Childhood trauma is a well-established risk factor for psychosis, paranoia, and substance use, with cannabis being a modifiable environmental factor that exacerbates these vulnerabilities. This study examines the interplay between childhood trauma, cannabis use, and paranoia using standard tetrahydrocannabinol (THC) units as a comprehensive measure of cannabis exposure.

Data were derived from the Cannabis&Me study, an observational, cross-sectional, online survey of 4,736 participants. Childhood trauma was assessed using a modified Childhood Trauma Screen Questionnaire, while paranoia was measured via the Green Paranoid Thoughts Scale. Cannabis use was quantified using weekly standard THC units. Structural equation modeling (SEM) was employed to evaluate direct and indirect pathways between trauma, cannabis use, and paranoia.

Childhood trauma was strongly associated with paranoia, particularly emotional, and physical abuse (β = 16.10, q < 0.001; β = 16.40, q < 0.001). Cannabis use significantly predicted paranoia (β = 0.009, q < 0.001). Interactions emerged between standard THC units and both emotional abuse (β = 0.011, q < 0.001) and household discord (β = 0.011, q < 0.001). SEM revealed a small but significant indirect effect of trauma on paranoia via cannabis use (β = 0.004, p = 0.017).

These findings highlight childhood trauma as a primary driver of paranoia, with cannabis use amplifying its effects. While trauma had a strong direct impact, cannabis played a significant mediating role. Integrating standard THC units into psychiatric research and clinical assessments may enhance risk detection and refine intervention strategies, particularly for childhood trauma-exposed individuals.

Depressive symptoms are highly prevalent in first-episode psychosis (FEP) and worsen clinical outcomes. It is currently difficult to determine which patients will have persistent depressive symptoms based on a clinical assessment. We aimed to determine whether depressive symptoms and post-psychotic depressive episodes can be predicted from baseline clinical data, quality of life, and blood-based biomarkers, and to assess the geographical generalizability of these models.

Two FEP trials were analyzed: European First-Episode Schizophrenia Trial (EUFEST) (n = 498; 2002–2006) and Recovery After an Initial Schizophrenia Episode Early Treatment Program (RAISE-ETP) (n = 404; 2010–2012). Participants included those aged 15–40 years, meeting Diagnostic and Statistical Manual of Mental Disorders IV criteria for schizophrenia spectrum disorders. We developed support vector regressors and classifiers to predict changes in depressive symptoms at 6 and 12 months and depressive episodes within the first 6 months. These models were trained in one sample and externally validated in another for geographical generalizability.

A total of 320 EUFEST and 234 RAISE-ETP participants were included (mean [SD] age: 25.93 [5.60] years, 56.56% male; 23.90 [5.27] years, 73.50% male). Models predicted changes in depressive symptoms at 6 months with balanced accuracy (BAC) of 66.26% (RAISE-ETP) and 75.09% (EUFEST), and at 12 months with BAC of 67.88% (RAISE-ETP) and 77.61% (EUFEST). Depressive episodes were predicted with BAC of 66.67% (RAISE-ETP) and 69.01% (EUFEST), showing fair external predictive performance.

Predictive models using clinical data, quality of life, and biomarkers accurately forecast depressive events in FEP, demonstrating generalization across populations.

Physiological signals conveyed by the vagus nerve may generate quiescent psychological states conducive to contemplative practices. This suggests that vagal neurostimulation could interact with contemplative psychotherapies (e.g. mindfulness and compassion-based interventions) to augment their efficacy.

In a fully factorial experimental trial, healthy adults (n = 120) were randomized to transcutaneous vagus nerve stimulation (tVNS) plus Self-Compassion-Mental-Imagery Training (SC-MIT) or alternative factorial combinations of stimulation (tVNS or sham) plus mental imagery training (MIT: SC-MIT or Control-MIT). Primary outcomes were self-reported state self-compassion, self-criticism, and heart rate variability (HRV). Exploratory outcomes included state mindfulness and oculomotor attentional bias to compassion-expressing faces. Most outcomes were assessed acutely on session 1 at the pre-stimulation (T1), peri-stimulation (T2), and post-MIT + stimulation (T3) timepoints, and after daily stimulation+MIT sessions (eight sessions).

During session 1, a significant Timepoint × Stimulation × MIT interaction (p = 0.025) was observed, reflecting a larger acute T1→T3 increase in state self-compassion after tVNS+SC-MIT, with similar rapid effects on state mindfulness. Additionally, significant Session × MIT and Session × Stimulation interactions (p ≤ 0.027) on state mindfulness (but not self-compassion) suggested that tVNS+SC-MIT’s effects may accumulate across sessions for some outcomes. By contrast, changes in state self-criticism and compassion-related attentional bias were only moderated by MIT (not stimulation) condition. HRV was unaffected by stimulation or MIT condition.

tVNS augmented the effects of SC-MIT and might, therefore, be a useful strategy for enhancing meditation-based psychotherapies. Our findings also highlight the value of oculomotor attentional metrics as responsive markers of self-compassion training and the continued need for sensitive indices of successful vagal stimulation.

Functional impairment in daily activities, such as work and socializing, is part of the diagnostic criteria for major depressive disorder and most anxiety disorders. Despite evidence that symptom severity and functional impairment are partially distinct, functional impairment is often overlooked. To assess whether functional impairment captures diagnostically relevant genetic liability beyond that of symptoms, we aimed to estimate the heritability of, and genetic correlations between, key measures of current depression symptoms, anxiety symptoms, and functional impairment.

In 17,130 individuals with lifetime depression or anxiety from the Genetic Links to Anxiety and Depression (GLAD) Study, we analyzed total scores from the Patient Health Questionnaire-9 (depression symptoms), Generalized Anxiety Disorder-7 (anxiety symptoms), and Work and Social Adjustment Scale (functional impairment). Genome-wide association analyses were performed with REGENIE. Heritability was estimated using GCTA-GREML and genetic correlations with bivariate-GREML.

The phenotypic correlations were moderate across the three measures (Pearson’s r = 0.50–0.69). All three scales were found to be under low but significant genetic influence (single-nucleotide polymorphism-based heritability [h2SNP] = 0.11–0.19) with high genetic correlations between them (rg = 0.79–0.87).

Among individuals with lifetime depression or anxiety from the GLAD Study, the genetic variants that underlie symptom severity largely overlap with those influencing functional impairment. This suggests that self-reported functional impairment, while clinically relevant for diagnosis and treatment outcomes, does not reflect substantial additional genetic liability beyond that captured by symptom-based measures of depression or anxiety.

Few studies have examined attention-deficit/hyperactivity disorder (ADHD) symptoms in middle- and older-aged adults. We aim to examine the phenotypic expression of ADHD symptoms in these age groups.

This study comprised a random sample (N = 1,562) from the US Health and Retirement Study 2016, a representative US sample aged 50 years and over. ADHD symptoms were assessed based on the Adult ADHD Self-Report Scale.

In the primary analysis, 10 competing confirmatory factor analytic models of ADHD symptoms in middle- and older-aged adults were compared. The best-fitting model was hierarchical with a general ADHD factor at the apex and underneath symptom factors of inattention, hyperactivity, and impulsivity (ꭓ2 = 319.34, df = 91.71, P = 0.00, TLI = 0.98, CFI = 0.96, RMSEA = 0.04, 95% CI = 0.04–0.05). In complementary analyses, this model was a satisfactory fit to the data: (1) in individuals without a history of cognitive impairment or dementia, and when the general ADHD factor was specified to load on (2) cognitive function, (3) depressive symptoms (which showed adequate fit), and (4) ADHD polygenic scores, (5) in middle- and older-aged adults, and (6) when weighted to represent the US population.

These results imply a hierarchical representation of ADHD symptoms in middle- and older-aged adults consisting of a general factor at the apex with neurocognitive and genetic correlates and underneath symptom factors of inattention, hyperactivity, and impulsivity. Collectively, this model offers a novel framework to study the mechanisms of ADHD symptoms in middle- and older-aged adults and points to treatment targets.

The management of persistent physical symptoms poses a challenge in many healthcare settings, including primary care. Psychological treatments that involve exposure have shown promise for several conditions where patients suffer from persistent physical symptoms and unwanted responses to these. It is unclear, however, to what extent exposure therapy has effects beyond existing routine care interventions and who benefits the most.

A randomized controlled trial at a primary care center in Stockholm, Sweden compared 10 weeks of internet-delivered exposure therapy (n = 80) to healthy lifestyle promotion (HLP; n = 81) for patients bothered by at least one persistent physical symptom. The primary outcome was the mean reduction in subjective somatic symptom burden (Patient Health Questionnaire 15) as measured week-by-week up to the post-treatment assessment. Secondary outcomes included symptom preoccupation, anxiety, depression symptoms, and functional impairment.

Patients contributed 1544 datapoints during treatment. The primary analysis showed no significant advantage of exposure therapy versus HLP in the reduction of mean somatic symptom burden (d = 0.14; p = 0.220). In secondary analyses, exposure showed superiority in the reduction of symptom preoccupation (d = 0.31; p = 0.033) but not anxiety, depression symptoms, or functional impairment. A higher somatic symptom burden or symptom preoccupation before treatment was predictive of a larger advantage of exposure versus HLP.

Exposure therapy does not appear to show noteworthy average benefit over HLP, with the exception of symptom preoccupation. Substantial benefits are seen in patients with very high symptom burden or symptom preoccupation.

Late-onset depression (LOD) is featured by disrupted cognitive performance, which is refractory to conventional treatments and increases the risk of dementia. Aberrant functional connectivity among various brain regions has been reported in LOD, but their abnormal patterns of functional network connectivity remain unclear in LOD.

A total of 82 LOD and 101 healthy older adults (HOA) accepted functional magnetic resonance imaging scanning and a battery of neuropsychological tests. Static functional network connectivity (sFNC) and dynamic functional network connectivity (dFNC) were analyzed using independent component analysis, with dFNC assessed via a sliding window approach. Both sFNC and dFNC contributions were classified using a support vector machine.

LOD exhibited decreased sFNC among the default mode network (DMN), salience network (SN), sensorimotor network (SMN), and language network (LAN), along with reduced dFNC of DMN-SN and SN-SMN. The sFNC of SMN-LAN and dFNC of DMN-SN contributed the most in differentiating LOD and HOA by support vector machine. Additionally, abnormal sFNC of DMN-SN and DMN-SMN both correlated with working memory, with DMN-SMN mediating the relationship between depression and working memory. The dFNC of SN-SMN was associated with depressive severity and multiple domains of cognition, and mediated the impact of depression on memory and semantic function.

This study displayed the abnormal connectivity among DMN, SN, and SMN that involved the relationship between depression and cognition in LOD, which might reveal mutual biomarkers between depression and cognitive decline in LOD.

In psychiatry, there is a drive to reduce institutionalization, the risk of which starts with the index admission. In first-episode psychosis (FEP), the proportion of people admitted to hospital at initial presentation is still unknown.

This systematic review aimed to determine the proportion of people with FEP who are admitted at initial presentation (within 30 days from point of first contact with psychiatry) and the influence of individual, clinical, and service factors on admission risk. Four databases were searched from inception until June 2023: PubMed, Embase, PsycINFO, and CINAHL. The pooled proportion of people admitted was calculated using a random-effects model. Analyses were further stratified according to individual, clinical, and service factors.

Of 7,455 abstracts screened, 18 studies with 19,854 participants were included. The proportion of people admitted overall was 51% (k = 18, 95% confidence interval [CI]: 37–65%; I2: 99.56%). The proportion admitted involuntarily was 31% (k = 6, 95% CI: 23–40%; I2: 95.26%). Sub-analyses for sex, diagnosis, and early intervention service access did not show significant differences between groups. The proportion of people with a short duration of untreated psychosis (DUP) admitted was 59% (k = 2, 95% CI: 56–63%) vs. 37% (k = 2, 95% CI: 33–41%) for long DUP, which was significant (p < 0.001). High inter-study heterogeneity was observed.

Results demonstrate that over half of the people are hospitalized when initially presenting for FEP, a high proportion, with consequences for individuals and health services at large. First, service contact must be prioritized as an opportunity for appropriate intervention, to either avoid unwarranted hospitalizations or if hospitalization is required, to ensure the application of focused therapeutic objectives within intended timeframes.

Establishing appropriate action–outcome associations can allow animals and humans to control behavior and the environment in a goal-directed manner. Deficits in instrumental learning in psychosis have been widely reported in past studies, but the results remain elusive.

To explore the consistent neural representations of instrumental learning in functional magnetic resonance imaging (fMRI) in individuals with psychosis, a total of 18 studies (458 individuals with psychosis and 454 controls) were included in our coordinate-based meta-analysis.

Patients with psychosis presented increased activation in the left middle occipital gyrus, insula, and lingual and postcentral gyri; decreased activation in cortico-striato-thalamo-cortical (CSTC) networks, including the dorsal striatum, insula, thalamus, middle cingulate cortex, posterior cingulate cortex, dorsolateral, orbital, and medial prefrontal cortices (DLPFC, OFC, and mPFC), cerebellum, and associated sensory areas, during instrumental learning. Moreover, mPFC hypoactivation was negatively associated with the percentage of first-generation antipsychotic users, and insula hyperactivation was negatively associated with the percentage of medicated individuals.

Our study revealed that the CSTC circuit could facilitate action-based reward learning in psychosis and may help explain the neuropathological mechanisms underlying these deficits in this disorder.

Preclinical evidence suggests that diazepam enhances hippocampal γ-aminobutyric acid (GABA) signalling and normalises a psychosis-relevant cortico-limbic-striatal circuit. Hippocampal network dysconnectivity, particularly from the CA1 subfield, is evident in people at clinical high-risk for psychosis (CHR-P), representing a potential treatment target. This study aimed to forward-translate this preclinical evidence.

In this randomised, double-blind, placebo-controlled study, 18 CHR-P individuals underwent resting-state functional magnetic resonance imaging twice, once following a 5 mg dose of diazepam and once following a placebo. They were compared to 20 healthy controls (HC) who did not receive diazepam/placebo. Functional connectivity (FC) between the hippocampal CA1 subfield and the nucleus accumbens (NAc), amygdala, and ventromedial prefrontal cortex (vmPFC) was calculated. Mixed-effects models investigated the effect of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on CA1-to-region FC.

In the placebo condition, CHR-P individuals showed significantly lower CA1-vmPFC (Z = 3.17, PFWE = 0.002) and CA1-NAc (Z = 2.94, PFWE = 0.005) FC compared to HC. In the diazepam condition, CA1-vmPFC FC was significantly increased (Z = 4.13, PFWE = 0.008) compared to placebo in CHR-P individuals, and both CA1-vmPFC and CA1-NAc FC were normalised to HC levels. In contrast, compared to HC, CA1-amygdala FC was significantly lower contralaterally and higher ipsilaterally in CHR-P individuals in both the placebo and diazepam conditions (lower: placebo Z = 3.46, PFWE = 0.002, diazepam Z = 3.33, PFWE = 0.003; higher: placebo Z = 4.48, PFWE < 0.001, diazepam Z = 4.22, PFWE < 0.001).

This study demonstrates that diazepam can partially restore hippocampal CA1 dysconnectivity in CHR-P individuals, suggesting that modulation of GABAergic function might be useful in the treatment of this clinical group.

Deep brain stimulation (DBS) is being investigated as a treatment for patients with refractory major depressive disorder (MDD). However, little is known about how DBS exerts its antidepressive effects. Here, we investigated whether ventral anterior limb of the internal capsule stimulation modulates a limbic network centered around the amygdala in patients with treatment-resistant MDD.

Nine patients underwent resting state functional magnetic resonance scans before DBS surgery and after 1 year of treatment. In addition, they were scanned twice within 2 weeks during the subsequent double-blind cross-over phase with active and sham treatment. Twelve matched controls underwent scans at the same time intervals to account for test–retest effects. The imaging data were investigated with functional connectivity (FC) analysis and dynamic causal modelling.

Results showed that 1 year of DBS treatment was associated with increased FC of the left amygdala with precentral cortex and left insula, along with decreased bilateral connectivity between nucleus accumbens and ventromedial prefrontal cortex. No changes in FC were observed during the cross-over phase. Effective connectivity analyses using dynamic causal models revealed widespread amygdala-centric changes between presurgery and 1 year follow-up, while the cross-over phase was associated with insula-centric changes between active and sham stimulation.

These results suggest that ventral anterior limb of the internal capsule DBS results in complex rebalancing of the limbic network involved in emotion, reward, and interoceptive processing.

Functional disorders (FDs) are associated with internalizing disorders (IDs). Studies investigating the nature of these associations over time are limited. We tested the direction of causation between measures of IDs (major depressive disorder [MDD], generalized anxiety disorder [GAD]) and FDs (fibromyalgia [FM] and myalgic encephalomyelitis/chronic fatigue syndrome [ME/CFS]) measured across two waves of longitudinal data (N = 108,034 and N = 73,590).

The Lifelines Cohort Study is a large prospective population-based cohort study in the northeast of the Netherlands. We tested competing causal models for the longitudinal association between IDs and FDs and, to follow-up results from the model with all IDs and FDs, tested the direction of causation between MDD and FM.

FDs were more stable over time than IDs. Initial model comparisons support a bidirectional relationship between most IDs and FDs. Follow-up analyses support a unidirectional model where FM predicts MDD over time (β = 0.14, 95% confidence interval = [0.11, 0.18]), but not vice versa.

The cross-time associations between ME/CFS, MDD, and GAD appear bidirectional (causal in both directions). Our results are consistent with, but not demonstrative of, a causal relationship from FM to MDD. The consequences of specific FDs vary, underscoring the value of studying these conditions as distinct constructs.

We investigate whether, in Swedish national registers, social and psychiatric outcomes for six major psychiatric and substance disorders – drug use disorder (DUD), alcohol use disorder (AUD), major depression (MD), bipolar disorder (BD), anxiety disorder (AD), and schizophrenia (SZ) – reflect the primary genetic risk for each disorder and the level of genetic heterogeneity.

We utilize Genetic Risk Ratios – defined as the ratio of the genetic risk for secondary disorders to the genetic risk for the primary disorder – derived from Family Genetic Risk Scores. Poor social outcome was defined by a common factor of four variables: receipt of social welfare, sick leave, early retirement pension, and residence in a socially deprived area. Psychiatric outcome was defined as days of inpatient psychiatric hospitalization.

With poorer social outcomes, the primary genetic risks rose robustly for all disorders except SZ, as did the secondary genetic risks for DUD, AUD, and attention-deficit hyperactivity disorder. With poorer psychiatric outcomes, available only for BD and SZ, the primary genetic risks increased sharply. Overall, MD, AD, and BD became substantially more genetically heterogenous as their social outcomes became poorer, while for AUD, DUD, and SZ, the increase in heterogeneity was more modest. By contrast, with poorer psychiatric outcome, genetic risks for SZ became substantially more genetically homogeneous, with a similar but less robust trend seen for BD.

Despite important differences between our primary disorders, social and psychiatric outcomes are often robust indices of genetic risk and can reflect the levels of genetic heterogeneity.

Genetic research on nicotine dependence has utilized multiple assessments that are in weak agreement.

We conducted a genome-wide association study (GWAS) of nicotine dependence defined using the Diagnostic and Statistical Manual of Mental Disorders (DSM-NicDep) in 61,861 individuals (47,884 of European ancestry [EUR], 10,231 of African ancestry, and 3,746 of East Asian ancestry) and compared the results to other nicotine-related phenotypes.

We replicated the well-known association at the CHRNA5 locus (lead single-nucleotide polymorphism [SNP]: rs147144681, p = 1.27E−11 in EUR; lead SNP = rs2036527, p = 6.49e−13 in cross-ancestry analysis). DSM-NicDep showed strong positive genetic correlations with cannabis use disorder, opioid use disorder, problematic alcohol use, lung cancer, material deprivation, and several psychiatric disorders, and negative correlations with respiratory function and educational attainment. A polygenic score of DSM-NicDep predicted DSM-5 tobacco use disorder criterion count and all 11 individual diagnostic criteria in the independent National Epidemiologic Survey on Alcohol and Related Conditions-III sample. In genomic structural equation models, DSM-NicDep loaded more strongly on a previously identified factor of general addiction liability than a “problematic tobacco use” factor (a combination of cigarettes per day and nicotine dependence defined by the Fagerström Test for Nicotine Dependence). Finally, DSM-NicDep showed a strong genetic correlation with a GWAS of tobacco use disorder as defined in electronic health records (EHRs).

Our results suggest that combining the wide availability of diagnostic EHR data with nuanced criterion-level analyses of DSM tobacco use disorder may produce new insights into the genetics of this disorder.

Child video game playing (“gaming”) may lead to decreased child academic motivation. Conversely, children with low academic motivation may seek fulfillment through gaming. We examined bidirectional associations between child gaming and academic motivation across middle childhood.

Our analyses are based on 1,631 children (boys = 785) followed in the context of the Quebec Longitudinal Study of Child Development. Data on gaming and academic motivation were collected repeatedly at ages 7, 8, and 10. Measures of child gaming were parent-reported and reflect daily video game playing time. Measures of academic motivation were child self-reported and reflect enjoyment in learning mathematics, reading, and writing. To disentangle the directionality of associations, we estimated a random-intercept cross-lagged panel model to estimate bidirectional, within-person associations between gaming and academic motivation in a cohort of school-aged Canadian children.

Our results revealed unidirectional associations whereby more frequent gaming by boys at age 7 years predicted lower academic motivation at age 8 years (β = −.11, 95% confidence interval [CI]: −.22 to −.01), and similarly, gaming by boys at age 8 years predicted lower academic motivation at age 10 years (β = −.10, 95% CI: −.19 to −.01). Changes in boys’ academic motivation did not contribute to subsequent changes in gaming. There were no associations between gaming and academic motivation for girls.

More time devoted to gaming among school-aged boys is associated with reduced academic motivation during a critical developmental period for the development of academic skills. Fostering healthy gaming habits may help promote academic motivation and success.

In the treatment of obsessive-compulsive disorder (OCD) with antidepressant medication, the earliest reliable indication of treatment failure remains uncertain. We investigated if non-improvement following 4 weeks of treatment predicts nonresponse at the end of the trial.

We conducted a random-effects bivariate diagnostic accuracy study using individual patient data from industry-sponsored short-term trials of adults with OCD receiving selective serotonin reuptake inhibitors or clomipramine, submitted for marketing approval. The primary outcome was accuracy of non-improvement (<25% reduction on the Yale–Brown Obsessive Compulsive Scale [YBOCS] after 4 weeks) in predicting nonresponse (<35% YBOCS reduction at trial endpoint [10–13 weeks]). Secondary outcomes were accuracy of non-improvement after 6 weeks, nonresponse after 8 weeks, and inclusion of Clinical Global Impression Scale – Improvement in definitions of improvement and response. We performed meta-regressions for sex, age, severity, trial duration, dosing regimen, and compound.

In 11 studies totaling 1,753 patients, non-improvement at week 4 predicted subsequent nonresponse (positive predictive value, PPV) in 86% of cases (95% confidence interval [CI] = 83–88%). Sensitivity was 78%, specificity was 70%, and the negative predictive value was 60%. Secondary outcomes showed similar PPV after 6 weeks and a PPV of 93% for nonresponse after 8 weeks. Predictive accuracy was significantly higher in men relative to women (β = −0.64, 95% CI = −1.12 to −0.16, p = 0.0089).

Patients with OCD who do not improve after 4 weeks of antidepressants will likely not respond to short-term treatment. Thus, a change in strategy should be considered after 4 weeks without treatment benefits.

Depression and anxiety are prevalent mental health disorders. While sleep duration has been extensively studied, sleep regularity may play a critical role. We aimed to examine associations between objectively measured sleep regularity and incident depression and anxiety and to investigate whether meeting recommended sleep duration modifies these associations.

In 79,666 UK Biobank participants without baseline depression or anxiety, wrist accelerometers worn for 7 days yielded a sleep regularity index (SRI) and average sleep duration. SRI was categorized as irregular (≤51), moderately irregular (52–70), or regular (≥71). Sleep duration was classified by age-specific recommendations (7–9 hours for ages 18–64 years; 7–8 hours for over 65 years). Cox regression models assessed associations between sleep parameters and mental health outcomes.

During a median follow-up of 7.5 years, 1,646 participants developed depression, and 2,097 developed anxiety. Compared to irregular sleepers, regular sleepers had a 38% lower depression risk (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.52–0.73) and a 33% lower anxiety risk (HR, 0.67; 95%CI, 0.58–0.77). Participants with both irregular sleep and nonrecommended duration exhibited the highest risks (depression HR, 1.91; 95%CI, 1.55–2.35; anxiety HR, 1.61; 95%CI, 1.35–1.93). Notably, irregular sleepers who met duration guidelines still faced elevated risks (depression HR, 1.48; 95%CI, 1.18–1.86; anxiety HR, 1.35; 95%CI, 1.11–1.64).

Greater sleep regularity is independently associated with lower depression and anxiety risk regardless of sleep duration, suggesting that sleep–wake consistency should be considered in mental health promotion strategies alongside traditional sleep duration recommendations.

Schizophrenia (SCZ) and genetic high-risk (GHR) individuals exhibit deficits in brain functional networks and cognitive function, potentially impacted by SCZ risk genes. This study aims to delineate these impairments in SCZ and GHR individuals, and further explore how risk genes affect brain networks and executive function.

A total sample size of 292 participants (100 SCZ, 68 GHR, and 124 healthy controls [HCs]) in the study. The Wisconsin Card Sorting Test (WCST) and resting-state functional magnetic resonance imaging (rs-fMRI) are utilized to evaluate executive function and brain network topology. SCZ-related polygenic risk scores (SCZ-PRS) were used to evaluate genetic risk levels. WCST and PRS were not applied to all participants.

Significant reductions in nodal efficiency and degree centrality (Dnodal) were observed within the right median cingulate and paracingulate gyri (MCPG_R) in both SCZ and GHR groups, compared to HCs. There were significant correlations between SCZ-PRS, Dnodal in MCPG_R, and WCST scores. Moreover, Dnodal in MCPG_R completely mediated the relationship between SCZ-PRS and executive function. The enrichment analysis of these risk genes indicates their involvement in biological processes of signal transduction and synaptic transmission.

This study highlights the pivotal role of impaired cingulate function in mediating the effects of genetic risks on executive deficits, offering new insights into the genetic-neuro-cognitive nexus in schizophrenia and potential targets for clinical interventions.