) across ancestries. SCZ-PRS was associated with lower cognition across ancestries (b = −0.43, FDR-p = 0.02), higher CBCL total problems, anxious/depressed, rule-breaking and aggressive behaviors in European youth (b range = 0.16–0.33, FDR-p < 0.04), and depressive disorders in Admixed American youth (OR = 1.37, FDR-p = 0.02). Results remained consistent when SCZ-PRS and SCZ-FH were jointly modeled. Some SCZ-FH associations weakened when income-to-needs was accounted for, suggesting that SCZ-FH may capture both genetic and environmental influences.

SCZ-FH showed associations with broad psychopathology, while SCZ-PRS was associated with cognition and specific symptoms in European youth. Findings highlight their complementary role in SCZ risk assessment and the need to improve PRS utility across ancestries.

Antipsychotics are first-line treatments for schizophrenia, yet many patients show inadequate response. Clozapine, the gold standard for treatment-resistant schizophrenia, remains underutilised due to safety and monitoring concerns.

To evaluate the adverse effects of clozapine in schizophrenia through a meta-analysis of randomised controlled trials (RCTs).

We systematically searched MEDLINE, CENTRAL, Embase, PsycINFO, ClinicalTrials.gov and WHO ICTRP up to 10 October 2024 for RCTs comparing clozapine (as either monotherapy or combination therapy) with other antipsychotics. We assessed 37 distinct adverse outcomes. Risk ratios were calculated for dichotomous outcomes and standardised mean differences for continuous outcomes, with confidence intervals.

A total of 116 RCTs (n = 8431) were included. In 69 monotherapy RCTs (n = 6281), clozapine showed no difference in either mortality (risk ratio 1.01, 95% CI: 0.50, 2.01, prevalence 0.1%) or discontinuation due to adverse effects (risk ratio 1.18, 95% CI: 0.91, 1.53, prevalence 7.2%). Agranulocytosis risk was nearly tripled (risk ratio 2.81, 95% CI: 0.97, 8.12, prevalence 0.7%), although with wide confidence intervals. Clozapine increased the risk of seizures (risk ratio 3.61, 95% CI: 1.80, 7.95, prevalence 3.1%) and orthostatic hypotension/bradycardia/syncope (risk ratio 1.66, 95% CI: 1.00, 2.77, prevalence 11%). No difference was found for myocarditis/cardiomyopathy (risk ratio 0.33, 95% CI: 0.01, 8.13). Clozapine increased the risk of leukopenia, hypersalivation, sedation, tachycardia, hypertension, constipation, nausea/vomiting, fever, flu-like syndrome and headache. In 47 combination RCTs (n = 2150), clozapine combinations were not associated with increased risk of severe adverse effects; no cases of agranulocytosis (21 RCTs, n = 894) or seizures (8 RCTs, n = 313) were reported in trials that explicitly assessed these outcomes.

Life-threatening adverse events remain rare with clozapine. With appropriate monitoring, its safety profile supports broader and potentially earlier use. Future studies should refine monitoring protocols and explore additional indications.