Psychological Medicine

ImportanceTo support treatment assignment, mechanistic biomarkers should be selectively sensitive to specific interventions. Here, we examine whether different components of reinforcement learning in humans satisfy this necessary precondition. We focus on pharmacological manipulations of dopamine and serotonin that form the backbone of first-line management of common mental illnesses such as depression and anxiety. ObjectiveTo perform a meta-analysis of pharmacological manipulations of dopamine and serotonin and examine whether they show distinct associations with reinforcement learning components in humans. Data SourcesOvid MEDLINE/PubMed, Embase, and PsycInfo databases were searched for studies published between January 1, 1946 and January 19, 2023 (repeated April 9, 2024, and October 15, 2024) investigating dopaminergic or serotonergic effects on reward/punishment processes in humans, according to PRISMA guidelines. Study SelectionStudies reporting randomized, placebo-controlled, dopaminergic or serotonergic manipulations on a behavioral outcome from a reward/punishment processing task in healthy humans were included. Data Extraction and SynthesisStandardized mean difference (SMD) scores were calculated for the comparison between each drug (dopamine/serotonin) and placebo on a behavioral reward or punishment outcome and quantified in random-effects models for overall reward/punishment processes and four main subcategories. Study quality (Cochrane Collaborations tool), moderators, heterogeneity, and publication bias were also assessed. Main Outcome(s) and Measure(s)Performance on reward/punishment processing tasks. ResultsIn total, 68 dopamine and 39 serotonin studies in healthy volunteers were included (Ndopamine=2291, Nplacebo=2284; Nserotonin=1491, Nplacebo=1523). Dopamine was associated with an increase in overall reward (SMD=0.18, 95%CI [0.09 0.28]) but not punishment function (SMD=-0.06, 95%CI [-0.26,0.13]). Serotonin was not meaningfully associated with overall punishment (SMD=0.22, 95%CI [-0.04,0.49]) or reward (SMD=0.02, 95%CI [-0.33,0.36]). Importantly, dopaminergic and serotonergic manipulations had distinct associations with subcomponents. Dopamine was associated with reward learning/sensitivity (SMD=0.26, 95%CI [0.11,0.40]), reward discounting (SMD=-0.08, 95%CI [-0.14,-0.01]) and reward vigor (SMD=0.32, 95%CI [0.11,0.54]). By contrast, serotonin was associated with punishment learning/sensitivity (SMD=0.32, 95%CI [0.05,0.59]), reward discounting (SMD=-0.35, 95%CI [-0.67,-0.02]), and aversive Pavlovian processes (within-subject studies only; SMD=0.36, 95%CI [0.20,0.53]). Conclusions and RelevancePharmacological manipulations of both dopamine and serotonin have measurable associations with reinforcement learning in humans. The selective associations with different components suggests that reinforcement learning tasks could form the basis of selective, mechanistically interpretable biomarkers to support treatment assignment. Key pointsO_ST_ABSQuestionC_ST_ABSDo pharmacological manipulations of dopamine and serotonin affect components of reinforcement learning in humans? FindingsUpregulating dopamine is associated with increased reward learning/sensitivity and reward response vigor, and decreased reward discounting. Upregulation of serotonin is associated with increased punishment learning/sensitivity and decreased reward discounting. MeaningPharmacological manipulations of dopamine and serotonin have dissociable associations with different components of reinforcement learning. This forms a necessary basis for the development of selective markers for treatment assignment.

IMPORTANCEIndividuals with psychiatric disorders have increased risk of cardiometabolic diseases (CMDs). Evaluating how psychiatric genetic liability relates to CMD may clarify mechanisms. OBJECTIVEIdentify genetic overlap between psychiatric disorders and CMDs independent of cross-disorder pleiotropy, BMI, and smoking. DESIGN, SETTING, AND PARTICIPANTSThree Northern European cohorts (the Swedish Twin Registry, the Estonian Biobank, and the Norwegian Mother, Father and Child Cohort Study [MoBa]) totaling 355,159 individuals. Associations with CMDs were estimated as adjusted odds ratios (AORs) from logistic models mutually adjusted for all psychiatric PRSs and in models additionally adjusting for body mass index (BMI) and smoking. Cohort-specific AORs were pooled by inverse-variance weighting. MAIN OUTCOMES AND MEASURESExposures were PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), anxiety disorder, posttraumatic stress disorder (PTSD), bipolar disorder, and schizophrenia. Outcomes were diagnoses of CMDs (hyperlipidemia, obesity, type 2 diabetes, hypertensive diseases, arteriosclerosis, ischemic heart disease, heart failure, thromboembolic disease, cerebrovascular disease, and arrhythmias), ascertained from electronic health records. RESULTSThe MDD PRS was associated with increased risk of all CMDs across analyses (AORs ranged from 1.13 [95% CI, 1.10-1.15] for heart failure to 1.02 [95% CI, 1.00-1.05] for arrhythmias). The ADHD PRS was associated with increased risk of all CMDs (AOR ranged from 1.11 [95% CI, 1.09-1.12] for obesity to 1.02 [95% CI, 1.01-1.03] for hyperlipidemia), however associations where attenuated when adjusting for BMI and smoking (lifestyle adjusted AOR for obesity: 1.03 [95% CI, 1.02-1.05]). When not mutually adjusting for all psychiatric PRSs, anxiety disorder and PTSD PRSs were associated with all CMDs; these associations diminished after adjustment. The bipolar and schizophrenia PRSs were inversely associated with most CMDs (AOR for schizophrenia PRS and obesity, 0.93 [95% CI, 0.92-0.94]). CONCLUSIONS AND RELEVANCEAssociations between psychiatric PRSs and CMDs diverged: ADHD, MDD, anxiety disorder, and PTSD PRSs were positively associated with CMDs, whereas bipolar and schizophrenia PRSs were inversely associated. Genetic liability to MDD showed robust associations with CMDs independent of cross-disorder pleiotropy, BMI, and smoking status, whereas associations between the ADHD PRS and CMDs were largely attenuated after adjustment for BMI and smoking. Key PointsO_ST_ABSQuestionC_ST_ABSIs genetic liability to specific psychiatric disorders associated with an increased risk of clinically diagnosed cardiometabolic diseases even after adjusting for cross-disorder psychiatric pleiotropy, body mass index, and smoking status? FindingsIn this study of cohorts in Sweden, Estonia, and Norway, genetic liability to major depressive disorder (MDD) showed stronger associations with cardiometabolic disease (CMD) compared to other psychiatric disorders. Genetic liability to anxiety disorder and PTSD showed associations with CMD that were attenuated when adjusting for cross-disorder psychiatric pleiotropy. Genetic liability to ADHD showed strong associations with obesity and type 2 diabetes that were strongly attenuated when adjusting for body mass index, and smoking status. Genetic liability to schizophrenia showed inverse associations with CMD. MeaningThese findings suggest that MDD has a distinctive genetic relationship with CMD compared to other psychiatric disorders and that the well-established phenotypic association between schizophrenia and CMD is not related to genetic factors.

ImportanceExcess adiposity is associated with mental illnesses, but the causality of these associations remains equivocal. ObjectiveTo examine the causal effect of adiposity on mental illnesses by summarizing and assessing evidence from Mendelian randomization (MR) studies. Study SelectionSearches were conducted on Embase, Medline, and Web of Science from database inception to January 8th 2024. Data Extraction and SynthesisStudies using MR study designs that estimated adiposity measures including body mass index, abdominal adiposity, peripheral adiposity, or body composition in relation to mental illnesses were included. Study quality was assessed with a scoring system reflecting MR study guidelines. Data were pooled in meta-analyses using random-effects models. Subgroup analyses were conducted by sex. Main Outcomes and MeasuresOutcomes were the presence or severity of depression, anxiety, eating disorders, bipolar disorder, obsessive compulsive disorder, post-traumatic stress disorder, schizophrenia, and related psychotic disorders. ResultsForty-one studies with 184 MR estimates were included in the systematic review; and 16 studies with 30 MR estimates were included in meta-analysis. Pooled estimates suggested that general adiposity was causally associated with depression (OR: 1.05, 95% CI, 1.00-1.10, p<0.001; I2=82.8%), though the effect size was modest and there was high heterogeneity. Subgroup difference by sex in the causal relationship was not observed (p=0.382). No evidence of causal associations was found between adiposity and other mental illnesses, though these analyses were characterized by high imprecision and heterogeneity. Conclusion and RelevanceGeneral adiposity appears to be causally associated with depression, suggesting psychological benefits of weight management. Evidence for causal associations between adiposity and other mental illnesses remains uncertain. Key PointsO_ST_ABSQuestionC_ST_ABSIs adiposity causally associated with mental illnesses? FindingsIn this systematic review of 41 Mendelian randomization studies, with 184 MR estimates, and meta-analysis of 30 MR estimates, general adiposity was causally associated with depression. There was no evidence of sex differences. Evidence of causal associations between adiposity and other mental illnesses was unclear. MeaningThe findings suggest that higher adiposity can cause depression, which highlights the psychological importance of weight management.

ObjectiveDrugs targeting the N-Methyl-D-aspartic acid (NMDA) system and the ability to learn new associations have been proposed as potential adjunct treatments to boost the success of exposure therapy for anxiety disorders. However, the effects of the NMDA partial agonist d-cycloserine on psychological treatment have been mixed. We investigated potential neurocognitive mechanisms underlying the clinical effects of d-cycloserine-augmented exposure, to inform the optimal combination of this and similar agents with psychological treatment. MethodsUnmedicated patients with panic disorder were randomised to single-dose d-cycloserine (250mg; N=17) or matching placebo (N=16) 2hrs before one session of exposure therapy. Neurocognitive markers were assessed one day after treatment, including reaction-time based threat bias for fearful faces and amygdala response to threat. Clinical symptom severity was measured using self-report and clinician-rated scales the day before and after treatment, and at 1- and 6-months follow-up. Analysis was by intention-to-treat. ResultsOne day after treatment, threat bias for fearful faces and amygdala threat response were attenuated in the drug compared to the placebo group. Lower amygdala magnitude predicted greater clinical improvement during follow-up across groups. D-cycloserine led to greater clinical recovery at 1-month follow-up (d-cycloserine 71% versus placebo 25%). DiscussionD-cycloserine-augmented single-session exposure therapy reduces amygdala threat response, and this effect predicts later clinical response. These findings highlight a neurocognitive mechanism by which d-cycloserine may exert its augmentative effects on psychological treatment and bring forward a marker that may help understand and facilitate future development of adjunct treatments with CBT for anxiety disorders. (D-cycloserine Augmented CBT for Panic Disorder; clinicaltrials.gov; NCT01680107)

There is substantial heterogeneity in the development of depression across early adolescence into adulthood. Yet, little is known about the risk factors underlying individual differences in the development of depression. For instance, despite the discovery of genetic variants for depression, there is also significant genetic overlap between depression and other mental disorders. Thus, depression may have etiologically complex (i.e., transdiagnostic) origins when accounting for its heterogeneous developmental presentations. This study examined the association between a transdiagnostic polygenic score for psychopathology (p-factor PGS) and depressive trajectories, spanning early adolescence into adulthood, in the National Longitudinal Study of Adolescent to Adult Health. We also examined whether the Research Domains Criteria (RDoC) negative valence (i.e., negative emotionality), positive valence (i.e., novelty seeking), and cognitive systems (i.e., picture vocabulary) could explain how the p-factor PGS eventuates into the various pathways of depressive development. Four trajectories of depression were identified: low depression (78.9%), low increasing (7.3%), high declining (8.2%), and early adult peaked (5.7%). The p-factor PGS was only associated with the trajectory that showed increasing depression over time - low increasing. There was also a specific indirect effect by which the association of p-factor PGS on early adult peaked and high declining depression was partially mediated by negative emotionality, but not by picture vocabulary or novelty seeking. Our findings reinforce the crucial role of development in genetically-informed RDoC models of depression, as there appear to be distinct correlates and risk factors that underlie the various developmental pathways of depression. Clinical implications were also discussed. General Scientific SummaryThere are individual differences in how depression symptoms progress over time, but little is known about the risk factors that underlie these various patterns of development. This study suggests that there are distinct correlates and risk factors that underlie the various developmental pathways of depression. We found that transdiagnostic polygenic risks for psychopathology are directly associated with worsening patterns of adolescent to adult depression and indirectly associated with the less severe patterns of depression via negative emotionality.

IntroductionPsychedelics are emerging as potential treatments for neuropsychiatric conditions, with evidence suggesting a single administration can lead to enduring behavioural changes. While the underlying putative mechanism(s) remain unclear, there is evidence supporting altered learning as a key candidate. AimThis systematic review examined studies assessing the effects of psychedelics on associative learning in both humans and animals. MetodsElectronic databases were searched up until 13/01/2025 for studies investigating any difference in learning after psychedelic administration. Results31 studies were included (29 in animals, 2 in humans). Classical and operant conditioning paradigms were employed, including fear extinction, conditioned avoidance, and reversal learning. Studies assessed acute and post-acute effects, however repeated dosing paradigms often obscured this distinction. There was considerable heterogeneity in study designs, paradigms, drug administration timings and doses, and behavioural effects appeared to be influenced by dose, timing, training intensity, and sex. Due to between-study heterogeneity, a meta-analysis was not possible. Evidence suggests that psychedelic administration enhances associative learning in animals across paradigms, although findings were not entirely consistent. Possible mechanisms identified were increased prediction error sensitivity, serotonin receptor agonism, and structural plasticity. Learning enhancements may extend into the post-acute phase and appear to depend on active environmental engagement during this window. ConclusionStudies suggest that psychedelics enhance associative learning in animals; however, these findings are yet to be translated into humans. Understanding whether a period of enhanced learning follows the psychedelic experience may have important implications for psychedelic-assisted psychotherapy, where behavioural changes must generalise and persist beyond the drug-induced state.

ImportanceCognitive impairment is a common feature of both symptomatic and remitted states of depression that is associated with poorer psychosocial outcomes and treatment non-response. As such, finding treatments to maintain or enhance cognition in people with depression is imperative. ObjectiveTo investigate the efficacy and moderators of computerized cognitive training (CCT) for cognitive and functional outcomes in people with depression. Data SourcesMEDLINE, EMBASE and PsycINFO databases were screened from inception through to 08 September 2022, with no language or publication type restrictions. Study SelectionTwo independent reviewers conducted duplicate study screening and assessed against the following inclusion criteria: (1) adults (mean age 18 years or older) with depression, (2) CCT with minimum three hours practice, (3) active or passive control group, (4) cognitive and/or functional outcomes measured at baseline and post-intervention, (5) randomized controlled trials. Of 4245 identified studies, 34 met selection criteria. Data Extraction and SynthesisThe methods used followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data extraction and risk of bias assessment using the revised Cochrane Risk of Bias Tool (RoB2) was conducted independently by two reviewers. Analyses were conducted using robust variance estimation. OutcomesThe primary outcome was change from baseline to post-intervention in overall cognition. Secondary outcomes were depressive symptoms, psychiatric symptoms, psychosocial functioning, daily functioning, subjective cognition, global cognition and domain-specific cognitive function. ResultsThirty-four studies encompassing 39 comparisons and 2041 unique participants met inclusion criteria. The pooled effect size of CCT was small for both overall cognition (g=0.28; 95% CI 0.17 to 0.38; P<.001; {tau}2=0.078; I2=47%; 95% prediction interval -0.31 to 0.86) and depressive symptoms (g=0.23; 95% CI 0.08 to 0.39; P=.004; {tau}2=0.066; I2=45%; 95% prediction interval -0.32 to 0.78). Benefits of CCT were also found for psychosocial functioning, subjective cognition, fluid reasoning, long-term memory and retrieval, low working memory, shifting, inhibition and processing speed. Greater CCT dose and multidomain programs were associated with greater cognitive response to CCT. There was no evidence for difference across clinical subtypes or between delivery modalities. Conclusions and RelevanceThis systematic review and meta-analysis indicates that CCT is an efficacious intervention for overall cognition, depressive symptoms, psychosocial functioning, subjective cognition, and many domain-specific cognitive functions for people with depression.

BackgroundThere is considerable variability in emotional and behavioural outcomes of children whose mothers experience depression. Few longitudinal studies have examined potential contributions of dimensions of paternal involvement in the association between maternal postnatal depression (PND) and offspring development. MethodsWe examined pathways from maternal PND at 8 weeks postnatally (assessed using the Edinburgh Postnatal Depression Scale) to offspring emotional and behavioural development at 7 years (assessed using the Strengths and Difficulties Questionnaire) through behavioural, affective and cognitive child-focused and mother-influenced dimensions of paternal involvement in 3,434 members of the UK-based birth cohort, the Avon Longitudinal Study of Parents and Children. Analyses were adjusted for a range of baseline confounders and paternal postnatal depression (PND) as an intermediate confounder. ResultsMaternal PND was associated with higher levels of some aspects of child-focused and mother-influenced paternal involvement in models accounting for paternal PND, however these pathways were not associated with offspring emotional and behavioural development at age 7 years. There was strong evidence of direct effect from maternal PND to offspring development, but no evidence of mediation through the combination of all indirect pathways through child-focused and mother-influenced paternal involvement. However, higher levels of father-child conflict were associated with increased risk of offspring emotional and behavioural difficulties, and this pathway mediated a proportion of the maternal PND to offspring risk. Additionally, maternal PND was associated with paternal PND, which, in turn, was associated with lower levels of child-focused and mother-influenced paternal involvement. ConclusionsThe positive associations between maternal PND and some aspects of paternal involvement suggest that non-depressed fathers may engage in compensatory parenting strategies in response to maternal PND, which although important may not be sufficient in reducing the adverse impact of maternal PND on offspring emotional and behavioural development. Conflictual father-child relationships emerged as a risk factor for adverse offspring development and as an explanatory mechanism in the association between maternal PND and offspring development. These results suggest that interventions that reduce father-child conflict may reduce the risk of emotional and behavioural difficulties in offspring of depressed mothers.

BackgroundPsychiatric and somatic problems are highly prevalent, often co-occur and share part of their genetic background. Low socio-economic status (SES) is a risk factor for both. We examined whether low SES amplifies the effects of genetic susceptibility on depression, anxiety, body mass index (BMI), waist-hip-ratio (WHR), smoking and alcohol use, investigating and aggregated outcomes. MethodsData came from the population-based Lifelines Cohort Study (n=50,761). Anxiety, depression, body mass index, waist-hip-ratio, smoking, and alcohol use were analyzed individually and collectively using confirmatory factor analysis to model shared variance among outcomes. Polygenic risk scores (PRSs) were calculated based on recent genome-wide association studies (GWASs) of specific conditions. We performed GWASs and derived PRS of aggregated outcomes using genomic structural equation modelling (SEM). A latent SES factor was generated by educational attainment, occupational status, and disposable household income. Interaction effects of SES indices with PRSs were estimated using linear mixed regression. ResultsEight of ten PRSs-by-SES interactions were significant (ps<0.05) for depression, anxiety, BMI, smoking, and aggregated outcome level, but not for WHR (p=0.07) and alcohol use (p=0.67). Lower SES amplified the effects of PRSs on depression, anxiety, BMI, and smoking. At the aggregated outcome level, interaction effects were mostly smaller than effects for individual outcomes. ConclusionsOur study demonstrates polygenic risk-by-SES interaction effects on depression, anxiety, BMI, and smoking. However, the effects were attenuated for PRSs derived from genomic SEM and aggregated outcomes, indicating limited additional etiological insights from modelling genetic and phenotypic overlap.

ImportanceDepression and anxiety are common mood disorders that show higher prevalence in adults with joint hypermobility, a consequence of a constitutional variant of connective tissue structure. In adolescents, an association between mood disorder and hypermobility may enhance the potential understanding of risk factors for emotional disorder and provide opportunities for early intervention approaches. ObjectiveTo test the hypothesis that joint hypermobility, a consequence of constitutional variant of connective tissue, is associated with common mental illness in adolescents. DesignThis was a longitudinal prospective study. SettingThe Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective ongoing general population birth cohort study based in Avon County, England. ParticipantsThe original data set comprised 6105 individuals from the cohort with data available on joint hypermobility at age 14 years; a sub-sample (n=3803) had later psychiatric assessments. Measurement of ExposureJoint hypermobility was measured by physical examination at age 14 and 18 years, using the Beighton Scale Main Outcome and MeasuresParticipants were assessed at age 18 years. ICD-10 diagnoses of Depression and Anxiety were obtained using the Clinical Interview Schedule-Revised (CIS-R) and levels of anxiety quantified using the Anxiety Sensitivity Index (ASI) ResultsPresence of generalized joint hypermobility (GJH) at age 14 years predicted depression at 18 years in males (Odds Ratio (OR) 2.10; 95%CI, 1.17-3.76) but not females After accounting for missing data it was determined that this relationship was mediated by heart rate, a potential measure of physiological arousal. Symptomatic hypermobility ((GJH plus chronic widespread pain (CWP)) at age 18 years was further associated with the presence of anxiety disorder (OR 3.13; 95% CI 1.52-6.46) and level of anxiety (Beta = 0.056, t(3315)=3.27), depressive disorder (adjusted OR 3.52; 95%CI, 1.67 - 7.40) and degree of psychiatric symptomatology (Beta 0.096, t(2064)=4.38) Conclusions and relevanceGeneralized joint hypermobility and symptomatic hypermobility are associated with common mental disorders in adolescence. Consideration of hypermobility may provide important opportunities for intervention to mitigate psychiatric disorder. KEY POINTSO_ST_ABSQuestionC_ST_ABSIs joint hypermobility related to depression and anxiety in adolescence? FindingsIn this longitudinal study presence of generalized joint hypermobility at 14 predicted subsequent adolescent depression in males only and this relationship was mediated by heart rate. At age 18 symptomatic hypermobility was associated with both presence of anxiety and depression and psychiatric symptom severity. MeaningGeneralized joint hypermobility and symptomatic hypermobility are associated with common mental disorders in adolescence.

BackgroundAnorexia nervosa (AN) is a severe psychiatric disorder associated with profound malnutrition, multisystem medical complications, and one of the highest mortality rates among mental illnesses. Despite decades of research into its biological and neurocognitive mechanisms, effective pharmacological treatments remain limited. While systematic reviews synthesize results from published studies, clinical trial registries offer a complementary perspective by capturing ongoing research efforts, discontinued studies, and emerging therapeutic strategies that may not yet be reflected in the published literature. ObjectiveThis study aimed to characterize the landscape of clinical research in AN by systematically analyzing studies registered on ClinicalTrials.gov. MethodsWe conducted a structured analysis of studies registered on ClinicalTrials.gov related to AN. Trial characteristics, including study design, intervention type, phase classification, geographic distribution, and recruitment status, were extracted and analyzed using an automated text-based classification pipeline. ResultsNearly 400 studies investigating AN were identified over the past 25 years. Approximately 71% were classified as interventional studies; however, a large proportion were not associated with conventional clinical trial phases, suggesting that many registered trials correspond to mechanistic or exploratory investigations rather than therapeutic development programs. The geographic distribution of studies revealed a strong predominance of North America and Western Europe. A substantial proportion of trials were terminated or discontinued, highlighting the significant challenges associated with conducting interventional studies in this population. Observational studies generally included larger sample sizes than interventional trials. ConclusionsRegistry-based analyses provide valuable insights into the evolving landscape of clinical research in AN. Despite considerable scientific activity, important gaps remain between mechanistic knowledge and the development of therapeutic interventions. Understanding these gaps may help inform future translational research strategies aimed at improving treatment options for this severe disorder.

Background and AimsExperiencing a traumatic event may lead to Posttraumatic Stress Disorder (PTSD), including symptoms such as flashbacks and hyperarousal. Individuals suffering from PTSD are at increased risk of cardiovascu-lar disease (CVD), but it is unclear why. This study assesses shared genetic liability and potential causal pathways between PTSD and CVD. MethodsWe leveraged summary-level data of genome-wide association studies (PTSD: N= 1,222,882; atrial fibril-lation (AF): N=482,409; coronary artery disease (CAD): N=1,165,690; hypertension: N=458,554; heart failure (HF): N=977,323). First, we estimated genetic correlations and utilized genomic structural equation modeling to identify a common genetic factor for PTSD and CVD. Next, we assessed biological, behavioural, and psychosocial factors as potential mediators. Finally, we employed multivariable Mendelian randomiza-tion to examine causal pathways between PTSD and CVD, incorporating the same potential mediators. ResultsSignificant genetic correlations were found between PTSD and CAD, HT, and HF (rg =0.21-0.32, p[&le;] 3.08 {middle dot} 10*16), but not between PTSD and AF. Insomnia, smoking, alcohol dependence, waist-to-hip ratio, and inflammation (IL6, C-reactive protein) partly mediated these associations. Mendelian randomization indicated that PTSD causally increases CAD (IVW OR=1.53, 95% CIs=1.19-1.96, p=0.001), HF (OR=1.44, CIs=1.08-1.92, p=0.012), and to a lesser degree hypertension (OR=1.25, CIs=1.05-1.49, p=0.012). While insomnia, smoking, alcohol, and inflammation were important mediators, independent causal effects also remained. ConclusionsIn addition to shared genetic liability between PTSD and CVD, we present strong evidence for causal effects of PTSD on CVD. Crucially, we implicate specific lifestyle and biological mediators (insomnia, substance use, inflammation) which has important implications for interventions to prevent CVD in PTSD patients. Translational perspectiveThe significant mental and physical strain experienced by patients suffering from Post-traumatic Stress Disorder (PTSD) remains a domain necessitating further insight for the development of effective intervention strategies. Our study elucidates the complex genetic architecture that underlies the relationship between PTSD and cardiovascular disease. We present evidence supporting a causal link from PTSD to coronary artery disease and heart failure. Further, we identify various mediators of this causality, including inflammatory markers, substance use, waist-to-hip ratio and sleep deprivation. Our work calls for tar-geted preventive and therapeutic approaches to reduce the dual burden of mental and physical disease in PTSD patients.

BackgroundThis study elucidates the intricate relationship between stressful life events and the development of ADHD symptoms in children, acknowledging the considerable variability in individual responses. By examining these differences, we aim to uncover the unique combinations of factors contributing to varying levels of vulnerability and resilience among children. MethodsUtilizing longitudinal data from the Adolescent Brain Cognitive Development study (baseline: N=6303, age=9.9), we applied Generalized Random Forest to model the non-linear relationships among genetic predispositions, brain features, and environmental factors. ResultsSignificant individual variability was observed in childrens ADHD symptoms post-stress, particularly at the 1-year and 2-year follow-ups. At the 1-year follow-up, increased vulnerability was indicated by heightened parental mental health problems and a lower polygenic risk score for smoking. By the 2-year follow-up, escalated parental mental health disorders, higher ADHD polygenic risk scores, and altered structural connectivity in the cognitive control network were significant contributors to individual differences. ConclusionsThese findings underscore the importance of integrating environmental, genetic, and neural variables to identify children vulnerable or resilient to developing ADHD symptoms following early-life stress. This study demonstrates how multimodal data combined with non-parametric machine-learning can advance precision psychology and psychiatry, aiding targeted support for affected children.

BackgroundUnderstanding the nature of cognitive deficits in anxiety and depression may identify intervention targets and help prevent functional decline. This study used observational and genetic methods to investigate the association of anxiety and depression with emotion recognition, response inhibition, and working memory, in young adulthood. MethodsThe Avon Longitudinal Study of Parents and Children (ALSPAC) is a large prospective birth cohort study. Participants completed regular postal questionnaires and in-clinic assessments, starting from September 6, 1990. Data collection is ongoing. Linear regression was used to assess 1) cross-sectional associations between anxiety, depression, and cognition at age 24 (n = 2,187) and 2) prospective associations between anxiety and depression at age 18 and cognition at age 24 (n = 1,855). Mendelian randomization analyses were conducted to assess causal pathways between anxiety, depression, and cognition. ResultsPrimary analyses were conducted on 3,087 participants following multiple imputation. There was evidence for anxiety being associated with a decreased recognition of happiness (b = -0.27, 95% CI -0.54 to 0.01, p = .045), and depression being associated with an increased recognition of sadness (b = 0.35, 95% CI 0.07 to 0.64, p = .016). Anxiety was negatively associated with working memory (b = -0.14, 95% CI -0.24 to 0.04, p = .005), but no association was found for depression (b = 0.06, 95% CI -0.05 to 0.16, p = .284). There was no evidence for any association with response inhibition. Results from Mendelian randomization analyses were inconclusive, likely due to low statistical power. ConclusionsThere was little evidence that anxiety and depression are associated with significant impairments in executive functioning. However, both anxiety and depression were associated with altered emotion recognition. This may inform the development of interventions that target psychosocial functioning.

BackgroundDevelopmental psychological trauma can impact several key neurocognitive domains, including reward processing, and is associated with increased risk of psychosis in adulthood. Aberrant reinforcement learning (RL), an important component of reward processing, has been implicated in the pathophysiology of psychosis by altering information processing through changes in hierarchical predictive coding. We therefore sought to investigate RL in survivors of developmental trauma and its relationship to psychotic experiences. MethodsWe recruited two groups of adults, one with self-reported exposure to multiple forms of developmental trauma (n=115), and a control group without any known history of maltreatment (n=85). Participants completed measures of psychotic experiences (Community Assessment of Psychic Experiences) and undertook a probabilistic selection task designed to assess RL from positive versus negative outcomes. We analysed group differences for main effects and investigated relationships between developmental trauma, RL and psychotic experiences using regression modelling and mediation analysis. ResultsDevelopmental trauma was associated with psychotic experiences (adjusted R2=0.41, p=0.004) and impaired RL (Fdf=6.291,89, p=0.014). Impaired RL mediated the association between developmental trauma and psychotic experiences (indirect effect {beta} = 0.60, 95% CI, 0.01-1.36). ConclusionsOur findings implicate aberrant RL as a possible mechanism through which developmental trauma may increase risk of psychosis. Further research is therefore warranted to understand the specific processes that characterise these putative trauma-induced vulnerability mechanisms and how they may contribute to the development of psychopathology.

While healthy lifestyle behaviours such as eating a high-quality diet are strongly linked to better mental health, our understanding of how adherence to specific national recommendations in at-risk populations can affect mental health outcomes is limited. This study investigates the relationship between adherence to the Australian diet, physical activity, alcohol use, and smoking guidelines and mental health outcomes in 182 adults experiencing psychological distress. By pooling data from both arms of the CALM trial, a non-inferiority study comparing lifestyle-based therapy to psychotherapy, we examined how adherence to national lifestyle guidelines and specific dietary components over eight weeks was associated with depression and anxiety outcomes. Higher diet quality (RR: 0.93; 0.91), greater physical activity (RR: 0.51; 0.63) and limiting alcohol consumption (RR: 0.59; 0.63) according to guidelines was linked to reduced risk of depression (PHQ-9) and anxiety (GAD-7) respectively, while increased intake of ultra-processed foods was associated with higher risk (RR:1.03; 1.23). Notably, the impact of intake of certain nutrients, such as fibre and omega-6 fatty acids, differed between depression and anxiety outcomes. These findings highlight the importance of integrating lifestyle modification into mental health prevention and treatment strategies and suggest that prescribing dietary behaviours based on national guidelines may offer practical mental health benefits.

Altered affect and cognitive dysfunction are transdiagnostic, burdensome, and pervasive features of many psychiatric conditions which remain poorly understood and have few efficacious treatments. Research on the genetic architecture of these phenotypes and causal relationships between them may provide insight into their aetiology and comorbidity. Using data from the Lifelines Cohort Study, we conducted genome-wide association studies (GWAS) on positive and negative affect and four cognitive domains (working memory, reaction time, visual learning and memory, executive function). Using publicly available large GWAS on related - albeit distinct-phenotypes (depression, anxiety, wellbeing, general cognitive ability [GCA]) we conducted genetic correlation and Mendelian randomization (MR) analyses to examine genetic overlap and causal relationships. We identified one genome-wide hit (p<5x10-8) for reaction time, and many loci with suggestive associations (p<5x10-6; N range= 11-20 independent hits) for other phenotypes. For most phenotypes, gene mapping and tissue expression analysis of suggestive hits from the GWAS showed increased gene expression in brain tissue compared to other tissues. As predicted, negative affect is genetically correlated with mental health phenotypes (depression rg=0.51; anxiety rg=0.70; wellbeing rg = -0.71) and cognitive domains are genetically correlated with GCA and brain volume (rg [&le;] 0.66). Genetic correlations between negative and positive affect suggest that they are dissociable constructs (rg = -0.18) with negative affect having higher genetic overlap with GCA than positive affect (rg =-0.19 vs -0.06). This could indicate that negative affect has a higher shared neural basis with GCA than positive affect and/or GCA and negative affect may exhibit causal relationships. MR analyses suggest potential causal effects of higher GCA on reduced negative affect, reduced risk of depression and anxiety, and higher wellbeing, but little impact on positive affect. We also report evidence for potential causal effects of depression and lower wellbeing on reduced GCA. Taken together, these results suggests that GCA may be a valid target for negative affect (but not positive affect) and depression and wellbeing may be valid targets for GCA.

Increasing evidence suggests that personalizing treatment for depression requires a refined understanding of how interventions affect distinct symptom domains, rather than focusing on total symptom scores. Different treatments may influence specific symptoms in unique ways, and these symptoms can interact dynamically - a relationship that can be explored using network modeling. In this observational, naturalistic study, we applied single-symptom and network analyses to examine symptom changes in depressed inpatients (total n=108) receiving either treatment as usual (TAU; psychotherapy and pharmacotherapy) (n=62) or adjunctive repetitive transcranial magnetic stimulation (rTMS) (n=46). While overall symptom reduction and changes within individual symptom domains did not differ significantly between groups, network analyses revealed marked differences in symptom interrelations: In the TAU group, loss of energy and depressed mood emerged as the most central symptoms within the course of symptom change, whereas in the rTMS group, loss of interest and decreased concentration were most central and influential. These findings highlight the importance of examining treatment effects at the single-symptom level and considering the complex interconnections among symptoms when evaluating and personalizing interventions for depression.

BackgroundCannabis and tobacco use are consistently associated with major depressive disorder (MDD) in conventional observational studies. However, these substances are often co-used, and the independent causal role of cannabis use in risk of MDD remains unclear. MethodsUnivariable and multivariable MR (MVMR) were used to explore the total and independent causal effects of genetic liability to tobacco use and cannabis use on MDD. Our primary estimator was the inverse-variance weighted (IVW) method, with other methods as sensitivity analyses. For the exposures, we used genome-wide association study (GWAS) summary statistics among European ancestry individuals for several tobacco use (i.e., smoking initiation, smoking continuation, smoking heaviness) and cannabis use (i.e., cannabis initiation, cannabis use disorder [CUD]) phenotypes. For the outcome, a GWAS of MDD was conducted using individual-level data from UK Biobank. ResultsUnivariable MR indicated a causal effect of smoking initiation on MDD (odds ratio [OR]IVW = 1.34, 95% confidence interval [CI] = 1.27 - 1.42), with consistent but weaker evidence for smoking continuation (ORIVW = 1.13, 95% CI = 0.93 - 1.37) and smoking heaviness (ORIVW = 1.15, 95% CI = 0.99 - 1.33). There was no clear evidence for a causal effect of cannabis initiation on MDD (ORIVW = 1.00, 95% CI = 0.91- 1.11). Univariable MR indicated some evidence for a causal effect of CUD on MDD (ORIVW = 1.14, 95% CI = 1.04 - 1.25), which attenuated to the null when adjusting for liability to smoking initiation (ORMVMR-IVW = 1.03, 95% CI = 0.97 - 1.08). ConclusionsThis study provides limited evidence for an independent causal effect of cannabis use on MDD, and stronger evidence for an independent causal effect of tobacco use on MDD. Analyses were limited by low power, and future research should triangulate these findings with results from high-quality observational studies.

Structured AbstractO_ST_ABSImportanceC_ST_ABSPsychiatric disorders display high levels of comorbidity and genetic overlap, necessitating multivariate approaches for parsing convergent and divergent psychiatric risk pathways. Identifying gene expression patterns underlying cross-disorder risk also stands to propel drug discovery and repurposing in the face of rising levels of polypharmacy. ObjectiveTo identify gene expression patterns underlying genetic convergence and divergence across psychiatric disorders along with existing pharmacological interventions that target these genes. DesignThis genomic study applied a multivariate transcriptomic method, Transcriptome-wide Structural Equation Modeling (T-SEM), to investigate gene expression patterns associated with four genomic factors indexing shared risk across 11 major psychiatric disorders. Follow-up tests, including overlap with gene sets for other outcomes and phenome-wide association studies, were conducted to better characterize T-SEM results. Public databases describing drug-gene pairs were used to identify drugs that could be repurposed to target genes found to be associated with cross-disorder risk. Main Outcomes and MeasuresGene expression patterns associated with genomic factors or disorder-specific risk and existing drugs that target these genes. ResultsIn total, T-SEM identified 451 genes whose expression was associated with the genomic factors and 41 genes with disorder-specific effects. We find the most hits for a Thought Disorders factor defined by bipolar disorder and schizophrenia. We identify 39 existing pharmacological interventions that could be repurposed to target gene expression hits for this same factor. Conclusions and RelevanceThe findings from this study shed light on patterns of gene expression associated with genetic overlap and uniqueness across psychiatric disorders. Future versions of the multivariate drug repurposing framework outlined here have the potential to identify novel pharmacological interventions for increasingly common, comorbid psychiatric presentations.