Psychopharmacology

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: 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.

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.

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: 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 and Aims: Synthetic opioids cause tens of thousands of deaths each year in North America, and there are indications that synthetic opioids are also becoming increasingly prevalent in the European drug market. This study aimed to examine high-risk substance use in the German drug-using community with a particular focus on the synthetic opioids fentanyl and nitazenes and related awareness, concerns, overdose experiences, and harm-reduction behavior. Design: Cross-sectional, observational online survey. Setting: Open drug-use scenes, addiction clinics, and substitution practices at numerous geographic locations throughout Germany, August to September 2025. Participants: 235 individuals aged 14+ from the drug using community (mean age 43.4 years; 57.9% male), 79.6% recruited by peers in open drug-use scenes. Measurements: The primary outcome was substances used within the past 12 months. In addition, sources, forms, routes of administration, and perceived changes in availability and price of (synthetic) opioids were assessed as well as risk perceptions, fears, harm-reduction behavior, and overdose-related experiences. Findings: 227 respondents reported substance use with an average of 6.2 substances, and 73.1% (95% confidence interval [CI] = 67.0-78.5%) had used at least one opioid in the past year. Synthetic opioids were consumed in many parts of Germany and across all age and gender groups. Among participants who experienced a shortage of their primary opioid in the past year, 25% (95% CI = 15.8-37.2%) reported having used fentanyl instead. 56.5% (95% CI = 36.8-74.3%) of individuals using synthetic opioids reported having experienced an overdose in the past twelve months. Most of the respondents perceived synthetic opioids as posing a high risk, and a substantial proportion expressed fear that they could be mixed into their own substances. However, only 9.9% (95% CI = 6.6-14.7%) use drug checking, although the vast majority stated they would use it if it were available to them. Conclusions: Synthetic opioids, including fentanyl and nitazenes, have entered the German drug scene, with users reporting high rates of overdose and limited access to harm reduction measures. Germany may be in an early phase of a synthetic opioid transition, warranting urgent expansion of surveillance, naloxone distribution, and drug checking services.

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.

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: 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: Prenatal substance exposure (PSE) occurs when an individual is exposed to substances in utero. PSEs may have lasting effects on mental health. We tested whether PSEs show threshold, cumulative, or individual substance associations with childhood psychiatric diagnoses. Methods: Clinical variables (demographics, ICD-9/10 diagnoses, PSE history) were extracted from electronic health records from the University of Minnesota Adoption Medicine Clinic. PSEs were identified from caregiver and child-protective-services narratives and/or toxicology (cord tissue/blood, meconium). For each ICD-9/10 diagnostic category, we fit logistic regression models comparing (1) exposure thresholds (0, 1, 2, 3, 4+ exposures), (2) a cumulative exposure count, and (3) individual substances to estimate marginal odds ratios (ORs) with 95% Confidence Intervals (CIs). Results: Psychiatric diagnoses increased with the number of PSEs. Relative to no exposure, odds of an Anxiety Disorder rose from OR 1.47 (95% CI 1.16-1.87) with one exposure to OR 2.03 (1.64-2.52) with >=4 exposures. Higher cumulative exposure scores were associated with Anxiety Disorders (OR 1.28, 1.18-1.38), Behavioral and Emotional Disorders (OR 1.42, 1.31-1.54), Substance Use Disorders (OR 1.52, 1.29-1.79), and Mood Disorders (OR 1.16, 1.04-1.30). Alcohol, tobacco, and marijuana exposures were associated with increased odds of at least one psychiatric diagnosis, and each substance showed at least one significant diagnostic cluster when modeled independently. Conclusion: Increasing numbers of PSEs were associated with higher odds of psychiatric diagnoses, with patterns varying by substance and outcome. These findings motivate research on exposure timing and combinations to support earlier identification and intervention for at-risk children.

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.

Amitriptyline is commonly prescribed for chronic pain, yet treatment response and tolerability vary substantially. Genetic variation in CYP2C19 and CYP2D6 influences amitriptyline metabolism, but evidence linking pharmacogene status to clinical outcomes in chronic pain is limited. Amitriptyline is typically prescribed for chronic pain at lower doses than for depression, which may reduce pharmacogenomic effects on clinical outcomes. We analysed 1,146 participants with chronic pain from the Australian Genetics of Depression Study who reported amitriptyline use, treatment outcomes, and genotype data. Metaboliser phenotypes were assigned using PharmCAT. Associations with self-reported effectiveness and discontinuation due to side effects were examined using regression models adjusted for age and sex. Only CYP2C19 intermediate metabolisers showed nominally lower odds of discontinuation and reduced likelihood of reporting moderate effectiveness. Overall, pharmacogenetic phenotypes were not significantly associated with patient-reported amitriptyline outcomes in chronic pain, potentially reflecting the lower doses typically prescribed for pain management.

Background: Psychedelics are emerging as potential management options for chronic musculoskeletal pain due to preliminary evidence of effectiveness and low addictive potential, but patients perceptions remain unknown. This study assessed patient perceptions regarding psilocybin for musculoskeletal pain. Methods: We conducted a cross-sectional survey of adults ([&ge;]19) with musculoskeletal pain attending a hospital-based orthopaedic clinic. Participants reported demographics, perceptions of psychedelics for pain management, and willingness to participate in psychedelic research. Multivariable regression explored factors associated with perceived analgesic potential, and willingness to try a full therapeutic dose of psilocybin or a microdose. Results: Among 295 participants, 73% reported moderate-to-severe pain; 75% used analgesics; of these, 41% used opioids (86/209). While 24% reported prior psychedelic use, only 3% had discussed psychedelics with a healthcare provider. Most perceived that psilocybin had moderate-to-high effectiveness for pain (76%). Most respondents endorsed a moderate-to-high willingness to try microdoses (58%) and macrodoses (53%) of psilocybin for pain. Prior non-therapeutic psychedelic use predicted a 1.05-unit increase in perceived analgesic potential on the 10-point scale (p=.013). Willingness to try a macrodose of psilocybin was most strongly associated with prior non-therapeutic (B=3.16) and therapeutic (B=2.42) psychedelic use; in contrast, pain severity had a significant but modest association, with a 0.21-point increase in willingness for every 1-unit increase in pain severity (p=.017). Similarly, willingness to try a microdose of psilocybin was predicted by non-therapeutic (B=2.82) and therapeutic (B=2.48) use, whereas the effects of pain severity (B=0.20) and younger age (B=-0.30) were significant but small. Most respondents (52%) reported moderate-to-high willingness to participate in a trial of psilocybin for pain relief, and health risks were the primary concern (33%). Conclusions: Study findings suggest a majority hold neutral-to-positive perceptions of psilocybin for pain. Addressing perceived barriers, including health effects and gaps in patient knowledge, should be considered when designing future trials.

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.

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.

Background: Conventional psychiatric screening instruments summarize symptoms within individual scales and prioritize cases with high single-instrument additive score severity. This design treats items as independent within instruments and ignores cross-instrument covariance structure, making it insensitive to respondents whose responses are distributed across multiple domains in unusual combinations that remain below threshold on every individual scale. Methods: We analyzed two cohorts spanning older and younger adults. Item prompts from depression, stress, anxiety, and sleep instruments were embedded into a shared semantic space using a pretrained sentence encoder. Principal component analysis of the item-prompt embeddings alone---with no use of respondent data at this stage---was used to construct a low-dimensional subspace retaining 80\% of variance in the item embedding matrix. Normalized participant responses were then projected into this subspace, with Jaccard-based stability analysis used as a check on dimensional robustness. Multivariate deviation from the cohort norm was quantified with Mahalanobis distance using Ledoit-Wolf covariance regularization. Candidate outliers were defined by the empirical 95th percentile of the cohort-specific distance distribution. To isolate response configurations not already captured by conventional single-instrument extreme-value logic, we excluded all outlier respondents who had endorsed any individual item at the maximum value of its Likert scale on any instrument. For the remaining outliers, anomalous components were backtracked to their original item loadings for interpretation. Results: In the older-adult Health and Retirement Study (HRS) cohort, principal component analysis of 27 item-prompt embeddings showed that a 10-dimensional subspace provided a stable representation of cross-instrument semantic structure. In the younger-adult Xinxiang cohort the corresponding stable solution was 16-dimensional. In each cohort, seven respondents remained as multivariate outliers despite falling below every single-instrument extreme-value threshold. These cases were not characterized by uniformly severe symptom scores but by unusual cross-domain response configurations that became visible only in the shared semantic covariance subspace. The response structure of the retained configurations differed across cohorts: older-adult cases more often involved weak endorsement of mood-labeled items alongside nonzero body- and sleep-related responses, whereas younger-adult cases more often involved incomplete response configurations spanning mood, sleep, stress, and self-harm-related items. Conclusions: A semantically aligned, auditable covariance subspace provides a practical tool for flagging unusual multivariate response configurations that single-instrument additive screening may not flag. The method is interpretable at the level of original item contributions. It should be understood as a hypothesis-generating screen for unusual response configurations requiring further clinical assessment, not as a diagnostic instrument. Outcome validity remains to be established by prospective study.

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.

Background Atrial fibrillation (AF) is a leading cause of stroke, cardiovascular morbidity, and mortality. Atrial myopathy, characterized by progressive metabolic, electrical, and structural changes, creates the arrhythmogenic substrate that drives AF. Defining the key drivers of atrial myopathic processes is essential for targeted therapies that can mitigate AF progression. Here we explore how reduced ERBB4 expression contributes to the development of left atrial myopathy. Methods We analyzed the Cleveland Clinic Biobank to compare left atrial ERBB4 levels in patients grouped by AF diagnosis. To investigate the impact of reduced ERBB4 levels on atrial tissue substrate, we created mouse models of cardiac-specific Erbb4 deficiency using Mlc2a (myosin light chain 2a)-Cre. Comprehensive physiological assessments were performed. Transcriptomic analyses of the left atrium were performed in an Erbb4 haploinsufficient mouse model and compared with human atrial datasets. Molecular validation of key dysregulated pathways was performed. Results We found that left atrial ERBB4 levels are reduced in patients with AF. Adult cardiomyocyte-specific Erbb4 heterozygous (Erbb4fl/+;Mlc2a-Cre) mice exhibited prolonged P-wave duration in the absence of ventricular dysfunction. Left atrial transcriptomic analysis in Erbb4 haploinsufficient mice showed upregulation of pathways related to fibrosis, apoptosis, and coagulation, and downregulation of pathways related to fatty acid metabolism and mitochondrial function, mirroring changes observed in pressure overload mouse models. A cross-species transcriptomic comparison revealed significant overlap between ERBB4-correlated gene expression and functional pathways in adult human atria and mice with Erbb4 haploinsufficiency. Validating the transcriptomic data, protein and functional assays demonstrated increased fibrosis, apoptosis, and oxidative stress in the mutant left atrial tissue. Conclusion Left atrial ERBB4 levels are reduced in AF patients. A mouse model of Erbb4 deficiency and human atrial transcriptomic analyses highlight a role for ERBB4 in supporting normal atrial metabolism while protecting against inflammation, apoptosis, and fibrosis.

Patients with primary immunodeficiency (PID) often face prolonged diagnostic delays and may increasingly turn to large language models (LLMs) to interpret their symptoms during this period. We evaluated whether an LLM could recognize PID from symptom descriptions derived from interviews with 21 PID patients. In a prior study, we showed that GPT-4o identified PID in 96% of cases when prompted with physician-written patient histories (Rider et al., JACI, 2024). Here, when prompted with symptom descriptions in patients' own words, GPT-5 identified PID in only 7 cases (33%), although it more broadly suggested immune system issues in 18 cases (81%). The gap between these findings indicates that LLMs are sensitive to the language and framing of symptom descriptions, performing substantially worse when patients describe their own symptoms in everyday language than when clinicians summarize patient histories in structured medical terms. This study underscores the need to carefully evaluate how LLMs are used in patient-facing applications.