Psychiatric Imaging

Lead Research Organisation: MRC London Institute of Medical Sciences

Abstract

Psychotic illnesses such as schizophrenia are common and amongst the top ten greatest causes of adult disability in the world. We urgently need new and better treatments. However, a major limit on developing better treatments is that we dont understand what leads to psychosis. The brain chemical messenger, dopamine, is known to be abnormal in the condition. It is also known that cannabis use, and some forms of social stress, increase the risk of psychosis. We aim to study how these risk factors affect the dopamine system, and see if differences in dopamine function explain why some vulnerable people develop psychosis and others do not. We also know that current treatments act down-stream of the dopamine abnormality, but it is not clear whether they make this abnormality better or worse. We will test whether the dopamine system is different in patients who do not respond to treatment, and if treatment increases the dopamine abnormality. Finally we will also test whether we can counter the dopamine abnormality by targeting its control mechanisms. These studies will help predict and prevent psychosis, and develop better treatments.

Technical Summary

Psychotic disorders such as schizophrenia are amongst the top ten causes of disability in adults- accounting for one in every ten hospital beds used in the UK. The main treatments, the antipsychotic drugs, were discovered over fifty years ago. Since then there has been limited progress as: i) the medications are still based on the same old principle (dopamine (DA) receptor blockade), ii) there are no good predictors of response so treatment proceeds by trial-and-error, and iii) current treatments are ineffective for one in three patients. A major limit for the development of new, rational treatments has been the lack of a defined etiology and limited knowledge of the pathophysiology of schizophrenia. As a result most drug development in the last fifty years has simply sought to emulate aspects of existing antipsychotics and/or has used empirical animal models (e.g.: conditioned avoidance response or PCP-induced locomotion) that were developed prior to clear knowledge of the pathophysiology.|However, there is now evidence of a defined neurochemical pathophysiology in psychosis. Over fifteen in vivo studies in the last decade point to one central fact: presynaptic DA dysfunction is the final common pathway leading to psychosis (data reviewed and synthesized in: Howes et al, B J Psuch, 2007 & Lyon et al. Schiz. Bull. doi:10.1093, 2009). For this reason understanding the causes and implications of presynaptic DA dysfunction is critical to the pathophysiology of psychosis and provides a framework for understanding risk factors, predicting onset and delivering new treatments as set out in a recent review of the area (Howes and Kapur, Schiz Bulletin, 2009). The programme is divided into four sections: (a) Risk factors to pathophysiology; (b) Predicting illness onset; (c) Pathophysiology to therapeutics; (d) Targets beyond dopamine.|The first section will investigate the effects of the two major environmental risk factors for psychosis - cannabis use and social stress/defeat - on DA function using F-DOPA and raclopride positron emission tomography (PET) in individuals exposed to these risk factors. Section 2 addresses the ultimate aim in therapeutics of psychosis - predicting and preventing its onset using PET and magnetic resonance imaging (MRI) to identify biomarkers and pathoetiological changes underlying the development of psychosis. One third of patients with established psychosis fail to respond to treatment. Section 3 will investigate the determinants and predictors of treatment response using PET and MR spectroscopy of dopamine and glutamate markers respectively. Section 4 investigates upstream modulators of DA to identify novel non-D2 targets for drug discovery using agents that act at DA autoreceptors and glutamatergic and other regulatory mechanisms.|These studies have the potential to identify prognostic markers for psychosis and new therapeutic avenues to treat established illness.|

Publications

10 25 50

 
Description Royal College Schizophrenia Treatment UK Guidelines
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact Management guidelines to all UK psychiatrists
 
Description Academy of Medical Sciences starter grant (emotion processing CUMI)
Amount £22,500 (GBP)
Organisation Academy of Medical Sciences (AMS) 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2012 
End 06/2013
 
Description Astra Zeneca Investigator Initiated Research
Amount £54,000 (GBP)
Organisation AstraZeneca 
Sector Private
Country United Kingdom
Start 01/2016 
End 01/2017
 
Description BMA Margaret Temple award for schizophrenia research
Amount £50,000 (GBP)
Organisation British Medical Association (BMA) 
Sector Learned Society
Country United Kingdom
Start 12/2015 
End 12/2017
 
Description Banco di Sardegna Foundation project grant
Amount € 32,000 (EUR)
Organisation Fondazione Banco di Sardegna 
Sector Charity/Non Profit
Country Italy
Start 09/2011 
End 09/2012
 
Description Brain
Amount £1,000 (GBP)
Organisation Guarantors of Brain 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2009 
End 06/2009
 
Description ECNP
Amount £1,000 (GBP)
Organisation European College of Neuropsychopharmacology (ECNP) 
Sector Learned Society
Country European Union (EU)
Start 09/2009 
End 10/2009
 
Description EU FP-7
Amount € 3,838,000 (EUR)
Organisation European Union 
Sector Public
Country European Union (EU)
Start 01/2013 
End 02/2018
 
Description EU Marie-Curie
Amount € 330,000 (EUR)
Organisation European Union 
Sector Public
Country European Union (EU)
Start 07/2013 
End 08/2017
 
Description Independent Investigators Scheme (NARSAD)
Amount $96,000 (USD)
Organisation Brain & Behaviour Research Foundation 
Sector Charity/Non Profit
Country United States
Start 08/2013 
End 09/2015
 
Description Investigator Grant
Amount £124,000 (GBP)
Organisation Autifony Therapeutics 
Sector Private
Country United Kingdom
Start 07/2018 
End 07/2020
 
Description King's India scholarship
Amount £107,771 (GBP)
Organisation King's College London 
Sector Academic/University
Country United Kingdom
Start 06/2016 
End 05/2019
 
Description MRC
Amount £350,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 08/2008 
End 08/2010
 
Description MRC Experimental Medicine Challenge Scheme
Amount £1,100,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 08/2016 
End 07/2019
 
Description March of Dimes
Amount £340,000 (GBP)
Organisation March of Dimes Foundation 
Sector Charity/Non Profit
Country United States
Start 12/2011 
End 12/2014
 
Description Maudsley Charity TREAT Project grant
Amount £297,000 (GBP)
Funding ID 666 
Organisation South London and Maudsley (SLAM) NHS Foundation Trust 
Department Maudsley Charity
Sector Charity/Non Profit
Country United Kingdom
Start 12/2012 
End 12/2015
 
Description NIHR
Amount £11,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 11/2011 
End 03/2012
 
Description NIHR BRC starter grant (apo)
Amount £16,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Comprehensive Biomedical Research Centre, Guy's and St Thomas
Sector Public
Country United Kingdom
Start 11/2012 
End 11/2013
 
Description Roche Investigator Initiated Research
Amount £254,000 (GBP)
Organisation F. Hoffmann-La Roche AG 
Sector Private
Country Global
Start 01/2015 
End 12/2016
 
Description Roche investigator initiated grant
Amount £72,000 (GBP)
Organisation F. Hoffmann-La Roche AG 
Sector Private
Country Global
Start 04/2017 
End 04/2018
 
Description Stratified Medicince
Amount £3,800,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 06/2014 
End 06/2019
 
Description Sunovion Investigator Initiated Grant
Amount £150,000 (GBP)
Organisation Sunovion Pharmaceuticals, Inc. 
Sector Private
Country United States
Start 12/2016 
End 12/2018
 
Description Wellcome
Amount £350,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2013 
End 02/2016
 
Description Wellcome
Amount £1,054,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2011 
End 10/2016
 
Description Wellcome Trust Clinical Research Training fellowship
Amount £356,554 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2015 
End 12/2019
 
Title Database of neurochemical function in healthy volunteers 
Description Database of PET imaging data on the dopaminergic and serotinergic systems in healthy volunteers and socio-demographic and psychological indices. 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2008 
Provided To Others? Yes  
Impact This has resulted in a number of publications describing the relationship between socio-demographic (including age, and substance misuse) and personality factors, and is being used by an EU consortium to develop novel approaches to PET image analysis 
 
Description Cannabis, ketamine and psychosis (UCL) 
Organisation University College London
Department Division of Psychology & Language Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We conducted imaging
Collaborator Contribution Our partners recruited subjects
Impact Publications- Freeman et al 2012 and others in submission
Start Year 2010
 
Description EDiPs- dopamine in murine model of dopamine dysfunction 
Organisation University of Queensland
Country Australia 
Sector Academic/University 
PI Contribution we are contributing imaging technology
Collaborator Contribution University of Brisbane, Australia- contributing mice;
Impact On going investigations
Start Year 2018
 
Description Hallucinators study 
Organisation University Medical Center Utrecht (UMC)
Department Department of Psychiatry
Country Netherlands 
Sector Multiple 
PI Contribution Acquiring and analysing data
Collaborator Contribution Provision of a unique cohort of subjects, contributing towards the costs of the study and funding research workers to conduct the study
Impact Publications in preparation
Start Year 2010
 
Description Imanova PDE 
Organisation Imanova
Country United Kingdom 
Sector Private 
PI Contribution Undertaking recruitment and measures in clinical population
Collaborator Contribution Development and provision of PET tracer
Impact Work in progress
Start Year 2012
 
Description In-SENS 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Teaching and training and sharing data
Collaborator Contribution Teaching and training and sharing data
Impact Increased cadre of researchers with clinical translation skills
Start Year 2013
 
Description In-SENS 
Organisation Brain & Behaviour Research Foundation
Country United States 
Sector Charity/Non Profit 
PI Contribution Teaching and training and sharing data
Collaborator Contribution Teaching and training and sharing data
Impact Increased cadre of researchers with clinical translation skills
Start Year 2013
 
Description In-SENS 
Organisation F. Hoffmann-La Roche AG
Country Global 
Sector Private 
PI Contribution Teaching and training and sharing data
Collaborator Contribution Teaching and training and sharing data
Impact Increased cadre of researchers with clinical translation skills
Start Year 2013
 
Description In-SENS 
Organisation Heinrich Heine University Düsseldorf
Country Germany 
Sector Academic/University 
PI Contribution Teaching and training and sharing data
Collaborator Contribution Teaching and training and sharing data
Impact Increased cadre of researchers with clinical translation skills
Start Year 2013
 
Description In-SENS 
Organisation Ludwig Maximilian University of Munich (LMU Munich)
Country Germany 
Sector Academic/University 
PI Contribution Teaching and training and sharing data
Collaborator Contribution Teaching and training and sharing data
Impact Increased cadre of researchers with clinical translation skills
Start Year 2013
 
Description In-SENS 
Organisation Sylics
Country Netherlands 
Sector Private 
PI Contribution Teaching and training and sharing data
Collaborator Contribution Teaching and training and sharing data
Impact Increased cadre of researchers with clinical translation skills
Start Year 2013
 
Description In-SENS 
Organisation University of Amsterdam
Country Netherlands 
Sector Academic/University 
PI Contribution Teaching and training and sharing data
Collaborator Contribution Teaching and training and sharing data
Impact Increased cadre of researchers with clinical translation skills
Start Year 2013
 
Description In-SENS 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution Teaching and training and sharing data
Collaborator Contribution Teaching and training and sharing data
Impact Increased cadre of researchers with clinical translation skills
Start Year 2013
 
Description In-SENS 
Organisation University of Helsinki
Country Finland 
Sector Academic/University 
PI Contribution Teaching and training and sharing data
Collaborator Contribution Teaching and training and sharing data
Impact Increased cadre of researchers with clinical translation skills
Start Year 2013
 
Description METSY 
Organisation Autonomous University of Madrid
Country Spain 
Sector Academic/University 
PI Contribution Sharing data and collaborating on developing a new diagnostic and predictive biomarker platform for psychosis and metabolic dysfunction
Collaborator Contribution Sharing data and expertise on analysis
Impact Harmonisation of data collection
Start Year 2013
 
Description METSY 
Organisation Koninklijke Philips Electronics N.V.
Department Philips
Country Global 
Sector Private 
PI Contribution Sharing data and collaborating on developing a new diagnostic and predictive biomarker platform for psychosis and metabolic dysfunction
Collaborator Contribution Sharing data and expertise on analysis
Impact Harmonisation of data collection
Start Year 2013
 
Description METSY 
Organisation University of Helsinki
Country Finland 
Sector Academic/University 
PI Contribution Sharing data and collaborating on developing a new diagnostic and predictive biomarker platform for psychosis and metabolic dysfunction
Collaborator Contribution Sharing data and expertise on analysis
Impact Harmonisation of data collection
Start Year 2013
 
Description METSY 
Organisation University of Turku
Country Finland 
Sector Academic/University 
PI Contribution Sharing data and collaborating on developing a new diagnostic and predictive biomarker platform for psychosis and metabolic dysfunction
Collaborator Contribution Sharing data and expertise on analysis
Impact Harmonisation of data collection
Start Year 2013
 
Description Mood and cognition 
Organisation University College London
Department Institute of Cognitive Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution We have undertaken the imaging side of the study
Collaborator Contribution Our partners have undertaken the behavioural testing
Impact Publications- Selvaraj et al Mol Psych 2012 and others in submission
Start Year 2011
 
Description Neurobiology of affect regulation-brain-gene (Oxford) 
Organisation University of Oxford
Department Department of Psychiatry
Country United Kingdom 
Sector Academic/University 
PI Contribution Acquisition and analysis of neuroimaging data
Collaborator Contribution Determination of genetic polymorphisms and analysis of data & research fellow support
Impact Publications: Decreased regional gray matter volume in S' allele carriers of the 5-HTTLPR triallelic polymorphism. Selvaraj S, Godlewska BR, Norbury R, Bose S, Turkheimer F, Stokes P, Rhodes R, Howes O, Cowen PJ. Mol Psychiatry. 2010 Nov 2
Start Year 2014
 
Description Psychosis CAG 
Organisation King's College London
Department Institute of Psychiatry, Psychology & Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution PET imaging of patients with schizophrenia and healthy volunteers
Collaborator Contribution Provision of unique clinical cohorts Funding of research fellows
Impact Publications: Delusional ideation, manic symptomatology and working memory in a cohort at clinical high-risk for psychosis: A longitudinal study. Broome MR, Day F, Valli I, Valmaggia L, Johns LC, Howes O, Garety P, McGuire PK. Eur Psychiatry. 2010 Oct 8. [Epub ahead of print] PMID: 20934858 [PubMed - as supplied by publisher] Related citations 3. A comprehensive review and model of putative prodromal features of bipolar affective disorder. Howes OD, Lim S, Theologos G, Yung AR, Goodwin GM, McGuire P. Psychol Med. 2010 Sep 14:1-11. Altered relationship between hippocampal glutamate levels and striatal dopamine function in subjects at ultra high risk of psychosis. Stone JM, Howes OD, Egerton A, Kambeitz J, Allen P, Lythgoe DJ, O'Gorman RL, McLean MA, Barker GJ, McGuire P. Biol Psychiatry. 2010 Oct 1;68(7):599-602. Epub 2010 Jul 17. PMID: 20638047 [PubMed - in process] Related citations 6. Abnormal frontostriatal interactions in people with prodromal signs of psychosis: a multimodal imaging study. Fusar-Poli P, Howes OD, Allen P, Broome M, Valli I, Asselin MC, Grasby PM, McGuire PK. Arch Gen Psychiatry. 2010 Jul;67(7):683-91. PMID: 20603449 The dopamine hypothesis of schizophrenia: version III--the final common pathway. Howes OD, Kapur S. Schizophr Bull. 2009 May;35(3):549-62. Epub 2009 Mar 26. Review. PMID: 19325164 [PubMed - indexed for MEDLINE]Free PMC ArticleFree text Related citations 22. Functionally defined regions may aid interpretation of striatal dopamine elevation in schizophrenia. Egerton A, McGuire PK, Howes OD. Schizophr Res. 2009 Apr;109(1-3):200. Epub 2009 Feb 27. No abstract available. PMID: 19250801 [PubMed - indexed for MEDLINE] Related citations 23. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Howes OD, Montgomery AJ, Asselin MC, Murray RM, Valli I, Tabraham P, Bramon-Bosch E, Valmaggia L, Johns L, Broome M, McGuire PK, Grasby PM. Arch Gen Psychiatry. 2009 Jan;66(1):13-20.PMID: 1912468 Abnormal prefrontal activation directly related to pre-synaptic striatal dopamine dysfunction in people at clinical high risk for psychosis. Fusar-Poli P, Howes OD, Allen P, Broome M, Valli I, Asselin MC, Montgomery AJ, Grasby PM, McGuire P. Mol Psychiatry. 2009 Dec 1 PMID: 19949389
Start Year 2006
 
Title PET diagnostic classifier for schizophrenia 
Description Multivariate image analytic system for diagnosing schizophrenia. The initial evaluation has been published and it is currently under refinement using additional clinical populations to determine its generalisability 
Type Diagnostic Tool - Imaging
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2010
Development Status Under active development/distribution
Impact It has provide insights into the pathophysiology of schizophrenia 
 
Description Central St Martin's College 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Primary Audience Public/other audiences
Results and Impact Presentation to ~80 art students who will develop a project based on this as part of their course work

Students producing art outputs as a result
Year(s) Of Engagement Activity 2010
 
Description Hearts and Minds event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Workshop on our research
Year(s) Of Engagement Activity 2016
 
Description Media interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Interviews for BBC and National Geographic TV channels discussing the group's research findings

Viewing figures are reported to be over 1 million for the BBC. The National Geographic broadcast is international as well as UK.
Year(s) Of Engagement Activity 2009,2010
 
Description Patient publication 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact Article in national patient and carer magazine (readership 50 000+)

Patient and carers contacted me for further information
Year(s) Of Engagement Activity 2007
 
Description RCPsych patient & carer education 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Web cast informing carers and patients about sexual dysfunction in schizophrenia and treatment options.

Patient and carer groups highlighted improved understanding of under-recognised aspect of the condition
Year(s) Of Engagement Activity 2012