The long-term effectiveness of a personality-targeted substance use prevention program on aggression from adolescence to early adulthood.

BACKGROUND: Addressing aggressive behavior in adolescence is a key step toward preventing violence and associated social and economic costs in adulthood. This study examined the secondary effects of the personality-targeted substance use preventive program Preventure on aggressive behavior from ages 13 to 20. METHODS: In total, 339 young people from nine independent schools (M age = 13.03 years, s.d. = 0.47, range = 12-15) who rated highly on one of the four personality traits associated with increased substance use and other emotional/behavioral symptoms (i.e. impulsivity, anxiety sensitivity, sensation seeking, and negative thinking) were included in the analyses (n = 145 in Preventure, n = 194 in control). Self-report assessments were administered at baseline and follow-up (6 months, 1, 2, 3, 5.5, and 7 years). Overall aggression and subtypes of aggressive behaviors (proactive, reactive) were examined using multilevel mixed-effects analysis accounting for school-level clustering. RESULTS: Across the 7-year follow-up period, the average yearly reduction in the frequency of aggressive behaviors (b = -0.42; 95% confidence interval [CI] -0.64 to -0.20; p < 0.001), reactive aggression (b = -0.22; 95% CI 0.35 to -0.10; p = 0.001), and proactive aggression (b = -0.14; 95% CI -0.23 to -0.05; p = 0.002) was greater for the Preventure group compared to the control group. CONCLUSIONS: The study suggests a brief personality-targeted intervention may have long-term impacts on aggression among young people; however, this interpretation is limited by imbalance of sex ratios between study groups.

Effect of a selective personality-targeted prevention program on 7-year illicit substance related outcomes: A secondary analysis of a cluster randomized controlled trial.

BACKGROUND: This study evaluated the efficacy of the selective personality-targeted PreVenture program in reducing cannabis and stimulant use over a 7-year period spanning adolescence and early adulthood. METHODS: A cluster randomized controlled trial was conducted in 14 Australian schools. Schools were randomized to PreVenture, a brief personality-targeted selective intervention, comprising two 90-minute facilitator-led sessions delivered one week apart, or a control group (health education as usual). Only students who scored highly on one of four personality traits (anxiety sensitivity, negative thinking, impulsivity, sensation seeking) were included. Students completed online self-report questionnaires between 2012 and 2019: at baseline; post-intervention; 1-, 2-, 3-, 5.5- and 7-years post-baseline. Outcomes were past 6-months cannabis use, stimulant use (MDMA, methamphetamine or amphetamine) and cannabis-related harms. RESULTS: The sample comprised 438 adolescents (Mage=13.4 years; SD=0.47) at baseline. Retention ranged from 51% to 79% over the 7-years. Compared to controls, the PreVenture group had significantly reduced odds of annual cannabis-related harms (OR=0.78, 95% CI=0.65-0.92). However, there were no significant group differences in the growth of cannabis use (OR=0.84, 95% CI=0.69-1.02) or stimulant use (OR=1.07, 95% CI=0.91-1.25) over the 7-year period. CONCLUSIONS: PreVenture was effective in slowing the growth of cannabis-related harms over time, however owing to missing data over the 7-year trial, replication trials may be warranted to better understand the impact of the PreVenture intervention on cannabis and stimulant use among young Australians. Alternative implementation strategies, such as delivering the intervention in later adolescence and/or providing booster sessions, may be beneficial.

High peak drinking levels mediate the relation between impulsive personality and injury risk in emerging adults.

BACKGROUND: Alcohol-induced injury is one of the leading causes of preventable morbidity and mortality. We investigated the relationship between impulsive personality and physical injury (e.g. falls, sports), and whether peak drinking quantity specifically, and/or risky behaviour more generally, mediates the relationship between impulsivity and injury in undergraduates. METHOD: We used data from the winter 2021 UniVenture survey with 1316 first- and second-year undergraduate students aged 18-25 years (79.5% female) from five Canadian Universities. Students completed an online survey regarding their demographics, personality, alcohol use, risky behaviours, and injury experiences. Impulsivity was measured with the substance use risk profile scale, past 30-day peak alcohol use with the quantity-frequency-peak Alcohol Use Index, general risky behaviour with the risky behaviour questionnaire, and past 6-month injury experience with the World Health Organization's (2017) injury measurement questionnaire. RESULTS: Of 1316 total participants, 12.9% (n = 170) reported having sustained a physical injury in the past 6 months. Mean impulsivity, peak drinking quantity, and risky behaviour scores were significantly higher among those who reported vs. did not report injury. Impulsivity and peak drinking quantity, but not general risky behaviour, predicted injury in a multi-level generalized mixed model. Mediation analyses supported impulsivity as both a direct predictor of physical injury and an indirect predictor through increased peak drinking (both p < .05), but not through general risky behaviour. CONCLUSION: Results imply emerging adults with impulsive tendencies should be identified for selective injury prevention programs and suggest targeting their heavy drinking to decrease their risk for physical injury.

Neuroscience-informed classification of prevention interventions in substance use disorders: An RDoC-based approach.

Neuroscience has contributed to uncover the mechanisms underpinning substance use disorders (SUD). The next frontier is to leverage these mechanisms as active targets to create more effective interventions for SUD treatment and prevention. Recent large-scale cohort studies from early childhood are generating multiple levels of neuroscience-based information with the potential to inform the development and refinement of future preventive strategies. However, there are still no available well-recognized frameworks to guide the integration of these multi-level datasets into prevention interventions. The Research Domain Criteria (RDoC) provides a neuroscience-based multi-system framework that is well suited to facilitate translation of neurobiological mechanisms into behavioral domains amenable to preventative interventions. We propose a novel RDoC-based framework for prevention science and adapted the framework for the existing preventive interventions. From a systematic review of randomized controlled trials using a person-centered drug/alcohol preventive approach for adolescents, we identified 22 unique preventive interventions. By teasing apart these 22 interventions into the RDoC domains, we proposed distinct neurocognitive trajectories which have been recognized as precursors or risk factors for SUDs, to be targeted, engaged and modified for effective addiction prevention.

Do anxiety symptoms and coping motives serially mediate the association between psychotic-like experiences and cannabis-related problems in undergraduate recent cannabis users?

Many Canadian emerging adults (ages 18-25 years) use cannabis, with 60 % of past-three-month users experiencing one or more cannabis-related problems (i.e., adverse consequences of use). While psychotic-like experiences (PLEs) and cannabis problems overlap, little is known about the mechanisms explaining this link. One hypothesis is that PLEs are distressing and give rise to anxiety, with which emerging adults attempt to cope through increased cannabis use, in turn increasing their risk for cannabis-related problems. We tested a chained-mediational model to determine if anxiety and coping-with-anxiety motives for cannabis use sequentially mediated the link between PLEs and cannabis problems in emerging adult undergraduates; a conditional process model tested for moderation by sex. Emerging adult cannabis users (N = 413; mean [SD] age = 19.1 [1.5] years; 71.9 % female) from five Canadian universities provided cross-sectional, self-report survey data in fall 2021. Validated measures of PLEs, anxiety, cannabis coping-with-anxiety motives, and cannabis-related problems were administered. Path analyses supported the hypothesized chained mediational indirect effect (b = 0.027, 95 % bootstrap CI [0.012, 0.050]). No direct effect was found (p =.698), suggesting that the PLEs-to-cannabis problems association is fully explained by anxiety and cannabis coping-with-anxiety motives. Inconsistent with hypotheses, mediation did not depend on sex (95 % CIs crossed zero); therefore, anxiety and cannabis coping-with-anxiety motives explain the link between PLEs and cannabis problems in emerging adults regardless of their sex. Results highlight anxiety and cannabis coping-with-anxiety motives as potentially important intervention targets in cannabis-using emerging adults with PLEs, possibly preventing the development/worsening of cannabis-related problems.

Normative Modeling of Brain Morphometry Across the Lifespan Using CentileBrain: Algorithm Benchmarking and Model Optimization.

We present an empirically benchmarked framework for sex-specific normative modeling of brain morphometry that can inform about the biological and behavioral significance of deviations from typical age-related neuroanatomical changes and support future study designs. This framework was developed using regional morphometric data from 37,407 healthy individuals (53% female; aged 3-90 years) following a comparative evaluation of eight algorithms and multiple covariate combinations pertaining to image acquisition and quality, parcellation software versions, global neuroimaging measures, and longitudinal stability. The Multivariate Factorial Polynomial Regression (MFPR) emerged as the preferred algorithm optimized using nonlinear polynomials for age and linear effects of global measures as covariates. The MFPR models showed excellent accuracy across the lifespan and within distinct age-bins, and longitudinal stability over a 2-year period. The performance of all MFPR models plateaued at sample sizes exceeding 3,000 study participants. The model and scripts described here are freely available through CentileBrain (https://centilebrain.org/).

Independent contribution of polygenic risk for schizophrenia and cannabis use in predicting psychotic-like experiences in young adulthood: testing gene × environment moderation and mediation.

BACKGROUND: It has not yet been determined if the commonly reported cannabis-psychosis association is limited to individuals with pre-existing genetic risk for psychotic disorders. METHODS: We examined whether the relationship between polygenic risk score for schizophrenia (PRS-Sz) and psychotic-like experiences (PLEs), as measured by the Community Assessment of Psychic Experiences-42 (CAPE-42) questionnaire, is mediated or moderated by lifetime cannabis use at 16 years of age in 1740 of the individuals of the European IMAGEN cohort. Secondary analysis examined the relationships between lifetime cannabis use, PRS-Sz and the various sub-scales of the CAPE-42. Sensitivity analyses including covariates, including a PRS for cannabis use, were conducted and results were replicated using data from 1223 individuals in the Dutch Utrecht cannabis cohort. RESULTS: PRS-Sz significantly predicted cannabis use (p = 0.027) and PLE (p = 0.004) in the IMAGEN cohort. In the full model, considering PRS-Sz and covariates, cannabis use was also significantly associated with PLE in IMAGEN (p = 0.007). Results remained consistent in the Utrecht cohort and through sensitivity analyses. Nevertheless, there was no evidence of a mediation or moderation effects. CONCLUSIONS: These results suggest that cannabis use remains a risk factor for PLEs, over and above genetic vulnerability for schizophrenia. This research does not support the notion that the cannabis-psychosis link is limited to individuals who are genetically predisposed to psychosis and suggests a need for research focusing on cannabis-related processes in psychosis that cannot be explained by genetic vulnerability.

The four-factor personality model and its qualitative correlates among opioid agonist therapy clients.

Background: The Four Factor Personality Vulnerability model identifies four specific personality traits (e.g., sensation seeking [SS], impulsivity [IMP], anxiety sensitivity [AS], and hopelessness [HOP]) as implicated in substance use behaviors, motives for substance use, and co-occurring psychiatric conditions. Although the relationship between these traits and polysubstance use in opioid agonist therapy (OAT) clients has been investigated quantitatively, no study has examined the qualitative expression of each trait using clients' voice. Method: Nineteen Methadone Maintenance Therapy (MMT) clients (68.4% male, 84.2% white, mean age[SD] = 42.71 [10.18]) scoring high on one of the four personality traits measured by the Substance Use Risk Profile Scale [SURPS] completed a semi-structured qualitative interview designed to explore their lived experience of their respective trait. Thematic analysis was used to derive themes, which were further quantified using content analysis. Results: Themes emerging from interviews reflected (1) internalizing and externalizing symptoms, (2) adversity experiences, and (3) polysubstance use. Internalizing symptoms subthemes included symptoms of anxiety, fear, stress, depression, and avoidance coping. Externalizing subthemes included anger, disinhibited cognitions, and anti-social and risk-taking behaviors. Adverse experiences subthemes included poor health, poverty, homelessness, unemployment, trauma, and conflict. Finally, polysubstance use subthemes include substance types, methods of use, and motives. Differences emerged between personality profiles in the relative endorsement of various subthemes, including those pertaining to polysubstance use, that were largely as theoretically expected. Conclusion: Personality is associated with unique cognitive, affective, and behavioral lived experiences, suggesting that personality may be a novel intervention target in adjunctive psychosocial treatment for those undergoing OAT.

The 3-year effects of a personality-targeted prevention program on general and specific dimensions of psychopathology.

This study aimed to examine the effect of a personality-targeted prevention program (Preventure) on trajectories of general and specific dimensions of psychopathology from early- to mid-adolescence. Australian adolescents (N = 2190) from 26 schools participated in a cluster randomized controlled substance use prevention trial. This study compared schools allocated to deliver Preventure (n = 13 schools; n = 466 students; Mage = 13.42 years), a personality-targeted selective intervention, with a control group (n = 7 schools; n = 235 students, Mage = 13.47 years). All participants were assessed for psychopathology symptoms at baseline, 6-, 12-, 24- and 36-months post-baseline. Outcomes were a general psychopathology factor and four specific factors: fear, distress, alcohol use/harms and conduct/inattention), extracted from a higher-order model. Participants who screened as 'high-risk' on at least one of four personality traits (negative thinking, anxiety sensitivity, impulsivity and sensation seeking) were included in intention-to-treat analyses. Intervention effects were examined using multi-level mixed models accounting for school-level clustering. Among high-risk adolescents, growth in general psychopathology was slower in the Preventure group compared to the control group (b = -0.07, p = 0.038) across the three years. After controlling for effects on general psychopathology, there were no significant, additional effects on the lower order factors. This study provides evidence for the effectiveness of a selective personality-targeted intervention in altering trajectories of general psychopathology during adolescence. This finding represents impacts on multiple symptom domains and highlights the potential for general psychopathology as an intervention target.

Do Anxiety Symptoms Mediate the Association Between Cannabis Use Frequency and Psychotic-Like Experiences in Emerging Adult Undergraduates?

OBJECTIVE: Cannabis is commonly used by Canadian emerging adults (ages 18-25 years), many of whom attend post-secondary institutions. Frequent cannabis use is linked with psychotic-like experiences (PLEs); however, the exact nature of this association remains unclear. Anxiety symptoms may mediate this association, as they are prevalent in emerging adults and have been independently linked with both cannabis use and PLEs. Past work found that anxiety mediated the association between cannabis use frequency and attenuated positive psychotic symptoms (further along the psychosis continuum than PLEs), however this research had yet to be validated in the Canadian population, and trait rather than state anxiety (frequency of anxiety symptoms) was studied. Thus, our primary objective was to examine if anxiety symptoms mediated the association between cannabis use frequency and PLEs in Canadian emerging adult undergraduates. Despite known sex differences in cannabis use, expression of anxiety, and PLEs, past work did not evaluate the potential impact of biological sex on the anxiety-mediated model, and thus is the secondary objective of the present study. METHODS: 1,266 first-/second-year emerging adult undergraduates from five Canadian universities provided cross-sectional, self-report survey data in fall 2021 semester. Validated measures of cannabis use frequency, anxiety, and PLEs were administered. RESULTS: Path analyses supported mediation from cannabis use to PLEs through anxiety (b = 0.07, P < 0.001, 95% bootstrap CI [0.03, 0.10]). No direct effect was found (P = 0.457), suggesting that the cannabis-to-PLEs association was mediated by anxiety. Mediation did not depend on biological sex (i.e., bootstrapped 95% CIs crossed zero). CONCLUSIONS: Anxiety symptoms mediated the association between cannabis use and PLEs in emerging adults regardless of their biological sex. Assuming replication in prospective research, results highlight anxiety as an important intervention target in frequent cannabis-using emerging adults, to potentially prevent development/worsening of PLEs, and in turn psychotic illness.

A longitudinal mediation study of peer victimization and resting-state functional connectivity as predictors of development of adolescent psychopathology.

Background: Peer victimization (PV) is associated with alterations in neural responses in regions subserving emotional regulatory processes and with increased risk of psychopathology during adolescence. The present study examined the longitudinal mediating effects of resting-state functional connectivity (rsFC) between adolescent PV and subsequent internalizing (depression and anxiety), and externalizing (conduct and hyperactivity/inattention) symptoms. Methods: 151 adolescents (baseline mean age 12-14; 54% males) were assessed and imaged three times during a five-year period. We focused on rsFC of a priori determined Regions-of-Interest (ROIs) guided by the literature (i.e., amygdala, anterior and posterior insula, anterior cingulate cortex, and medial prefrontal cortex). Multilevel mediation (MLM) analyses simultaneously examined the between-person, concurrent within-person, and lagged within-person associations between PV and internalizing/externalizing symptoms through changes in couplings of the amygdala with the other four ROIs. All models controlled for the effects of self-reported childhood maltreatment and sex differences. Results: An increased rsFC of the amygdala-posterior insula significantly mediated the lagged within-person association of PV and internalizing symptoms (ß = 0.144; 95% CI [0.018, 0.332]). This effect was significant regardless of childhood maltreatment, concurrent externalizing symptoms, and sex differences. The rsFC did not mediate the relationship between PV and externalizing symptoms. Conclusions: Results of this study suggest that adolescent PV may lead to long-lasting maladaptive neural communication between emotional response and sensory perception of pain (i.e., bottom-up emotion regulation) and that these neural responses may serve as unique markers for increased internalizing symptoms that appear in later adolescence in peer-victimized youth. These findings have implications for interventions targeting internalizing symptoms in victimized adolescents.

Longitudinal associations between adolescent catch-up sleep, white-matter maturation and internalizing problems.

Sleep is an important contributor for neural maturation and emotion regulation during adolescence, with long-term effects on a range of white matter tracts implicated in affective processing in at-risk populations. We investigated the effects of adolescent sleep patterns on longitudinal changes in white matter development and whether this is related to the emergence of emotional (internalizing) problems. Sleep patterns and internalizing problems were assessed using self-report questionnaires in adolescents recruited in the general population followed up from age 14-19 years (N = 111 White matter structure was measured using diffusion tensor imaging (DTI) and estimated using fractional anisotropy (FA). We found that longitudinal increases in time in bed (TIB) on weekends and increases in TIB-variability between weekdays to weekend, were associated with an increase in FA in various interhemispheric and cortico-striatal tracts. Extracted FA values from left superior longitudinal fasciculus mediated the relationship between increases in TIB on weekends and a decrease in internalizing problems. These results imply that while insufficient sleep might have potentially harmful effects on long-term white matter development and internalizing problems, longer sleep duration on weekends (catch-up sleep) might be a natural counteractive and protective strategy.

Personality-specific pathways from bullying victimization to adolescent alcohol use: a multilevel longitudinal moderated mediation analysis.

Bullying victimization is common in adolescence and has been associated with a broad variety of psychopathology and alcohol use. The present study assessed time-varying associations between bullying victimization and alcohol use through internalizing and externalizing symptoms and whether this indirect association throughout time is moderated by personality. This 5-year longitudinal study (3,800 grade 7 adolescents) used Bayesian multilevel moderated mediation models: independent variable was bullying victimization; moderators were four personality dimensions (anxiety sensitivity, hopelessness, impulsivity, and sensation seeking); internalizing symptoms (anxiety, depressive symptoms) and externalizing symptoms (conduct, hyperactivity problems) were the mediators; and alcohol use, the outcome. Results indicated significant between, within, and lagged effects on alcohol use through internalizing and externalizing symptoms. There were significant between and within effects on alcohol use through internalizing symptoms for adolescents with high anxiety sensitivity and hopelessness, and significant between, within, and lagged effects on alcohol use through externalizing symptoms for adolescents with high impulsivity and sensation seeking. These findings implicate two risk pathways that account for how bullying victimization enhances alcohol use risk and emphasize the importance of personality profiles that can shape the immediate and long-term consequences of victimization.

Development of the French version of the Davos Assessment of Cognitive Biases Scale in a non-clinical sample of young adults.

BACKGROUND: In accordance with continuum and cognitive behaviour models of psychosis, cognitive biases precede the onset and the maintenance of positive symptoms. The Davos Assessment of Cognitive Biases Scale (DACOBS), a self-report measure, was developed to explore the prevalence of specific cognitive biases. This study aims to validate the French version of this instrument. METHODS: We first translated the English version of the DACOBS into French. Then, using a sample of 213 French speaking young adults (mean age = 20.54, SD = 1.65; 83% females), we examined the factor structure, internal consistency, concurrent, and convergent validities of the current version. RESULTS: We found an 18-item, four-factor version of the French DACOBS comprising external attribution bias (five items), social cognition problems (five items), subjective cognition problems (five items), and safety behaviours (five items), provided best fit-to-data. Internal consistency for the resulting subscales ranged from acceptable to excellent (Cronbach's α range = .62-.86). All subscales were significantly, positively associated with a measure of psychotic-like experiences and positively associated with established measures of theoretically relevant constructs, demonstrating concurrent and convergent validity of the French DACOBS. CONCLUSIONS: The French DACOBS is a reliable and valid and reliable instrument assessing cognitive biases, in a French-speaking youth population. Ultimately, the French DACOBS may be used to identify at-risk youth which may benefit from cognitive interventions targeting cognitive biases, safety behaviours and social cognition which could potentially prevent transition to psychosis in youth.

Pathways from adolescent screen time to eating related symptoms: a multilevel longitudinal mediation analysis through self-esteem.

OBJECTIVE: Screen time and self-esteem have been shown to be important correlates of eating disorders in adolescence. However, there is an absence of longitudinal studies that distinguish between time-varying factors, accounting for parallel developmental changes and common underlying vulnerability. DESIGN: A total of 3,801 adolescents were administered self-report measures, annually, over the course of 5 years. The association of screen time (social media use, television watching, video gaming) on eating related symptoms was analyzed using a longitudinal Bayesian multilevel path analysis framework. Self-esteem was examined as a mediating factor in this model. This study investigated direct and indirect associations at between-person, concurrent within-person, and lagged-within-person levels, while controlling for gender. RESULTS: The findings revealed that all types of screen time exposure were significantly associated with eating related symptoms at between and within-person levels. A significant association at the lagged-within person level was only revealed for social media use. Self-esteem was found to be a significant mediating factor between screen time and eating related symptoms. CONCLUSION: An increase in social media use one year was associated with increased of eating related symptoms two years later through lower self-esteem. Implications for prevention are discussed.

Effect of Selective Personality-Targeted Alcohol Use Prevention on 7-Year Alcohol-Related Outcomes Among High-risk Adolescents: A Secondary Analysis of a Cluster Randomized Clinical Trial.

Importance: Alcohol consumption is one of the leading preventable causes of burden of disease worldwide. Selective prevention of alcohol use can be effective in delaying the uptake and reducing harmful use of alcohol during the school years; however, little is known about the durability of these effects across the significant transition from early adolescence into late adolescence and early adulthood. Objective: To examine the sustained effects of a selective personality-targeted alcohol use prevention program on alcohol outcomes among adolescents who report high levels of 1 of 4 personality traits associated with substance use. Design, Setting, and Participants: A cluster randomized clinical trial was conducted to assess the effectiveness of the selective personality-targeted PreVenture program on reducing the growth of risky alcohol use and related harms from early to late adolescence and early adulthood. Participants included grade 8 students attending 14 secondary schools across New South Wales and Victoria, Australia, in 2012 who screened as having high levels of anxiety sensitivity, negative thinking, impulsivity, and/or sensation seeking. Schools were block randomized to either the PreVenture group (7 schools) or the control group (7 schools). The primary end point of the original trial was 2 years post baseline; the present study extends the follow-up period from July 1, 2017, to December 1, 2019, 7 years post baseline. Data were analyzed from July 22, 2021, to August 2, 2022. Interventions: The PreVenture program is a 2-session, personality-targeted intervention designed to upskill adolescents to better cope with their emotions and behaviors. Main Outcomes and Measures: Self-reported monthly binge drinking, alcohol-related harms, and hazardous alcohol use measured by the Alcohol Use Disorders Identification Test-Concise consumption screener. Results: Of 438 participants (249 male [56.8%]; mean [SD] age, 13.4 [0.5] years) from 14 schools, 377 (86.2%) provided follow-up data on at least 2 occasions, and among those eligible, 216 (54.0%) participated in the long-term follow-up. Compared with the control condition, the PreVenture intervention was associated with reduced odds of any alcohol-related harm (odds ratio [OR], 0.81 [95% CI, 0.70-0.94]) and a greater mean reduction in the frequency of alcohol-related harms (ß = -0.22 [95% CI, -0.44 to -0.003]) at the 7.0-year follow-up. There were no differences in the odds of monthly binge drinking (OR, 0.80 [95% CI, 0.56-1.13]) or hazardous alcohol use (OR, 0.87 [95% CI, 0.59-1.27]) at the 7.0-year follow-up. Exploratory analyses at the 5.5-year follow-up showed that compared with the control condition, the PreVenture intervention was also associated with reduced odds of monthly binge drinking (OR, 0.87, [95% CI, 0.77-0.99]) and hazardous alcohol use (OR, 0.91 [95% CI, 0.84-0.99]), but this was not sustained. Conclusions and Relevance: This study demonstrated that a brief selective personality-targeted alcohol use prevention intervention delivered in the middle school years can have sustained effects into early adulthood. Trial Registration: anzctr.org.au Identifier: ACTRN12612000026820.

Childhood maltreatment mediates the effect of the genetic background on psychosis risk in young adults.

Childhood maltreatment (CM) and genetic vulnerability are both risk factors for psychosis, but the relations between them are not fully understood. Guided by the recent identification of genetic risk to CM, this study investigates the hypothesis that genetic risk to schizophrenia also increases the risk of CM and thus impacts psychosis risk. The relationship between schizophrenia polygenetic risk, CM, and psychotic-like experiences (PLE) was investigated in participants from the Utrecht Cannabis Cohort (N = 1262) and replicated in the independent IMAGEN cohort (N = 1740). Schizophrenia polygenic risk score (SZ-PRS) were calculated from the most recent GWAS. The relationship between CM, PRS, and PLE was first investigated using multivariate linear regression. Next, mediation of CM in the pathway linking SZ-PRS and PLE was examined by structural equation modeling, while adjusting for a set of potential mediators including cannabis use, smoking, and neuroticism. In agreement with previous studies, PLE were strongly associated with SZ-PRS (B = 0.190, p = 0.009) and CM (B = 0.575, p < 0.001). Novel was that CM was also significantly associated with SZ-PRS (B = 0.171, p = 0.001), and substantially mediated the effects of SZ-PRS on PLE (proportion mediated = 29.9%, p = 0.001). In the replication cohort, the analyses yielded similar results, confirming equally strong mediation by CM (proportion mediated = 34.7%, p = 0.009). Our results suggest that CM acts as a mediator in the causal pathway linking SZ-PRS and psychosis risk. These findings open new perspectives on the relations between genetic and environmental risks and warrant further studies into potential interventions to reduce psychosis risk in vulnerable people.

How do substance use disorders compare to other psychiatric conditions on structural brain abnormalities? A cross-disorder meta-analytic comparison using the ENIGMA consortium findings.

Alcohol use disorder (AUD) and cannabis use disorder (CUD) are associated with brain alterations particularly involving fronto-cerebellar and meso-cortico-limbic circuitry. However, such abnormalities have additionally been reported in other psychiatric conditions, and until recently there has been few large-scale investigations to compare such findings. The current study uses the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium method of standardising structural brain measures to quantify case-control differences and to compare brain-correlates of substance use disorders with those published in relation to other psychiatric disorders. Using the ENIGMA protocols, we report effect sizes derived from a meta-analysis of alcohol (seven studies, N = 798, 54% are cases) and cannabis (seven studies, N = 447, 45% are cases) dependent cases and age- and sex-matched controls. We conduct linear analyses using harmonised methods to process and parcellate brain data identical to those reported in the literature for ENIGMA case-control studies of major depression disorder (MDD), schizophrenia (SCZ) and bipolar disorder so that effect sizes are optimally comparable across disorders. R elationships between substance use disorder diagnosis and subcortical grey matter volumes and cortical thickness were assessed with intracranial volume, age and sex as co-variates . After correcting for multiple comparisons, AUD case-control meta-analysis of subcortical regions indicated significant differences in the thalamus, hippocampus, amygdala and accumbens, with effect sizes (0.23) generally equivalent to, or larger than |0.23| those previously reported for other psychiatric disorders (except for the pallidum and putamen). On measures of cortical thickness, AUD was associated with significant differences bilaterally in the fusiform gyrus, inferior temporal gyrus, temporal pole, superior frontal gyrus, and rostral and caudal anterior cingulate gyri. Meta-analysis of CUD case-control studies indicated reliable reductions in amygdala, accumbens and hippocampus volumes, with the former effect size comparable to, and the latter effect size around half of that reported for alcohol and SCZ. CUD was associated with lower cortical thickness in the frontal regions, particularly the medial orbitofrontal region, but this effect was not significant after correcting for multiple testing. This study allowed for an unbiased cross-disorder comparison of brain correlates of substance use disorders and showed alcohol-related brain anomalies equivalent in effect size to that found in SCZ in several subcortical and cortical regions and significantly greater alterations than those found in MDD in several subcortical and cortical regions. Although modest, CUD results overlapped with findings reported for AUD and other psychiatric conditions, but appear to be most robustly related to reduce thickness of the medial orbitofrontal cortex.

Greater male than female variability in regional brain structure across the lifespan.

For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.