Translational Psychiatry最新文献

This study aims to investigate the roles of decision-making processes and genetics in the co-occurrence of alcohol use and suicidal thoughts/behaviors (STB) in adolescence. We used data from the ABCD^® study (abcdstudy.org) and included behavioral (computerized tasks, self-report questionnaires) and genetic (polygenic scores [PGS]) measures related to cognitive (executive functions) and affective (delay-discounting, risk-taking, impulsivity) processes involved in decision-making. First, we evaluated the latent structure of decision-making in the full sample (N = 11,868) using a split-half exploratory and confirmatory factor analysis. Second, we evaluated the association between alcohol experimentation ( > 1 sip) and STB in three genetically-defined ancestry groups: European (EUR, N = 6080), African (AFR, N = 2085), and the Americas (AMR, N = 2712). We used logistic regressions to examine which PGS and behavioral factors were related to STB and tested the mediational effect of behavioral processes. STB prevalence was between 0.85-4.17%. Decision-making was best represented by three latent factors: cognitive, emotional-impulsivity, and premeditation-perseverance. Regression analyses showed that alcohol experimentation was related to STB in EUR only (OR = 1.44, 95%CI = 1.10;1.89). Lower tendencies on the emotional-impulsivity factor were related to lower STB in all groups (ORs 0.69-0.77), and better premeditation-perseverance were associated with lower STB in EUR (OR = 0.57) and AFR (OR = 0.72). In EUR, the association between alcohol experimentation and STB was mediated by the emotional-impulsivity (15.33%) and premeditation-perseverance (22.60%) latent factors. The associations between PGS for externalizing behaviors and STB also acted through the emotional impulsivity and perseverance-premeditation factors (mediations 6.98-10.30%). These findings suggest that decision-making-related processes may contribute to the alcohol use-STB co-occurrence.

There is an important need to advance medication development for alcohol use disorder (AUD). BP1.3656B, a highly potent and selective histamine H3 receptor inverse agonist/antagonist, has been developed. Preclinical studies revealed high affinity, good pharmacokinetic profile, good brain penetration, and favorable safety. BP1.3656B reduced alcohol drinking and alcohol-seeking behavior in rodents. Phase I studies revealed good tolerability/pharmacokinetic in humans. Positron emission tomography revealed high brain occupancy in humans. Based on this favorable profile, two trials were conducted in subjects with AUD. In non-treatment seekers, BP1.3656B had no impact on intravenous alcohol self-administration (IV-ASA). A randomized clinical trial testing three doses of BP1.3656B versus placebo in treatment-seekers with AUD showed no reduction of heavy drinking days. Collective results illustrate the challenges inherent to clinical translation of AUD therapies, and reinforce the use of Phase IIa human laboratory paradigms as an important tool to de-risk translation of innovative drug targets for AUD.

Major depressive disorder (MDD) remains a leading cause of disability worldwide, with current treatments limited by delayed onset and low efficacy. The serotonergic psychedelic N,N-dimethyltryptamine (DMT) has shown rapid antidepressant effects in early clinical studies, yet its mechanisms and efficacy remain poorly characterized in established models of depression. Here, we evaluated the effects of a single dose of DMT (30 mg/kg, i.p.) in male mice exposed to the Chronic Unpredictable Mild Stress (UCMS) paradigm, a robust mouse model recapitulating key features of MDD, including anhedonia and cognitive impairment. DMT administered after UCMS reversed depressive-like behavior and restored cognitive performance, outperforming chronic fluoxetine across most domains. When administered during the stress period, DMT mitigated anhedonic responses but did not rescue cognitive deficits, suggesting a long-lasting domain-specific efficacy. Exploratory assessments in anesthetized animals showed that DMT's behavioral and cellular benefits persisted under isoflurane, though the role of the psychedelic experience remains uncertain due to potential confounding effects of isoflurane not controlled for in our design. Histological analyses revealed that all DMT regimes significantly increased adult-born granule cell (abGC) integration and reduced the number of ectopically abnormally integrated abGCs. Together, our findings highlight the robust and multifaceted effects of DMT on behavior and neurogenesis, positioning it as a promising candidate for rapid-acting antidepressant strategies that target structural circuit repair.

Only a minority of alcohol users develop alcohol use disorder (AUD), and the extent to which vulnerability to this condition depends on sex remains insufficiently explored in preclinical research. Using an established model that reverse-translates key diagnostic criteria for AUD, we investigated this question in male and female rats. Criteria for addiction-like behavior assessed were: (i) the inability to refrain from alcohol-seeking, (ii) high motivation for alcohol, and (iii) continued alcohol use despite negative consequences, assessed using footshock punishment. We found that a larger proportion of females (12.90%) met all three criteria compared to males (6.45%). Sex-differences observed were independent of alcohol consumption history, footshock sensitivity, or basal anxiety levels. Factor analysis results support the existence of both shared and sex-specific behavioral dimensions underlying addiction vulnerability. Notably, while persistence in alcohol-seeking and motivation loaded similarly onto "Factor 1" in both sexes, resistance to punishment showed opposite loadings on "Factor 3" in males and females. Moreover, this factor was differentially correlated with the global addiction score across sexes, indicating that this behavioral dimension may contribute differently to addiction-like behaviors in males and females. Notably, impulsivity was strongly correlated with the number of addiction-like criteria in both male and female rats, underscoring its broad role in shaping the risk. In contrast, neither anxiety-like behavior, locomotor activity in a novel environment, nor social dominance were predictors of addiction-like behaviors. These results emphasize the need for sex-specific approaches in AUD research, revealing complex behavioral traits that influence addiction risk.

Approach-avoidance conflict (AAC), a laboratory representation of risky foraging, serves as mainstay of pre-clinical anxiety disorder research, motivated by an impact of anxiolytic drugs on cautious behaviour. While cautiousness appears to be a stable behavioural trait, growing evidence suggests that it is not strongly related to self-reported anxiety. Here, we ask more broadly which psychiatric symptom dimensions relate to AAC behaviour, using a cross-sectional, data-driven, exploration-confirmation approach across two large online samples (N1 = 315; N2 = 690). In a previously validated task, participants chose whether, and when, to approach rewards under varying threat probability and magnitude. They then completed a comprehensive psychiatric questionnaire battery with a known three-factor structure. A broad psychopathology factor, mainly related to impulsivity and OCD symptoms and not specifically linked with anxiety, showed the strongest relation to all behavioural readouts. Higher symptom scores related to decreased passive avoidance, increased behavioural inhibition, and reduced sensitivity to threat features. This factor was also associated with an altered subjective model of threat and reward relations in the environment. Broad and unspecific associations with same directional patterns but smaller magnitudes were found between individual questionnaire scores and behaviour, underscoring the status of transdiagnostic dimensions. Crucially, no associations were found between behaviour and transdiagnostic anxiety-depression, or with gender. This study highlights that cautiousness in AAC tasks is comprised of two components, which are independently associated with transdiagnostic psychopathology but not specifically or particularly strongly with self-reported trait anxiety. Our cross-sectional findings underline the complex interplay of behavioural predispositions and psychopathology.

Depression is a prevalent mental health condition that frequently remains undiagnosed, highlighting the need for objective and scalable screening tools. Heart rate variability (HRV) has emerged as a potential physiological marker of depression, and facial video-based HRV measurement offers a novel, contactless approach that could facilitate widespread, non-invasive depression screening. We analyzed data from 1453 individuals who completed facial video recordings and the Patient Health Questionnaire-9 (PHQ-9). A stacking ensemble classifier was developed using HRV features and basic demographic information to classify individuals with depressive symptoms. The ensemble incorporated four base learners (logistic regression, gradient boosting, XGBoost, and SVM) with an SVM meta-learner. Model performance was evaluated using 5-fold cross-validation. The stacking model achieved its best discrimination of AUROC 0.64 (AUPRC 0.45 and MCC 0.21). Incorporating demographic features alongside HRV improved performance over HRV alone. Feature importance analysis revealed that smoking status, sex, and medical comorbidities were the strongest contributors to the predictions. Facial video-derived HRV, combined with simple demographic factors, can moderately distinguish individuals with depressive symptoms in a contactless manner. Although predictive performance was modest, this non-invasive approach shows promise for accessible, large-scale depression screening.

Alcohol Use Disorder (AUD) is commonly associated with malnutrition, yet the relative contributions of inadequate intake versus alcohol-related metabolic disruption remain unclear. This scoping review summarizes existing literature on dietary intake patterns and diet quality among individuals with AUD, following the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews guidelines. A comprehensive, systematic search was conducted without date restrictions, and dietary intake was categorized by drinking status (active vs. abstinent). Across 41 included studies, only four reported on diet quality or assessed adherence to recommended nutrient intake. There was considerable variability in both the reporting of dietary variables and the assessment tools utilized across studies. Weighted averages showed that individuals with AUD generally had Body Mass Index (BMI) values in the normal range and reported adequate total caloric intake and macronutrient distribution during both active drinking and abstinence. However, despite seemingly sufficient intake, nutrient deficiencies are common in this population, likely due to alcohol-related interference with nutrient absorption, metabolism, and utilization. These findings underscore the need for AUD-specific nutritional guidelines, standardized dietary assessment methods, and more robust evaluations of diet quality. Integrating nutrition science into AUD research and clinical care may provide an opportunity to improve both treatment outcomes and long-term recovery.

The impact of adverse childhood experiences (ACEs), adverse adulthood experiences (AAEs), and their combined effects on the risk of incident irritable bowel syndrome (IBS) remains unclear. We aimed to investigate the risk of IBS associated with ACEs and AAEs. Participants free of IBS with available ACEs and AAEs data were included (N = 126,735). ACEs and AAEs were assessed separately using the Childhood Trauma Screener-5 item and custom-built questions, with different patterns identified through latent profile analysis. The primary endpoint was incident IBS. Cox proportional hazards models were used to estimate the relationship. During a median follow-up of 14.5 years, 2492 (2.0%) incident IBS cases were identified. Overall, 95,040 (75.0%), 3011 (2.4%), 17,409 (13.7%), and 11,275 (8.9%) participants were classified as low ACEs, high physical neglect, high emotional neglect, and high abuse patterns, respectively. Compared with low ACEs, those with high emotional neglect (HR = 1.38, 95%CI: 1.24-1.54) and abuse (HR = 1.64, 95%CI: 1.46-1.84) patterns during childhood showed an increased IBS risk. Similarly, 111,776 (88.2%), 7039 (5.6%), and 7920 (6.2%) participants were classified as low AAEs, high physical neglect, and high abuse. Compared to low AAEs, high physical neglect and abuse in adulthood had a 1.34-fold (95%CI: 1.15-1.56) and 1.54-fold (95%CI: 1.36-1.77) increased IBS risk. Joint analysis indicated that individuals with high abuse or emotional neglect in ACEs, combined with any pattern in AAEs, had a 39-161% higher IBS risk compared to those with low ACEs and AAEs. Both ACEs and AAEs are associated with higher IBS risk, with their joint effects aggravating the risk.

We aimed to understand longitudinal associations between Alzheimer's disease (AD) biomarkers in Autosomal Dominant AD (ADAD) across estimated years to symptom onset (EYO). Forty-five individuals (19 mutation carriers [EYO = -7.9 ± 11.7 years, APP N = 11; PSEN1 N = 8]) from Swedish ADAD families participated. All received baseline 18F-Flurodeoxyglucose (FDG) PET and cognitive testing, and a subset (N = 26) plasma glial fibrillary acidic protein (GFAP) measurement. Follow-up data collection (including 106 FDG scans) was performed over 7.4 ± 6.4 years (visits ranged from 1-5, EYO = -25.8 to +10.3 years in mutation carriers). Mixed effects models were applied to determine longitudinal associations. APP and PSEN1 mutation carriers showed different FDG uptake profiles from EYO = -20 to -10 years, with a hypermetabolism before hypometabolism in PSEN1 mutation carriers. Early increases in plasma GFAP were primarily related to subcortical FDG decreases and cognitive changes in APP mutation carriers compared to non-carriers. We provide evidence for gene-dependent biomarker trajectories in ADAD.

In the developing brain cholesterol is synthesized by both neurons and glia, and sterol biosynthesis peaks in early postnatal life. Genetic disruptions of sterol biosynthesis genes lead to complex intellectual and developmental disabilities. In addition, multiple commonly prescribed medications can impede sterol homeostasis. Of these, cariprazine (CAR) is one of the strongest prescription medications with sterol biosynthesis inhibiting side effects. CAR inhibits the final steps in cholesterol biosynthesis mediated by the enzyme dehydrocholesterol reductase 7 (DHCR7). This inhibition leads to accumulations of sterol precursors, including 7-dehydocholesterol (7-DHC). 7-DHC is the most oxidizable lipid known in mammals, and the 7-DHC derived oxysterols are toxic. There is limited information on CAR effects during lactation. We exposed lactating mice to daily CAR injections of 0.2 mg/kg CAR. At postnatal day 11 we found that CAR levels were similar in the brains of exposed pups and their lactating mothers. In addition, the exposed pup brains and livers had increased levels of 7-DHC and 8-DHC. This disruption of post-lanosterol sterol biosynthesis by CAR was not dependent on the sex of the pups or maternal genotype. However, CAR levels were genotype dependent, with Dhcr7^+/- animals showing lower levels of CAR than their wild-type littermates. In summary, our current study fills a knowledge gap: CAR is excreted through milk, accumulates in the brain of the lactating pups, and disrupts sterol biosynthesis (and potentially many other physiological processes) in the developing postnatal brain.