The temporal association between social isolation, distress, and psychotic experiences in individuals at clinical high-risk for psychosis.

BACKGROUND: Psychotic experiences (PEs) and social isolation (SI) seem related during early stages of psychosis, but the temporal dynamics between the two are not clear. Literature so far suggests a self-perpetuating cycle wherein momentary increases in PEs lead to social withdrawal, which, subsequently, triggers PEs at a next point in time, especially when SI is associated with increased distress. The current study investigated the daily-life temporal associations between SI and PEs, as well as the role of SI-related and general affective distress in individuals at clinical high risk (CHR) for psychosis. METHODS: We used experience sampling methodology in a sample of 137 CHR participants. We analyzed the association between SI, PEs, and distress using time-lagged linear mixed-effects models. RESULTS: SI did not predict next-moment fluctuations in PEs, or vice versa. Furthermore, although SI-related distress was not predictive of subsequent PEs, general affective distress during SI was a robust predictor of next-moment PEs. CONCLUSIONS: Our results suggest that SI and PEs are not directly related on a moment-to-moment level, but a negative emotional state when alone does contribute to the risk of PEs. These findings highlight the role of affective wellbeing during early-stage psychosis development.

Associations between childhood adversity, psychiatric symptoms, and self-esteem outcomes in adolescents and young adults: An experience sampling study.

OBJECTIVES: Self-esteem and self-esteem stability are important factors during adolescence and young adulthood that can be negatively impacted by childhood adversity and psychiatric symptoms. We examined whether childhood adversity and psychiatric symptoms are associated with decreased global self-esteem as well as increased self-esteem instability as measured with experience sampling method. In addition, we examined if childhood adversity moderates the association between psychiatric symptoms and self-esteem outcomes. METHODS: Our study consisted of 788 adolescents and young adults who were part of a twin pair. The twin structure was not of interest to the current study. Mean age was 16.8 (SD = 2.38, range: 14-25), 42% was male. We used a multilevel modeling approach to examine our hypotheses to account for the presence of twins in the data set. RESULTS: Childhood adversity and psychiatric symptoms were negatively associated with global self-esteem (respectively standardized ß = -.18, SE = 0.04, p < .0001 and standardized ß = -.45, SE = 0.04, p < .0001), with a larger effect for psychiatric symptoms. Similarly, both were associated with increased self-esteem instability (respectively standardized ß = .076, SE = 0.025, p = .002 and standardized ß = .11, SE = 0.021, p < .0001). In addition, interactions between childhood adversity and psychiatric symptoms on both global self-esteem (standardized ß = .06, SE = 0.01, p < .0001) and self-esteem instability (standardized ß = -.002, SE = 0.0006, p = .001) were found, showing that the negative association of psychiatric symptoms with self-esteem outcomes is less pronounced in young people with higher levels of childhood adversity, or formulated differently, is more pronounced in young people with little or no exposure to childhood adversity. CONCLUSION: Global self-esteem and self-esteem instability in young people are influenced by both current psychiatric symptomatology and exposure to childhood adversity. Those with more psychiatric symptoms show worse self-esteem and higher self-esteem instability, which is moderated by childhood adversity. For young people with high childhood adversity levels lower self-esteem and higher self-esteem instability are less influenced by reductions in psychiatric symptoms.

Polygenic risk, familial liability and stress reactivity in psychosis: an experience sampling study.

BACKGROUND: There is evidence for a polygenic contribution to psychosis. One targetable mechanism through which polygenic variation may impact on individuals and interact with the social environment is stress sensitization, characterized by elevated reactivity to minor stressors in daily life. The current study aimed to investigate whether stress reactivity is modified by polygenic risk score for schizophrenia (PRS) in cases with enduring non-affective psychotic disorder, first-degree relatives of cases, and controls. METHODS: We used the experience sampling method to assess minor stressors, negative affect, positive affect and psychotic experiences in 96 cases, 79 first-degree relatives, i.e. siblings, and 73 controls at wave 3 of the Dutch Genetic Risk and Outcome of Psychosis (GROUP) study. Genome-wide data were collected at baseline to calculate PRS. RESULTS: We found that associations of momentary stress with psychotic experiences, but not with negative and positive affect, were modified by PRS and group (all pFWE<0.001). In contrast to our hypotheses, siblings with high PRS reported less intense psychotic experiences in response to momentary stress compared to siblings with low PRS. No differences in magnitude of these associations were observed in cases with high v. low level of PRS. By contrast, controls with high PRS showed more intense psychotic experiences in response to stress compared to those with low PRS. CONCLUSIONS: This tentatively suggests that polygenic risk may operate in different ways than previously assumed and amplify reactivity to stress in unaffected individuals but operate as a resilience factor in relatives by attenuating their stress reactivity.

How to make mental health services more youth-friendly? A Delphi study involving young adults, parents and professionals.

INTRODUCTION: Although youth-friendly service characteristics have been previously identified, consensus among a representative group of stakeholders about which of these characteristics are truly relevant to the youth-friendliness of services is currently lacking. In our study, young adults, parents and professionals were consulted on this topic to reveal existing (dis)agreement. In addition, (dis)agreement on feasibility for implementation in clinical practice was also assessed. METHODS: A mixed-method Delphi approach was used with three online questionnaire rounds and a physical meeting. Young adults (18-26 years) and parents were part of a public panel and professionals were allocated to the professional panel. In the rounds, participants were asked to rate the importance and feasibility of each item. Subsequently, the percentage agreement (% of participants giving a score of 7 or above on a 9-point Likert scale) within and across panels was calculated. Consensus was assumed to have been reached when at least 70% agreement was achieved. A thematic analysis of the qualitative data, obtained in the rounds and the physical meeting, was performed to identify overarching themes and characteristics of relevance to the youth-friendliness of services. RESULTS: For 65% of the items included in the Delphi questionnaire, consensus on importance was reached within both panels. Participants showed more insecurity about the feasibility of these items, however. Our thematic analysis revealed reasons for disagreement between and within the panels. CONCLUSIONS: Our study revealed substantial between- and within-panel agreement on youth-friendly service characteristics. We recommend that the items for which consensus was reached should be used as a checklist in terms of youth mental health service development, design and delivery. The characteristics for which there was disagreement between and within the panels should inspire an ongoing trialogue between young adults, parents and professionals both on the individual level and the service level. PATIENT OR PUBLIC CONTRIBUTION: In this study, (parents of) young adults with lived experience were included as experts, including one of the coauthors. This coauthor contributed to the manuscript by having a final say about the included quotes.

Gender differences in the associations between childhood adversity and psychopathology in the general population.

PURPOSE: To explore gender differences of the associations between childhood adversity (CA) subtypes and psychiatric symptoms in the general population. METHODS: Data of 791 participants were retrieved from a general population twin cohort. The Symptom Checklist-90 Revised (SCL-90) and the Childhood Trauma Questionnaire were used to assess overall psychopathology with nine symptom domains scores and total CA with exposure to five CA subtypes, respectively. The associations between CA and psychopathology were analyzed in men and women separately and were subsequently compared. RESULTS: Total CA was associated with total SCL-90 and all symptom domains without significant gender differences. However, the analyses of CA subtypes showed that the association between emotional abuse and total SCL-90 was stronger in women compared to men [χ2(1) = 4.10, P = 0.043]. Sexual abuse was significantly associated with total SCL-90 in women, but emotional neglect and physical neglect were associated with total SCL-90 in men. Exploratory analyses of CA subtypes and SCL-90 subdomains confirmed the pattern of gender-specific associations. In women, emotional abuse was associated with all symptom domains, and sexual abuse was associated with all except phobic anxiety and interpersonal sensitivity. In men, emotional neglect was associated with depression, and physical neglect was associated with phobic anxiety, anxiety, interpersonal sensitivity, obsessive-compulsive, paranoid ideation, and hostility subdomains. CONCLUSION: CA is a trans-syndromal risk factor regardless of gender. However, differential associations between CA subtypes and symptom manifestation might exist. Abuse might be particularly associated with psychopathology in women, whereas neglect might be associated with psychopathology in men.

The role of identity in the development of depressive, anxiety, and psychosis symptoms in adolescents exposed to childhood adversity.

INTRODUCTION: Childhood adversity is a major risk factor for psychiatric disorders and has especially been associated with an admixture of depressive, anxiety, and psychosis symptoms. Identity formation, a main developmental task during adolescence, may be impacted by these adverse experiences and act as an important process in the association between childhood adversity and psychopathology. METHODS: We investigated the association between childhood adversity, identity formation, and depressive, anxiety, and psychosis symptoms cross-sectionally in 1913 Flemish adolescents between 11 and 20 years old (mean = 13.76, SD = 1.86). Adolescents completed questionnaires during the first wave of the SIGMA study between January 2018 and May 2019. RESULTS: Childhood interpersonal adversity was associated with increased identity confusion and decreased identity synthesis. Additionally, identity confusion was associated with increased self-reported levels of psychopathology and potentially mediated the association between childhood adversity and psychopathology. CONCLUSION: This study highlights the importance of promoting healthy identity formation in adolescents with and without exposure to adverse childhood experiences.

Coping and sleep quality in youth: An Experience Sampling study.

INTRODUCTION: Sleep quality is closely linked with mental health. Two factors that influence sleep are coping style and locus of control, yet these have not been investigated in daily life. In this study, we examined associations between coping styles and sleep quality in daily life and the potential mediating effect of daily locus of control in a sample of youth, a group particularly vulnerable to developing psychopathology. METHODS: Three hundred and seventy-nine youths from the TwinssCan study participated in an Experience Sampling study, assessing sleep quality as well as state locus of control over the most negative event from the previous day. Participants also completed the Utrecht Coping List, which assessed engagement, disengagement, and emotion-focused coping. RESULTS: Disengagement, "passive reaction," and emotion-focused coping were associated with lower daily sleep quality. State locus of control did not mediate any effects of coping styles on quality of sleep. CONCLUSIONS: Disengagement, "passive reaction," and emotion-focused coping were associated with decreased sleep quality during several consecutive days, which may put youths at risk for developing future insomnia, and strain their mental well-being over time. Thus, there may be value in asking about coping when a young individual presents with sleep problems; however, impaired coping when sleeping poorly should also be considered.

Comparing psychotic experiences in low-and-middle-income-countries and high-income-countries with a focus on measurement invariance.

BACKGROUND: The prevalence of psychotic experiences (PEs) is higher in low-and-middle-income-countries (LAMIC) than in high-income countries (HIC). Here, we examine whether this effect is explicable by measurement bias. METHODS: A community sample from 13 countries (N = 7141) was used to examine the measurement invariance (MI) of a frequently used self-report measure of PEs, the Community Assessment of Psychic Experiences (CAPE), in LAMIC (n = 2472) and HIC (n = 4669). The CAPE measures positive (e.g. hallucinations), negative (e.g. avolition) and depressive symptoms. MI analyses were conducted with multiple-group confirmatory factor analyses. RESULTS: MI analyses showed similarities in the structure and understanding of the CAPE factors between LAMIC and HIC. Partial scalar invariance was found, allowing for latent score comparisons. Residual invariance was not found, indicating that sum score comparisons are biased. A comparison of latent scores before and after MI adjustment showed both overestimation (e.g. avolition, d = 0.03 into d = -0.42) and underestimation (e.g. magical thinking, d = -0.03 into d = 0.33) of PE in LAMIC relative to HIC. After adjusting the CAPE for MI, participants from LAMIC reported significantly higher levels on most CAPE factors but a significantly lower level of avolition. CONCLUSION: Previous studies using sum scores to compare differences across countries are likely to be biased. The direction of the bias involves both over- and underestimation of PEs in LAMIC compared to HIC. Nevertheless, the study confirms the basic finding that PEs are more frequent in LAMIC than in HIC.

Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study.

The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.

Efficacy of Acceptance and Commitment Therapy in Daily Life in Early Psychosis: Results from the Multi-Center INTERACT Randomized Controlled Trial.

INTRODUCTION/OBJECTIVE: This study aimed to investigate efficacy of Acceptance and Commitment Therapy in Daily Life (ACT-DL), combining face-to-face therapy with an Ecological Momentary Intervention (EMI), in addition to treatment as usual (TAU) for psychotic distress, in comparison to TAU. METHODS: Individuals aged 15-65 years with clinically established ultra-high risk or first episode of psychosis were randomly assigned to TAU or ACT-DL+TAU. ACT-DL+TAU consisted of 8 ACT-sessions augmented with an EMI-app. The primary outcome was psychotic distress assessed with the Comprehensive Assessment scale of At Risk Mental State (CAARMS) at post-intervention and 6- and 12-month follow-up. Secondary outcomes were functioning, symptom severity, and momentary psychotic distress. We performed multivariate mixed models according to intent-to-treat principles. RESULTS: Between June 1, 2015 and December 31, 2018, 668 participants were referred, of whom 148 were randomized to ACT-DL+TAU (n = 71) or TAU (n = 77). One hundred and fifteen (78%) provided primary outcome data at least at one follow-up assessment. There was no evidence of greater reduction in the primary outcome measure CAARMS distress in ACT-DL+TAU compared to TAU (χ2(3) = 2.36; p = 0.50). However, out of the tested secondary outcomes, global functioning (χ2(3) = 9.05; p = 0.033), and negative symptoms (χ2(3) = 19.91; p<0.001) improved in ACT-DL+TAU compared to TAU, as did momentary psychotic distress (χ2(3) = 21.56; p < 0.001). CONCLUSIONS: INTERACT did not support a significant effect of ACT-DL over TAU on the primary outcome measure of psychotic distress as assessed with the CAARMS. Although significant improvements were found for some secondary outcome measures, further replication studies are needed to confirm the strength and specificity of these effects.

Early warning signals in psychopathology: what do they tell?

BACKGROUND: Despite the increasing understanding of factors that might underlie psychiatric disorders, prospectively detecting shifts from a healthy towards a symptomatic state has remained unattainable. A complex systems perspective on psychopathology implies that such symptom shifts may be foreseen by generic indicators of instability, or early warning signals (EWS). EWS include, for instance, increasing variability, covariance, and autocorrelation in momentary affective states-of which the latter was studied. The present study investigated if EWS predict (i) future worsening of symptoms as well as (ii) the type of symptoms that will develop, meaning that the association between EWS and future symptom shifts would be most pronounced for congruent affective states and psychopathological domains (e.g., feeling down and depression). METHODS: A registered general population cohort of adolescents (mean age 18 years, 36% male) provided ten daily ratings of their affective states for 6 consecutive days. The resulting time series were used to compute EWS in feeling down, listless, anxious, not relaxed, insecure, suspicious, and unwell. At baseline and 1-year follow-up, symptom severity was assessed by the Symptom Checklist-90 (SCL-90). We selected four subsamples of participants who reported an increase in one of the following SCL-90 domains: depression (N = 180), anxiety (N = 192), interpersonal sensitivity (N = 184), or somatic complaints (N = 166). RESULTS: Multilevel models showed that EWS in feeling suspicious anticipated increases in interpersonal sensitivity, as hypothesized. EWS were absent for other domains. While the association between EWS and symptom increases was restricted to the interpersonal sensitivity domain, post hoc analyses showed that symptom severity at baseline was related to heightened autocorrelations in congruent affective states for interpersonal sensitivity, depression, and anxiety. This pattern replicated in a second, independent dataset. CONCLUSIONS: The presence of EWS prior to symptom shifts may depend on the dynamics of the psychopathological domain under consideration: for depression, EWS may manifest only several weeks prior to a shift, while for interpersonal sensitivity, EWS may already occur 1 year in advance. Intensive longitudinal designs where EWS and symptoms are assessed in real-time are required in order to determine at what timescale and for what type of domain EWS are most informative of future psychopathology.

Measuring resilience prospectively as the speed of affect recovery in daily life: a complex systems perspective on mental health.

INTRODUCTION: There is growing evidence that mental disorders behave like complex dynamic systems. Complex dynamic systems theory states that a slower recovery from small perturbations indicates a loss of resilience of a system. This study is the first to test whether the speed of recovery of affect states from small daily life perturbations predicts changes in psychopathological symptoms over 1 year in a group of adolescents at increased risk for mental disorders. METHODS: We used data from 157 adolescents from the TWINSSCAN study. Course of psychopathology was operationalized as the 1-year change in the Symptom Checklist-90 sum score. Two groups were defined: one with stable and one with increasing symptom levels. Time-series data on momentary daily affect and daily unpleasant events were collected 10 times a day for 6 days at baseline. We modeled the time-lagged effect of daily unpleasant events on negative and positive affect after each unpleasant event experienced, to examine at which time point the impact of the events is no longer detectable. RESULTS: There was a significant difference between groups in the effect of unpleasant events on negative affect 90 min after the events were reported. Stratified by group, in the Increase group, the effect of unpleasant events on both negative (B = 0.05, p < 0.01) and positive affect (B = - 0. 08, p < 0.01) was still detectable 90 min after the events, whereas in the Stable group this was not the case. CONCLUSION: Findings cautiously suggest that adolescents who develop more symptoms in the following year may display a slower affect recovery from daily perturbations at baseline. This supports the notion that mental health may behave according to the laws of a complex dynamic system. Future research needs to examine whether these dynamic indicators of system resilience may prove valuable for personalized risk assessment in this field.

Neurobehavioural mechanisms of threat generalization moderate the link between childhood maltreatment and psychopathology in emerging adulthood

Background: Childhood maltreatment is a transdiagnostic risk factor for later psychopathology and has been associated with altered brain circuitry involved in the processing of threat and safety. Examining threat generalization mechanisms in young adults with childhood maltreatment and psychiatric symptoms may elucidate a pathway linking early-life adversities to the presence of subclinical psychopathology. Methods: We recruited youth aged 16­25 years with subclinical psychiatric symptomatology and healthy controls. They were dichotomized into 2 groups: 1 with a high level of childhood maltreatment (n = 58) and 1 with no or a low level of childhood maltreatment (n = 55). Participants underwent a functional MRI threat generalization paradigm, measuring self-reported fear, expectancy of an unconditioned stimulus (US) and neural responses. Results: We observed interactions between childhood maltreatment and threat generalization indices on subclinical symptom load. In individuals reporting high levels of childhood maltreatment, enhanced generalization in self-reported fear and US expectancy was related to higher levels of psychopathology. Imaging results revealed that in the group with high levels of childhood maltreatment, lower activation in the left hippocampus during threat generalization was associated with a higher symptom load. Associations between threat generalization and psychopathology were nonsignificant overall in the group with no or low levels of childhood maltreatment. Limitations: The data were acquired in a cross-sectional manner, precluding definitive insight into the causality of childhood maltreatment, threat generalization and psychopathology. Conclusion: Our results suggest that threat generalization mechanisms may moderate the link between childhood maltreatment and subclinical psychopathology during emerging adulthood. Threat generalization could represent a vulnerability factor for developing later psychopathology in individuals being exposed to childhood maltreatment.

TwinssCan - Gene-Environment Interaction in Psychotic and Depressive Intermediate Phenotypes: Risk and Protective Factors in a General Population Twin Sample.

Meta-analyses suggest that clinical psychopathology is preceded by dimensional behavioral and cognitive phenotypes such as psychotic experiences, executive functioning, working memory and affective dysregulation that are determined by the interplay between genetic and nongenetic factors contributing to the severity of psychopathology. The liability to mental ill health can be psychometrically measured using experimental paradigms that assess neurocognitive processes such as salience attribution, sensitivity to social defeat and reward sensitivity. Here, we describe the TwinssCan, a longitudinal general population twin cohort, which comprises 1202 individuals (796 adolescent/young adult twins, 43 siblings and 363 parents) at baseline. The TwinssCan is part of the European Network of National Networks studying Gene-Environment Interactions in Schizophrenia project and recruited from the East Flanders Prospective Twin Survey. The main objective of this project is to understand psychopathology by evaluating the contribution of genetic and nongenetic factors on subclinical expressions of dimensional phenotypes at a young age before the onset of disorder and their association with neurocognitive processes, such as salience attribution, sensitivity to social defeat and reward sensitivity.

Evidence for interaction between genetic liability and childhood trauma in the development of psychotic symptoms.

PURPOSE: Whilst childhood trauma (CT) is a known risk factor across the spectrum of psychosis expression, little is known about possible interplay with genetic liability. METHODS: The TwinssCan Study collected data in general population twins, focussing on expression of psychosis at the level of subthreshold psychotic experiences. A multilevel mixed-effects linear regression analysis was performed including 745 subjects to assess the interaction between genetic liability and CT. The Symptom Checklist-90 (SCL-90-R) score of the co-twin was used as an indirect measure of genetic liability to psychopathology, while the Childhood Trauma Questionnaire Short-Form (CTQ-SF) was used to assess CT in the domains of physical, emotional and sexual abuse, as well as physical and emotional neglect. The Community Assessment of Psychic Experience (CAPE) questionnaire was used to phenotypically characterize psychosis expression. RESULTS: In the model using the CAPE total score, the interaction between CT and genetic liability was close to statistical significance (χ2 = 5.6, df = 2, p = 0.06). Analyses of CAPE subscales revealed a significant interaction between CT and genetic liability (χ2 = 8.8, df = 2, p = 0.012) for the CAPE-negative symptoms subscale, but not for the other two subscales (i.e. positive and depressive). CONCLUSION: The results suggest that the impact of CT on subthreshold expression of psychosis, particularly in the negative subdomain, may be larger in the co-presence of significant genetic liability for psychopathology.

Sensitivity to Peer Evaluation and Its Genetic and Environmental Determinants: Findings from a Population-Based Twin Study.

Adolescents and young adults are highly focused on peer evaluation, but little is known about sources of their differential sensitivity. We examined to what extent sensitivity to peer evaluation is influenced by interacting environmental and genetic factors. A sample of 354 healthy adolescent twin pairs (n = 708) took part in a structured, laboratory task in which they were exposed to peer evaluation. The proportion of the variance in sensitivity to peer evaluation due to genetic and environmental factors was estimated, as was the association with specific a priori environmental risk factors. Differences in sensitivity to peer evaluation between adolescents were explained mainly by non-shared environmental influences. The results on shared environmental influences were not conclusive. No impact of latent genetic factors or gene-environment interactions was found. Adolescents with lower self-rated positions on the social ladder or who reported to have been bullied more severely showed significantly stronger responses to peer evaluation. Not genes, but subjective social status and past experience of being bullied seem to impact sensitivity to peer evaluation. This suggests that altered response to peer evaluation is the outcome of cumulative sensitization to social interactions.

Gene-based interaction analysis shows GABAergic genes interacting with parenting in adolescent depressive symptoms.

BACKGROUND: Most gene-environment interaction studies (G × E) have focused on single candidate genes. This approach is criticized for its expectations of large effect sizes and occurrence of spurious results. We describe an approach that accounts for the polygenic nature of most psychiatric phenotypes and reduces the risk of false-positive findings. We apply this method focusing on the role of perceived parental support, psychological control, and harsh punishment in depressive symptoms in adolescence. METHODS: Analyses were conducted on 982 adolescents of Caucasian origin (Mage (SD) = 13.78 (.94) years) genotyped for 4,947 SNPs in 263 genes, selected based on a literature survey. The Leuven Adolescent Perceived Parenting Scale (LAPPS) and the Parental Behavior Scale (PBS) were used to assess perceived parental psychological control, harsh punishment, and support. The Center for Epidemiologic Studies Depression Scale (CES-D) was the outcome. We used gene-based testing taking into account linkage disequilibrium to identify genes containing SNPs exhibiting an interaction with environmental factors yielding a p-value per single gene. Significant results at the corrected p-value of p < 1.90 × 10-4 were examined in an independent replication sample of Dutch adolescents (N = 1354). RESULTS: Two genes showed evidence for interaction with perceived support: GABRR1 (p = 4.62 × 10-5 ) and GABRR2 (p = 9.05 × 10-6 ). No genes interacted significantly with psychological control or harsh punishment. Gene-based analysis was unable to confirm the interaction of GABRR1 or GABRR2 with support in the replication sample. However, for GABRR2, but not GABRR1, the correlation of the estimates between the two datasets was significant (r (46) = .32; p = .027) and a gene-based analysis of the combined datasets supported GABRR2 × support interaction (p = 1.63 × 10-4 ). CONCLUSIONS: We present a gene-based method for gene-environment interactions in a polygenic context and show that genes interact differently with particular aspects of parenting. This accentuates the importance of polygenic approaches and the need to accurately assess environmental exposure in G × E.

Exposure to environmental factors increases connectivity between symptom domains in the psychopathology network.

BACKGROUND: We investigated to what degree environmental exposure (childhood trauma, urbanicity, cannabis use, and discrimination) impacts symptom connectivity using both continuous and categorical measures of psychopathology. METHODS: Outcomes were continuous symptom dimensions of self-reported psychopathology using the Self-report Symptom Checklist-90-R in 3021 participants from The Early Developmental Stages of the Psychopathology (EDSP) study and binary DSM-III-R categories of mental disorders and a binary measure of psychotic symptoms in 7076 participants from The Netherlands Mental Health Survey and Incidence Study (NEMESIS-1). For each symptom dimension in the EDSP and mental disorder in the NEMESIS-1 as the dependent variable, regression analyses were carried out including each of the remaining symptom dimensions/mental disorders and its interaction with cumulative environmental risk load (the sum score of environmental exposures) as independent variables. RESULTS: All symptom dimensions in the EDSP and related diagnostic categories in the NEMESIS-1 were strongly associated with each other, and environmental exposures increased the degree of symptom connectivity in the networks in both cohorts. CONCLUSIONS: Our findings showing strong connectivity across symptom dimensions and related binary diagnostic constructs in two independent population cohorts provide further evidence for the conceptualization of psychopathology as a contextually sensitive network of mutually interacting symptoms.

Childhood trauma and childhood urbanicity in relation to psychotic disorder.

BACKGROUND: Urban upbringing and childhood trauma are both associated with psychotic disorders. However, the association between childhood urbanicity and childhood trauma in psychosis is poorly understood. The urban environment could occasion a background of social adversity against which any effect of childhood trauma increases. Also, any impact of the urban environment on likelihood of exposure to childhood trauma could be stronger in children who later develop psychotic disorder. The aim of this study was twofold: (1) to investigate whether childhood urbanicity moderates the effect of childhood trauma, in a model predicting psychotic disorder; (2) to investigate whether there is an association between the urban environment and childhood trauma and whether this is moderated by genetic liability for psychotic disorder. METHODS: Patients with a diagnosis of non-affective psychotic disorder (n = 1119) and 589 healthy controls from the Netherlands and Belgium were studied. Childhood trauma was assessed with the Dutch version of the Childhood Trauma Questionnaire Short Form. Urban exposure was defined at four levels, considering the population density, using data from Statistics Netherlands and the equivalent database in Belgium. RESULTS: There was a significant interaction between childhood urbanicity on the one hand and childhood trauma on the other, indicating that trauma was significantly associated with psychotic disorder, with increasing odds ratios for higher levels of childhood urbanicity. In addition, there was weak evidence that childhood urbanicity was associated with childhood trauma in the patient group: higher levels of childhood urbanicity were associated with higher trauma scores. CONCLUSION: The urban environment may moderate the risk-increasing effect of childhood trauma for psychotic disorder and childhood urbanicity may be a risk factor for childhood trauma in individuals who later develop psychotic disorder.

Epidemiological, neurobiological, and genetic clues to the mechanisms linking cannabis use to risk for nonaffective psychosis.

Epidemiological studies have shown that the association between cannabis and psychosis is robust and consistent across different samples, with compelling evidence for a dose-response relationship. Because longitudinal work indicates that cannabis use precedes psychotic symptoms, it seems reasonable to assume a causal relationship. However, more work is needed to address the possibility of gene-environment correlation (for example, genetic risk for psychosis causing onset of cannabis use). Moreover, knowledge about underlying biological mechanisms linking cannabis use and psychosis is still relatively limited. In order to understand how cannabis use may lead to an increased risk for psychosis, in the present article we (a) review the epidemiological, neurobiological, and genetic evidence linking cannabinoids and psychosis, (b) assess the quality of the evidence, and finally (c) try to integrate the most robust findings into a neurodevelopmental model of cannabis-induced psychosis and identify the gaps in knowledge that are in need of further investigation.