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Background: Psychotic experiences, social functioning and general psychopathology are important targets for early intervention in individuals with Ultra-High-Risk state (UHR) and a first-episode psychosis (FEP). Acceptance and Commitment Therapy (ACT) is a promising, next-generation Cognitive Behavioural Therapy (CBT) that aims to modify these targets, but evidence on sustainable change and its underlying mechanisms in individuals' daily lives remains limited. The aim of the INTERACT study is to investigate the efficacy of a novel ecological momentary intervention, Acceptance and Commitment Therapy in Daily Life (ACT-DL) in a multi-centre randomised controlled trial of individuals with UHR or FEP., Methods/design: In a multi-centre randomised controlled trial, individuals aged 16-65 years with UHR or FEP will be randomly allocated to ACT-DL in addition to treatment as usual (TAU) as the experimental condition or a control condition of TAU only, which will include - for the entire study period - access to routine mental health care and, where applicable, CBT for psychosis (CBTp). Outcomes will be assessed at baseline (i.e. before randomisation), post-intervention (i.e. after the 8-week intervention period), and 6-month and 12-month follow-ups (i.e. 6 and 12 months after completing the intervention period) by blinded assessors. The primary outcome will be distress associated with psychotic experiences, while secondary outcomes will include (momentary) psychotic experiences, social functioning and psychopathology. Process measures to assess putative mechanisms of change will include psychological flexibility, stress sensitivity and reward experiences. In addition, acceptability, treatment adherence and treatment fidelity of ACT-DL will be assessed., Discussion: The current study is the first to test the efficacy of ACT-DL in individuals with UHR and FEP. If this trial demonstrates the efficacy of ACT-DL, it has the potential to significantly advance the treatment of people with UHR and FEP and, more generally, provides initial support for implementing mHealth interventions in mental health services., Trial Registration: Netherlands Trial Register, ID: NTR4252. Registered on 26 September 2013.

Aims.: Self-reported psychotic experiences (SRPE) by individuals from the general population are often unconfirmed by clinical interview and referred to as 'false-positive' (FP) SRPE. FP SRPE have been suggested to represent the mildest form of risk along the extended psychosis continuum. However, little is known about their (clinical) outcome and evolution over time. Aims of this study were to prospectively examine, in individuals with FP SRPE, (1) the prevalence of remission, persistence and transition to validated PE at 3-year follow-up; (2) potential baseline psychopathological and psychosocial predictors of persistence of FP SRPE and transition to validated PE; and (3) whether those with persistent FP SRPE and validated PE already differed on psychopathology and psychosocial factors at baseline. We tested the hypotheses that (i) individuals with FP SRPE would be more likely to have SRPE and validated PE at follow-up; and (ii) that FP SRPE would be predictive of lower functioning and more psychopathology and help-seeking behaviour at follow-up., Methods.: Baseline (n = 6646) and 3-year follow-up (n = 5303) data of the second the Netherlands Mental Health Survey and Incidence Study (NEMESIS-2), a general population research project on prevalence, incidence, course and consequences of psychiatric disorders was used. Self-report of PE was followed by clinical interview to determine clinical validity. The presence of mood, anxiety and substance use disorders, childhood adversity, help-seeking and functioning as well as PE characteristics (number, frequency, distress and impact) were used in the analyses which included only individuals with complete data for both assessments waves (n = 4683)., Results.: At baseline, 454 participants had any FP SRPE; of these 372 participants had complete follow-up data available. Those with baseline FP SRPE were significantly more likely to report SRPE (OR = 3.58; 95% CI 2.38-5.40, p < 0.001) and validated PE (OR = 6.26; 95% CI 3.91-10.02, p < 0.001) at follow-up. Baseline FP SRPE also predicted the presence of mood and anxiety disorders, reduced functioning and help-seeking at follow-up. Several baseline psychopathological, psychosocial and PE characteristics were predictive for the persistence of SRPE. These factors also differentiated groups with FP SRPE or validated PE from those with remitted FP SRPE at follow-up., Conclusions.: 'FP SRPE' are not truly 'false' as they index risk for the development of clinically relevant psychotic symptoms, development of mood and anxiety disorders and reduced functioning. Self-reported PE, even unconfirmed, warrant 'watchful waiting' and follow-up over time, especially when they are reported by individuals with reduced psychosocial functioning and general psychiatric problems.

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.)

Cognitive impairments in patients with psychotic disorder have been associated with poor functioning and increased symptom severity. Furthermore, childhood trauma (CT) exposure has been associated with worse cognitive functioning as well as co-occurrence of affective-anxious-psychosis symptoms or a 'mixed phenotype of psychopathology' (MP), which in turn is associated with greater symptom severity, and poor functioning. This study aims to evaluate if cognition could be associated with CT/MP. 532 patients with non-affective psychotic patients were assessed on CT, symptom profile, cognition, functioning, and symptom severity at baseline and 3 and 6-year follow-up. Four subgroups were made according to trauma exposure (CT- or CT+) and presence of a mixed phenotype (MP- or MP+): CT-/MP (n=272), CT-/MP+ (n=157), CT+/MP- (n=49), and CT+/MP+ (n=54). Mixed-effects multilevel regression, linear regression, and Tobit analyses were performed. Patients with both CT and MP showed lower verbal learning and memory than CT-/MP+ individuals (p<0.001). No other significant differences were found among the 4 subgroups. No cognitive decline was found at follow-up, neither in the CT+/MP- nor in CT-/MP- group. Lower cognition was not associated with increased symptom severity or poor functioning at follow-up, neither in the CT+/MP- nor in CT-/MP- group. Although cognitive impairments and CT may be related to clinical or functional features of psychotic disorder, and cognitive functioning could be affected by CT exposure, cognition does not discriminate subgroups of patients stratified by CT exposure and MP., (Copyright © 2017 Elsevier B.V. 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.)

Childhood trauma exposure is a robust environmental risk factor for psychosis. However, not all exposed individuals develop psychotic symptoms later in life. The Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265) has been suggested to moderate the psychosis-inducing effects of childhood trauma in clinical and nonclinical samples. Our study aimed to explore the interaction effect between childhood trauma and the BDNF Val66Met polymorphism on subclinical psychotic experiences (PEs). This was explored in two nonclinical independent samples: an undergraduate and technical-training school student sample (n = 808, sample 1) and a female twin sample (n = 621, sample 2). Results showed that childhood trauma was strongly associated with positive and negative PEs in nonclinical individuals. A BDNF Val66Met x childhood trauma effect on positive PEs was observed in both samples. These results were discordant in terms of risk allele: while in sample 1 Val allele carriers, especially males, were more vulnerable to the effects of childhood trauma regarding PEs, in sample 2 Met carriers presented higher PEs scores when exposed to childhood trauma, compared with Val carriers. Moreover, in sample 2, a significant interaction was also found in relation to negative PEs. Our study partially replicates previous findings and suggests that some individuals are more prone to develop PEs following childhood trauma because of a complex combination of multiple factors. Further studies including genetic, environmental and epigenetic factors may provide insights in this field., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

This study examines the longitudinal associations between psychotic experiences (PE) and incident suicidal ideation and behaviour in the general population, and to what degree the association may be confounded by non-psychotic psychopathology. Data from three prospective, general population cohorts were combined into one dataset (n=15,837) and analysed using logistic regression, controlling for continuous measures of depression, anxiety and mania symptoms. Analyses were conducted in the entire sample, and in subsamples stratified by presence or absence of mental disorders. The presence of PE at baseline increased the risk of incident suicidal ideation and behaviour. However, adjustment for dimensional measures of psychopathology reduced effect sizes, although PE remained significantly associated with suicide attempts. Further examination of the associations revealed that PE were only associated with suicide attempts in individuals with at least one mental disorder. Similarly, in individuals without mental disorders, the risk of suicidal ideation increased as PE co-occurred with more symptom domains. The results of this study confirm that individuals with PE are at increased risk of suicidal ideation and behaviour. However, these associations are not specific, but reflect the increased risk of suicidal ideation in individuals with subthreshold multidimensional psychopathology and suicide attempts in individuals with co-occurring mental disorders., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

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

Introduction: Stereotype awareness--or an individual's perception of the degree to which negative beliefs or stereotypes are held by the public--is an important factor mediating public stigma, self-stigma and their negative consequences. Research is required to assess how individuals become more sensitive to perceive stereotypes, pointing the way to therapeutic options to reduce its negative effects and increase stigma resilience. Because perception and interpretation can be guided by belief systems, and childhood trauma (CT) is reported to impact such beliefs, CT is explored in relation to stereotype awareness (SA) in persons with psychosis, their siblings and controls., Method: Data from the GROUP project (Genetic Risk and Outcome of Psychosis) were analyzed. SA was measured by devaluation scales which assess a respondent's perception of the degree to which stereotypes about people with mental illness and about their families are held by the public. CT was measured using the Childhood Trauma Questionnaire (short form)., Results: In patients, symptoms of disorganization and emotional distress were associated with SA about people with mental illness. In siblings, schizotypal features were associated with both types of SA (more schizotypy = more SA). In both patients and siblings, CT was associated with both types of SA (more CT = more SA), independent of symptoms (patients) or schizotypy (siblings)., Conclusion: CT in people with psychosis and their siblings may sensitize to SA. Thus, CT may not only impact on risk for illness onset, it may also increase SA associated with mental illness, potentially interfering with the recovery process. CT-induced SA may indicate a heightened sensitivity to threat, which may also impact psychopathology.

Introduction: Stigma is an important environmental risk factor for a variety of outcomes in schizophrenia. In order to understand and remediate its effects, research is required to assess how stigma experiences are processed at the level of the individual. To this end, stereotype awareness (SA) with respect to people with mental illness and their families was explored in persons with psychotic disorder., Method: Data from the Dutch Genetic Risk and OUtcome of Psychosis project (GROUP) were analyzed. SA was measured using scales that assess a respondent's perception of common opinions about people with a mental illness and their families., Results: People with higher level of self-esteem were less aware of stereotypes about patients and families. People with more severe psychopathology reported more awareness of stereotypes about families, not about patients., Conclusion: Enhancing psychological resources, by increasing self-esteem and the ability to cope with symptoms, can be targeted to diminish stereotype threat and improve stigma resilience. Interventions can be tailored to individual differences to increase their impact. Furthermore, in order to diminish detrimental consequences of negative stereotypes, mental health professionals, health educators and experts by experience can inform the public about mental illness and stigma.

Background: In order to assess the importance of environmental and genetic risk on transition from health to psychotic disorder, a prospective study of individuals at average (n = 462) and high genetic risk (n = 810) was conducted., Method: A three-year cohort study examined the rate of transition to psychotic disorder. Binary measures indexing environmental exposure (combining urban birth, cannabis use, ethnicity and childhood trauma) and proxy genetic risk (high-risk sibling status) were used to model transition., Results: The majority of high-risk siblings (68%) and healthy comparison subjects (60%) had been exposed to one or more environmental risks. The risk of transition in siblings (n = 9, 1.1%) was higher than the risk in healthy comparison subjects (n = 2, 0.4%; OR(adj) = 2.2,95%CI:5-10.3). All transitions (100%) were associated with environmental exposure, compared to 65% of non-transitions (p = 0.014), with the greatest effects for childhood trauma (OR(adj) = 34.4,95%CI:4.4-267.4), cannabis use (OR = 4.1,95%CI:1.1, 15.4), minority ethnic group (OR = 3.8,95%CI:1.2,12.8) and urban birth (OR = 3.7,95%CI:0.9,15.4). The proportion of transitions in the population attributable to environmental and genetic risk ranged from 28% for minority ethnic group, 45% for urban birth, 57% for cannabis use, 86% for childhood trauma, and 50% for high-risk sibling status. Nine out of 11 transitions (82%) were exposed to both genetic and environmental risk, compared to only 43% of non-transitions (p = 0.03)., Conclusion: Environmental risk associated with transition to psychotic disorder is semi-ubiquitous regardless of genetic high risk status. Careful prospective documentation suggests most transitions can be attributed to powerful environmental effects that become detectable when analysed against elevated background genetic risk, indicating gene-environment interaction.

Recent studies have provided robust evidence for an association between childhood trauma (CT) and psychosis. Meta-analyses have quantified the association, pointing to odds ratios in the order of around 3, and prospective studies have shown that reverse causation is unlikely to explain the association. However, more work is needed to address the possibility of a gene-environment correlation, that is, whether genetic risk for psychosis predicts exposure to CT. Nevertheless, multiple studies have convincingly shown that the association between CT and psychosis remains strong and significant when controlling for genetic risk, in agreement with a possible causal association. In addition, several studies have shown plausible psychological and neurobiological mechanisms linking adverse experiences to psychosis, including induction of social defeat and reduced self-value, sensitization of the mesolimbic dopamine system, changes in the stress and immune system, and concomitant changes in stress-related brain structures, such as the hippocampus and the amygdala, findings that should be integrated, however, in more complex models of vulnerability. It is currently unclear whether genetic vulnerability plays a role in conferring the mental consequences of adversity, and which genes are likely to be involved. The current, limited evidence points to genes that are not specifically involved in psychosis but more generally in regulating mood (serotonin transporter gene), neuroplasticity (brain-derived neurotrophic factor), and the stress-response system (FKBP5), in line with a general effect of CT on a range of mental disorders, rather than suggesting specificity for psychosis.