Threat, hostility and violence in childhood and later psychotic disorder: population-based case-control study.

BACKGROUND: A growing body of research suggests that childhood adversities are associated with later psychosis, broadly defined. However, there remain several gaps and unanswered questions. Most studies are of low-level psychotic experiences and findings cannot necessarily be extrapolated to psychotic disorders. Further, few studies have examined the effects of more fine-grained dimensions of adversity such as type, timing and severity. AIMS: Using detailed data from the Childhood Adversity and Psychosis (CAPsy) study, we sought to address these gaps and examine in detail associations between a range of childhood adversities and psychotic disorder. METHOD: CAPsy is population-based first-episode psychosis case-control study in the UK. In a sample of 374 cases and 301 controls, we collected extensive data on childhood adversities, in particular household discord, various forms of abuse and bullying, and putative confounders, including family history of psychotic disorder, using validated, semi-structured instruments. RESULTS: We found strong evidence that all forms of childhood adversity were associated with around a two- to fourfold increased odds of psychotic disorder and that exposure to multiple adversities was associated with a linear increase in odds. We further found that severe forms of adversity, i.e. involving threat, hostility and violence, were most strongly associated with increased odds of disorder. More tentatively, we found that some adversities (e.g. bullying, sexual abuse) were more strongly associated with psychotic disorder if first occurrence was in adolescence. CONCLUSIONS: Our findings extend previous research on childhood adversity and suggest a degree of specificity for severe adversities involving threat, hostility and violence.

'Walk this way': results from a pilot randomised controlled trial of a health coaching intervention to reduce sedentary behaviour and increase physical activity in people with serious mental illness.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of premature death among people with serious mental illness (SMI). Sedentary behaviour (SB) is an independent risk factor for CVD and mortality and people with SMI are highly sedentary. We developed a health coaching intervention called 'Walk this Way' to reduce SB and increase physical activity (PA) in people with SMI and conducted a pilot randomised controlled trial (RCT) to test its feasibility and acceptability. METHODS: We randomised people with SMI from three community mental health teams into either the WTW intervention or treatment as usual. The WTW intervention lasted 17 weeks and included an initial education session, fortnightly coaching, provision of pedometers and access to a weekly walking group. Objective SB and PA were measured with accelerometers. Cardiometabolic risk factors and wellbeing measures were collected. RESULTS: We recruited 40 people of whom 33 (82.5%) were followed up. 13/20 (65%) of participants allocated to the coaching intervention completed it. In the intervention group SB decreased by 56 min and total PA increased by 32 min per day on average which was sustained 6 months later. There was no change in PA or SB in the control group. When interviewed, participants in the intervention found the intervention helpful and acceptable. No adverse events were reported from the intervention. CONCLUSIONS: The intervention was feasible and acceptable to participants. Preliminary results were encouraging with improvement seen in both SB and PA. A larger study is needed to assess the effectiveness of the intervention and address any implementation challenges. TRIAL REGISTRATION: ISRCTN Registry identifier: ISRCTN37724980 , retrospectively registered 25 September 2015.

Effects of aripiprazole and haloperidol on neural activation during a simple motor task in healthy individuals: A functional MRI study.

The dopaminergic system plays a key role in motor function and motor abnormalities have been shown to be a specific feature of psychosis. Due to their dopaminergic action, antipsychotic drugs may be expected to modulate motor function, but the precise effects of these drugs on motor function remain unclear. We carried out a within-subject, double-blind, randomized study of the effects of aripiprazole, haloperidol and placebo on motor function in 20 healthy men. For each condition, motor performance on an auditory-paced task was investigated. We entered maps of neural activation into a random effects general linear regression model to investigate motor function main effects. Whole-brain imaging revealed a significant treatment effect in a distributed network encompassing posterior orbitofrontal/anterior insula cortices, and the inferior temporal and postcentral gyri. Post-hoc comparison of treatments showed neural activation after aripiprazole did not differ significantly from placebo in either voxel-wise or region of interest analyses, with the results above driven primarily by haloperidol. We also observed a simple main effect of haloperidol compared with placebo, with increased task-related recruitment of posterior cingulate and precentral gyri. Furthermore, region of interest analyses revealed greater activation following haloperidol compared with placebo in the precentral and post-central gyri, and the putamen. These diverse modifications in cortical motor activation may relate to the different pharmacological profiles of haloperidol and aripiprazole, although the specific mechanisms underlying these differences remain unclear. Evaluating healthy individuals can allow investigation of the effects of different antipsychotics on cortical activation, independently of either disease-related pathology or previous treatment. Hum Brain Mapp 38:1833-1845, 2017. © 2017 Wiley Periodicals, Inc.

Smoking-related violence in a mental health setting following the implementation of a comprehensive smoke-free policy: A content analysis of incident reports.

Smoke-free policies in mental health settings are important to protect health but are often impeded by staff concerns that physical violence may increase. We aimed to address the literature gap about the frequency, nature, and management of physical violence in relation to smoking. We compared the antecedents and containment of smoking-related incidents of physical violence over a two-year period, (12 months when an indoor-only smoke-free policy was in place, followed by 12 months after a new comprehensive smoke-free policy was introduced) using incident reports completed by staff in a large mental health organization in London, UK. Sixty-one smoking-related incidents occurred during the indoor-only smoke-free policy period; 32 smoking-related incidents occurred during the comprehensive smoke-free policy. We identified four antecedent categories for physical violence: i) patient request to smoke denied by staff; ii) during a supervised smoking break; iii) staff response to a patient breach of the smoke-free policy iv) asking for, trading or stealing smoking materials. The antecedent pattern changed across the two policy periods, with fewer incidents of denying a patient's request to smoke and a greater number of incidents involving staff responding to breaches occurring after the introduction of the comprehensive smoke-free policy. The prohibition of smoking breaks removed this source of violence. Timeout and PRN medication were the most common containment interventions. Understanding the context of smoking-related violence may inform clinical guidelines about its prevention and management.

A comparison between self-report and interviewer-rated retrospective reports of childhood abuse among individuals with first-episode psychosis and population-based controls.

The typical reliance on self-report questionnaires in retrospective case-control studies of childhood abuse and psychotic disorders has been criticised, due to the potential for recall bias associated with, amongst other factors, cognitive impairments and detachment from reality, among individuals with psychosis. One way to establish if any substantial bias may exist is to examine whether the concordance of reports of childhood abuse established from retrospective self-report methods versus more comprehensive interviewer-rated assessments differ between individuals with psychosis and controls. Data from the Childhood Adversity and Psychosis (CAPsy) study were used to examine the accuracy, strength of agreement, and convergent validity of two distinct retrospective measures of childhood abuse: a self-report questionnaire (the Childhood Trauma Questionnaire; CTQ) and a comprehensive interview (the Childhood Experiences of Care and Abuse schedule; CECA). In a sample of 234 cases with first-episode psychosis and 293 controls, we found no strong evidence that the validity of the two measures differed between cases and controls. For reports of sexual and emotional abuse, we found fair levels of agreement between CECA and CTQ ratings in both groups (kappa coefficients 0.43-0.53), moderate to high sensitivity and specificity, and reasonably high convergent validity (tetrachoric correlations of 0.78-0.80). For physical abuse, convergent validity was slightly lower in cases compared with controls. Both measures can be used in future studies to retrospectively assess associations between childhood abuse and psychotic phenomena, but time-permitting, the CECA is preferable as it provides additional important contextual details of abuse exposure.

Threatening Life Events and Difficulties and Psychotic Disorder.

OBJECTIVE: Stressful life events have been implicated in the onset of psychotic disorders, but there are few robust studies. We sought to examine the nature and magnitude of associations between adult life events and difficulties and first-episode psychoses, particularly focusing on contextual characteristics, including threat, intrusiveness, and independence. METHOD: This study forms part of the Childhood Adversity and Psychosis Study (CAPsy), an epidemiological case-control study in London, United Kingdom. Data on life events and difficulties (problems lasting 4 wk or more) during 1 year prior to onset (cases) or interview (controls) were assessed using the semi-structured Life Events and Difficulties Schedule (LEDS). Data were available on 253 individuals with a first episode of psychosis and 301 population-based controls. RESULTS: We found strong evidence that odds of exposure to threatening and intrusive events in the 1 year prior to onset were substantially higher among cases compared with controls, independent of age, gender, ethnicity, and social class (ORs > 3). This was consistent across diagnostic categories. We found further evidence that the effect of threatening events and difficulties was cumulative (1 event odds ratio [OR] 2.69 [95% confidence interval (CI) 1.51-4.79]; 2 events OR 4.87 [95% CI 2.34-10.16]; ≥3 events OR 5.27 [95% CI 1.83-15.19]; 1 difficulty OR 3.02 [95% CI 1.79-5.09]; 2 difficulties OR 9.71 [95% CI 4.20-22.40]; ≥3 difficulties OR 12.84 [95% CI 3.18-51.85]). CONCLUSIONS: Threatening and intrusive life events and difficulties are common in the year pre-onset among individuals with a first episode of psychosis. Such experiences may contribute to the development of psychotic disorders.

Is it possible for people with severe mental illness to sit less and move more? A systematic review of interventions to increase physical activity or reduce sedentary behaviour.

Individuals with severe mental illness (SMI) (schizophrenia-spectrum, bipolar disorder and major depressive disorder) die 10-20 years prematurely due to physical disorders such as cardiovascular disease. Physical activity (PA) is effective in preventing and managing these conditions in the general population, however individuals with SMI engage in substantially less PA and more sedentary behaviour (SB) compared to healthy counterparts. Furthermore, the effectiveness of intervening to increase PA or reduce SB in SMI populations is unknown. Therefore, we systematically reviewed studies measuring changes in PA or SB following behavioural interventions in people with SMI. A systematic search of major databases was conducted from inception until 1/3/2018 for behavioural interventions reporting changes in PA or SB in people with SMI. From 3018 initial hits, 32 articles were eligible, including 16 controlled trials (CT's; Treatment n = 1025, Control n = 1162) and 16 uncontrolled trials (n = 655). Of 16 CTs, seven (47%) reported significant improvements in PA, although only one found changes with an objective measure. Of 16 uncontrolled trials, 3 (20%) found improvements in PA (one with objective measurement). No intervention study had a primary aim of changing SB, nor did any note changes in SB using an objective measure. In conclusion, there is inconsistent and low quality evidence to show that interventions can be effective in changing PA or SB in this population. Future robust randomized controlled trials, using objectively-measured PA/SB as the primary outcome, are required to determine which behavioural interventions are effective in improving the sedentary lifestyles associated with SMI. Systematic review registration- PROSPERO registration number CRD42017069399.

Modeling the Interplay Between Psychological Processes and Adverse, Stressful Contexts and Experiences in Pathways to Psychosis: An Experience Sampling Study.

Several integrated models of psychosis have implicated adverse, stressful contexts and experiences, and affective and cognitive processes in the onset of psychosis. In these models, the effects of stress are posited to contribute to the development of psychotic experiences via pathways through affective disturbance, cognitive biases, and anomalous experiences. However, attempts to systematically test comprehensive models of these pathways remain sparse. Using the Experience Sampling Method in 51 individuals with first-episode psychosis (FEP), 46 individuals with an at-risk mental state (ARMS) for psychosis, and 53 controls, we investigated how stress, enhanced threat anticipation, and experiences of aberrant salience combine to increase the intensity of psychotic experiences. We fitted multilevel moderated mediation models to investigate indirect effects across these groups. We found that the effects of stress on psychotic experiences were mediated via pathways through affective disturbance in all 3 groups. The effect of stress on psychotic experiences was mediated by threat anticipation in FEP individuals and controls but not in ARMS individuals. There was only weak evidence of mediation via aberrant salience. However, aberrant salience retained a substantial direct effect on psychotic experiences, independently of stress, in all 3 groups. Our findings provide novel insights on the role of affective disturbance and threat anticipation in pathways through which stress impacts on the formation of psychotic experiences across different stages of early psychosis in daily life.

Effects of aripiprazole and haloperidol on neural activation during the n-back in healthy individuals: A functional MRI study.

OBJECTIVE: Antipsychotic drugs target neurotransmitter systems that play key roles in working memory. Therefore, they may be expected to modulate this cognitive function via their actions at receptors for these neurotransmitters. However, the precise effects of antipsychotic drugs on working memory function remain unclear. Most studies have been carried out in clinical populations, making it difficult to disentangle pharmacological effects from pathology-related brain activation. In this study, we aim to investigate the effects of two antipsychotic compounds on brain activation during working memory in healthy individuals. This would allow elucidation of the effects of current antipsychotic treatments on brain function, independently of either previous antipsychotic use or disease-related pathology. METHODS: We carried out a fully counterbalanced, randomised within-subject, double-blinded and placebo-controlled, cross-over study of the effects of two antipsychotic drugs on working memory function in 17 healthy individuals, using the n-back task. Participants completed the functional MRI task on three separate occasions (in randomised order): following placebo, haloperidol, and aripiprazole. For each condition, working memory ability was investigated, and maps of neural activation were entered into a random effects general linear regression model to investigate main working memory function and linear load. Voxel-wise and region of interest analyses were conducted to attain regions of altered brain activation for each intervention. RESULTS: Aripiprazole did not lead to any changes in neural activation compared with placebo. However, reaction time to a correct response was significantly increased following aripiprazole compared to both placebo (p=0.046) and haloperidol (p=0.02). In contrast, compared to placebo, haloperidol dampened activation in parietal (BA 7/40; left: FWE-corr. p=0.005; FWE-corr. right: p=0.007) and frontal (including prefrontal; BA 9/44/46; left: FWE-corr. p=0.009; right: FWE-corr. p=0.014) cortices and the left putamen (FWE-corr. p=0.004). Compared with aripiprazole, haloperidol dampened activation in parietal cortex (BA7/40; left: FWE-corr. p=0.034; right: FWE-corr. p=0.045) and the left putamen (FWE-corr.p=0.015). Haloperidol had no effect on working memory performance compared with placebo. CONCLUSION: Cognitive functions are known to be impaired in schizophrenia and as such are an important target of treatments. Elucidating the mechanisms by which antipsychotic medications alter brain activation underlying cognition is essential to advance pharmacological treatment of this disorder. Studies in healthy individuals can help elucidate some of these mechanisms, whilst limiting the confounding effect of the underlying disease-related pathology. Our study provides evidence for immediate and differential effects of single-dose haloperidol and aripiprazole on brain activation during working memory in healthy individuals. We propose that these differences likely reflect their different receptor affinity profiles, although the precise mechanisms underlying these differences remain unclear.

Effects of antipsychotics on cortisol, interleukin-6 and hippocampal perfusion in healthy volunteers.

This randomized within-subject, double blind study aimed to compare the effects of a single dose of two different antipsychotics (haloperidol and aripiprazole) on cortisol, interleukin (IL)-6 and hippocampal regional Cerebral Blood Flow (rCBF) in the same 17 healthy male individuals. Subjects received a single dose of haloperidol (3mg), aripiprazole (10mg) and placebo, in a randomized order on three study appointments. We measured salivary cortisol levels at multiple time points, IL-6 levels from plasma samples, and resting cerebral blood flow (rCBF), using a pulsed continuous arterial spin labeling (pCASL) sequence (1.5T). We found significantly lower cortisol levels in the haloperidol condition (F(2,32)=5.78, p=0.007), than in either placebo (p=0.013; CI=0.45, 0.406) or aripiprazole (p=0.037; CI=-0.520, -0.014). Interleukin-6 levels were also lower following haloperidol (F(2,22)=4.19, p=0.048) in comparison with placebo (p=0.02; CI=0.14, 1.8), but not with aripiprazole. Finally, we found a greater rCBF in the right (peak voxel: T=6.47, p<0.0001) and left (peak voxel T=5.17, p<0.01) hippocampus following haloperidol compared with placebo, and at trend level also in the left hippocampus following aripiprazole compared with placebo (T=4.07, p=0.057). These differences in hippocampal rCBF after both antipsychotics were no longer evident (haloperidol) or present at trend level (aripiprazole), after controlling for cortisol and IL-6 levels. Our findings suggest that haloperidol can directly regulate the hypothalamic-pituitary-adrenal (HPA) axis and immune system through a pharmacological action via D2 receptor antagonism. Finally, our data suggest that the increased hippocampal rCBF is a manifestation of the reduction in IL-6 and cortisol which follows the administration of haloperidol.

Stress Sensitivity, Aberrant Salience, and Threat Anticipation in Early Psychosis: An Experience Sampling Study.

While contemporary models of psychosis have proposed a number of putative psychological mechanisms, how these impact on individuals to increase intensity of psychotic experiences in real life, outside the research laboratory, remains unclear. We aimed to investigate whether elevated stress sensitivity, experiences of aberrant novelty and salience, and enhanced anticipation of threat contribute to the development of psychotic experiences in daily life. We used the experience sampling method (ESM) to assess stress, negative affect, aberrant salience, threat anticipation, and psychotic experiences in 51 individuals with first-episode psychosis (FEP), 46 individuals with an at-risk mental state (ARMS) for psychosis, and 53 controls with no personal or family history of psychosis. Linear mixed models were used to account for the multilevel structure of ESM data. In all 3 groups, elevated stress sensitivity, aberrant salience, and enhanced threat anticipation were associated with an increased intensity of psychotic experiences. However, elevated sensitivity to minor stressful events (χ(2)= 6.3,P= 0.044), activities (χ(2)= 6.7,P= 0.036), and areas (χ(2)= 9.4,P= 0.009) and enhanced threat anticipation (χ(2)= 9.3,P= 0.009) were associated with more intense psychotic experiences in FEP individuals than controls. Sensitivity to outsider status (χ(2)= 5.7,P= 0.058) and aberrantly salient experiences (χ(2)= 12.3,P= 0.002) were more strongly associated with psychotic experiences in ARMS individuals than controls. Our findings suggest that stress sensitivity, aberrant salience, and threat anticipation are important psychological processes in the development of psychotic experiences in daily life in the early stages of the disorder.

Identifying gene-environment interactions in schizophrenia: contemporary challenges for integrated, large-scale investigations.

Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G × E), however, so far, thorough replication of findings is rare and G × E research still faces several conceptual and methodological challenges. In this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G × E research, drawing on the example of a large, international, multi-center study into the identification and translational application of G × E in schizophrenia. While such investigations are now well underway, new challenges emerge for G × E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotype.