Psychological Medicine最新文献

Background: Sexual minorities have continuously been found to experience poorer mental health compared to the general population, despite promising changes in attitudes and legislation throughout the 21st century in many Western countries. The present study is one of the first to assess group-level changes over time in mental health among sexual minorities compared to their heterosexual counterparts.

Methods: We used four waves of a Finnish population-based survey spanning 16 years (2006-2022) to compare heterosexual and sexual minority adults on depression and anxiety symptoms, alcohol use, and sexual distress.

Results: Sexual minority individuals reported more depression and anxiety symptoms, sexual distress, and alcohol use relative to their heterosexual counterparts at all time points. There were no group differences in the direction or rate of change in group means from 2006 to 2022. Depression and anxiety symptoms showed equally large increases, and alcohol use showed equally large decreases among both heterosexual and sexual minority participants.

Conclusions: Contrary to our expectations based on minority stress theory, differences in mental health between sexual minority and heterosexual individuals persist despite changes in the sociolegal status of sexual minorities during the first two decades of the 21st century. Our findings align with the increasing general trend in anxiety and depression symptoms, which seems to affect the whole population regardless of sexual orientation. We conclude that the effect of legislative societal improvements seems to be small, and the mental health gap between sexual minority and heterosexual adults is likely maintained by factors not included in our study.

Background: Mitochondrial dysfunction has been implicated in the pathogenesis of major depressive disorder (MDD); however, the causal contributions of specific mitochondrial genes across regulatory layers remain unclear.

Methods: We integrated genome-wide association study summary statistics from the Psychiatric Genomics Consortium and FinnGen with quantitative-trait-locus (QTL) datasets for DNA methylation, gene expression (eQTL), and protein abundance. Mitochondrial genes were annotated using the MitoCarta3.0 database. Summary-based Mendelian randomization and Bayesian colocalization were applied to assess causal relationships, with colocalization determined by the posterior probability of a shared causal variant (PPH4), and the false discovery rate used for multiple-testing correction. Brain-specific effects were evaluated using Genotype-Tissue Expression eQTL data. Prioritized genes were ranked based on cross-omics consistency and replication evidence.

Results: Five mitochondrial genes were prioritized. TDRKH showed consistent associations across methylation, transcription, and protein levels, with hypermethylation at cg24503712 linked to reduced expression and a lower risk of MDD (Tier 1). METAP1D (Tier 2) demonstrated protective effects at both the transcript and protein levels. LONP1, FIS1, and SCP2 (Tier 3) exhibited consistent but complex regulatory patterns. Several signals were replicated in brain tissues, including TDRKH in the caudate and METAP1D in the cortex.

Conclusions: This study provides multi-omics evidence for the causal involvement of mitochondrial genes in MDD. TDRKH and METAP1D emerged as key candidates, offering promising targets for future mechanistic research and therapeutic development.

Background: Anhedonia and depression symptoms have been linked to potential deficits in reward learning. However, how anhedonia impacts the ability to adjust and learn about the effort required to obtain rewards remains unclear.

Methods: We examined young people (N = 155, 16-25 years) with a range of depression and anhedonia symptoms using a probabilistic instrumental reward and effort learning task. Participants were asked to learn which options to choose to maximize reward or minimize effort for reward. We compared the exerted effort (button pressing speed) for high (puppy images) vs low (dog images) rewards and collected subjective reports of "liking," "wanting," and "willingness to exert effort." Computational models were fit to the learning data and estimated parameter values were correlated with depression and anhedonia symptoms.

Results: As depression symptoms and consummatory anhedonia increased, reward liking decreased, and as anticipatory anhedonia increased, liking, wanting, and willingness to exert effort for reward decreased.Participants exerted more effort for high rewards than for low rewards, but anticipatory anhedonia diminished this difference.Higher consummatory anhedonia was associated with poorer reward and effort learning, and with increased temperature parameter values for both learning types, indicating a higher tendency to make exploratory choices. Higher depression symptoms were associated with lower reward learning accuracy.

Conclusion: We provide novel evidence that anhedonia is associated with difficulties in modulating effort as a function of reward value and with the underexploitation of low effort and high reward options. We suggest that addressing these impairments could be a novel target for intervention in anhedonic young people.

Background: Childbirth-related post-traumatic stress disorder (CB-PTSD) is an underrecognized condition with consequences for mothers and infants. This study aimed to determine risk factors for CB-PTSD symptoms across countries within a stress-diathesis framework, focusing on antenatal, birth-related, and postpartum predictors.

Methods: The INTERSECT cross-sectional survey (April 2021-January 2024) included 11,302 women at 6-12 weeks postpartum. The study was carried out across maternity services in 31 countries. Outcomes were CB-PTSD diagnosis, symptom severity, and perceived traumatic birth, assessed with the City Birth Trauma Scale. Multiple risk factors were assessed, including preexisting vulnerability, pregnancy, birth, and infant-related factors. All models were adjusted for country-level variation as a random effect.

Results: Models explained substantial variance across all outcomes (conditional R² = 0.53-0.58). Negative birth experience was the strongest predictor (e.g. odds ratio [OR] = 0.82, 95% confidence interval [CI] = 0.80-0.84 for diagnosis). Ongoing maternal complications predicted both CB-PTSD diagnosis and symptoms (e.g. OR = 1.61, 95% CI = 1.41-1.84), and major infant complications were associated with CB-PTSD diagnosis (OR = 1.63, 95% CI = 1.29-2.07). Reports of perceived danger to self or infant (criterion A) were linked to higher CB-PTSD symptoms and traumatic birth ratings (e.g., β =0.25, 95% CI = 0.21-0.29). Other predictors reached significance but showed small effects.

Conclusions: Findings support a stress-diathesis framework, showing that while pre-existing vulnerabilities contribute, birth-related stressors exert the strongest influence. Trauma-informed maternity care should prioritize these factors, with attention to women's appraisals of birth.

The high incidence of new cases of anxiety disorders highlights the need for scalable preventive interventions, which can be achieved through information and communication technologies. To our knowledge, no meta-analysis has been conducted to evaluate purely digital preventive interventions for anxiety in all types of populations. The aim of this study was to assess the effectiveness of digital interventions for the prevention of anxiety disorders. Systematic searches were conducted in six electronic databases (PubMed, PsycINFO, EMBASE, Web of Science, OpenGrey, and CENTRAL) from inception to December 12, 2024. Inclusion criteria for the studies were as follows: (1) randomized controlled trials (RCTs), (2) psychological or psychoeducational digital interventions to prevent anxiety, and (3) all types of populations without anxiety at baseline of the study. A total of 15 studies (19 comparisons; 6093 participants) were included in the systematic review. One study was identified as an outlier and was therefore excluded from the meta-analysis. The pooled analysis showed a small effect in favor of preventive interventions among non-anxious and varied populations (standardized mean difference = -0.32, 95% confidence interval: -0.44 to -0.20; p < 0.001). Sensitivity analyses supported the robustness of this finding. We found no evidence of publication bias. Heterogeneity was high, however, a meta-regression that included one variable (country, the Netherlands) explained 100% of the variance. All RCTs, except two, had a high risk of bias, and the quality of the evidence, according to Grading of Recommendations Assessment, Development, and Evaluation, was very low. There is a need to develop and evaluate new digital preventive interventions with a rigorous methodology.

Background: Neuroticism, a personality trait linked to both cardiovascular and psychiatric disorders, has been associated with cognitive decline and increased dementia risk, though the underlying neural mechanisms remain unclear. Mapping its relationship with brain structure could provide valuable insights into neural pathways and targets for early intervention.

Methods: We examined brain-wide associations between neuroticism and structural neuroimaging metrics derived from T1-, T2-weighted, and diffusion MRI in 36,901 dementia-free UK Biobank participants. Bonferroni-significant associations underwent bidirectional two-sample Mendelian randomization to evaluate the evidence for a causal relationship. Given that neuroticism is generally stable across adulthood and challenging to modify, we assessed whether these associations were mediated by health conditions (depression, anxiety, hypertension, ischemic heart disease [IHD], and diabetes) that are both consequences of neuroticism and known risk factors for dementia, and also modifiable through widely available and efficacious therapeutic interventions.

Results: Higher neuroticism was found to be associated with reduced grey matter volumes in the frontal and limbic regions, as well as widespread differences in white matter microstructure, particularly in thalamic radiations. Genetic analyses supported a potential causal effect of neuroticism on increased diffusivity in thalamic radiations. Hypertension mediated the associations between neuroticism and both grey and white matter measures, while depression and anxiety primarily mediated associations with white matter microstructure. Contributions from IHD and diabetes were minimal.

Conclusions: Neuroticism is linked to widespread structural brain differences that contribute to poorer brain health, and targeting vascular and mental health may help mitigate its impact.

Background: Given substantial comorbidity among, and considerable heterogeneity within, psychiatric diagnoses, researchers have suggested alternative systems for classifying psychopathology. The Hierarchical Taxonomy of Psychopathology (HiTOP) is a recently proposed framework for understanding mental disorders based on how symptoms and diagnoses tend to cluster across individuals. While the model is grounded in existing research and supported by recent meta-analytic evidence, its structure has not yet been directly tested using large, representative clinical datasets. In this study, we used electronic health record (EHR) data to examine the overall organization of mental disorders as proposed by HiTOP, with the goal of informing future research on biological and environmental risk factors as well as important life outcomes.

Methods: Data were drawn from the All of Us Research Program, a landmark nationwide US biobank initiative designed to advance population-scale health research, and included participants' psychiatric diagnoses and sociodemographic correlates as documented in their EHRs. A total of 127,963 participants and 39 primary diagnoses were identified. We analyzed patterns of co-occurrence among psychiatric diagnoses to identify broader psychopathology dimensions, assess the overall structure of mental disorders, and clarify the placement of conditions that have been inconsistently categorized in past research. Several competing dimensional models were compared based on their statistical fit and complementary assessments of factor strength, specificity, and reproducibility.

Results: A model identifying six broad and correlated dimensions - Fear, Distress, Externalizing, Substance Use, Thought Problems, and Neurodevelopmental Disorders - provided the best fit to the data. This structure was highly consistent across analyses and showed strong split-half replicability and meaningful associations with relevant clinical and demographic characteristics.

Conclusions: These findings support a 6-factor model of psychopathology that broadly resembles major dimensions in the HiTOP framework. By addressing key gaps in the literature, this study advances our understanding of the structure and correlates of mental disorders. The results offer a foundation for more nuanced investigations into the etiology, progression, and treatment of mental health conditions.

Background: Psychotic-like experiences (PLEs) are considered a subclinical component of psychosis continuum. Studies indicate that PLEs arise from multimodal factors, yet research comprehensively examining these factors together remains scarce. Using a large youth sample, we present the first model that simultaneously examines multimodal factors related to PLEs. As a secondary aim, we evaluate the model's ability to explain psychosis in an external validation cohort that included individuals experiencing psychosis.

Methods: After applying variable selection including generalized estimating equations, correlation filtering, Least Absolute Shrinkage and Selection Operator model to 741 variables (i.e., environmental factors, cognitive appraisals, clinical variables, cognitive functioning, and structural brain connectome measures), obtained PLEs predictors (N = 27) and covariates (i.e., age, sex, IQ) were included in the classification model based on Elastic Net algorithm for predicting high/low PLEs in 396 healthy participants aged 14-24 (M_age = 19.72 ± 2.5). We externally validated PLE-related predictors in a clinical sample comprising first-episode psychosis patients (n = 19), their siblings (n = 20), and healthy controls (n = 19).

Results: Eleven factors, including environmental and cognitive appraisals, along with 16 structural network properties spanning frontal, temporal, occipital, and parietal regions, were identified as important predictors of PLEs. The model's performance was moderate in predicting low versus high PLEs (accuracy = 75%, AUC = 0.750). Specificity was high (84.2%) in distinguishing siblings from patients.

Conclusions: Multimodal features, including environmental burden, cognitive schemas, and brain network alterations, predict PLEs and partially generalize to clinical psychosis. These variables may reflect intermediate phenotypes across the psychosis spectrum, offering insights into both vulnerability and resilience.

Background: The nosology of mania has long been a conundrum. Prior studies have alternately concluded that it is an internalizing disorder, a thought disorder, or a unique condition. Unfortunately, nearly all existing studies assessed symptoms cross-sectionally. This is problematic for syndromes that follow a more episodic course, such as mania. Here, we test whether including a history of episodes, not simply current symptoms, can help resolve the placement of mania in the meta-structure of psychopathology.

Methods: First-admission patients with psychosis from the Suffolk County Mental Health Project (N = 337) were followed across 20 years. Internalizing, thought disorder, and mania symptoms were assessed at year 20, whereas corresponding episodes (i.e. depressive, psychotic, and manic) were assessed across three intervals spanning the previous 20 years. We tested five models to determine whether mania (current and past) loaded onto the internalizing factor, the thought disorder factor, or an independent factor. A final model was validated against established markers of bipolar disorder.

Results: For depression and psychosis, current and past markers were congruent in loading onto internalizing and thought disorder factors, respectively. However, current and past markers of mania diverged: current mania was most strongly related to the thought disorder dimension, whereas past mania formed an independent factor. Classic correlates of mania - including family history, genetic risk, and neuropsychological function - were associated only with the history of mania dimension.

Conclusions: Including illness course in structural models of psychopathology suggests that mania is distinguished from internalizing and thought disorder factors, whereas assessments of current symptoms place it with psychosis. These findings require independent validation, but if replicated, they would support a separate spectrum of mania defined by the occurrence of episodes across the lifetime.

Background: Major depressive disorder (MDD) is a heterogeneous with underlying mechanisms that are insufficiently studied. We aimed to identify functional connectivity (FC)-based subtypes of MDD and investigate their biological mechanisms.

Methods: Consensus clustering of FC patterns was applied to a population of 829 MDD patients from the REST-Meta-MDD database, with validity assessed across multiple dimensions, including atlas replication, cross-validated classification, and drug-naïve subgroup analysis. Regression models were used to quantify FC alterations in each MDD subgroup compared with 770 healthy controls, and to analyze spatial associations between FC alterations and publicly available gene transcriptomic and neurotransmitter receptor/transporter density databases.

Results: Two stable MDD subtypes emerged: hypoconnectivity (n = 527) and hyperconnectivity (n = 299), which had both shared and distinct regions with remarkable FC alterations (i.e. epicenters) in the default mode network.There were several common enriched genes (e.g. axon/brain development, synaptic transmission/organization, etc.) related to FC alterations in both subtypes. However, glial cell and neuronal differentiation genes were specifically enriched in the hypoconnectivity and hyperconnectivity subtypes, respectively.Both subtypes showed spatial associations between FC alterations and serotonin receptor/transporter density. In the hypoconnectivity subtype, FC alterations correlated with GABA and acetylcholine receptor densities, while norepinephrine transporter and glutamate receptor densities were linked to the hyperconnectivity subtype.

Conclusions: Our findings suggested the presence of two neuroimaging subtypes of MDD characterized by hypoconnectivity or hyperconnectivity, demonstrating robust reproducibility. The two subtypes had both shared and distinct genetic mechanisms and neurotransmitter receptor/transporter profiles, suggesting potential clinical implications for this heterogeneous disorder.