Pathways to psychosis: Investigating environmental, cognitive and genetic mechanisms underlying development of psychotic experiences in young adults

Lead Research Organisation: Cardiff University
Department Name: School of Medicine

Abstract

Schizophrenia is a severe psychiatric disorder that imposes a substantial burden on sufferers and their families, and is one of the leading causes of disability worldwide. Although treatments for schizophrenia exist there is a pressing need for more effective treatments and for interventions to prevent people from developing this disorder.

Schizophrenia is characterised by hallucinations (for example hearing voices) and delusions (for example an irrational belief that people are plotting to kill you). These are called psychotic experiences, and whilst schizophrenia affects about 1% of the population over the course of their lives, psychotic experiences occur much more commonly, affecting about 5% of adolescents and young adults. Although for most people these experiences are short lived and resolve completely, for some they persist, and may develop over time into a psychotic illness such as schizophrenia.

We aim to study the development of psychotic experiences from childhood through early adulthood to understand more about what causes these to develop, and what factors lead to recovery from these, or conversely, to deterioration and progression to a psychotic illness. We are particularly interested in examining the role of: i) social adversity during childhood and adolescence, characterised for example by childhood maltreatment or repeated victimization from bullying, and ii) cannabis use, on increasing the risk of developing psychotic experiences.
Social adversity and cannabis use can cause abnormalities in regulation of dopamine, an important neurotransmitter in the brain. This is of particular interest as there is very good evidence that increased dopamine activity in a specific brain pathway is a key biological abnormality underlying schizophrenia.

However, whilst there is good evidence of dopamine abnormalities underlying schizophrenia, it is not known how having too much dopamine can lead to someone hearing a voice that isn't there, or developing a belief that someone is plotting to kill them. Studies in cognitive neuroscience go some way to explaining this by demonstrating that altered dopamine function can affect how people perceive stimuli in their environment, and the inferences that they make about these events. For example, people with schizophrenia are more likely to interpret unimportant background stimuli as having important personal relevance, reach decisions based on insufficient evidence, and misattribute self-generated thoughts or speech as coming from an external source.

We aim to study whether abnormalities on cognitive tests of perception and inference are associated with psychotic experiences in young adults, and whether experiences of social adversity and cannabis use are also associated with deficits in these cognitive tests. This work can provide a model whereby social adversity or cannabis can lead to psychotic experiences through effects on perception and inference (via altered dopamine function). This work is important because cognitive processes influencing perception and inference are modifiable, and therefore evidence that they play a role in developing psychotic experiences will prioritize these as potential targets for psychological interventions to prevent people from developing schizophrenia.

Furthermore, although genetic effects play a critical role in determining risk of developing schizophrenia it is not known how this risk is expressed during development from childhood through early adulthood. We will examine how genetic risk for schizophrenia affects a broad range of psychopathology as well as intellectual ability and performance on cognitive tests of perception and inference. By combining work on genetic, psychological and social mechanisms we will increase our understanding of the pathways leading to development of psychotic experiences, to help inform interventions for treatment and prevention of schizophrenia.

Technical Summary

This proposal aims to examine the development of psychotic experiences, at-risk mental states and psychotic disorder from childhood through to early adulthood in the general population, and to investigate social-environmental, cognitive and genetic mechanisms underlying this. We will measure psychotic outcomes in participants of the population-based ALSPAC birth cohort when they are age 24-25, a critical period as this is the peak age of incidence for schizophrenia. ALSPAC has a wealth of detailed information already available on the cohort participants including data from semi-structured interviews of psychotic experiences during childhood and adolescence that will allow us to track these experiences during development and study their impact on functioning and transition into psychotic disorder during early adulthood.

We will also examine the effects of social adversity and cannabis use on trajectories of psychotic experiences, and study how deficits in cognitive processes relating to perception and inference relate both to psychotic experiences in early adulthood, and to earlier experiences of social adversity and cannabis use. This work can inform us as to how these environmental exposures lead to development of psychotic phenomena, and help identify targets for interventions. We will also examine how genetic risk for schizophrenia, indexed by a composite measure of common alleles conferring increased risk of this disorder, is manifest phenotypically during development from childhood through early adulthood in a population-based sample, including expression of risk through cognitive processes relating to perception and inference. To address these questions we will use appropriate statistical techniques including structural equation models and mixture modeling techniques to examine changes in repeated measures over time, marginal structural models to deal with time-varying confounding, and multiple imputation to address issues relating to attrition.

Planned Impact

The aim of this research is to understand more about the development of psychotic experiences from childhood through to young adulthood, and about the bio-psycho-social mechanisms underlying this. The personal and economic burden of psychotic disorders is substantial, and there is a pressing need for more effective therapies to treat psychosis, and to prevent transition in high-risk individuals. This research project is focused on questions that will have an impact beyond the academic environment, with other beneficiaries described below.

Service users and families
Understanding more about the cognitive mechanisms that translate biological abnormalities into the experience of hearing voices or development of delusional beliefs is critical to aid the development of effective psychological treatments for psychosis. Identifying relevant cognitive processes to target for such interventions will benefit patients with psychotic experiences by improving outcomes and reducing disability across a broad spectrum of clinical diagnoses. This will also benefit the pharmaceutical industry as it will inform the development of new markers for use as surrogate endpoints in experimental medicine and early phase clinical trials. A better understanding of how psychotic experiences develop will also benefit patients and their families by reducing the stigma associated with psychotic disorders.

Young people in the community
Identifying modifiable dysfunctional cognitive processes involved in the aetiology of psychosis will also inform preventive interventions. The potential for such interventions to be applied at a population (for example school) level rather than targeting high-risk individuals will confer a greater public health impact on reducing psychosis and other adverse outcomes that result from dysfunctional cognitive processes. This is particularly attractive as it means that young people who are not engaged in clinical services will also benefit, whilst applying interventions at a broad level also reduces stigma associated with targeted approaches. In the longer term this will benefit young people by reducing their risk of transition into clinical disorder. Improving cognitive biases will also improve relationships and social and occupational functioning, thus having economic impact as well as improving quality of life. A greater understanding of long-term effects of victimization on development of psychosis will enhance the drive to target and reduce the occurrence of such behaviour in schools and work places. This will confer benefits to all individuals within such organisations and lead to benefits in relation to other (non-psychotic) aspects of mental health and well-being, as well as improving quality of life.

Public sector, policy and practice
Our work previously on the relationship between cannabis use and psychosis has been presented to government advisory boards and contributed to debates about policy. It has also been used to inform the public about the possible mental health consequences of use of this drug. Through engagement with the young people involved in this study, and with the wider public (as detailed in the Pathways to Impact), the work from this project can benefit members of the general public by providing information that can help them make informed decisions about use of cannabis, and about their level of risk if, for example, they have an increased inherited risk of psychosis. This research will increase the quality of information contributing to the debate about the effects of cannabis use amongst policy-makers and the wider public.
Understanding the risk of transition from psychotic experiences to disorder, and factors influencing this will benefit practitioners who are often faced with difficult questions about risk prediction when robust estimates from large population-based samples are not available. Such knowledge can help them advise high-risk individuals appropriately.

Publications

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Davies J (2018) Adverse life outcomes associated with adolescent psychotic experiences and depressive symptoms. in Social psychiatry and psychiatric epidemiology

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Guyatt AL (2018) Association of copy number variation across the genome with neuropsychiatric traits in the general population. in American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics

 
Description Investigating genetic and environmental risk for psychosis mediated through L-Type voltage gated calcium channels
Amount £764,295 (GBP)
Funding ID MR/R011397/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 05/2018 
End 10/2021
 
Description Mapping Neurodevelopmental Trajectories for Adult Psychiatric Disorder: ALSPAC-MRI-II
Amount £1,762,268 (GBP)
Funding ID MR/S003436/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2019 
End 03/2023
 
Description Pathfinders Grant
Amount £1,497,192 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2018 
End 03/2020
 
Description Population-based studies of the incidence, prevalence and consequences of posttraumatic stress disorder in the changing demographic landscape of Sweden
Amount 5,874,000 kr (SEK)
Organisation FORTE: (Swedish Research Council for Health, Working Life and Welfare) 
Sector Academic/University
Country Sweden
Start 04/2019 
End 03/2022
 
Description Research Grant
Amount € 329,048 (EUR)
Funding ID HRA-PHR-2015-1293 
Organisation Health Services Executive 
Sector Public
Country Ireland
Start 07/2016 
End 07/2019
 
Description Tracking Trajectories of Psychopathology from Infancy to Young Adulthood: an Irish national longitudinal cohort study
Amount € 357,142 (EUR)
Funding ID ILP-PHR-2019-009 
Organisation Health Research Board (HRB) 
Sector Public
Country Ireland
Start 01/2020 
End 01/2024
 
Description Aetiology of psychosis - Cambridge 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution Grant lead, analysis of data, writing papers
Collaborator Contribution n/a
Impact MRC Research Grants, publications
Start Year 2010
 
Description Aetiology of psychosis - UCL 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Grant lead, analysis of data, writing papers
Collaborator Contribution n/a
Impact MRC research grants & publications
Start Year 2013
 
Description Biomarkers for psychosis - RCSI 
Organisation Royal College of Surgeons in Ireland
Country Ireland 
Sector Academic/University 
PI Contribution Co-app on grant, obtaining data, co-authoring papers
Collaborator Contribution Led grant application and co-authored/led papers
Impact HBI Research Grants Publications
Start Year 2014
 
Description Bipolar - Glasgow 
Organisation University of Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution Grant lead, co-supervising student
Collaborator Contribution n/a
Impact MHRUK studentship and publications
Start Year 2015
 
Description PTSD and psychosis - Lancaster 
Organisation Lancaster University
Country United Kingdom 
Sector Academic/University 
PI Contribution Preparation of grant application
Collaborator Contribution n/a
Impact Grant application
Start Year 2015
 
Description PTSD and psychosis - Liverpool 
Organisation University of Liverpool
Country United Kingdom 
Sector Academic/University 
PI Contribution Preparation of grant application (Bentall) Publications (Gage)
Collaborator Contribution Co-authored and led publications Led grant application
Impact Publications
Start Year 2015
 
Description PTSD and psychosis - Manchester 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution Preparation of grant application
Collaborator Contribution Leading grant application
Impact Grant application
Start Year 2015
 
Description Psychiatric epidemiology - Adelaide 
Organisation University of Adelaide
Country Australia 
Sector Academic/University 
PI Contribution Provided data, planned co-authorship
Collaborator Contribution planned co-authorship
Impact None yet
Start Year 2018
 
Description Psychiatric epidemiology - UoB 
Organisation University of Bristol
Department School of Social and Community Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Grant lead, analysis of data, writing papers
Collaborator Contribution n/a
Impact MRC Research Grants
 
Description Psychosis epidemiology - KI 
Organisation Karolinska Institute
Country Sweden 
Sector Academic/University 
PI Contribution Analysis of data, writing papers, contribution to grant
Collaborator Contribution Analysis of data, writing papers, leading grant
Impact Grants and publications
 
Description Psychosis epidemiology - Melbourne 
Organisation Orygen Youth Health
Country Australia 
Sector Hospitals 
PI Contribution Publications
Collaborator Contribution Publications
Impact Publications
Start Year 2019
 
Description Psychosis epidemiology - Mt Sinai 
Organisation Mount Sinai Hospital (USA)
Country United States 
Sector Hospitals 
PI Contribution Preparation & submission of grant applications
Collaborator Contribution Grant funding
Impact Publications Research Grant
Start Year 2015
 
Description Psychosis epidemiology - RCSI 
Organisation Royal College of Surgeons in Ireland
Country Ireland 
Sector Academic/University 
PI Contribution Grant lead, analysis of data, writing papers
Collaborator Contribution n/a
Impact MRC & HBRI Research Grants, publications
Start Year 2010
 
Description Psychosis epidemiology - Warwick 
Organisation University of Warwick
Country United Kingdom 
Sector Academic/University 
PI Contribution Grant lead, analysis of data, writing papers
Collaborator Contribution n/a
Impact MRC Research Grants & publications
Start Year 2012
 
Description BAP 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Talk on research
Year(s) Of Engagement Activity 2015
 
Description Continuing Medical Education item 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact We were invited to provide develop the work from one of our publications arising from this grant as a series of CME questions, primarily aimed at psychiatry trainees
This was only done recently so too early to gauge impact
Year(s) Of Engagement Activity 2020
 
Description Interview on study 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact To engage public in research study
Year(s) Of Engagement Activity 2015
 
Description Keynote lecture at the Tokyo Academy of Medical Sciences 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Keynote address about our work on psychotic experiences in the ALSPAC cohort funded by MRC grant. This led to new collaborations and development of joint research projects
Year(s) Of Engagement Activity 2019
 
Description Malta Talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Research presentation
Year(s) Of Engagement Activity 2017
 
Description Malta talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk on research
Year(s) Of Engagement Activity 2015
 
Description Media interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Interview describing work from this grant to increase dissemination of results to a wider academic / clinical audience
Only recently done so too early to gauge impact
Year(s) Of Engagement Activity 2020
URL https://www.healio.com/psychiatry/schizophrenia/news/online/%7B2f46fd6b-b811-42d9-83f4-61294b203050%...
 
Description Podcast 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Podcast in American Journal of Psychiatry describing one of the publications arising from this grant.
Only recently done so impact not known as yet
Year(s) Of Engagement Activity 2020
 
Description Presentation at BAP 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Research presentation
Year(s) Of Engagement Activity 2016
 
Description Schizophrenia International Research Society Biennial meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gave a presentation at the SIRS biennial meeting in Florence which resulted in research related questions and debate.
Year(s) Of Engagement Activity 2016
 
Description Talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Talk on research
Year(s) Of Engagement Activity 2016
 
Description Talk at WCE Conference. Tokyo 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk about work funded by this grant to other researchers, many of who are involved with setting up a similar cohort in Tokyo to the one we used for our work
Collaborations since then are contributing to joint pieces of work that will lead to publications and potentially new grant applications
Year(s) Of Engagement Activity 2018
 
Description WCPG talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk to disseminate our research funded by MRC grant. Interest and discussions and new collaboration that has led to a grant application - though hard to know to what extent this could be attributed to this talk per se
Year(s) Of Engagement Activity 2018
 
Description Winter School 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact Delivered talk: Psychosocial interventions - a basic introduction
Year(s) Of Engagement Activity 2016
 
Description Winter School in Psychiatry 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Undergraduate students
Results and Impact Two day event at Hadyn Ellis aimed at medical undergraduates.
Year(s) Of Engagement Activity 2018
URL http://www.eventbrite.co.uk/e/winter-school-in-psychiatry-2018-tickets-40548337168
 
Description Youth Mental Health 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Meeting to devise policy recommendations to present to EU government
Year(s) Of Engagement Activity 2014
 
Description interview on paper 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact To educate readers about our research
Year(s) Of Engagement Activity 2016