International Journal of Neuropsychopharmacology

Background: Childhood adversity (CA) is recognized as a distal risk-factor for suicide attempts (SA) in individuals with psychiatric disorders. However, not all individuals with experiences of CA will engage in SA. Contributing to this relationship may be proximal factors such as impulsivity, inward anger and self-aggression. However, these factors are often conceptually blended and measured in different samples. We sought to clarify association among CA and personality factors in persons with SA. Methods: Participants from two studies comprised individuals with a diagnosed psychiatric disorder and history of SA (n= 139) and individuals with depressive disorder (clinical controls, CC; n= 24). We investigated self-reported levels of CA, impulsivity, inward anger, and self-aggression between the SA and CC (pcorr< .012). We tested the relationship among the factors using regression (pcorr<.017) and mediation model (indirect effects, p<.05) within the SA group. Sensitivity models were run controlling for age, gender, symptom severity, trait anger, and externally oriented aggression. Results: SA group had higher impulsivity (pcorr=.067) in a model controlled for age and gender. Other factors did not differ among groups. Within the SA group the analyses revealed positive association among CA and personality factors (pcorr<.06) in basic and model with age and gender, however the association was not specific for internally (self) oriented factors (coefficient comparison, p<.07). Parallel mediation model indicated that CA had indirect effect on self-aggression through impulsivity (p=.001) and to a lesser extent through inward anger (p=.066). Generally, models controlling for cognitive depression symptoms showed less prominent effects (pcorr>.1). Limitations: The study was cross-sectional and did not include behavioral tasks (state) measures of proximal factors. Conclusions: CA and personality factors showed similar severity levels among the SA and CC groups suggesting they may relate to broader psychopathologies, rather than specifically to SA. The association of CA with anger and aggression was unspecific to internally oriented factors indicating the need for more precise measuring instruments developed specifically for individuals with SA. Overall, the study highlights personality factors as being associated with risk in broader vulnerable populations.

Alzheimer's disease (AD) is characterized by complex alterations in synaptic, glial, neuronal and inflammatory markers. Given its emerging role at the interface of synaptic dysfunction and inflammation, the astrocytic marker GFAP may represent a cross-domain hub linking synaptic, neuronal and inflammatory alterations. Using multivariate and network-based analyses we examined the relationships among cerebrospinal fluid (CSF) biomarkers of astrocytic activation and synaptic failure, inflammation, and neurodegeneration in biologically confirmed AD patients and healthy controls (HC). We studied 60 AD patients and 40 HC. CSF concentrations of Neurogranin, SNAP-25, CAP2, NfL, GFAP, IL-1 , IL-1{beta}, IL-8, MCP-1, TNF were measured. Associations were assessed using Spearman correlations, LASSO regression, and network analysis to characterize multivariate dependency structures. Compared with controls, AD patients showed significantly higher CSF levels of Neurogranin, SNAP-25, CAP2, NfL, GFAP, IL-1{beta}, TNF- .. In AD, synaptic biomarkers were strongly intercorrelated and associated with astroglial activation, inflammatory markers, and tau-related pathology. Network analysis identified GFAP as a cross-domain hub linking synaptic, inflammatory, and neurodegenerative domains in AD. In controls, GFAP was mainly associated with neuronal injury markers. Network-based modelling revealed a disease-related reorganization of biomarker connectivity in AD, with GFAP occupying a central cross-domain position, supporting a systems-level view of AD pathophysiology.

Background: Tobacco use is prevalent in clinical high risk for psychosis (CHR-P) population and has widespread negative health consequences, but understanding of its neural substrates is limited. Abnormal default mode network (DMN) may underlie tobacco dependence in CHR-P. We investigated how tobacco use relates to DMN connectivity and how CHR-P status impacts this relationship. Methods: We used baseline substance use and resting-state functional magnetic resonance imaging data from the North American Prodrome Longitudinal Study (NAPLS2; CHR-P: n=211, mean age 19.2, 37.9% female; healthy control: n=132, mean age 19.9, 47.7% female). Voxel-wise connectivity was calculated from the left lateral parietal (LLP) node of the DMN to the rest of the brain. We regressed LLP-brainwide connectivity against tobacco use frequency in the past month to generate a spatial map of how connectivity relates to current tobacco use. Results: Brainwide connectivity analysis identified two clusters in R hippocampus (peak voxel at MNI [+30,-12,-27]) and in L parahippocampus (peak voxel at MNI [-27,-27,-27]), where higher LLP-cluster connectivity was associated with more frequent tobacco use. LLP - R hippocampus connectivity was higher in current tobacco users compared to non-tobacco users (t=-3.5466, df=101.88, p=0.0006), and higher in CHR-P than controls (t=-2.8651, df=279.47, p=0.0049). Among current tobacco users, there was a significant tobacco-by-diagnosis interaction on LLP - R hippocampus connectivity (estimate=0.306, SE=0.149, t=2.051, p=0.045) such that heavier tobacco use predicted hyperconnectivity only in CHR. Conclusions: More frequent tobacco use was associated with higher DMN-hippocampal connectivity in both CHR-P and controls. CHR-P diagnosis enhanced this relationship.

Background: Attention Deficit Hyperactivity Disorder (ADHD) is characterized by persistent inattention, hyperactivity, and impulsivity. While documented in children, research on its persistence into young adulthood in Jordan remains scarce. This gap is critical given the cognitive demands of higher education. This study estimated attention deficit hyperactivity disorder (ADHD) symptom prevalence among Jordanian university students, examined associations with gender and academic performance, and identified barriers to mental health service accessibility. Methods: A descriptive cross-sectional study using web-based sampling recruited 389 university students (aged [&ge;] 18 years) from various Jordanian universities. Participants completed an online survey, incorporating the validated English and Arabic versions of the Adult ADHD Self-Report Scale (ASRS-v1.1) to assess symptom prevalence, alongside inquiries regarding demographics, academic history, and barriers to care. Results: The prevalence of probable ADHD was 37.5% (n=146). Males constituted a significantly higher proportion of positive cases (69.9%) compared to females (30.1%). A strong statistical association was found between positive ADHD screening and negative academic impact (p<0.001), as well as negative effects on emotional well-being (p<0.001). Comorbidities including anxiety disorders and emotional abuse were significantly linked to probable ADHD (p=0.019). Notably, positive-screened participants were significantly more likely to cite social stigma as a primary barrier to seeking professional help (p=0.024). Conclusion: Self-reported ADHD symptoms are highly prevalent among Jordanian university students, correlating with substantial academic underachievement and emotional dysfunction. These findings highlight an urgent need for targeted university-based screening programs, academic accommodations, and de-stigmatization campaigns to facilitate early intervention and improve educational outcomes in this population.

In a single-blind randomized controlled trial, we investigated the effectiveness of real-time fMRI neurofeedback delivered in 7 runs over three sessions across two weeks in N = 65 patients with alcohol use disorder. The intervention targeted modulation of ventral striatal cue reactivity to alcohol-related cues as well as enhancement of prefrontal control mechanisms in the right inferior frontal gyrus. The study design incorporate three experimental groups that either were instructed to downregulate a ventral striatum signal, upregulate the right inferior frontal gyrus, or upregulate negative functional connectivity between these two structures. In two active control groups participants were instructed to either up- or downregulate the primary auditory cortex. We did not find an effect of ventral striatal downregulation or negative connectivity feedback, and a reduced striatal activation in the right inferior frontal gyrus upregulation group was accompanied by concurrent lower activation in the target structure, suggesting that our intended modulation approaches were not effective. Identified problems that might have contributed to this unexpected outcome might have been the use of continuous feedback presentation that potentially confuses regulation target and reward processing in the ventral striatum, counterintuitive regulation directions, a lack of explicit strategy guidance and transparency about the targeted process, and generally the difficulty to recruit a sufficient number of eligible voluntary participants for a well-powered study with a complex design. These insights emphasize the complex challenges of real-time fMRI neurofeedback interventions for the treatment of substance use disorders and could provide guidance for the development of more effective future approaches.

Background: Prior neuroimaging suggests brain differences between children with attention deficit hyperactivity disorder due to prenatal alcohol exposure (ADHD+PAE) and non-exposed children with ADHD due to other, e.g., familial, causes (ADHD-PAE). There has been interest in regional brain levels of ;gamma-aminobutyric acid (GABA) and glutamate (Glu) measured in vivo with magnetic resonance spectroscopy (MRS) as possible indicators of local inhibitory, respectively, excitatory activity in ADHD. For the first time, we report here a comparison of GABA and Glu in ADHD+PAE vs. ADHD-PAE. Methods: At 3 T, we used J-difference-edited single-voxel MRS to assay GABA and Glu in 28 children with ADHD+PAE, 20 with ADHD-PAE, and 28 typically developing (TD) controls, all aged 8-14 years. MRS was sampled from midline anterior middle cingulate cortex (aMCC), the cognitive cingulate considered functionally relevant to ADHD. Spectra were fit with custom software, including a unique technique for isolating the GABA signal from the confounding macromolecular baseline (MMBL). Results: aMCC GABA was higher in ADHD+PAE and ADHD-PAE than in TD. GABA increased with age in TD, but not in ADHD+PAE or ADHD-PAE. Similar effects were observed for the ratios GABA/Glu and GABA/Glx. For GABA+MMBL (GABA+) these effects were not seen, rather GABA+ and MMBL increased with age for the ADHD+PAE group only. No significant effects were found for Glu or Glx. Conclusions: GABA in the aMCC does not distinguish the two etiologies of ADHD, rather elevated GABA that follows an abnormal developmental appears to be common to both. High GABA may reflect increased inhibition of the aMCC impairing its cognitive functions. GABA+ results in ADHD may not tract reliably with underlying GABA values. Negative results for Glu and Glx should be reexamined at shorter echo-times.

Background Treatment guidelines for borderline personality disorder (BPD) recommend assessment, diagnosis, and psychoeducation. We report on the feasibility and safety of a randomized controlled trial protocol of online psychoeducation, assessment, and personalized feedback as an immediate first step of care for BPD. Methods Newly diagnosed participants were randomized to receive 10 videos about BPD or general mental health for two weeks. Half the participants receiving BPD videos were randomized to receive personalized feedback on changes in symptom ratings and cognitive performance. Ecological momentary assessment (EMA) evaluated interpersonal interactions, emotions, and behaviors for 30 days. BPD symptoms, depression, and personality functioning were assessed at baseline, after videos, after feedback, and one month later. Results Eighty-two participants were randomized into three conditions that did not differ significantly in terms of demographics or baseline variables. Dropout occurred for 32.9% of the sample. No differences in rate of emergency room visits, hospitalizations, or other escalations in level of care were reported among groups. Satisfaction was higher for those receiving psychoeducational videos about BPD. Improvement in BPD knowledge in the psychoeducation conditions was significantly greater than the control condition. No statistically significant differences were found regarding reduction of BPD symptoms. The psychoeducation with feedback arm showed significantly greater improvements in self-impairment compared to controls with medium effect size at the final timepoint. Modeling of the relationship between time spent alone and BPD symptoms showed a positive correlation in the control condition, but in the group receiving both psychoeducation about BPD and feedback, this relationship was negative. Conclusion Online psychoeducational videos and assessment were safe, feasible, and acceptable to participants with newly diagnosed BPD. Psychoeducation with personalized feedback appears to be more effective than either BPD or general psychoeducation alone in improving deficits in self-functioning, which may relate to an increased capacity to be alone with fewer symptoms. The protocol was registered with ClinicalTrials.gov (NCT05358925, https://clinicaltrials.gov/study/NCT05358925) on April 28th, 2022.

Background: While growing enthusiasm for the therapeutic potential of classic psychedelics has led to a rise in non-clinical use, attention to persisting adverse effects has emerged with delay. A subset of individuals reports persisting complications such as hallucinogen persisting perception disorder (HPPD), depersonalization/derealization disorder (DDD), anxiety and depression. Yet few medical services are equipped to address these complications. Aims: This qualitative study examines how societal, medical, and media discourses shape the experiences of individuals with persisting psychedelic-related complications, focusing on help-seeking trajectories. Methods: Thirteen semi-structured interviews with adults experiencing persisting psychedelic-related psychological symptoms (four women, nine men, age 19-49 years; HPPD (n = 10), DDD (n = 6), depression (n = 1), and anxiety (n = 1)) were conducted within a larger study on these complications. Data were analysed using reflexive thematic analysis. Reporting followed the COREQ guidelines. Results: Three interrelated themes emerged: (1) The dissonance between expectation and harm - idealised media and scientific portrayals of psychedelics shaped initial use and complicated recognition of adverse outcomes; (2) Stigma, silence, and self-blame - prohibitionist discourse and internalised shame significantly inhibited help-seeking; and (3) Between systemic absence and self-organised support - participants encountered clinical unpreparedness and epistemic dismissal, which often led them to rely on online peer communities and self-management strategies. Positive clinical encounters, characterised by professional expertise and nonjudgmental engagement, were experienced as helpful. Conclusions: Adequate clinical and conceptual frameworks for persisting psychedelic-related complications are lacking. An interdisciplinary, experience-informed approach integrating realistic risk communication, clinician training, and destigmatisation is required to support affected individuals.

Objective: Biopsychosocial models recognize multiple determinants of post-trauma mental disorders, but their relative and interactive effects remain unclear. We quantified the independent contribution of traumatic event severity, preexisting vulnerability, social support, and coping capacity, and tested mediation pathways. Methods: In a Brazilian clinical sample reporting traumatic or stressful events (N = 612), constructs were operationalized as composite scores and a dichotomous clinical outcome was derived from intake assessments. Logistic regression (n = 594) and structural equation modeling evaluated prediction and mediation. Results: Vulnerability was the strongest risk factor (OR = 1.46, p < .001) and social support the main protective factor (OR = 0.60, p < .001). Traumatic event severity remained an independent predictor (OR = 1.39, p < .001), whereas coping capacity was not significant (OR = 0.94, p = .410). Discrimination was good (AUC = 0.80). Mediation indicated vulnerability reduced social support and coping capacity, with a significant indirect effect via social support. Conclusions: Findings support a multifactorial model centered on a triad of vulnerability, social support, and traumatic exposure. Risk is shaped primarily by preexisting vulnerability and relational context, alongside a direct trauma effect, providing a clinically relevant framework for assessment and intervention.

Aim: To determine whether the neural phenotype (whole-brain resting-state functional connectivity pattern) of attention deficit hyperactivity disorder associated with prenatal alcohol exposure (ADHD+PAE) differs from that in unexposed children with ADHD of probable familial origin (ADHD-PAE). Method: Resting-state functional MRI was acquired from 26 children with ADHD+PAE, 25 with ADHD-PAE, and 25 typically developing (TD) children, all aged 8-13 years. Mean connectivity matrices based on the Cole-Anticevic Brainwide Network Parcellation of the brain were compared between the groups. Results: Within the frontoparietal network (FPN), children with ADHD+PAE showed widespread lower group-mean connectivity than children with ADHD-PAE; effects were concentrated primarily in cerebellar-cerebral cortical and cerebral cortical-cerebral cortical connections. Children with ADHD-PAE showed widespread hyperconnectivity relative to TD children. Children with ADHD+PAE showed mixed hyper- and hypoconnectivity relative to TD. Interpretation: These results are consistent with other MRI findings indicating that ADHD+PAE is neurally distinct from ADHD-PAE; PAE may be associated with broadly reduced connectivity, especially across cerebellar-cerebral cortical systems.

Forensic patients often have complex and costly healthcare needs, even following discharge from secure care. However, little is known about their health and justice outcomes after community reintegration. To address this gap in the literature, we conducted a systematic review and meta-analysis to estimate the incidence of key post-discharge outcomes among community-discharged forensic patients, including any reoffending, violent reoffending, reconvictions, readmissions, all-cause mortality, and suicide. We systematically searched PsycINFO, Embase, CINAHL, Medline, PubMed, and ProQuest Dissertations from database inception to May 2025 (PROSPERO CRD42024529265). Random-effect meta-analyses were used to generate pooled incidence estimates, with heterogeneity quantified using prediction intervals. A total of 49 studies met inclusion criteria (total patient n = 18,871) and contributed to the meta-analyses. The pooled incidence rate per 100,000 person-years was: any reoffending 3,889 (95% CI 2,055, 7,359; 95% PI 290, 52,136); violent reoffending 1,851 (95% CI 1,229, 2,789; 95% PI 201, 17,068); reconvictions 3,291 (95% CI 2,591, 4,179; 95% PI 950, 11,394); readmissions 7,945 (95% CI 5,507, 11,463; 95% PI 1,225, 51,548); all-cause mortality 1,789 (95% CI 1,341, 2,388; 95% PI 673, 4,756); and suicide 407 (95% CI 319, 519; 95% PI 225, 735). Overall, the reoffending rate for forensic patients discharged to the community was lower than that reported for other cohorts of people charged with general and violent offences. However, despite typically receiving long admission periods, discharged forensic patients continue to experience high rates of readmission, all-cause mortality, and suicide relative to other psychiatric patient groups in the community. Together, our findings highlight a need for enhanced post-discharge suicide support for forensic patients living in the community to better facilitate successful, long-term reintegration.

Background: Sleep debt and irregular sleep patterns are highly prevalent amongst adolescents. However, whether the absence of these sleep behaviours protects against subsequent depression remains unclear. Here, we examined the association of sleep debt, weekend catch-up sleep (WCS), and social jetlag (SJL) in adolescence with depression in young adulthood and identified underlying biopsychosocial mechanisms. Methods: Secondary data analyses were conducted using the Avon Longitudinal Study of Parents and Children. Bedtimes and wake-up times on school days and weekends (i.e., sleep duration) and sleep need were self-reported at 15 years. This was used to generate sleep debt (sleep need minus school day sleep duration), WCS (weekend sleep duration minus school day sleep duration), and SJL (absolute difference in the midpoint of sleep times between school days and weekends). Depression was assessed at 24 years with the Clinical Interview Schedule-Revised. Common mental health symptoms, biological, and school-related factors at 17 years were the mediators. Results: Logistic regression analyses revealed that greater WCS (adjusted odds ratio [AOR]=0.90; 95% CI=0.84-0.97; p=0.004) and lower sleep debt (AOR=1.10; 95% confidence interval [CI]=1.03-1.18; p=0.005) at age 15 reduced the likelihood of depression at 24 years. Irritability at 17 years partially mediated the relationship between sleep debt and depression (bias-corrected estimate=0.003; 95% CI=0.002-0.004; p<0.001). Conclusions: Adolescents who experience less sleep debt (i.e., less discrepancies between their actual sleep and their perceived sleep need) and those who extend their sleep duration on weekends are at reduced risk for depression in young adulthood. These findings underscore the need for greater opportunities for adolescents to obtain more hours of sleep to protect them against later poor mental health outcomes, such as depression. Keywords: Sleep; longitudinal studies; depression; ALSPAC

Background: Individuals with mild cognitive impairment (MCI) experience cognitive and functional declines that can negatively impact mood and reduce feelings of self-efficacy. These changes can also lead to elevated distress in care partners (CPs). Therefore, interventions that address quality of life and psychosocial factors in people with MCI and their CPs are needed. Objective: The present study evaluated the impact of a multidomain lifestyle program, the Cognitive Empowerment Program (CEP), on changes in psychosocial functioning, particularly empowerment, in people with MCI and their CPs. Methods: Participants were 94 people with MCI (Mean= 75.1 years old, 45.7% female, 81.9% white) and their CPs (Mean= 69.1 years old, 71.3% female, 87.3% white) that completed the 12-month CEP program comprised of physical, cognitive, and psychosocial interventions. Questionnaires were administered pre- and post-program to assess empowerment, self-efficacy, meaning and purpose, depression, and stress in participants with MCI alongside empowerment, depression, stress, and caregiving burden in CPs. Results: After completing the CEP program, participants with MCI endorsed higher empowerment and self-efficacy as well as fewer symptoms of depression and perceived stress. CPs endorsed feeling more empowered despite elevated caregiver burden. Conclusions: These results suggest multidomain lifestyle programs can positively impact wellbeing in MCI. Future research should focus on refining delivery models, exploring integration with pharmacological treatments, prioritizing inclusion of diverse populations, and measuring long-term outcomes to strengthen the reach and impact of programs like CEP.

In some countries, melatonin is sold without a physician prescription and dosage is unregulated. Transdermal products have become popular including those marketed for children. We measured consumer assumptions about these products among adult residents of the United States, analyzed lot-to-lot variability, and compared the pharmacokinetics of melatonin administered in oral, lotion, and bath product forms. Survey respondents (n=199) believed oral melatonin was more effective than transdermal products and that all melatonin products were relatively safe. Melatonin lotion products analyzed by HPLC displayed lot-to-lot variability as well as changes in formulation and product claims. To determine pharmacokinetics, three different treatments (oral tablets, lotion, and bath immersion) were administered to twelve undergraduate participants in a randomized, crossover design. Five additional participants completed bath product treatment only. Participants collected saliva samples up to 48 hours after administration, which were analyzed for melatonin by enzyme-linked immunosorbent assay. Oral (n=11) and lotion formulations (n=12) caused maximum salivary melatonin levels within 30 minutes after administration, but bath immersion did not cause increases in saliva melatonin (n=17). The half-life of oral melatonin was 1.17 [0.69 -- 1.65] hours versus 5.72 [3.75 -- 7.68] hours for lotion treatment (p = 0.011, effect size r = 0.770). Melatonin lotion may pose a risk to consumers who assume it is safe and less effective than oral tablets, when in fact it may be very potent and remain at high physiological levels into the following day. This study is registered on clinicaltrials.gov (NCT06382610) and was funded by the Sleep Research Society.

ABSTRACT Background: Self medication with analgesics and non steroidal anti inflammatory drugs (NSAIDs) is common in low- and middle income countries and may expose users to preventable adverse outcomes. Evidence from Guinea remains scarce. This study aimed to estimate the prevalence of self medication with analgesics and NSAIDs among pharmacy clients in urban Conakry, identify associated factors, and describe clinical risk situations. Methods: We conducted a pharmacy based analytical cross sectional study in 30 private pharmacies across Conakry, Guinea. A total of 1,032 participants seeking analgesics or NSAIDs were enrolled between November 3, 2012, and April 5, 2013. Self-medication was defined as acquisition or use without a valid medical prescription. Factors associated with self-medication were analysed using multivariable logistic regression. Results: Among 1,032 participants, 603 reported self medication (prevalence 58.4%). Previous unsupervised use was reported by 78.7%. The most frequently used medicines were paracetamol (56.9%, n=587), diclofenac (21.3%, n=220), ibuprofen (17.9%, n=185), and aspirin (3.9%, n=40). Overall, 68.0% (n=702) reported no knowledge of potential adverse effects. Clinical risk situations were frequent: gastrointestinal disorders (41.3%, n=426), hypertension (9.2%, n=95), and pregnancy exposure among reproductive age women (26.0%). In multivariable analysis, self medication was independently associated with previous analgesic/NSAID use (aOR = 2.8, 95% CI: 2.1 to 3.6), lack of knowledge of adverse effects (aOR = 1.9, 95% CI: 1.4 to 2.5), informal occupation (aOR = 1.6, 95% CI: 1.2 to 2.2), and age 18 to 59 years (aOR = 1.5, 95% CI: 1.1 to 2.1). Conclusions: In this pharmacy based study conducted in urban Conakry, self medication with analgesics and NSAIDs was common and frequently associated with limited awareness of potential adverse effects. These findings support the need for strengthened pharmaceutical regulation, pharmacist-led counselling, health literacy interventions, and improved access to primary care. Keywords: self medication; analgesics; NSAIDs; paracetamol; diclofenac; ibuprofen; pharmacy; Guinea; Conakry; drug safety; public health.

Aims. The risk of cognitive decline after losing a spouse remained mixed. This study aims to investigate the association between spousal loss and risk of cognitive decline, assess whether this association varies by sex and age, and identify modifiable factors. Methods. We conducted a prospective cohort study using harmonized data from six population-based aging surveys: the US Health and Retirement Study and its sister surveys in England, Mexico, China, India, and South Africa, incorporating their respective Harmonized Cognitive Assessment Protocol (HCAP) sub-studies. Spousal loss (yes vs no) was the exposure. Cognitive outcomes (i.e., orientation, memory, executive function, and language), were assessed using HCAP neuropsychological batteries. We conducted parallel analyses in six cohorts. Associations between spousal loss and cognitive outcomes were estimated using generalized linear models, and summarised estimates were derived via random-effects meta-analyses. Sex stratification and restricted cubic spines were used to examine how these associations vary by sex and age, respectively. Results. The analytical cohort consisted of 18,551 individuals aged 61.22 (SD 6.30) to 71.37 (SD 7.33) years. Widowhood prevalence ranged from 14.1% in CHARLS to 53.9% in HAALSI and was consistently higher in women. Spousal loss was associated with poorer memory (multivariable-adjusted {beta} = -0.07, 95% CI -0.12 to -0.01) and executive function (multivariable-adjusted {beta} = -0.08, 95% CI -0.13 to -0.03) in the meta-analysis, with no significant associations for orientation or language. While results were generally consistent in five cohorts, the ELSA showed divergent patterns (orientation: {beta} = 0.10, 95% CI 0.06 to 0.13; memory: {beta} = 0.05, 95% CI 0.02 to 0.08; language: {beta} = 0.16, 95% CI 0.12 to 0.19). Sex-stratified analyses indicated poorer executive function among men (multivariable-adjusted {beta} = -0.14, 95% CI -0.19 to -0.08) and poorer memory among women (multivariable-adjusted {beta} = -0.07, 95% CI -0.14 to -0.01) following widowhood. Nonlinear age-related effects on cognition were observed in ELSA, LASI, and HAALSI. Higher education, internet use, and BMI were negatively associated with the risk of cognitive decline among widowed participants. Conclusions. Spousal loss is associated with domain- and sex-specific differences in cognitive performance, with substantial heterogeneity across study populations. Future research should integrate biopsychosocial markers to develop context-sensitive interventions for widowed older adults.

Abstract Schizophrenia (SCZ) and bipolar disorder (BPD) are highly heritable psychiatric disorders with complex polygenic architectures. Genome-wide association studies (GWASs) have identified numerous common variant associations, but rarer variants detectable through whole-genome sequencing (WGS) remain underexplored. We conducted rare variant association analysis using WGS data from the Portuguese Island Collection (PIC), including 28 families with SCZ (n = 53) and 41 families with BPD (n = 83) cases, and population controls (n = 62). Following ANNOVAR and CADD annotation, burden analysis of deleterious variants showed that both affected and unaffected family members from SCZ and BPD pedigrees had significantly higher burdens of rare deleterious variants compared to controls (p < 0.0001), with no significant differences observed between affected and unaffected relatives, consistent with shared familial genetic liability. Polygenic Risk Score (PRS) analysis confirmed significant genetic contributions to both disorders within PIC. Association analyses were subsequently performed using SAIGE-GENE+ identifying 483 and 583 nominally significant (suggestive associations) gene sets (p-value [&le;] 0.05; FDR > 0.05) for SCZ and BPD, respectively, including gene sets related to neurotransmission, synaptic function and structure, neurodevelopment, and neuroinflammation as well as major signaling pathways. Cross disorder overlaps also identified shared suggestive enrichment of GABA and glutamate signaling, synaptic signaling, and Wnt signaling gene sets in both SCZ and BPD. These findings support shared rare variant burden within multiplex psychiatric families and highlight the role of gene-set based rare variant analysis in identifying neurobiological pathways relevant to SCZ and BPD. Keywords: WGS, Rare Variants, Schizophrenia, Bipolar Disorder

Background: Adverse childhood experiences (ACEs) are traumatic or adverse events in early life that can have lasting effects on behavioral, emotional, and psychological functioning. Prior research suggests ACEs relate to later psychiatric outcomes through threshold, cumulative, and individual-specific risk patterns. Few studies, however, have operationalized all three models to test ACE-specific associations with diagnosed psychiatric disorders in individuals who are adopted or with foster care histories. Methods: We conducted a cross-sectional retrospective study using electronic health record data from foster care and adopted patients aged 0-21 years old seen at the University of Minnesota Adoption Medicine Clinic (UMN-AMC) between 2014-2024. Extracted measures included ACE history, demographics, and psychiatric diagnoses. We used latent class analysis and logistic regression to identify clusters of adversity and estimate associations with psychiatric diagnosis domains, adjusting for Sex and Age at Initial Visit. Results: ACEs showed a threshold pattern across psychiatric domains, with higher ACE counts associated with greater odds of psychiatric diagnoses. Individual risk modeling indicated that exposure to abuse or violence was associated with higher odds of psychiatric diagnoses. Across cumulative and individual risk approaches, Anxiety Disorders, Mood Disorders, and Behavioral or Emotional Disorders showed the greatest sensitivity to adversity. Conclusion: Current ACE models may not fully capture neurodevelopmental impacts reflected in diagnosed psychiatric disorders among adolescents, particularly in high-risk groups such as foster and adopted individuals. In a large clinic sample our findings support a nuanced association between ACEs and later psychiatric diagnoses and highlight the need for ACE-focused assessment, prevention, and treatment strategies tailored to foster care and adopted populations.

Background: Cannabis use is highly prevalent among emerging adults (18-25 years), a developmental period marked by ongoing neurodevelopment and heightened risk for cannabis use disorder (CUD). Structural alterations in the orbitofrontal cortex (OFC) and medial prefrontal/anterior cingulate cortex (mPFC/ACC) have been linked to cannabis use, though findings remain inconsistent in directionality. To address this, we examined cortical thickness and surface area of the OFC and mPFC/ACC subregions using the high-resolution Glasser atlas, allowing for more granular characterization of associations with CUD severity. Method: One hundred eleven emerging adults (41% male, aged=20.6{+/-}1.1 years) reporting significant alcohol and/or cannabis use completed clinical assessments and structural MRI. The OFC and mPFC/ACC were segmented into seven and six subregions per hemisphere, respectively. Multiple linear regressions tested associations between cortical thickness or surface area and DSM-5 CUD symptom count, controlling for alcohol use and intracranial volume. Subregions surviving false discovery rate correction were examined in relation to depression, trauma-related symptoms, impulsivity, and cannabis use motives. Results: Greater CUD severity was associated with lower cortical surface area and greater cortical thickness in OFC and mPFC/ACC subregions. Lower OFC surface area was correlated with coping- and enhancement-related cannabis use motives. Lower mPFC/ACC surface area and greater thickness were associated with more severe depression, trauma-related symptoms, and impulsivity. Conclusion: In high-risk emerging adults, greater CUD symptom burden is associated with lower surface area and greater thickness in OFC and mPFC/ACC subregions. Using the high-resolution Glasser atlas, these findings provide a more precise characterization of structural correlates of CUD and highlight potential neurobiological markers linked to affective and motivational processes underlying cannabis use.

Background. Something in discourse with a person experiencing psychosis often "feels off" before formal assessment is completed, yet this disturbance has not been quantified at the level of ongoing dyadic conversation. Prior work has largely treated patient speech in isolation, limiting our capacity to measure how communicative disruption emerges within clinical exchange. Methods. We applied a three-level decomposition of conversational alignment in 109 patients with psychotic disorders (26 female) and 60 healthy controls (22 female) at baseline and 12 months (n = 115). Register divergence (dAUCnorm) captured lexical distance between interviewer and patient; embedding-based synchrony (rembed) measured semantic trajectory coupling; within-speaker coherence was computed separately for each speaker. We used linear mixed-effects models adjusted for timepoint and participant clustering. Results. Patients showed significantly greater lexical-semantic divergence from the interviewer (d = 0.48, p < .001) and reduced embedding-based synchrony (d = -0.59, p < .001), both effects replicating at each time point. Critically, the interviewer's within-speaker coherence was reduced during conversations with patients (d = -0.33, p = .016), indicating that the disruption extends beyond the patient to the interaction itself. Register divergence tracked impoverished thinking and synchrony tracked disorganized thinking (both FDR-corrected q = .038). Group differences were persistent at 12 months, indicating a partially stable profile. Conclusions. Conversational alignment in psychosis reveals a dyadic failure of semantic coordination that destabilizes the interviewing clinician's coherence even when patient narrative continuity is preserved. These transcript-derived alignment metrics offer a scalable approach to quantifying interpersonal communicative function from routine clinical encounters.