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.

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.

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.

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.

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.

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.

DSM-5 specifies bulimia nervosa (BN) severity based on specific thresholds of compensatory behavior frequency. There is limited empirical support for such severity groupings. Limited support could be because the DSM-5’s compensatory behavior frequency cutpoints are inaccurate or because compensatory behavior frequency does not capture true underlying differences in severity. In support of the latter possibility, some work has suggested shape/weight overvaluation or use of single versus multiple purging methods may be better severity indicators. We used structural equation modeling (SEM) Trees to empirically determine the ideal variables and cutpoints for differentiating BN severity, and compared the SEM Tree groupings to alternate severity classifiers: the DSM-5 indicators, single versus multiple purging methods, and a binary indicator of shape/weight overvaluation.

Treatment-seeking adolescents and adults with BN (N = 1017) completed self-report measures assessing BN and comorbid symptoms. SEM Trees specified an outcome model of BN severity and recursively partitioned this model into subgroups based on shape/weight overvaluation and compensatory behaviors. We then compared groups on clinical characteristics (eating disorder symptoms, depression, anxiety, and binge eating frequency).

SEM Tree analyses resulted in five severity subgroups, all based on shape/weight overvaluation: overvaluation <1.25; overvaluation 1.25–3.74; overvaluation 3.75–4.74; overvaluation 4.75–5.74; and overvaluation ≥5.75. SEM Tree groups explained 1.63–6.41 times the variance explained by other severity schemes.

Shape/weight overvaluation outperformed the DSM-5 severity scheme and single versus multiple purging methods, suggesting the DSM-5 severity scheme should be reevaluated. Future research should examine the predictive utility of this severity scheme.

Based on an efficacious face-to-face theory-driven psychological therapy for persecutory delusions in the context of psychosis, we set out to develop a scalable guided 6-month online program. The aim was an intervention that patients can easily access and use, produces large clinical effects, and can be supported by a range of mental health professionals in less contact time than face-to-face therapy. We report here the proof-of-concept testing. At least moderate-sized clinical effects were required to progress to a randomized controlled trial (RCT).

In the 6-month Feeling Safer online program, a certified medical device, patients complete a brief assessment and then are provided with up to 10 modules that match their difficulties. Regular remote meetings with a mental health professional also take place. These may be supplemented by in-person visits. A pre- to post-treatment cohort trial was conducted with 14 patients with persistent persecutory delusions. The primary outcome was the Psychotic Symptoms Rating Scale (PSYRATS)-Delusions.

Satisfaction and usability ratings of the program were high. Very large reductions in persecutory delusions were observed (PSYRATS mean reduction = 7.1, 95% C.I. = 3.4, 10.8, n = 13, Cohen’s d = 3.0). There were large improvements in paranoia, anxiety, depression, agoraphobic distress, psychological wellbeing, meaningful activity, personal recovery, recovering quality of life, and moderate improvements in insomnia, agoraphobic avoidance, and quality of life.

The clinical effects associated with Feeling Safer were very high, comparable to those seen in the evaluations of the face-to-face therapy, and enable progression to an RCT.

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.

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.

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.

Parental psychopathology is a known risk factor for child autistic-like traits. However, symptom-level associations and underlying mechanisms are poorly understood.

We utilized network analyses and cross-lagged panel models to investigate the specific parental psychopathology related to child autistic-like traits among 8,571 adolescents (mean age, 9.5 years at baseline), using baseline and 2-year follow-up data from the Adolescent Brain Cognitive Development study. Parental psychopathology was measured by the Adult Self Report, and child autistic-like traits were measured by three methods: the Kiddie Schedule for Affective Disorders and Schizophrenia for DSM-5 autism spectrum disorder (ASD) subscale, the Child Behavior Checklist ASD subscale, and the Social Responsiveness Scale. We also examined the mediating roles of family conflict and children’s functional brain connectivity at baseline.

Parental attention-deficit/hyperactivity problems were central symptoms and had a direct and the strongest link with child autistic-like traits in network models using baseline data. In longitudinal analyses, parental attention-deficit/hyperactivity problems at baseline were the only significant symptoms associated with child autistic-like traits at 2-year follow-up (β = 0.014, 95% confidence interval [0.010, 0.018], FDR q = 0.005), even accounting for children’s comorbid behavioral problems. The observed association was significantly mediated by family conflict (proportion mediated = 11.5%, p for indirect effect <0.001) and functional connectivity between the default mode and dorsal attention networks (proportion mediated = 0.7%, p for indirect effect = 0.047).

Parental attention-deficit/hyperactivity problems were associated with elevated autistic-like traits in offspring during adolescence.

Weight suppression represents the difference between highest and current body weight and predicts maintenance of bulimia nervosa and related syndromes (BN-S). This study tested a biobehavioral model of binge-eating severity in which greater weight suppression links to reduced leptin, which links to reduced glucagon-like peptide 1 (GLP-1) release, which links to both decreased reward satiation and increased reward valuation, which link, respectively, to excessive food intake and loss of control while eating – the defining features of DSM-5 binge-eating episodes.

Women (N = 399) who met DSM-5 criteria for bulimia nervosa or another eating disorder with binge eating (n = 321) or had no lifetime eating disorder symptoms (n = 78) participated in a multi-visit protocol, including structured clinical interviews, height, weight, weight history, percent body fat, fasting leptin, post-prandial GLP-1 response to a fixed meal, and self-report and behavioral assessments of food reward satiation (ad lib meal) and food and nonfood reward valuation (progressive ratio tasks).

A structural equation model (SEM) demonstrated excellent fit to data with significant pathways from greater weight suppression to lower leptin, to blunted GLP-1 response, to lower reward satiation, to larger eating/binge-eating episode size, with significant indirect paths through leptin, GLP-1, and reward satiation. SEM with paths via reward valuation to loss of control eating demonstrated inadequate fit.

Findings specifically link reduced GLP-1 response to severity of binge-episode size and support weight history assessment in eating disorders, DSM-5 over ICD-11 criteria for binge eating, and may inform future clinical trials of GLP-1 agonists for BN-S.

Major depressive disorder (MDD) is a complex and heterogeneous disorder, and this heterogeneity poses a significant challenge for advancing precision medicine in patients with MDD. MRI-based subtyping analysis has been widely employed to address the heterogeneity of MDD patients. In this study, we investigated the subtypes of first-episode and drug-naive (FEDN) MDD patients based on the individualized structural covariance network (IDSCN).

In this study, we used T1-weighted anatomical images of 164 FEDN MDD patients and 164 healthy controls from the REST-meta-MDD consortium. The IDSCN of participants was obtained using the network template perturbation method. Subtypes of FEDN MDD were identified using k-means clustering analysis, and differences in neuroimaging findings and clinical symptoms between the identified subtypes were compared using two-sample t-tests.

This study identified two subtypes of FEDN MDD: subtype 1 (n = 117) and subtype 2 (n = 47) by characterizing 10 edges that were significantly altered in at least 5% of patients (i.e., 8 patients) in the IDSCN. Compared with subtype 2, subtype 1 had significantly higher anxiety symptom scores, stronger structural covariance edges in 9 edges within the thalamus, and a significantly reduced gray matter volume (GMV) in the frontal and parietal regions, and in the thalamus.

Our results suggest that patients with FEDN MDD can be classified into two different subtypes based on their IDSCN, providing an important reference for personalized treatment and precision medicine for patients with FEDN MDD.

Interventions at frequently used suicide locations that restrict access to means, encourage help-seeking, and increase the likelihood of intervention by a third party are effective in preventing suicide at such sites. However, there have been concerns that such efforts may displace suicides to other sites. It is important to synthesize the evidence on suicide displacement effects.

We conducted a systematic search of Medline, PsycINFO, Scopus, and Google for eligible studies from their inception to February 20, 2025. Meta-analyses were conducted to assess the pooled effects of interventions on suicides at frequently used locations and other sites, and on overall suicides involving the same method.

Our search identified 17 studies. Meta-analyses showed a reduction in suicides at the intervention sites (pooled incidence rate ratio [IRR] 0.09, 95% confidence interval [95% CI] 0.04–0.21) and no evidence of changes in suicides at other sites after restricting access to means was deployed alone. The pooled IRR for nearby sites (same type) was 0.99 (95% CI 0.72–1.38); for other sites (same type), it was 0.99 (95% CI 0.76–1.29); and for other sites (different/unspecified type), it was 1.19 (95% CI 0.90–1.58). There was an overall reduction in suicides involving the same method during the post-intervention period (IRR 0.77, 95% CI 0.65–0.92). Similar patterns were observed when restricting access to means was assessed alone or with other interventions.

Suicide numbers at other sites did not change after interventions such as restricting access to means were deployed at frequently used locations.

There is growing evidence that smoking increases the risk of developing psychiatric disorders, but the underlying mechanisms are largely unknown. We examine brain structure as a potential pathway between smoking and psychiatric disease liability.

We test associations between smoking (initiation, cigarettes per day, cessation, lifetime use) and depression, bipolar disorder, and schizophrenia, with and without correcting for volume of the amygdala, hippocampus, lateral and medial orbitofrontal cortex, superior frontal context, and cortical thickness and surface area. We use three methods that use summary statistics of genome-wide association studies to investigate genome-wide and local genetic overlap (genomic structural equation modeling, local analysis of (co)variant association), as well as causal associations (Mendelian randomization).

While we find causal effects of smoking on brain volume in different brain areas, and with psychiatric disorders, brain volume did not seem to mediate the effect of smoking on psychiatric disorders.

While these findings are limited by characteristics of the included summary statistics (e.g. sample size), we conclude that brain volume of these areas is unlikely to explain a substantial part of any effect of smoking on psychiatric disorders. Nevertheless, genetic methods are valuable tools for exploring other potential mechanisms, such as brain functional connectivity, foregoing the need to collect all phenotypes in one dataset.