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Objective: To test whether polygenic risk score for schizophrenia (PRS‐S) interacts with childhood adversity and daily‐life stressors to influence momentary mental state domains (negative affect, positive affect, and subtle psychosis expression) and stress‐sensitivity measures. Methods: The data were retrieved from a general population twin cohort including 593 adolescents and young adults. Childhood adversity was assessed using the Childhood Trauma Questionnaire. Daily‐life stressors and momentary mental state domains were measured using ecological momentary assessment. PRS‐S was trained on the latest Psychiatric Genetics Consortium schizophrenia meta‐analysis. The analyses were conducted using multilevel mixed‐effects tobit regression models. Results: Both childhood adversity and daily‐life stressors were associated with increased negative affect, decreased positive affect, and increased subtle psychosis expression, while PRS‐S was only associated with increased positive affect. No gene–environment correlation was detected. There is novel evidence for interaction effects between PRS‐S and childhood adversity to influence momentary mental states [negative affect (b = 0.07, P = 0.013), positive affect (b = −0.05, P = 0.043), and subtle psychosis expression (b = 0.11, P = 0.007)] and stress‐sensitivity measures. Conclusion: Exposure to childhood adversities, particularly in individuals with high PRS‐S, is pleiotropically associated with emotion dysregulation and psychosis proneness. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the longitudinal relationship between subclinical psychotic symptoms and social functioning in a representative general population sample of adolescents. Method: Data were derived from a routine general health screening of 1909 adolescents in a circumscribed region. Baseline measurement was in the second grade of secondary school (T0), and follow‐up occurred approximately 2 years later (T1). Social functioning and subclinical psychotic symptoms of hallucinations and delusions were assessed at both time points. Results: Baseline (T0) social problems preceded follow‐up (T1) subclinical delusions, but not T1 subclinical hallucinations. Similarly, T0 delusions preceded social problems at T1, but T0 hallucinations did not. Conclusion: This longitudinal general population study demonstrated a bidirectional association between social problems and delusions, but found no link between social problems and hallucinations. This may reflect a downward negative spiral where delusional thoughts and social problems reinforce each other. [ABSTRACT FROM AUTHOR]

Background: Suicide is a major cause of death among youth. Childhood trauma (CT) has emerged as a leading environmental risk factor for suicidal ideation (SI). The present study intends to understand the association between CT and SI in a sample of twins, highlighting the relevance of CT per se, regardless of genetic vulnerability., Methods: Data were derived from a general population young twin study, the TwinssCan project (N = 796; mean age = 17.4). Different types of CT (physical, emotional and sexual) were explored with CTQ and SI through SCL-90-R. The discordance within twin-pairs was used to dissect the genetic and CT effects in SI., Results: Total CT and all subdomains were associated with an increased risk for SI. The within-pair differences analysis in monozygotic and dizygotic twins suggested that part of this association is not attributable to genetic predisposition, which points out the relevance of CT itself upon the increase of SI. This result converged with CT subdomain analyses of physical abuse and neglect., Limitations: While within-pair twin analyses control for genetic risk, additional environmental shared and individual characteristics should be controlled for (such as poverty or protective factors). More detailed information on SI would be of great interest to better capture the complexity of this construct., Conclusion: CT appears to be an important environmental risk factor for SI and at least partly independent of Gene-Environment correlation (rGE). This study highlights the importance of including the history of CT in psychiatric evaluations of patients. The burden of the psychosocial environment on SI could be disentangled by further research on environmental risk and protective factors., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Previous studies assessing the hypothesis that the construct of 'aberrant salience' is associated with psychosis and psychotic symptoms showed conflicting results. For this reason, the association between measures to index aberrant salience and subclinical psychotic symptoms in a general population sample was analysed. In addition, genetic vulnerability was added to the analysis as a modifier to test the hypothesis that modification by genetic vulnerability may explain variability in the results., Methods: The TwinssCan project obtained data from general population twins (N = 887). CAPE (Community Assessment of Psychic Experience) scores were used to index psychotic experiences. Aberrant salience was assessed with white noise task and ambiguous situations task., Results: Measures of aberrant salience were not associated with psychotic experiences, nor was there evidence for an interaction with genetic predisposition in this association (Z = 1.08, p = 0.282)., Conclusions: Various studies including the present could not replicate the association between aberrant salience and psychotic experiences in general population samples. The conflicting findings might be explained by moderation by genetic vulnerability, but results are inconsistent. If there was evidence for a main effect or interaction, this was in the positive symptom scale only. On the other hand, the association was more robust in so-called 'ultra-high risk' patients and first episode psychosis patients. Thus, this association may represent a state-dependent association, present only at the more severe end of the psychosis spectrum., (© 2024. The Author(s).)

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 [χ 2 (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., (© 2023. The Author(s).)

The present study examines whether neuroticism is predicted by genetic vulnerability, summarized as polygenic risk score for neuroticism (PRS N ), in interaction with bullying, parental bonding, and childhood adversity. Data were derived from a general population adolescent and young adult twin cohort. The final sample consisted of 202 monozygotic and 436 dizygotic twins and 319 twin pairs. The Short Eysenck Personality questionnaire was used to measure neuroticism. PRS N was trained on the results from the Genetics of Personality Consortium (GPC) and United Kingdom Biobank (UKB) cohorts, yielding two different PRS N . Multilevel mixed-effects models were used to analyze the main and interacting associations of PRS N , childhood adversity, bullying, and parental bonding style with neuroticism. We found no evidence of gene-environment correlation. PRS N thresholds of .005 and .2 were chosen, based on GPC and UKB datasets, respectively. After correction for confounders, all the individual variables were associated with the expression of neuroticism: both PRS N from GPC and UKB, childhood adversity, maternal bonding, paternal bonding, and bullying in primary school and secondary school. However, the results indicated no evidence for gene-environment interaction in this cohort. These results suggest that genetic vulnerability on the one hand and negative life events (childhood adversity and bullying) and positive life events (optimal parental bonding) on the other represent noninteracting pathways to neuroticism., Competing Interests: The authors have no relevant financial or nonfinancial interests to disclose., (© The Author(s) 2023.)

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.

Initial affective and psychotic reactivity to daily stressors is altered in psychosis, and most notably in early psychosis. In addition to altered initial stress reactivity, results from studies using Experience Sampling Methodology (ESM) and psychophysiological measures indicate that impaired recovery from mild stressors may also be a risk factor for mental illness. The current ESM study investigated affective recovery from daily stressors in chronic psychosis patients (CP; n = 162), individuals at early stages of psychosis (EP; n = 127), and healthy volunteers (HV; n = 220) assessing fluctuations in negative affect (NA), tension, and suspiciousness ten times a day on six consecutive days. Recovery was operationalized for all three variables as the return to baseline (i.e., level at t -1 ) following the first stressful event of a day (i.e., t 0 ). The EP group showed a delayed recovery of NA (t 1 -t 3 : B = 0.185; p = .007 and B = 0.228; p = .002) and suspiciousness (t 1 : B = 0.223; p = .010 and B = 0.291; p = .002) compared to HV and CP, respectively. Delayed recovery was detected for tension as well (t 1 -t 2 : EP > HV: B = 0.242; p = .040 and EP > CP: B = 0.284; p = .023), but contrary to both other momentary states, this effect disappeared when controlling for subsequent stressful events. There were no significant differences in recovery between HV and CP. These results suggest that in EP, stressful daily events have longer-lasting effects on overall negative affect and subclinical psychotic-like experiences. Future studies should incorporate physiological and endocrine measures in order to integrate recovery patterns of the different stress systems., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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 (χ 2  = 5.6, df = 2, p = 0.06). Analyses of CAPE subscales revealed a significant interaction between CT and genetic liability (χ 2  = 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.

Objective: Results from experimental studies suggest that psychosis and psychosis liability are associated with increased cortisol levels and blunted cortisol reactivity, and that use of antipsychotics may reduce these aberrations. Here, we report on overall cortisol, diurnal slope, and cortisol stress reactivity in everyday life in psychosis and psychosis liability using the experience sampling method (ESM)., Methods: Our sample consisted of individuals diagnosed with psychotic disorder currently on (MPD; n = 53) or off antipsychotic medication (NMPD; n = 20), first-degree relatives of psychotic patients (REL; n = 47), and healthy volunteers (HV; n = 67). Saliva samples were collected throughout the day on six consecutive days and analyzed for cortisol levels. Simultaneously, stressfulness of the current activity was assessed with ESM questionnaires., Results: We found no group differences in overall cortisol level between groups, but REL had a steeper diurnal slope than HV; in MPD a trend was found in the same direction. Regarding reactivity to stressful activities, results indicated attenuation of the cortisol response in both patient groups compared to HV., Conclusion: These results do not confirm reports of increased cortisol levels in psychosis, but provide evidence of stress-related cortisol alterations in everyday life., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Childhood trauma exposure has been associated with a clinically relevant mixed phenotype of psychopathology composed of depressive, anxiety, and psychosis symptoms, across healthy and clinical samples. Altered stress-reactivity after exposure to childhood trauma may be a plausible underlying mechanism explaining this association. In a general population sample of female twins (T0 = 564; T1 = 483), associations between childhood trauma exposure and symptom profile (no symptoms, isolated symptoms, or a mixed phenotype) on the one hand, and daily life stress reactivity on the other were investigated. Daily life stress reactivity was measured using the Experience Sampling Method (ESM), and was defined as negative affect reactivity to minor daily life stressors. Individuals exposed to childhood trauma who reported a mixed phenotype of psychopathology showed a significant increase in emotional reactivity to daily life stress (activity and social stress), compared with trauma-exposed individuals without a mixed phenotype. In the trauma-exposed mixed phenotype group, increased emotional reactivity to event-stress predicted more severe symptoms at ± 14 month follow-up. This study found evidence that may link heightened emotional reactivity to stress in individuals with a trauma history to the risk for later comorbid psychopathology., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The network analysis of intensive time series data collected using the Experience Sampling Method (ESM) may provide vital information in gaining insight into the link between emotion regulation and vulnerability to psychopathology. The aim of this study was to apply the network approach to investigate whether genetic liability (GL) to psychopathology and childhood trauma (CT) are associated with the network structure of the emotions "cheerful," "insecure," "relaxed," "anxious," "irritated," and "down"-collected using the ESM method. Methods: Using data from a population-based sample of twin pairs and siblings (704 individuals), we examined whether momentary emotion network structures differed across strata of CT and GL. GL was determined empirically using the level of psychopathology in monozygotic and dizygotic co-twins. Network models were generated using multilevel time-lagged regression analysis and were compared across three strata (low, medium, and high) of CT and GL, respectively. Permutations were utilized to calculate p values and compare regressions coefficients, density, and centrality indices. Regression coefficients were presented as connections, while variables represented the nodes in the network. Results: In comparison to the low GL stratum, the high GL stratum had significantly denser overall ( p = 0.018) and negative affect network density ( p < 0.001). The medium GL stratum also showed a directionally similar (in-between high and low GL strata) but statistically inconclusive association with network density. In contrast to GL, the results of the CT analysis were less conclusive, with increased positive affect density ( p = 0.021) and overall density ( p = 0.042) in the high CT stratum compared to the medium CT stratum but not to the low CT stratum. The individual node comparisons across strata of GL and CT yielded only very few significant results, after adjusting for multiple testing. Conclusions: The present findings demonstrate that the network approach may have some value in understanding the relation between established risk factors for mental disorders (particularly GL) and the dynamic interplay between emotions. The present finding partially replicates an earlier analysis, suggesting it may be instructive to model negative emotional dynamics as a function of genetic influence.

Background: An association between white noise speech illusion and psychotic symptoms has been reported in patients and their relatives. This supports the theory that bottom-up and top-down perceptual processes are involved in the mechanisms underlying perceptual abnormalities. However, findings in nonclinical populations have been conflicting., Objectives: The aim of this study was to examine the association between white noise speech illusion and subclinical expression of psychotic symptoms in a nonclinical sample. Findings were compared to previous results to investigate potential methodology dependent differences., Methods: In a general population adolescent and young adult twin sample (n = 704), the association between white noise speech illusion and subclinical psychotic experiences, using the Structured Interview for Schizotypy-Revised (SIS-R) and the Community Assessment of Psychic Experiences (CAPE), was analyzed using multilevel logistic regression analyses., Results: Perception of any white noise speech illusion was not associated with either positive or negative schizotypy in the general population twin sample, using the method by Galdos et al. (2011) (positive: ORadjusted: 0.82, 95% CI: 0.6-1.12, p = 0.217; negative: ORadjusted: 0.75, 95% CI: 0.56-1.02, p = 0.065) and the method by Catalan et al. (2014) (positive: ORadjusted: 1.11, 95% CI: 0.79-1.57, p = 0.557). No association was found between CAPE scores and speech illusion (ORadjusted: 1.25, 95% CI: 0.88-1.79, p = 0.220). For the Catalan et al. (2014) but not the Galdos et al. (2011) method, a negative association was apparent between positive schizotypy and speech illusion with positive or negative affective valence (ORadjusted: 0.44, 95% CI: 0.24-0.81, p = 0.008)., Conclusion: Contrary to findings in clinical populations, white noise speech illusion may not be associated with psychosis proneness in nonclinical populations.

Objective: Focusing on temporal associations between momentary (or state) loneliness, appraisal of social company, and being alone in daily life may help elucidate mechanisms that contribute to the development of prolonged (or trait) loneliness and major depressive disorder (MDD). We aim to examine if (a) a self-reinforcing loop between loneliness, negative appraisals of social company, and being alone in daily life may contribute to trait loneliness; (b) this possible self-reinforcing loop may also contribute to the development of MDD, by testing differences in temporal relationships between these social elements in participants who did or did not develop MDD during follow-up; and (c) any of these social elements at baseline predicted a MDD at follow-up., Methods: A female general population sample (n = 417) participated in an experience sampling method (ESM) study. Time-lagged analyses between loneliness, appraisal of social company, and being alone were examined at baseline, and their associations with the development of MDD during 20 months follow-up were investigated., Results: State loneliness was followed by an increase in negative appraisals of social company and a higher frequency of being alone. Further, negative appraisals of social company were associated with a higher frequency of being alone afterward. Only the latter was significant in the transition to MDD group. Trait loneliness predicted MDD during follow-up., Conclusions: Avoiding social contact after appraising company more negatively may contribute to the development of MDD.

Introduction: Negative social evaluation is associated with psychopathology. Given the frequency of evaluation through increasingly prevalent virtual social networks, increased understanding of the effects of this social evaluation is urgently required., Methods: A new digital social peer evaluation experiment (digi-SPEE) was developed to mimic everyday online social interactions between peers. Participants received mildly negative feedback on their appearance, intelligence, and congeniality. Two hundred and forty-one young people [58.9% female, aged 18.9 years (15 to 34)] from an ongoing novel general population twin study participated in this study. Positive affect (PA), negative affect (NA), implicit self-esteem, and cortisol were assessed before and after exposure to the social evaluation experiment., Results: The social evaluation experiment decreased PA (B=-5.25, p<.001) and implicit self-esteem (B=-.19; p<.001), whereas it increased NA (B=5.99; p<.001) and cortisol levels (B=.07; p<.001). Females (PA: B=-7.62; p<.001; NA: B=8.28; p<.001) and participants with higher levels of general psychological distress (PA: B=-.04, p=.035; NA: B=.06; p=.028) showed stronger affective responses. Stressor-induced cortisol increase was stronger in adolescents under the age of 18 than in participants 18 years and older (B=-.06, p=.002)., Conclusion: The digi-SPEE represents a social evaluation stressor that elicits biological and implicit and explicit mental changes that are relevant to mechanisms of psychopathology., Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors.

Background: With the development of mHealth, it is possible to treat patients in their natural environment. Mobile technology helps to bridge the gap between the therapist's office and the "real world." The ACT in Daily Life training (ACT-DL) was designed as an add-on intervention to help patients practice with acceptance and commitment therapy in their daily lives. The ACT-DL consists of two main components: daily monitoring using experience sampling and ACT training in daily life., Objectives: To assess the acceptability and feasibility of the ACT-DL in a general outpatient population. A secondary objective was to conduct a preliminary examination of the effectiveness of the ACT-DL., Methods: An observational comparative study was conducted. The experimental group consisted of 49 patients who volunteered for ACT-DL, and the control group consisted of 112 patients who did not volunteer. As part of an inpatient treatment program, both groups received a 6-week ACT training. Participants went home to continue their treatment on an outpatient basis, during which time the experimental group received the 4-week add-on ACT-DL. Acceptability and feasibility of the ACT-DL was assessed weekly by telephone survey. Effectiveness of the ACT-DL was evaluated with several self-report questionnaires ( Flexibility Index Test (FIT-60): psychological flexibility, Brief Symptom Inventory: symptoms, Utrechtse Coping List: coping, and Quality of life visual analog scale (QoL-VAS): quality of life)., Results: More than three-quarters of the participants (76%) completed the full 4-week training. User evaluations showed that ACT-DL stimulated the use of ACT in daily life: participants practiced over an hour a week (mean 78.8 minutes, standard deviation 54.4), doing 10.4 exercises (standard deviation 6.0) on average. Both ACT exercises and metaphors were experienced as useful components of the training (rated 5 out of 7). Repeated measures ANCOVA did not show significant effects of the ACT-DL on psychological flexibility (P=.88), symptoms (P=.39), avoidant coping (P=.28), or quality of life (P=.15)., Conclusions: This is the first study that uses experience sampling to foster awareness in daily life in combination with acceptance and commitment therapy to foster skill building. Adherence to the ACT-DL was high for an intensive mHealth intervention. ACT-DL appears to be an acceptable and feasible mHealth intervention, suitable for a broad range of mental health problems. However, short-term effectiveness could not be demonstrated. Additional clinical trials are needed to examine both short-term and long-term effects., Competing Interests: Conflicts of Interest: None declared.

Early life stress may have a lasting impact on the developmental programming of the dopamine (DA) system implicated in psychosis. Early adversity could promote resilience by calibrating the prefrontal stress-regulatory dopaminergic neurotransmission to improve the individual's fit with the predicted stressful environment. Aberrant reactivity to such match between proximal and distal environments may, however, enhance psychosis disease risk. We explored the combined effects of childhood adversity and adult stress by exposing 12 unmedicated individuals with a diagnosis of non-affective psychotic disorder (NAPD) and 12 healthy controls (HC) to psychosocial stress during an [18F]fallypride positron emission tomography. Childhood trauma divided into early (ages 0-11 years) and late (12-18 years) was assessed retrospectively using a questionnaire. A significant group x childhood trauma interaction on the spatial extent of stress-related [18F]fallypride displacement was observed in the mPFC for early (b = -8.45, t(1,23) = -3.35, p = .004) and late childhood trauma (b = -7.86, t(1,23) = -2.48, p = .023). In healthy individuals, the spatial extent of mPFC DA activity under acute psychosocial stress was positively associated with the severity of early (b = 7.23, t(11) = 3.06, p = .016) as well as late childhood trauma (b = -7.86, t(1,23) = -2.48, p = .023). Additionally, a trend-level main effect of early childhood trauma on subjective stress response emerged within this group (b = -.7, t(11) = -2, p = .07), where higher early trauma correlated with lower subjective stress response to the task. In the NAPD group, childhood trauma was not associated with the spatial extent of the tracer displacement in mPFC (b = -1.22, t(11) = -0.67), nor was there a main effect of trauma on the subjective perception of stress within this group (b = .004, t(11) = .01, p = .99). These findings reveal a potential mechanism of neuroadaptation of prefrontal DA transmission to early life stress and suggest its role in resilience and vulnerability to psychosis.

Stress is an important risk factor in the etiology of psychotic disorder. Preclinical work has shown that stress primarily increases dopamine (DA) transmission in the frontal cortex. Given that DA-mediated hypofrontality is hypothesized to be a cardinal feature of psychotic disorder, stress-related extrastriatal DA release may be altered in psychotic disorder. Here we quantified for the first time stress-induced extrastriatal DA release and the spatial extent of extrastriatal DA release in individuals with non-affective psychotic disorder (NAPD). Twelve healthy volunteers (HV) and 12 matched drug-free NAPD patients underwent a single infusion [(18)F]fallypride positron emission tomography scan during which they completed the control and stress condition of the Montreal Imaging Stress Task. HV and NAPD did not differ in stress-induced [(18)F]fallypride displacement and the spatial extent of stress-induced [(18)F]fallypride displacement in medial prefrontal cortex (mPFC) and temporal cortex (TC). In the whole sample, the spatial extent of stress-induced radioligand displacement in right ventro-mPFC, but not dorso-mPFC or TC, was positively associated with task-induced subjective stress. Psychotic symptoms during the scan or negative, positive and general subscales of the Positive and Negative Syndrome Scale were not associated with stress-induced [(18)F]fallypride displacement nor the spatial extent of stress-induced [(18)F]fallypride displacement in NAPD. Our results do not offer evidence for altered stress-induced extrastriatal DA signaling in NAPD, nor altered functional relevance. The implications of these findings for the role of the DA system in NAPD and stress processing are discussed.

Stressful life events increase the risk for psychosis, and the subjective experience of stress related to daily life activities drives moment-to-moment variation in psychotic intensity. Positron emission tomography (PET) studies suggest that dopaminergic (DAergic) activity mediates the behavioral response to an experimental stressor. However, it is not known how alterations in this DAergic stress response relate to the subjective experience of stress in real life situations assessed in momentary assessment studies. This study combined [18F]fallypride PET with an Experience Sampling ambulatory assessment approach to examine the association between the prefrontal DAergic response to experimentally induced stress and real life psychotic reactivity to the subjective experience of stress in daily life. Healthy first-degree relatives of individuals with a psychotic disorder (N = 14) and healthy controls (N = 11) participated in (a) a psychosocial [18F]fallypride PET stress paradigm and (b) an experience sampling study, using a structured diary approach. Mixed multilevel random intercept models revealed that stress-induced [18F]fallypride displacement, indicative of DAergic activity, in ventromedial prefrontal cortex (VMPFC) was associated with psychotic reactivity to daily life stress in the entire sample. Lower levels of [18F]fallypride displacement to stress predicted increased psychotic reactivity to daily life stress. This study combined PET neuroimaging with real life behavioral assessments in the investigation of psychotic symptoms; we showed decreased [18F]fallypride displacement to stress in VMPFC to be associated with increased psychotic reactivity to daily life stress. The preliminary evidence in this study demonstrates that it is possible to acquire a grasp on how brain function is associated with contextualized experience, which has relevance for neuroimaging studies in general., ((PsycINFO Database Record (c) 2015 APA, all rights reserved).)

Introduction: The aim of the present study was to investigate the effects of mindfulness-based cognitive therapy (MBCT) on suicidal ideation in an open-label randomised controlled trial of patients with residual depressive symptoms. Furthermore, this study aimed at examining whether an effect of MBCT on suicidal ideation was dependent on a reduction in depression severity, worry and rumination, or an increase in mindfulness., Methods: One hundred and thirty participants were randomised to a treatment arm (treatment as usual plus MBCT) or a wait list arm. Change in depression, change in worry, change in rumination and change in mindfulness were entered as covariates in a repeated measures ANOVA in order to assess to what degree MBCT-induced changes in suicidal ideation were independent from changes in these parameters., Results: There was a significant group×time (pre vs. post) interaction on suicidal ideation indicating a significant reduction of suicidal ideation in the MBCT group, but not in the control group. The interaction remained significant after addition of the above covariates. Change in worry was the only covariate associated with change in suicidal ideation, causing a moderate reduction in the interaction effect size., Conclusions: The results suggest that MBCT may affect suicidal ideation in patients with residual depressive symptoms and that this effect may be mediated, in part, by participants' enhanced capacity to distance themselves from worrying thoughts., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Recent human and animal studies suggest that epigenetic mechanisms mediate the impact of environment on development of mental disorders. Therefore, we hypothesized that polymorphisms in epigenetic-regulatory genes impact stress-induced emotional changes. A multi-step, multi-sample gene-environment interaction analysis was conducted to test whether 31 single nucleotide polymorphisms (SNPs) in epigenetic-regulatory genes, i.e. three DNA methyltransferase genes DNMT1, DNMT3A, DNMT3B, and methylenetetrahydrofolate reductase (MTHFR), moderate emotional responses to stressful and pleasant stimuli in daily life as measured by Experience Sampling Methodology (ESM). In the first step, main and interactive effects were tested in a sample of 112 healthy individuals. Significant associations in this discovery sample were then investigated in a population-based sample of 434 individuals for replication. SNPs showing significant effects in both the discovery and replication samples were subsequently tested in three other samples of: (i) 85 unaffected siblings of patients with psychosis, (ii) 110 patients with psychotic disorders, and iii) 126 patients with a history of major depressive disorder. Multilevel linear regression analyses showed no significant association between SNPs and negative affect or positive affect. No SNPs moderated the effect of pleasant stimuli on positive affect. Three SNPs of DNMT3A (rs11683424, rs1465764, rs1465825) and 1 SNP of MTHFR (rs1801131) moderated the effect of stressful events on negative affect. Only rs11683424 of DNMT3A showed consistent directions of effect in the majority of the 5 samples. These data provide the first evidence that emotional responses to daily life stressors may be moderated by genetic variation in the genes involved in the epigenetic machinery.

A previous study reported that social stress sensitivity is moderated by the brain-derived-neurotrophic-factor(Val66Met) (BDNF rs6265) genotype. Additionally, positive emotions partially neutralize this moderating effect. The current study aimed to: (i) replicate in a new independent sample of subjects with residual depressive symptoms the moderating effect of BDNF(Val66Met) genotype on social stress sensitivity, (ii) replicate the neutralizing impact of positive emotions, (iii) extend these analyses to other variations in the BDNF gene in the new independent sample and the original sample of non-depressed individuals. Previous findings were replicated in an experience sampling method (ESM) study. Negative Affect (NA) responses to social stress were stronger in "Val/Met" carriers of BDNF(Val66Met) compared to "Val/Val" carriers. Positive emotions neutralized the moderating effect of BDNF(Val66Met) genotype on social stress sensitivity in a dose-response fashion. Finally, two of four additional BDNF SNPs (rs11030101, rs2049046) showed similar moderating effects on social stress-sensitivity across both samples. The neutralizing effect of positive emotions on the moderating effects of these two additional SNPs was found in one sample. In conclusion, ESM has important advantages in gene-environment (GxE) research and may attribute to more consistent findings in future GxE research. This study shows how the impact of BDNF genetic variation on depressive symptoms may be explained by its impact on subtle daily life responses to social stress. Further, it shows that the generation of positive affect (PA) can buffer social stress sensitivity and partially undo the genetic susceptibility., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

In the development of psychotic symptoms, environmental and genetic factors may both play a role. The reported association between childhood trauma and psychotic symptoms could therefore be moderated by single nucleotide polymorphisms (SNPs) associated with the stress response, such as FK506-binding protein 5 (FKBP5) and brain-derived neurotrophic factor (BDNF). Recent studies investigating childhood trauma by SNP interactions have inconsistently found the hippocampus to be a potential target underlying these interactions. Therefore, more detailed modelling of these effects, using appropriate covariates, is required. We examined whether BDNF/FKBP5 and childhood trauma interactions affected two proxies of hippocampal integrity: (i) hippocampal volume and (ii) cognitive performance on a block design (BD) and delayed auditory verbal task (AVLT). We also investigated whether the putative interaction was different for patients with a psychotic disorder (n = 89) compared to their non-psychotic siblings (n = 95), in order to elicit possible group-specific protective/vulnerability effects. SNPs were rs9296158, rs4713916, rs992105, rs3800373 (FKBP5) and rs6265 (BDNF). In the combined sample, no BDNF/FKBP5 by childhood trauma interactions were apparent for either outcome, and BDNF/FKBP5 by childhood trauma interactions were not different for patients and siblings. The omission of drug use and alcohol consumption sometimes yielded false positives, greatly affected explained error and influenced p-values. The consistent absence of any significant BDNF/FKBP5 by childhood trauma interactions on assessments of hippocampal integrity suggests that the effect of these interactions on psychotic symptoms is not mediated by hippocampal integrity. The importance of appropriate statistical designs and inclusion of relevant covariates should be carefully considered.

Evidence suggests that affect plays a role in the development of psychosis but the underlying mechanism requires further investigation. This study examines the moment-to-moment dynamics between negative affect (NA) and paranoia prospectively in daily life. A female general population sample (n = 515) participated in an experience sampling study. Time-lagged analyses between increases in momentary NA and subsequent momentary paranoia were examined. The impact of childhood adversity, stress sensitivity (impact of momentary stress on momentary NA), and depressive symptoms on these time-lagged associations, as well as associations with follow-up self-reported psychotic symptoms (Community Assessment of Psychic Experiences and the Symptom Checklist-90-Revised) were investigated. Moments of NA increase resulted in a significant increase in paranoia over 180 subsequent minutes. Both stress sensitivity and depressive symptoms impacted on the transfer of NA to paranoia. Stress sensitivity moderated the level of increase in paranoia during the initial NA increase, while depressive symptoms increased persistence of paranoid feelings from moment to moment. Momentary paranoia responses to NA increases were associated with follow-up psychotic symptoms. Examination of microlevel momentary experience may thus yield new insights into the mechanism underlying co-occurrence of altered mood states and psychosis. Knowledge of the underlying mechanism is required in order to determine source and place where remediation should occur.

Objective: Patients diagnosed with a psychotic disorder and their first-degree relatives display increased reactivity to stress. Theory predicts that experience of psychosocial stress is associated both with ventromedial prefrontal and mesolimbic dopamine neurotransmission. However, while there is evidence of aberrant striatal dopamine processing in psychotic disorder, the role of the prefrontal cortex remains under-researched. This study aimed at investigating stress-induced in vivo dopamine release in ventromedial prefrontal cortex (vmPFC) of individuals at familial risk for psychosis., Method: Fourteen healthy first-degree relatives of patients with a diagnosis of psychotic disorder and 10 control subjects underwent a single dynamic positron emission tomography (PET) scanning session after intravenous administration of 183.2 (SD = 7.6) MBq [(18)F]fallypride. Psychosocial stress was initiated at 100 min postinjection using a computerized mental arithmetic task with social evaluative threat components. PET data were analyzed using the linearized simplified reference region model. Regression analyses were performed to compare the spatial extent of task-related ligand displacement between control subjects and relatives and to find how it related to self-rated experiences of psychosocial stress and psychosis., Results: First-degree relatives displayed hyporeactive dopamine signaling in the vmPFC in response to stress. Increased levels of subjectively rated stress were associated with increased intensity of psychotic experiences. This effect was particularly pronounced in first-degree relatives., Conclusion: Although previous studies have hypothesized a role for prefrontal dopamine dysfunction in psychosis, this study, to our knowledge, is the first in vivo human imaging study showing attenuated (ie, hyporeactive) dopamine stress neuromodulation in vmPFC of individuals at familial risk for psychosis.

Context: Paranoia embodies altered representation of the social environment, fuelling altered feelings of social acceptance leading to further mistrust. Mindfulness-based cognitive therapy (MBCT) may relieve paranoia and reduce its impact on social acceptance., Objective: To determine whether MBCT alters momentary feeling of paranoia and social acceptance in daily life., Design: Randomized controlled trial of daily-life repeated measures (up to 120 per participant) before and after allocation to MBCT or waiting list control., Participants: Volunteer sample of 130 eligible men and women with residual affective dysregulation after at least one episode of major depressive disorder., Interventions: Eight weeks of MBCT in groups of 10-15 participants in addition to participants' usual treatment., Outcome Measures: Daily-life ratings of paranoia and social acceptance. This manuscript concerns additional analyses of the original trial; hypotheses were developed after data collection (focus initially on depressive symptoms) but before data analysis., Results: Sixty-six participants were assigned to the waiting list control group and 64 to the MBCT intervention group, of whom 66 and 61 respectively were included in the per-protocol analyses. Intention-to-treat analyses revealed a significant group by time interaction in the model of momentary paranoia (b = -.18, p<0.001, d = -0.35) and social acceptance (b = .26, p<0.001, d = 0.41). Paranoia levels in the intervention group were significantly reduced (b = -.11, p<0.001) and feelings of social acceptance significantly increased (b = .18, p<0.001), whereas in the Control condition a significant increase in paranoia (b = .07, p = 0.008) and a decrease in social acceptance was apparent (b = -.09, p = 0.013). The detrimental effect of paranoia on social acceptance was significantly reduced in the MBCT, but not the control group (group by time interaction: b = .12, p = 0.022)., Conclusions: MBCT confers a substantial benefit on subclinical paranoia and may interrupt the social processes that maintain and foster paranoia in individuals with residual affective dysregulation., Trial Registration: Netherlands Trial Register NTR1084.

Catechol-O-methyltransferase (COMT) plays an essential role in degradation of extracellular dopamine in prefrontal regions of the brain. Although a polymorphism in this gene, COMT Val(158)Met, affects human behavior in response to stress little is known about its effect on dopaminergic activity associated with the human stress response, which may be of interest for stress-related psychiatric disorders such as psychosis. We aimed to investigate the effect of variations in COMT genotype on in vivo measures of stress-induced prefrontal cortex (PFC) dopaminergic processing and subjective stress responses. A combined sample of healthy controls and healthy first-degree relatives of psychosis patients (n = 26) were subjected to an [(18)F]fallypride Positron Emission Tomography scan. Psychosocial stress during the scan was induced using the Montreal Imaging Stress Task and subjective stress was assessed every 12 minutes. Parametric t-maps, generated using the linear extension of the simplified reference region model, revealed an effect of COMT genotype on the spatial extent of [(18)F]fallypride displacement. Detected effects of exposure to psychosocial stress were unilateral and remained restricted to the left superior and right inferior frontal gyrus, with Met-hetero- and homozygotes showing less [(18)F]fallypride displacement than Val-homozygotes. Additionally, Met-hetero- and homozygotes experienced larger subjective stress responses than Val-homozygotes. The direction of the effects remained the same when the data was analyzed separately for controls and first-degree relatives. The human stress response may be mediated in part by COMT-dependent dopaminergic PFC activity, providing speculation for the neurobiology underlying COMT-dependent differences in human behaviour following stress. Implications of these results for stress-related psychopathology and models of dopaminergic functioning are discussed.

Subclinical psychotic experiences at the level of the general population are common, forming an extended psychosis phenotype with clinical psychosis. Persistence of subclinical experiences is associated with transition to later mental disorder. Increased daily life stress reactivity is considered an endophenotype for psychotic disorders. We examined, in a longitudinal framework, whether baseline momentary assessment markers of stress reactivity would predict persistence of subclinical psychotic experiences over time. In a general population sample of female twins (N = 566), the Experience Sampling Method (ESM; repetitive random sampling of momentary emotions, psychotic experiences and context) was used to assess (emotional and psychotic) daily life stress reactivity. Persistence of subclinical psychotic experiences was based on the Community Assessment of Psychic Experiences (CAPE), assessed three times over 14 months post-baseline. It was investigated whether baseline daily life emotional and psychotic stress reactivity predicted persistence of psychotic experiences over time. Higher levels of emotional stress reactivity (a decrease in positive and an increase in negative affect in response to stress), and increased psychotic reactivity to daily stress was found in individuals with persistent psychotic experiences over time compared to individuals with transient psychotic experiences. The results suggest that markers of daily life stress reactivity may predict "macro-level" persistence of normally transient expression of psychotic liability over time. Linking daily life markers of altered reactivity in terms of emotions and psychotic experiences to longitudinal persistence of psychotic experiences, associated with increased risk of transition to overt mental disorder, may contribute to earlier and more accurate diagnosis of risk.

Background: FK506 binding protein 5 (FKBP5) has repeatedly been shown to be a critical determinant of post-traumatic stress disorder (PTSD) and depression following childhood trauma., Aims: To examine the role of FKBP5-trauma interactions in the partly stress-related psychosis phenotype., Method: In 401 general population twins, four functional polymorphisms were examined in models of psychosis and cortisol, and followed up in models of psychosis in three samples at different familial liability (175 controls, 200 unaffected siblings and 195 patients with a psychotic disorder)., Results: The most consistent finding was an interaction between childhood trauma and rs9296158/rs4713916 on psychotic symptoms and cortisol in the twin sample, combined with a directionally similar interaction in siblings (rs4713916) and patients (rs9296158), A-allele carriers at both polymorphisms being most vulnerable to trauma., Conclusions: Trauma may increase the risk of psychosis through enduring changes in the cortisol feedback loop, similar to that for PTSD, suggesting comparable biological mechanisms for psychosis across diagnostic boundaries.

Purpose: Everyday functioning is an important outcome for studies of the developmental psychopathology of adolescence. An unbiased, well-validated, and easy-to-use instrument to specifically assess normal adolescent functioning is not yet available. The current study aimed to introduce and validate the Multidimensional Adolescent Functioning Scale (MAFS)., Methods: The MAFS was developed by clinical consensus, resulting in a 23-item self-report questionnaire with three distinct subscales: general functioning, family-related functioning, and peer-related functioning. MAFS data were collected in a general population sample (N = 842; mean age = 15.0 years [standard deviation = .4]) at baseline and again at 1- and 3-year follow-up. Psychometric analyses included confirmatory factor analysis, calculations of internal consistency, scale correlations, and correlations with the abridged General Health Questionnaire., Results: Confirmatory factor analysis showed that the hypothesized 3-factor structure fits well to the MAFS data. All scales showed adequate internal consistency (greatest lower bound: .75-.91) and sufficient discriminative ability (scale intercorrelations: ρ = .15-.52). Of the scales, general functioning was most strongly correlated with the General Health Questionnaire, whereas family- and peer-related functioning showed weaker correlations with this general measure. The results were stable across repeated measurements and gender groups., Conclusions: The MAFS is an easy-to-use instrument with good psychometric characteristics, which could be suitable for a broad range of future research applications, especially when a multidimensional and unbiased indication of normal adolescent functioning is required., (Copyright © 2013 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Mental disorders may be reducible to sets of symptoms, connected through systems of causal relations. A clinical staging model predicts that in earlier stages of illness, symptom expression is both non-specific and diffuse. With illness progression, more specific syndromes emerge. This paper addressed the hypothesis that connection strength and connection variability between mental states differ in the hypothesized direction across different stages of psychopathology., Methods: In a general population sample of female siblings (mostly twins), the Experience Sampling Method was used to collect repeated measures of three momentary mental states (positive affect, negative affect and paranoia). Staging was operationalized across four levels of increasing severity of psychopathology, based on the total score of the Symptom Check List. Multilevel random regression was used to calculate inter- and intra-mental state connection strength and connection variability over time by modelling each momentary mental state at t as a function of the three momentary states at t-1, and by examining moderation by SCL-severity., Results: Mental states impacted dynamically on each other over time, in interaction with SCL-severity groups. Thus, SCL-90 severity groups were characterized by progressively greater inter- and intra-mental state connection strength, and greater inter- and intra-mental state connection variability., Conclusion: Diagnosis in psychiatry can be described as stages of growing dynamic causal impact of mental states over time. This system achieves a mode of psychiatric diagnosis that combines nomothetic (group-based classification across stages) and idiographic (individual-specific psychopathological profiles) components of psychopathology at the level of momentary mental states impacting on each other over time.

Psychotic disorders are thought to represent altered neural function. However, research has failed to map diagnostic categories to alterations in neural networks. It is proposed that the basic unit of psychotic psychopathology is the moment-to-moment expression of subtle anomalous experiences of subclinical psychosis, and particularly its tendency to persist from moment-to-moment in daily life, under the influence of familial, environmental, emotional and cognitive factors.In a general population twin sample (n = 579) and in a study of patients with psychotic disorder (n = 57), their non-psychotic siblings (n = 59) and unrelated controls (n = 75), the experience sampling paradigm (ESM; repetitive, random sampling of momentary mental states and context) was applied. We analysed, in a within-person prospective design, (i) transfer of momentary anomalous experience at time point (t-1) to time point (t) in daily life, and (ii) moderating effects of negative affect, positive affect, daily stressors, IQ and childhood trauma. Additionally, (iii) familial associations between persistence of momentary anomalous experience and psychotic symptomatology were investigated. Higher level of schizotypy in the twins (but not higher level of psychotic symptoms in patients) predicted more persistence of momentary anomalous experience in daily life, both within subjects and across relatives. Persistence of momentary anomalous experience was highest in patients, intermediate in their siblings and lowest in controls. In both studies, persistence of momentary anomalous experience was moderated by higher levels of negative affect, daily stressors and childhood trauma (only in twins), and by lower levels of positive affect. The study of alterations in the moment-to-moment transfer of subtle anomalous experience of psychosis, resulting in their persistence, helps to explain why psychotic and emotional dysregulation tend to cluster in a single phenotype such as schizophrenia, and how familial and environmental risks increase the risk of expression of psychosis from, first, subtle momentary anomalous experience to, second, observable clinical symptoms.

Background: Cross-sectional studies have indicated that alterations in social functioning, particularly interpersonal functioning, are associated with the occurrence of psychotic symptoms and experiences at different levels of the extended psychosis phenotype (ranging from population psychometric expression of liability to overt psychotic disorder). However, more research is needed on the development of this association over time., Methods: Cross-lagged path modeling was used to analyze bidirectional, longitudinal associations between 4 dimensions of subclinical psychotic experiences (persecutory ideation, bizarre experiences, perceptual abnormalities, and magical thinking) and interpersonal functioning in an adolescent general population sample (N = 881 at T1, N = 652 at T2, and N = 512 at T3) assessed 3 times in 3 years., Results: All symptom dimensions showed some association with interpersonal functioning over time, but only bizarre experiences and persecutory ideation were consistently and longitudinally associated with interpersonal functioning. Poorer interpersonal functioning predicted higher levels of bizarre experiences and persecutory ideation at later measurement points (both T1 to T2 and T2 to T3)., Conclusions: Poor interpersonal functioning in adolescence may reflect the earliest expression of neurodevelopmental alterations preceding expression of psychotic experiences in a symptom-specific fashion.

Background: The interplay between the catechol-O-methyltransferase (COMT) Val158Met polymorphism and environmental stress may have etiological relevance for psychosis, but differential effects have been reported in healthy control and patient groups, suggesting that COMT Val158Met interactions with stress may be conditional on background genetic risk for psychotic disorder., Methods: Patients with a nonaffective psychotic disorder (n = 86) and control participants (n = 109) were studied with the experience sampling method (a structured diary technique) in order to assess stress, negative affect and momentary psychotic symptoms in the flow of daily life., Results: Multilevel analyses revealed significant three-way interactions between group status (patient or control), COMT genotype and stress in the model of negative affect (χ(2)(2) = 13.26, P < 0.01) as well as in the model of momentary psychotic symptoms (χ(2)(2) = 6.92, P < 0.05). Exploration of the three-way interaction revealed that in patients, COMT genotype moderated the association between stress and negative affect (χ(2)(4) = 11.50, P < 0.005), as well as the association between stress and momentary psychosis (χ(2)(4) = 12.79, P < 0.005). Met/Met genotype patients showed significantly increased psychotic and affective reactivity to stress in comparison to the Val/Met and Val/Val genotypes. In contrast, healthy controls did not display large or significant COMT Val158Met X stress interactions., Conclusions: Important differences exist in the effect of COMT Val158Met on stress reactivity, which may depend on background risk for psychotic disorder. Differential sensitivity to environmental stress occasioned by COMT Val158Met may be contingent on higher order interactions with genetic variation underlying psychotic disorder., (© 2010 Blackwell Publishing Ltd.)

Rodent studies suggest that prefrontal dopamine neurotransmission plays an important role in the neural processing of psychosocial stress. Human studies investigating stress-induced changes in dopamine levels, however, have focused solely on striatal dopamine transmission. The aim of this study was to investigate in vivo dopamine release in the human prefrontal cortex in response to a psychosocial stress challenge, using the highly selective dopamine D₂/₃ PET radioligand [¹⁸F]fallypride in healthy subjects. Twelve healthy subjects (age (y): 39.8; SD=15.8) underwent a single dynamic Positron Emission Tomography (PET) scanning session after intravenous administration of 185.2 (SD=10.2) MBq [¹⁸F]fallypride. Psychosocial stress was initiated at 100 min postinjection. PET data were analyzed using the linearized simplified reference region model (LSRRM), which accounts for time-dependent changes in [¹⁸F]fallypride displacement. Voxel-based statistical maps, representing specific D₂/₃ binding changes, were computed to localize areas with increased ligand displacement after task initiation, reflecting dopamine release. The psychosocial stress challenge induced detectable amounts of dopamine release throughout the prefrontal cortex, with dopaminergic activity in bilateral ventromedial prefrontal cortex being associated with subjectively rated experiences of psychosocial stress. The novel finding that a mild psychosocial stress in humans induces increased levels of endogenous dopamine in the PFC indicates that the dynamics of the dopamine-related stress response cannot be interpreted by focusing on mesolimbic brain regions alone., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The recent advent of genome-wide mass-marker technology has resulted in renewed optimism to unravel the genetic architecture of psychotic disorders. Genome-wide association studies have identified a number of common polymorphisms robustly associated with schizophrenia, in ZNF804A, transcription factor 4, major histocompatibility complex, and neurogranin. In addition, copy number variants (CNVs) in 1q21.1, 2p16.3, 15q11.2, 15q13.3, 16p11.2, and 22q11.2 were convincingly implicated in schizophrenia risk. Furthermore, these studies have suggested considerable genetic overlap with bipolar disorder (particularly for common polymorphisms) and neurodevelopmental disorders such as autism (particularly for CNVs). The influence of these risk variants on relevant intermediate phenotypes needs further study. In addition, there is a need for etiological models of psychosis integrating genetic risk with environmental factors associated with the disorder, focusing specifically on environmental impact on gene expression (epigenetics) and convergence of genes and environment on common biological pathways bringing about larger effects than those of genes or environment in isolation (gene-environment interaction). Collaborative efforts that bring together expertise in statistics, genetics, epidemiology, experimental psychiatry, brain imaging, and clinical psychiatry will be required to succeed in this challenging task., (© 2010 Blackwell Publishing Ltd.)

Epidemiological research has shown that stressful environmental factors can play an aetiological role in the development of psychosis. However, the mechanism underlying the link between stress and psychosis is still not fully understood. In this article it is argued that the interaction between stressful environmental factors and epigenetic factors can bring about psychological and biological changes. Both types of change can be referred to as 'sensitisation'. The underlying mechanism of sensitisation can be interpreted on the one hand as cognitive misinterpretations (psychological sensitisation) and on the other hand as altered dopaminergic neurotransmission (biological sensitisation). Both of these deviations can facilitate the onset and persistence of psychotic symptoms. With the help of epidemiological research at psychometric level sensitisation can be quantified as (i) stress-induced persistence (indicating continuous sensitisation) of the normally transient expression of subclinical psychotic experiences during adolescence and early adulthood and as (ii) the increased risk of transition from gradually more persistent subclinical psychotic experiences to a clinical psychotic disorder.

Previous evidence reviewed in Schizophrenia Bulletin suggests the importance of a range of different environmental factors in the development of psychotic illness. It is unlikely, however, that the diversity of environmental influences associated with schizophrenia can be linked to as many different underlying mechanisms. There is evidence that environmental exposures may induce, in interaction with (epi)genetic factors, psychological or physiological alterations that can be traced to a final common pathway of cognitive biases and/or altered dopamine neurotransmission, broadly referred to as "sensitization," facilitating the onset and persistence of psychotic symptoms. At the population level, the behavioral phenotype for sensitization may be examined by quantifying, in populations exposed to environmental risk factors associated with stress or dopamine-agonist drugs, (1) the increased rate of persistence (indicating lasting sensitization) of normally transient developmental expressions of subclinical psychotic experiences and (2) the subsequent increased rate of transition to clinical psychotic disorder.