Kathryn Hubbard

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 (χ2 = 6.3, P = 0.044), activities (χ2 = 6.7, P = 0.036), and areas (χ2 = 9.4, P = 0.009) and enhanced threat anticipation (χ2 = 9.3, P = 0.009) were associated with more intense psychotic experiences in FEP individuals than controls. Sensitivity to outsider status (χ2 = 5.7, P = 0.058) and aberrantly salient experiences (χ2 = 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.

Psychological processes underlying the association between childhood trauma and psychosis in daily life: an experience sampling study

Background Evidence has accumulated that implicates childhood trauma in the aetiology of psychosis, but our understanding of the putative psychological processes and mechanisms through which childhood trauma impacts on individuals and contributes to the development of psychosis remains limited. We aimed to investigate whether stress sensitivity and threat anticipation underlie the association between childhood abuse and psychosis. Method We used the Experience Sampling Method to measure stress, threat anticipation, negative affect, and psychotic experiences in 50 first-episode psychosis (FEP) patients, 44 At-Risk Mental State (ARMS) participants, and 52 controls. Childhood abuse was assessed using the Childhood Trauma Questionnaire. Results Associations of minor socio-environmental stress in daily life with negative affect and psychotic experiences were modified by sexual abuse and group (all pFWE < 0.05). While there was strong evidence that these associations were greater in FEP exposed to high levels of sexual abuse, and some evidence of greater associations in ARMS exposed to high levels of sexual abuse, controls exposed to high levels of sexual abuse were more resilient and reported less intense negative emotional reactions to socio-environmental stress. A similar pattern was evident for threat anticipation. Conclusions Elevated sensitivity and lack of resilience to socio-environmental stress and enhanced threat anticipation in daily life may be important psychological processes underlying the association between childhood sexual abuse and psychosis.

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.

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.

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.

Further evidence of a cumulative effect of social disadvantage on risk of psychosis

Background A growing body of evidence suggests that indicators of social disadvantage are associated with an increased risk of psychosis. However, only a few studies have specifically looked at cumulative effects and long-term associations. The aims of this study are: To compare the prevalence of specific indicators of social disadvantage at, and prior to, first contact with psychiatric services in patients suffering their first episode of psychosis and in a control sample. To explore long-term associations, cumulative effects, and direction of effects. Method We collected information on social disadvantage from 332 patients and from 301 controls recruited from the local population in South London. Three indicators of social disadvantage in childhood and six indicators of social disadvantage in adulthood were analysed. Results Across all the domains considered, cases were more likely to report social disadvantage than were controls. Compared with controls, cases were approximately two times more likely to have had a parent die and approximately three times more likely to have experienced a long-term separation from one parent before the age of 17 years. Cases were also more likely than controls to report two or more indicators of adult social disadvantage, not only at first contact with psychiatric services [odds ratio (OR) 9.5], but also at onset of psychosis (OR 8.5), 1 year pre-onset (OR 4.5), and 5 years pre-onset (OR 2.9). Conclusions Greater numbers of indicators of current and long-term exposure are associated with progressively greater odds of psychosis. There is some evidence that social disadvantage tends to cluster and accumulate.

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 (CTs; 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.

Mentoring During the Transition from Care to Prevent Depression: Care Leavers’ Perspectives

A small-scale consultation of care leavers in South London was undertaken in 2013–2014, in order to inform a pilot mentoring scheme to reduce depression in young women through supporting their transition from care to independence. Research on the social factors implicated in the onset and course of depression indicates that social support during stressful events can be protective. Youth mentoring is now widely offered to disadvantaged young people. This paper examines what some young people told us about if and how our proposed mentoring intervention might help in maintaining their well-being through the stress of leaving care. Eleven participants of focus group discussions told us they could see clear benefits in receiving mentoring at this time, and discussed the kind of mentor and activities they might like. However, most did not want a mentor now. Thematic analysis of the discussions arising identified unpaid, open-ended ‘natural mentoring’ relationships as particularly important to them in maintaining their well-being. We consider the fit with related research, and emerging new policy, and the implications for our proposed study, and conclude that supporting the establishment and continuation of natural mentoring is a particularly promising way forward.

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.

Book review: Education, family and child & adolescent health

In recent years, we have seen a renewed interest in the role of childhood experiences on an individual’s health and wellbeing, with income, adversity, urbanicity and social support having all been shown to have a significant effect later in life. This book highlights the current research and ideas on the specific effect that both education and family history may have on an individual’s lifestyle and attitude to work in later life. In order to address the spectrum of developmental challenges and unite various fields, the authors draw from a multidisciplinary pool of academics and clinicians from medicine, psychology and educational sciences to compile a collection of essays through which they aim to bridge theoretical and research concepts and findings, with clinical practice. The book is split into three sections titled ‘Family’, ‘Child & Adolescent Development’ and ‘Education’, with each section consisting of a number of essays from renowned experts. Part 1, ‘Family’, covers the key expected themes of parental health and relationships, but also includes chapters on ‘The Impact of Grandparents on their Grandchildren’ and ‘The Psychological and Social Impacts of Having a Child with a Disability’. The inclusion of more specialist areas of research adds an extra dimension to the book, which continues with later essays including ‘Migration, Health and Education’ and ‘Discussing Museum Learning Practices for Children with Disabilities’. The broad range of topics throughout the text makes for an interesting and varied read, while also ensuring that there is minimal repetition of information between chapters. Each essay provides an in-depth literature review of the topic and tends to be split into subchapters which are clearly labelled, allowing the reader to be easily signposted to their area of interest. While the authors state this book is aimed at a wide audience of medical, education and health professionals, I would recommend this text to students who are still completing training. I believe the book would act as a great basis to start their reading and learning about the area, providing sufficient background and details to give a solid understanding of current ideas and research. The authors have intentionally kept complex terminology and statistical jargon to a minimum in order to ensure a wider audience, and this, along with the high-quality writing from eminent authors in the field, has resulted in a clear and easily accessible text.