Psychotic-like experiences (PLEs) are associated with cognitive impairment and premature mortality, which may be indicative of accelerated biological ageing. Epigenetic clocks provide a measure of biological age based on DNA methylation, yet the long-term relationship between epigenetic ageing and PLEs remains largely unclear. We tested the relationship between epigenetic ageing and PLEs using a 17-year longitudinal approach.

Epigenetic ageing was calculated using four epigenetic clocks (DunedinPACE, Cortical EpiAge, Horvath, and PCGrimAge) in a sample from the Avon Longitudinal Study of Parents and Children (ALSPAC), a large population-based birth cohort (n = 1840, 56.8% females). We modeled epigenetic ageing from up to three repeated measures collected between ages 7 and 24 using a linear mixed-effects model to calculate (1) average epigenetic age [mean-centered intercept] and (2) rate of epigenetic ageing over this 17-year period [slope]. We then compared these two measures between individuals who developed PLEs in early adulthood (n = 95) against those who did not (n = 1745).

Results showed that a faster rate (slope) of longitudinal PCGrimAge was predictive of PLEs (OR = 1.79, 95% CI [1.13–2.85], p = .014), although this association was no longer significant after adjusting for smoking. There was a non-significant effect in the same direction for other clocks. Average epigenetic age (mean-centered intercept) was not associated with PLEs.

Our findings suggest that the observed association between accelerated rate of epigenetic ageing, measured with PCGrimAge, from childhood to early adulthood, and the development of PLEs in early adulthood may be explained by smoking.

Despite the high prevalence of generalized anxiety among young adults, studies investigating factors that shape the course of these symptoms during the twenties are scarce. In addition, generalized anxiety can manifest in different ways, but it is unclear whether symptoms cluster under distinct dimensions in this age group. The current study addressed these gaps using data from the Twins Early Development Study. First, we examined genetic and environmental contributions to continuity and change in generalized anxiety symptoms in young adulthood and the heritability of a latent factor reflecting stability over this period. Next, to explore potential dimensions of generalized anxiety, we investigated the factorial structure of symptoms as well as etiological influences underpinning the different factors.

The sample comprised 6,429 twin pairs. Generalized anxiety was assessed at six waves (age 23–26 years).

Genetic factors largely accounted for continuity and environmental factors for change in symptom severity. Furthermore, the heritability of stable generalized anxiety (60%) was substantially higher than that at any single time point (39–46%). Regarding the factorial structure of symptoms, we found evidence of two dimensions: worry-avoidance and somatic-distress symptoms. Genetic correlations (rG = 0.77–0.91) between the two dimensions were higher than environmental correlations (rE = 0.26–0.65).

The current findings suggest that extracting temporal stability provides the strongest opportunity to identify genetic influences on generalized anxiety. Moreover, the results indicate that differences between generalized anxiety dimensions are more likely attributable to environmental than genetic effects.

Individuals can intentionally process task-relevant information while ignoring task-irrelevant information. This study aims to investigate how to promote forgetting of task-irrelevant information through noninvasive brain stimulation, utilizing direct suppression and thought substitute inhibition mechanisms.

Participants were cued to either remember task-relevant information while forgetting task-irrelevant information (IR condition) or to forget task-irrelevant items while remembering task-relevant information (IF condition). High-frequency rTMS was applied to activate the left ventrolateral prefrontal cortex (VLPFC, n = 32), right dorsolateral prefrontal cortex (DLPFC, n = 32), or vertex cortex (control condition, n = 32).

Compared to vertex stimulation, (1) The Left VLPFC stimulation promoted the memory of task-relevant information in the IR condition, and resulted in a memory deficit for the task-irrelevant information in the IF condition (active forgetting). (2) The Right DLPFC stimulation promoted the forgetting of task-irrelevant information in the IF condition (active forgetting) and facilitated the memory of task-relevant information in the IR condition.

Stimulating left VLPFC or right DLPFC can promote active forgetting. Noninvasive brain stimulation can effectively regulate memory control.

Understanding the mechanisms of major depressive disorder (MDD) improvement is a key challenge to determining effective personalized treatments.

To identify a data-driven pattern of clinical improvement in MDD and to quantify neural-to-symptom relationships according to antidepressant treatment, we performed a secondary analysis of the publicly available dataset EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care). In EMBARC, participants with MDD were treated either by sertraline or placebo for 8 weeks (Stage 1), and then switched to bupropion according to clinical response (Stage 2). We computed a univariate measure of clinical improvement through a principal component (PC) analysis on the variations of individual items of four clinical scales measuring depression, anxiety, suicidal ideas, and manic-like symptoms. We then investigated how initial clinical and neural factors predicted this measure during Stage 1 by running a linear model for each brain parcel’s resting-state global brain connectivity (GBC) with individual improvement scores during Stage 1.

The first PC (PC1) was similar across treatment groups at stages 1 and 2, suggesting a shared pattern of symptom improvement. PC1 patients’ scores significantly differed according to treatment, whereas no difference in response was evidenced between groups with the Clinical Global Impressions Scale. Baseline GBC correlated with Stage 1 PC1 scores in the sertraline but not in the placebo group.

Using data-driven reduction of symptom scales, we identified a common profile of symptom improvement with distinct intensity between sertraline and placebo.

Mapping from data-driven symptom improvement onto neural circuits revealed treatment-responsive neural profiles that may aid in optimal patient selection for future trials.

Virtual reality (VR) may improve psychological treatments for psychotic disorders. We investigated the effects of VR-based cognitive behavior therapy for paranoid ideation (VR-CBTp) compared to standard CBTp.

We conducted a pragmatic, single-blind, randomized clinical trial in seven mental health centers across the Netherlands and Belgium. A total of 98 participants with a psychotic spectrum disorder and paranoid ideation were randomized to a maximum of 16 sessions of VR-CBTp (n = 48) or CBTp (n = 50). The primary outcome was momentary paranoia, measured with the experience sampling method (ESM) at posttreatment. Secondary measures, assessed at baseline, posttreatment, and 3-month follow-up, included symptoms (paranoia, hallucination, depression, cognition, and anxiety related), social functioning, self-esteem, and schemes.

Both groups showed reductions in momentary paranoia between baseline and posttreatment (n = 56, b = −15.0, effect size [ES] = 0.65), but those were greater for VR-CBT (interaction b = 8.3, ES = 0.62). Reductions remained at follow-up (n = 50, b = −10.7, ES = 0.57) but not the interaction. Limited ESM compliance resulted in data loss; however, secondary paranoia measures did confirm improvements (ES range = 0.66–1.15, n = 78–81), but not the interaction. Both groups improved in symptoms, self-esteem, and social functioning. Interaction effects in favor of VR-CBTp were found for safety behavior, depression, and self-esteem at posttreatment, and self-esteem and anxiety at follow-up. For VR-CBTp, 37.5% did not complete treatment; for CBTp, this was 24.0%. Completers, on average, received 12.7 (VR-CBTp: standard deviation [SD] = 3.9) and 15.1 (CBTp: SD = 2.5) sessions.

Both CBTp and VR-CBTp are efficacious treatments for paranoid ideation, but VR-CBTp may be somewhat more effective. Limitations concern missing primary outcome data and a lower sample size than anticipated.

Mentalizing defines the set of social cognitive imaginative activities that enable interpretation of behaviors as arising from intentional mental states. Mentalization impairments have been related to childhood trauma (CT) and are widely present in people suffering from mental disorders. Nevertheless, the link between CT exposure, mentalization abilities, and related psychopathology remains unclear. This study aims to systematically review the evidence in this domain.

A Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-compliant systematic review of literature published until December 2022 was conducted through an Ovid search (Medline, Embase, and PsycINFO). The review was registered in the Prospective Register of Systematic Reviews (PROSPERO) (CRD42023455602).

Twenty-nine studies were included in the qualitative synthesis. Twenty studies (69%) showed a significant negative correlation between CT and mentalization. There was solid evidence for this association in patients with psychotic disorders, as almost half the studies focused on this population. The few studies focusing on unipolar depression, personality disorders, and opioid addiction also reported a negative impact of CT on mentalization. In contrast, evidence for post-traumatic stress disorder was inconsistent, and no evidence was found for bipolar disorder. When stratifying for subtypes of CT, there was solid evidence that neglect (physical and emotional) decreased mentalization capacity, while abuse (physical, emotional, or sexual) was not associated with mentalization impairments.

Although causality cannot be established, there was substantial evidence that CT negatively affects mentalization across various psychiatric disorders, particularly psychotic disorders. These findings highlight the potential of targeting mentalization impairments in prevention and treatment strategies aiming to reduce the incidence and the social functioning burden of mental illness.

Stress leads to neurobiological changes, and failure to regulate these can contribute to chronic psychiatric issues. Despite considerable research, the relationship between neural alterations in acute stress and coping with chronic stress is unclear. This longitudinal study examined whole-brain network dynamics following induced acute stress and their role in predicting chronic stress vulnerability.

Sixty military pre-deployment soldiers underwent a lab-induced stress task where subjective stress and resting-state functional magnetic resonance imaging were acquired repeatedly (before stress, after stress, and at recovery, 90 min later). Baseline depression and post-traumatic stress symptoms were assessed, and again a year later during military deployment. We used the Leading Eigenvector Dynamic Analysis framework to characterize changes in whole-brain dynamics over time. Time spent in each state was compared across acute stress conditions and correlated with psychological outcomes.

Findings reveal significant changes at the network level from acute stress to recovery, where the frontoparietal and subcortical states decreased in dominance in favor of the default mode network, sensorimotor, and visual states. A significant normalization of the frontoparietal state activity was related to successful psychological recovery. Immediately after induced stress, a significant increase in the lifetimes of the frontoparietal state was associated with higher depression symptoms (r = 0.49, p < .02) and this association was also observed a year later following combat exposure (r = 0.49, p < .009).

This study revealed how acute stress-related neural alterations predict chronic stress vulnerability. Successful recovery from acute stress involves reducing cognitive–emotional states and enhancing self-awareness and sensory–perceptual states. Elevated frontoparietal activity is suggested as a neural marker of vulnerability to chronic stress.

Children born very preterm (VPT; ≤32 weeks’ gestation) are at higher risk of developing behavioural problems, encompassing socio-emotional processing and attention, compared to term-born children. This study aimed to examine multi-dimensional predictors of late childhood behavioural and psychiatric outcomes in very preterm children, using longitudinal clinical, environmental, and cognitive measures.

Participants were 153 VPT children previously enrolled in the Evaluation of Preterm Imaging study who underwent neuropsychological assessments at 18–24 months, 4–7 years and 8–11 years as part of the Brain Immunity and Psychopathology following very Preterm birth (BIPP) study. Predictors of late childhood behavioural and psychiatric outcomes were investigated, including clinical, environmental, cognitive, and behavioural measures in toddlerhood and early childhood. Parallel analysis and exploratory factor analysis were conducted to define outcome variables. A prediction model using elastic-net regularisation and repeated nested cross-validation was applied to evaluate the predictive strength of these variables.

Factor analysis revealed two key outcome factors in late childhood: externalising and internalising-socio-emotional problems. The strongest predictors of externalising problems were response inhibition, effortful control and internalising symptoms in early childhood (cross-validated R2=.256). The strongest predictors of internalising problems were autism traits and poor cognitive flexibility in early childhood (cross-validated R2=.123). Cross-validation demonstrated robust prediction models, with higher accuracy for externalising symptoms.

Early childhood cognitive and behavioural outcomes predicted late childhood behavioural and psychiatric outcomes in very preterm children. These findings underscore the importance of early interventions targeting cognitive development and behavioural regulation to mitigate long-term psychiatric risks in very preterm children.

Compelling evidence claims that gut microbial dysbiosis may be causally associated with major depressive disorder (MDD), with a particular focus on Alistipes. However, little is known about the potential microbiota–gut–brain axis mechanisms by which Alistipes exerts its pathogenic effects in MDD.

We collected data from 16S rDNA amplicon sequencing, untargeted metabolomics, and multimodal brain magnetic resonance imaging from 111 MDD patients and 102 healthy controls. We used multistage linked analyses, including group comparisons, correlation analyses, and mediation analyses, to explore the relationships between the gut microbiome (Alistipes), fecal metabolome, brain imaging, and behaviors in MDD.

Gut microbiome analysis demonstrated that MDD patients had a higher abundance of Alistipes relative to controls. Partial least squares regression revealed that the increased Alistipes was significantly associated with fecal metabolome in MDD, involving a range of metabolites mainly enriched for amino acid, vitamin B, and bile acid metabolism pathways. Correlation analyses showed that the Alistipes-related metabolites were associated with a wide array of brain imaging measures involving gray matter morphology, spontaneous brain function, and white matter integrity, among which the brain functional measures were, in turn, associated with affective symptoms (anxiety and anhedonia) and cognition (sustained attention) in MDD. Of more importance, further mediation analyses identified multiple significant mediation pathways where the brain functional measures in the visual cortex mediated the associations of metabolites with behavioral deficits.

Our findings provide a proof of concept that Alistipes and its related metabolites play a critical role in the pathophysiology of MDD through the microbiota–gut–brain axis.

Executive functioning (EF) impairments are widely known to represent transdiagnostic risk factors of psychopathology. However, a recent alternative account has been proposed, according to which EF impairments emerge as consequences of psychopathology.

Using a longitudinal cross-lagged panel network analysis approach, we tested these competing theoretical accounts at different stages during adolescence. We used data from the Brazilian High-Risk Cohort Study for the Development of Childhood Psychiatric Disorders, in which 61% of individuals at wave 1 were selected due to their high risk for psychopathology. Participants were assessed across three assessment waves during early (wave 1: n = 1,992, mean age = 10.20 years) and middle adolescence (wave 2: n = 1,633, mean age = 13.48 years; wave 3: n = 1,439, mean age = 18.20 years). We examined associations between working memory, inhibitory control, and broad-band measures of psychopathology.

During early adolescence, lower inhibitory control was a risk factor for externalizing problems that, in turn, predicted lower working memory capacity. During middle adolescence, bidirectional associations became more prominent: inhibitory control and working memory functioned as both risk factors and consequences. Externalizing problems both predicted and were predicted by poor inhibitory control. Internalizing and externalizing symptoms showed bidirectional associations over time. Externalizing problems predicted more internalizing symptoms, whereas internalizing symptoms predicted fewer externalizing problems during middle adolescence.

Our results corroborate dynamic theories that describe executive dysfunctions as precursors and consequences of psychopathology in middle adolescence.

There has been debate about the frequency and severity of antidepressant withdrawal effects.

We set out to appraise and reanalyze an influential systematic review by Henssler and colleagues that concluded that withdrawal effects are not particularly common and rarely severe. We repeated the meta-analysis, including only studies where data were derived from systematic measures of withdrawal symptoms.

Most data in the Henssler review are derived from pharmaceutical industry–sponsored efficacy studies in which withdrawal was a minor consideration. Shortcomings of the review include the use of spontaneously reported adverse events to estimate withdrawal symptoms, potential misclassification of withdrawal symptoms as relapse, inclusion of data from retrospective case-note studies, short duration of prior antidepressant use, short observation periods, the overlooking of differences between placebo and drug withdrawal effects, and the use of questionable proxies for severe withdrawal. There were also discrepancies and uncertainties in some figures used. In our reanalysis, we included only the five studies that used a systematic and relevant method to assess the incidence of any withdrawal symptom. Prior treatment was short-term (12 weeks or less) in all but one of these. The pooled percentage was 55% (95% confidence interval, CI, 31% to 81%; N = 601) without subtracting nocebo effects, with high heterogeneity.

Henssler’s review is based on unreliable data and does not provide an adequate basis for the evaluation of antidepressant withdrawal effects. Further good-quality research on antidepressant withdrawal is required.

Postpartum depression is prevalent among Black women and associated with intersecting systemic factors and interpersonal discrimination. However, gaps remain in understanding pregnancy-related changes in discrimination experiences that influence postpartum mental health and could inform preventive interventions. We hypothesized that young Black women would experience increasing levels of discrimination across the transition to parenthood, heightening depression risk relative to non-pregnant peers.

Participants comprised 335 Black primiparous women (ages 17-30 at delivery) and 335 age- and discriminationmatched non-pregnant controls from the Pittsburgh Girls Study. Self-reported discrimination experiences were collected at four timepoints: two years pre-pregnancy, one year pre-pregnancy, pregnancy, and one year postpartum for the childbearing sample, with corresponding data from the non-pregnant sample across the same interval (matched pairwise).

Linear increases in discrimination were observed for the nonpregnant participants (BS = .480, SE = .090, p <.001), while childbearing participants showed no overall changes, though younger age predicted greater increases over time. For childbearing participants, both baseline discrimination (BI = .626, SE = .077, p < .001) and increasing discrimination (BS = 2.55, SE = .939, p < .01) predicted postpartum depressive symptoms, controlling for pre-pregnancy depression. Among non-pregnant participants, only baseline discrimination predicted later depression (BI = .912, SE = .081, p < .001).

Experiencing increasing levels of interpersonal discrimination across the transition to parenthood may heighten postpartum depression risk among young Black women, indicating a need for interventions supporting well-being and promoting resilience before, during and after pregnancy.

Spontaneous mentalizing refers to the capacity to attribute mental states to oneself and others without explicit prompts or conscious deliberation. This process enables individuals to comprehend and anticipate social behaviors in a more intuitive manner. Individuals diagnosed with schizophrenia frequently demonstrate deficits in this domain, which contribute to impaired social functioning. The present meta-analysis aims to assess the extent of spontaneous mentalizing impairments in schizophrenia.

A comprehensive search was conducted in four prominent databases: MEDLINE, EMBASE, CENTRAL, and Web of Science. Following the review of the retrieved records and subsequent citation searching, a total of 15 studies were selected for inclusion in the quantitative synthesis. The data of 526 patients diagnosed with schizophrenia and 536 controls were subjected to analysis. Effect sizes for intentionality and appropriateness were computed utilizing weighted or standardized mean differences, and heterogeneity was evaluated.

Patients with schizophrenia exhibited substantial impairments in intentionality and appropriateness during mentalizing tasks, with large effect sizes. No significant differences were observed in random movement tasks, although patients also demonstrated deficits in interpreting goal-directed movements. Furthermore, high heterogeneity in some outcomes and variability in study methodologies were also noted.

This analysis corroborates substantial spontaneous mentalizing deficits in schizophrenia, underscoring their potential role in impaired social functioning. In conjunction with previous analyses, the present findings emphasize the pervasive nature of mentalizing deficits in schizophrenia, encompassing explicit, implicit, and spontaneous dimensions. These results hold significant implications for therapeutic strategies designed to augment social cognition in individuals with schizophrenia.

Major depressive disorder (MDD) is a disabling psychiatric condition in which physical activity provides clinical benefits. While exercise effectively alleviates depressive symptoms, its biological mechanisms remain unclear.

This systematic review investigated the neurobiological effects of physical exercise on biomarkers in adults with MDD through randomized controlled trials, including studies assessing exercise interventions and reporting data on their biological effects.

A total of 30 studies, including 2194 participants, were included, examining the effects of physical exercise on various biological systems in patients with MDD. Exercise interventions had mixed effects on inflammatory markers, including interleukins, C-reactive protein, and tumor necrosis factor-α, suggesting a potential but inconsistent anti-inflammatory role. Neurotrophic factors, such as brain-derived neurotrophic factor showed promise as biomarkers of treatment response, but their role in clinical improvements remained inconclusive. Findings for the stress-response system, including cortisol and monoaminergic systems, primarily involving serotonin and dopamine, were limited and variable. Exercise demonstrated potential benefits in reducing oxidative stress and enhancing β-endorphin levels, although these effects were not consistently observed.

This systematic review adopted a broader perspective than prior studies, exploring less-studied biological systems and identifying several limitations in the included studies, including small sample sizes, varying methodologies, and a predominant focus on biochemical markers. Future research should prioritize larger, standardized trials and particularly employ omics approaches to better understand the biological mechanisms underlying the effects of exercise in MDD. The findings highlight the complexity of exercise’s biological effects and emphasize the need for further research to clarify its mechanisms.

Difficulties in executive functions (EFs) and internalizing and externalizing problems are prospectively related. However, it remains unclear whether the bidirectional relations between specific EF components and internalizing and externalizing problems at the within-person level vary across developmental stages in childhood and early adolescence.

This study utilized data from seven waves of the Early Childhood Longitudinal Study, Kindergarten Class of 2010–2011 (ECLS-K: 2011), following a nationally representative sample of 15,055 children (mean age at baseline = 5.63 years, SD = 0.37; age range = 4.02–7.83) from kindergarten through fifth grade. Internalizing and externalizing problems and inhibitory control were assessed using teacher-reported measures, while working memory and cognitive flexibility were evaluated using standardized cognitive tasks. Data were analyzed using a random intercept cross-lagged panel model, adjusting for the complex sampling design.

Working memory negatively predicted internalizing problems from kindergarten to first grade, with no significant link to externalizing problems. Cognitive flexibility showed limited effects, with only spring kindergarten externalizing problems predicting lower cognitive flexibility in first grade. Inhibitory control negatively predicted internalizing problems in early childhood, while internalizing problems positively predicted inhibitory control during the kindergarten-to-first-grade transition. Externalizing problems consistently reduced inhibitory control over time. Notably, inhibitory control negatively predicted externalizing problems until third grade but positively predicted them from third to fourth grade.

The findings suggest that while certain EFs can protect against internalizing and externalizing problems in early childhood, these symptoms may also influence EF development, with these interactions evolving as children transition into adolescence.

Depression is closely associated with abnormalities in brain function. Traditional static functional connectivity analyses offer limited insight into the temporal variability of brain activity. Recent advances in dynamic analyses enable a deeper understanding of how depression relates to temporal fluctuations in brain activity.

This study utilized a large resting-state functional magnetic resonance imaging dataset (N = 696) to examine the association between brain dynamics and depression. Two complementary approaches were employed. Hidden Markov modeling (HMM) was used to identify discrete brain states and quantify their temporal switching patterns; temporal variability was computed within and between large-scale functional networks to capture time-varying fluctuations in functional connectivity.

Depression scores were positively associated with switching rate and negatively associated with maximum fractional occupancy. Furthermore, depression scores were significantly associated with greater temporal variability both within and between networks, with particularly strong effects observed in the default mode network, ventral attention network, and frontoparietal network. Together, these findings suggest that individuals with higher depression scores exhibit more unstable brain dynamics.

Our findings reveal that individuals with higher depression levels exhibit greater instability in brain state transitions and increased temporal variability in functional connectivity across large-scale networks. This instability in brain dynamics may contribute to difficulties in emotion regulation and cognitive control. By capturing whole-brain temporal patterns, this study offers a novel perspective on the neural basis of depression.