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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. ispartof: ACTA PSYCHIATRICA SCANDINAVICA vol:141 issue:5 pages:465-475 ispartof: location:United States status: published

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.

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

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., t0). The EP group showed a delayed recovery of NA (t1-t3: B = 0.185; p = .007 and B = 0.228; p = .002) and suspiciousness (t1: 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 (t1-t2: 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. ispartof: SCHIZOPHRENIA RESEARCH vol:213 pages:1-8 ispartof: location:Netherlands status: Published online

BackgroundThe earliest stages of the pluripotent psychopathology on the pathway to psychotic disorders is represented by emotional dysregulation and subtle psychosis expression, which can be measured using the Ecological Momentary Assessment (EMA). However, it is not clear to what degree common genetic and environmental risk factors for psychosis contribute to variation in these early expressions of psychopathology.MethodsIn this largest ever EMA study of a general population twin cohort including 593 adolescents and young adults between the ages of 15 and 35 years, we tested whether polygenic risk score for schizophrenia (PRS-S) interacts with childhood adversity (the Childhood Trauma Questionnaire score) and daily-life stressors to influence momentary mental state domains (negative affect, positive affect, and subtle psychosis expression) and stress-sensitivity measures.ResultsBoth 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. We have provided novel evidence for interaction effects between PRS-S and childhood adversity to influence momentary mental states [negative affect (b = 0.07, 95% CI 0.01 to 0.13, P = 0.013), positive affect (b = −0.05, 95% CI −0.10 to −0.00, P = 0.043), and subtle psychosis expression (b = 0.11, 95% CI 0.03 to 0.19, P = 0.007)] and stress-sensitivity measures.ConclusionExposure to childhood adversities, particularly in individuals with high PRS-S, is pleiotropically associated with emotional dysregulation and psychosis proneness.

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. ispartof: SOCIAL PSYCHIATRY AND PSYCHIATRIC EPIDEMIOLOGY vol:54 issue:9 pages:1045-1054 ispartof: location:Germany status: published

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.

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

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. ispartof: Frontiers in Psychology vol:8 issue:NOV ispartof: location:Switzerland status: published

BackgroundAn 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.ObjectivesThe 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.MethodsIn 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.ResultsPerception 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).ConclusionContrary 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.

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.

BACKGROUND: Emotional dysregulation and subtle psychosis expression mark the earliest manifestation of psychopathology. Furthermore, using Ecological Momentary Assessment (EMA), studies indicate that emotional and psychotic reactivity to daily-life stressors are associated with psychosis expression in individuals at varying clinical stages (e.g. service users, clinical high-risk, or first episode psychosis). The question arises how fluctuations of those momentary mental states persist and transit into more distinct clinical outcomes (e.g. psychotic spectrum disorder). In this context, studies using the EMA previously showed that environmental vulnerabilities (i.e. childhood adversities) are consistently associated with increased and persistent emotional and psychotic reactivity. However, the effects of molecular genetic liability for schizophrenia on this association have not been investigated. Therefore, in the largest EMA study to date, we aim to test whether polygenic risk for schizophrenia (PRS) interacts with childhood adversity on momentary mental states (negative affect, positive affect and subtle psychosis expression). METHODS: A prospective population-based twin cohort from multi-birth registry in Flanders, Belgium, collected data from April 2010 to April 2014 in the first wave of the TwinssCan project. The study sample included 593 adolescents and young adults between the ages of 15 and 35 years. Childhood Adversity was assessed using the Childhood Trauma Questionnaire. Momentary mental state domains (negative affect, positive affect and subtle psychosis expression) were measured using EMA. Emotional states were the mean sore of items concerning negative affect (I feel anxious, lonely, down, insecure and irritated) and positive affect (I feel cheerful, satisfied, relaxed, and globally feeling well, respectively). Subtle psychosis expression was the mean score of items concerning psychotic-like experiences (suspiciousness, being afraid of losing control, racing thoughts, pervasive thoughts, and difficulties to express thoughts). Genetic risk was estimated by PRS, which was trained on the latest Psychiatric Genetics Consortium schizophrenia meta-analysis, adjusted for the first 2 population principal components. The analyses were conducted using multilevel tobit regression with age and sex included as a priori covariates. RESULTS: Exposure to childhood adversity was associated with increased negative affect (b = 0.13, 95% CI 0.07 to 0.19, P < 0.001), decreased positive affect (b = -0.12, 95% CI 0.17 to -0.06, P < 0.001), and increased subtle psychosis expression (b = 0.18, 95% CI 0.10 to 0.26, P < 0.001). PRS was only associated with increased positive affect (b = 0.08, 95% CI 0.03 to 0.14, P < 0.001), and no gene–environment correlation was detected (b = -0.01, 95% CI -0.03 to 0.02, P = 0.676). PRS moderated the association of childhood adversity with all momentary mental states, negative affect (b = 0.07, 95% CI 0.01 to 0.13, P = 0.013), positive affect (b = -0.05, 95% CI -0.10 to -0.00, P = 0.043), and subtle psychosis expression (b = 0.11, 95% CI 0.03 to 0.19, P = 0.007). CONCLUSIONS: PRS moderated the influence of childhood adversity on all emotional regulation and subtle psychosis expression. This is in line with hypothesis arguing that the experience of early-life stressors during critical neurodevelopmental periods may lead to the imbalance of stress mechanisms and subsequently cause emotional and behavioral problems. Genetic vulnerability and early-lifetime stressors pleiotropically co-participate in driving emotional dysregulation and psychosis proneness.

BackgroundFK506 binding protein 5 (FKBP5) has repeatedly been shown to be a critical determinant of post-traumatic stress disorder (PTSD) and depression following childhood trauma.AimsTo examine the role of FKBP5-trauma interactions in the partly stress-related psychosis phenotype.MethodIn 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).ResultsThe 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.ConclusionsTrauma 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.

BackgroundReduced hippocampal size and increased stress sensitivity are associated with psychotic disorder and familial risk for psychosis. However, to what degree the hippocampus is implicated in daily life stress reactivity has not yet been examined. The current study investigated (i) whether familial risk (the contrast between controls, patients and siblings of patients) moderated the relationship between hippocampal volume (HV) and emotional daily stress reactivity and (ii) whether familial risk (the contrast between controls and siblings of patients) moderated the relationship between HV and cortisol daily stress reactivity.MethodT1-weighted magnetic resonance imaging (MRI) scans were acquired from 20 patients with schizophrenia, 37 healthy siblings with familial risk for schizophrenia and 32 controls. Freesurfer 5.0.0 was used to measure HV. The experience sampling method (ESM), a structured momentary assessment technique, was used to assess emotional stress reactivity, that is the effect of momentary stress on momentary negative affect (NA). In addition, in the control and sibling groups, cortisol stress reactivity was assessed using momentary cortisol levels extracted from saliva.ResultsMultilevel linear regression analyses revealed a significant three-way interaction between group, HV and momentary stress in both the model of NA and the model of cortisol. Increased emotional stress reactivity was associated with smaller left HV in patients and larger total HV in controls. In line with the results in patients, siblings with small HV demonstrated increased emotional and cortisol stress reactivity compared to those with large HV.ConclusionsHV may index risk and possibly disease-related mechanisms underlying daily life stress reactivity in psychotic disorder.

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. ispartof: PLoS One vol:11 issue:3 ispartof: location:United States status: published

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.

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.

BackgroundExperimental studies have indicated that social contact, even when it is neutral, triggers paranoid thinking in people who score high on clinical or subclinical paranoia. We investigated whether contextual variables are predictive of momentary increases in the intensity of paranoid thinking in a sample of participants ranging across a psychometric paranoia continuum.MethodThe sample (n=154) consisted of 30 currently paranoid patients, 34 currently non-paranoid patients, 15 remitted psychotic patients, 38 high-schizotypy participants, and 37 control subjects. Based on their total score on Fenigstein's Paranoia Scale (PS), three groups with different degrees of paranoia were defined. The Experience Sampling Method (ESM), a structured diary technique, was used to assess momentary social context, perceived social threat and paranoia in daily life.ResultsThere were differences in the effect of social company on momentary levels of paranoia and perceived social threat across the range of trait paranoia. The low and medium paranoia groups reported higher levels of perceived social threat when they were with less-familiar compared to familiar individuals. The medium paranoia group reported more paranoia in less-familiar company. The high paranoia group reported no difference in the perception of social threat or momentary paranoia between familiar and unfamiliar contacts.ConclusionsParanoid thinking is context dependent in individuals with medium or at-risk levels of trait paranoia. Perceived social threat seems to be context dependent in the low paranoia group. However, at high levels of trait paranoia, momentary paranoia and momentary perceived social threat become autonomous and independent of social reality.

SUMMARY 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 (χ2(2) = 13.26, P < 0.01) as well as in the model of momentary psychotic symptoms (χ2(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 (χ2(4) = 11.50, P < 0.005), as well as the association between stress and momentary psychosis (χ2(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.

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.

Lataster T, Collip D, Lardinois M, van Os J, Myin-Germeys I. Evidence for a familial correlation between increased reactivity to stress and positive psychotic symptoms. Objective: This study tested the hypothesis that stress-reactivity may represent an intermediary phenotype underlying positive psychotic symptoms. It was examined whether: (i) stress-reactivity clusters within families of psychotic patients and (ii) stress-reactivity in relatives cosegregates with positive symptoms in patients. Method: The sample consisted of 40 patients and 47 siblings of these patients. The Experience Sampling Method (ESM – a structured diary technique) was used to measure stress-reactivity. Positive symptoms in patients were measured with the Comprehensive Assessment of Symptoms and History. Results: Within-trait, cross-sib associations showed a significant association between stress-reactivity in the patient and stress-reactivity in their siblings. Significant cross-trait, cross-sib associations were established showing a significant association between positive psychotic symptoms in the patient and stress-reactivity in the sibling. Conclusion: The findings show familial clustering of increased stress-reactivity, suggesting common aetiological influences, probably both genetic and environmental, underlying stress-reactivity in the siblings and patients. In addition, the results underscore the hypothesis that increased stress-reactivity is an unconfounded mechanism of risk underlying the positive symptoms of psychotic disorders.

Background Studies using the event sampling method (ESM), a structured diary technique measuring subjective experiences and emotional fluctuations in daily life, have consistently shown that individuals reporting psychotic experiences display a heightened emotional reactivity to minor stressors—a neuropsychological mechanism that likely contributes to the development and perpetuation of psychotic experiences. Except a few undersized non-replicated candidate-gene studies showing an association between genetic variations and elevated momentary stress reactivity, genetic underpinnings of emotion reactivity to momentary stressors have not been investigated. Therefore, by leveraging a large general population twin dataset of ESM, we aimed to investigate—for the first time—whether the polygenic risk score (PRS) for schizophrenia moderates stress reactivity (psychotic experiences (PE) and negative affect (NA) in response to momentary stress). Methods Data were derived from a general population adolescent and young adult twin sample. The total sample included 638 participants (Monozygotic = 202, Dizygotic = 436). ESM variables were randomly measured at 10 times/day over 6 consecutive days. For the main analyses, we assessed ESM information on PE (suspiciousness, loss of control, racing thoughts, pervasive thoughts, difficulties to express thoughts), NA (feeling lonely, anxious, listless, down, guilty), and event-related stress (pleasantness of the most important event since last entry); and for additional explorative analyses we assessed social stress (participants were asked with whom they are (e.g. nobody or family) and to rate the pleasantness of the social situation). PRS were trained on the results from the Psychiatric Genetics Consortium-2 SZ. Multilevel regression analyses, taking into account of multiple observations nested within twins who were clustered within family, were used to analyze the moderating effects of PRS (at p-value < 0.05) on the relationship between momentary stress and NA or PE. All analyses were adjusted for age, sex and 2 principle components. Results There were significant main effects of momentary stress (event stress: b = 0.065, p < 0.001, 95% CI = 0.048, 0.082; social stress: b = 0.128; p < 0.001; 95% CI = 0.111, 0.145) on PE. However, neither the main effects of PRS on PE nor the interaction between PRS and momentary stress on PE were significant. The analysis with NA as dependent variable indicated main effects of momentary stress (event stress: b = 0.096; p

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.

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 [18F]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 [18F]fallypride displacement and the spatial extent of stress-induced [18F]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 [18F]fallypride displacement nor the spatial extent of stress-induced [18F]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.

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. ispartof: PloS one vol:9 issue:6 ispartof: location:United States status: published

A previous study reported that social stress sensitivity is moderated by the brain-derived-neurotrophic-factor(Va166Met) (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 BDNFVa66Met 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 BDNFVal66Met compared to "Val/Val" carriers. Positive emotions neutralized the moderating effect of BDNFVal66Met 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. (C) 2014 Elsevier B.V. and ECNP. All rights reserved.

Objective: Altered social reward functioning is associated with psychosis irrespective of stage and severity. Examining the role of social reward functioning prospectively in relation to psychotic experiences before these become persistent and potentially disabling can aid in elucidating social mechanisms that induce shifts toward more severe psychotic states, without the confounding effects of clinical disorder.Method: In a longitudinal general population sample (N=566), the experience sampling method (repetitive random sampling of momentary emotions and social context) was used to assess daily life social functioning at baseline. Persistence of subclinical psychotic experiences was based on the Community Assessment of Psychic Experiences assessed three times over 14months. Analyses examined to what degree i) social context and ii) appreciation thereof differentiated between those who did and did not develop persistent psychotic experiences.Results: Although individuals with persistent psychotic experiences did not differ in overall level of positive effect, the amount of time spent alone or the level of social satisfaction compared to individuals without persistent psychotic experiences, they were more sensitive to the rewarding effects of social company.Conclusion: Alterations in social reward experience may form one of the mechanisms that precede the development of the extended psychosis phenotype over time.

ObjectivePatients 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.MethodFourteen 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 [18F]fallypride. Psychosocial stress was initiated at 100min 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.ResultsFirst-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.ConclusionAlthough 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. published

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. ispartof: PLoS One vol:9 issue:3 ispartof: location:United States status: published

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. published