Glucocorticoid receptor antagonism and cognition in alcoholics

Lead Research Organisation: King's College London
Department Name: Addictions

Abstract

Alcohol dependence is a chronic relapsing disease, the incidence of which was recently estimated by the Department of Health to be 7% of the adult population. Currently, up to 90% of alcoholics who manage to stop drinking relapse back to the alcohol within a year. Alcohol dependence is a major health problem, and the alcohol consumption causes many other medical disorders and extensive social problems. Between 50 and 80% of alcoholics suffer from memory problems caused by the alcohol consumption and many also have other medical problems, particularly depression. The former symptoms are very difficult to treat, largely because the changes in the brain that cause the memory problems are not yet understood, and also because there are different patterns of excess alcohol drinking. If the mechanisms involved in the memory problems are understood, this will enable effective treatments to be developed that will improve quality of life and reduce health costs. Recent laboratory and clinical studies have suggested that changes in the brain when someone stops drinking excessively are responsible for memory deficits. Excess of the stress hormones known as glucocorticoids is known to result in damage to nerves in the brain and to result in memory loss, and these are released in high concentrations during alcohol detoxification. Work has also shown that a drug, mifepristone, that prevents actions of the important stress hormone cortisol on a particular brain protein, known as the Type II glucocorticoid receptor, has beneficial effects in those who suffer from memory problems and also in people who are clinically depressed, but this has not yet been studied in alcoholics. Laboratory studies, however, demonstrated that prevention of actions of cortisol at this receptor protein decreases the nerve damage caused by cessation of long term alcohol consumption. This project will measure the effects of the drug mifepristone in a group of alcoholics who enter the treatment unit to undergo alcohol detoxification. Measures will be made of performance in tests of cognitive ability, and also depressive symptoms, since the latter can contribute to memory loss. If the results of this project are positive it will suggest that the receptor protein is involved in the genesis of the memory deficits and/or the depressive symptoms. Such knowledge will aid the development of new treatments that would provide effective therapy for these problems that are suffered by large numbers of alcoholics.

Technical Summary

Alcoholism is a chronic disorder with high personal and NHS costs. Alcohol dependence includes a range of drinking behaviours and comorbidity with other mental disorders is common. There is little effective treatment, and the majority of abstinent alcoholics relapse within 12 months. A large proportion of alcoholics have cognitive deficits and many are clinically depressed. The causal mechanisms of the latter problems are little understood, but clinical and preclinical studies have suggested the hypothalamo-pituitary-adrenal axis could be important. There is considerable clinical and experimental evidence that alcohol withdrawal plays a major role in causing the memory deficits and this offers a window of opportunity for intervention. Recent laboratory investigations have indicated that the glucocorticoid Type II glucocorticoid receptor is involved in the neurotoxicity caused by withdrawal from chronic alcohol treatment. In addition, clinical studies in other mental disorders showed that antagonism of this receptor can alleviate both cognitive deficits and depressive symptomatology. This Proof of Concept study will demonstrate whether antagonism of this receptor by the drug mifepristone could have beneficial effects in alcoholics entering our Alcohol Assessment and Treatment Unit for detoxification. Exclusion criteria will be limited to physical health and ability to give informed consent, in order that the study will include a representative alcoholic population. Two treatment groups of equal size, stratified for alcohol dependence severity, age, depression/no depression and smoking/nonsmoking, will receive either mifepristone or placebo. In the third and fourth weeks after cessation of drinking, cognitive function will be examined using the CANTAB test battery; the Beck Depression scale will examine depressive symptoms once per week for four weeks after drinking cessation. Data analysis will examine potential influences of comorbid mental disorders, severity of dependence, withdrawal symptoms, number of prior detoxifications, withdrawal medication and other medication. The study will recruit males only, owing to the progesterone antagonist actions of mifepristone, but will demonstrate whether or not antagonism of this receptor has beneficial actions, the effect sizes, and whether specific symptoms are affected or changes seen in clients with particular comorbidity or level of alcohol withdrawal severity. Specific Type II glucocorticoid receptor antagonists are currently under development and could be used in future studies on a wider population. The results, whether positive or negative, will provide valuable information about the role of the Type II glucocorticoid receptor in cognitive function and depression in alcoholics that will be of great value in understanding the underlying mechanisms.

Publications

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publication icon
Beard E (2019) Predictive Validity, Diagnostic Accuracy and Test-Retest Reliability of the Strength of Urges to Drink (SUTD) Scale. in International journal of environmental research and public health

 
Description CI invited to be chair of a NICE guideline development group and chair of a NICE quality standards expert group both on alcohol dependence
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
Impact NICE guidelines on assessment and clinical management of alcohol dependence due to be published in February 2011
 
Description Commissioning of AO service for alcohol in Southwark
Geographic Reach National 
Policy Influence Type Citation in other policy documents
 
Description Kings Health Partners alcohol strategy
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Participation in a advisory committee
 
Description Public Health England - alcohol care teams
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description MRC Cluster
Amount £10,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2009 
End 10/2010
 
Description MRC Studentship
Amount £70,475 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2011 
End 09/2014
 
Description Assertive outreach service in Southwark 
Organisation South London and Maudsley (SLAM) NHS Foundation Trust
Department Addictions Clinical Academic Group
Country United Kingdom 
Sector Academic/University 
PI Contribution Implementation of the assertive outreach model in Southwark as part of the ACTAD trial has led to support from the Kings Health Partners Addictions Clinical Academic Group, local services and the local commissioners. The commissioners have financially supported setting up an assertive outreach service with local acute hospitals. This service is a direct result of the ACTAD trial.
Collaborator Contribution We will be guiding the model of care and intervention delivery, providing training where appropriate and overseeing clinical supervision of the practitioners.
Impact None as yet, however we will have access to data generated as part of this collaboration.
Start Year 2012
 
Description Assertive outreach service in Southwark 
Organisation Southwark Primary Care Trust (PCT)
Country United Kingdom 
Sector Public 
PI Contribution Implementation of the assertive outreach model in Southwark as part of the ACTAD trial has led to support from the Kings Health Partners Addictions Clinical Academic Group, local services and the local commissioners. The commissioners have financially supported setting up an assertive outreach service with local acute hospitals. This service is a direct result of the ACTAD trial.
Collaborator Contribution We will be guiding the model of care and intervention delivery, providing training where appropriate and overseeing clinical supervision of the practitioners.
Impact None as yet, however we will have access to data generated as part of this collaboration.
Start Year 2012
 
Description CLRN support 
Organisation National Institute for Health Research
Country United Kingdom 
Sector Public 
PI Contribution The study team joined the network and requested funding for service support costs
Collaborator Contribution The Comprehensive Local Research Network awarded the research study funding to cover service support costs for the trial
Impact This funding allowed for the trial to recruit to a number of sites across the UK
Start Year 2011
 
Description MHRN support 
Organisation National Institute for Health Research
Department INVOLVE
Country United Kingdom 
Sector Public 
PI Contribution The Mental Health research Network were approached by the research team to support recruitment and set up of the research trial and the individual study sites.
Collaborator Contribution The Mental Health Research Network has helped set-up the research trail at the study sites and aided recruitment to the trial.
Impact Aided the research team in identifying the correct processes for trial set up at the local sites and helped build relationships with the local community alcohol teams and alcohol detoxification units.
Start Year 2011
 
Description NHS secondment 
Organisation South London and Maudsley (SLAM) NHS Foundation Trust
Country United Kingdom 
Sector Academic/University 
PI Contribution Funding was awarded in order to second a member of staff from the South London and Maudsley NHS Trust to be a member of the research team for 6 months.
Collaborator Contribution A member of staff from one of the South London and Maudsley NHS Trust community alcohol teams joined the research team and participated in study related tasks. They also helped foster relationships with the local community alcohol teams.
Impact Relationships between the research study team and the local community alcohol teams were expanded, aiding recruitment and awareness of the study. The member of staff was subsequently supported to apply for a PhD studentship from the SSA and was awarded funding to complete this in the field of alcohol research.
Start Year 2012
 
Description South London AHSN 
Organisation Epsom and St Helier University Hospitals NHS Trust
Country United Kingdom 
Sector Public 
PI Contribution I have been a vocal advocate for alcohol related activities and together with the strength of the alcohol research team and ongoing projects, alcohol is one of the 4 clinical priority areas of focus.
Collaborator Contribution The AHSN is a broad collaboration of partners contributing to supporting the four themes, including improving alcohol related outcomes for the south London population.
Impact The AHSN is currently developing it's workstreams.
Start Year 2013
 
Description South London AHSN 
Organisation Goldsmiths, University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution I have been a vocal advocate for alcohol related activities and together with the strength of the alcohol research team and ongoing projects, alcohol is one of the 4 clinical priority areas of focus.
Collaborator Contribution The AHSN is a broad collaboration of partners contributing to supporting the four themes, including improving alcohol related outcomes for the south London population.
Impact The AHSN is currently developing it's workstreams.
Start Year 2013
 
Description South London AHSN 
Organisation Guy's and St Thomas' NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution I have been a vocal advocate for alcohol related activities and together with the strength of the alcohol research team and ongoing projects, alcohol is one of the 4 clinical priority areas of focus.
Collaborator Contribution The AHSN is a broad collaboration of partners contributing to supporting the four themes, including improving alcohol related outcomes for the south London population.
Impact The AHSN is currently developing it's workstreams.
Start Year 2013
 
Description South London AHSN 
Organisation King's College Hospital NHS Foundation Trust (NCH)
Country United Kingdom 
Sector Public 
PI Contribution I have been a vocal advocate for alcohol related activities and together with the strength of the alcohol research team and ongoing projects, alcohol is one of the 4 clinical priority areas of focus.
Collaborator Contribution The AHSN is a broad collaboration of partners contributing to supporting the four themes, including improving alcohol related outcomes for the south London population.
Impact The AHSN is currently developing it's workstreams.
Start Year 2013
 
Description South London AHSN 
Organisation Kingston University London
Country United Kingdom 
Sector Academic/University 
PI Contribution I have been a vocal advocate for alcohol related activities and together with the strength of the alcohol research team and ongoing projects, alcohol is one of the 4 clinical priority areas of focus.
Collaborator Contribution The AHSN is a broad collaboration of partners contributing to supporting the four themes, including improving alcohol related outcomes for the south London population.
Impact The AHSN is currently developing it's workstreams.
Start Year 2013
 
Description South London AHSN 
Organisation Queen Elizabeth Hospital Birmingham
Country United Kingdom 
Sector Hospitals 
PI Contribution I have been a vocal advocate for alcohol related activities and together with the strength of the alcohol research team and ongoing projects, alcohol is one of the 4 clinical priority areas of focus.
Collaborator Contribution The AHSN is a broad collaboration of partners contributing to supporting the four themes, including improving alcohol related outcomes for the south London population.
Impact The AHSN is currently developing it's workstreams.
Start Year 2013
 
Description South London AHSN 
Organisation Roehampton University
Country United Kingdom 
Sector Academic/University 
PI Contribution I have been a vocal advocate for alcohol related activities and together with the strength of the alcohol research team and ongoing projects, alcohol is one of the 4 clinical priority areas of focus.
Collaborator Contribution The AHSN is a broad collaboration of partners contributing to supporting the four themes, including improving alcohol related outcomes for the south London population.
Impact The AHSN is currently developing it's workstreams.
Start Year 2013
 
Description South London AHSN 
Organisation Royal Marsden NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution I have been a vocal advocate for alcohol related activities and together with the strength of the alcohol research team and ongoing projects, alcohol is one of the 4 clinical priority areas of focus.
Collaborator Contribution The AHSN is a broad collaboration of partners contributing to supporting the four themes, including improving alcohol related outcomes for the south London population.
Impact The AHSN is currently developing it's workstreams.
Start Year 2013
 
Description South London AHSN 
Organisation South London Healthcare NHS Trust
Country United Kingdom 
Sector Public 
PI Contribution I have been a vocal advocate for alcohol related activities and together with the strength of the alcohol research team and ongoing projects, alcohol is one of the 4 clinical priority areas of focus.
Collaborator Contribution The AHSN is a broad collaboration of partners contributing to supporting the four themes, including improving alcohol related outcomes for the south London population.
Impact The AHSN is currently developing it's workstreams.
Start Year 2013
 
Description South London AHSN 
Organisation St George's Healthcare NHS Trust
Country United Kingdom 
Sector Public 
PI Contribution I have been a vocal advocate for alcohol related activities and together with the strength of the alcohol research team and ongoing projects, alcohol is one of the 4 clinical priority areas of focus.
Collaborator Contribution The AHSN is a broad collaboration of partners contributing to supporting the four themes, including improving alcohol related outcomes for the south London population.
Impact The AHSN is currently developing it's workstreams.
Start Year 2013
 
Description South London AHSN 
Organisation St George's University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution I have been a vocal advocate for alcohol related activities and together with the strength of the alcohol research team and ongoing projects, alcohol is one of the 4 clinical priority areas of focus.
Collaborator Contribution The AHSN is a broad collaboration of partners contributing to supporting the four themes, including improving alcohol related outcomes for the south London population.
Impact The AHSN is currently developing it's workstreams.
Start Year 2013
 
Description South London AHSN 
Organisation University of Greenwich
Country United Kingdom 
Sector Academic/University 
PI Contribution I have been a vocal advocate for alcohol related activities and together with the strength of the alcohol research team and ongoing projects, alcohol is one of the 4 clinical priority areas of focus.
Collaborator Contribution The AHSN is a broad collaboration of partners contributing to supporting the four themes, including improving alcohol related outcomes for the south London population.
Impact The AHSN is currently developing it's workstreams.
Start Year 2013
 
Description South London Collaborations for Leadership in Applied Health Research and Care 
Organisation King's College Hospital NHS Foundation Trust (NCH)
Country United Kingdom 
Sector Public 
PI Contribution Leadership of the alcohol research theme
Collaborator Contribution Support in development of the research
Impact Publications Development of a smartphone alcohol intervention app
Start Year 2014
 
Description DAAIM 'Experimental Medicine' Seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact A presentation was given on the trial including the theoretical background and study processes. Questions and discussion followed the talk where members of the audience expressed considerable interest in the trial.

The discussions following the talk raised questions that later contributed to decisions made in the trial committee meetings.
Year(s) Of Engagement Activity 2012
 
Description Departmental seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact The addictions deprtment were invited to a regular seminar where the trials theoretical background and progress was presented. This generated an interesting discussion afterwards.

Interest was expressed on the research and future projects.
Year(s) Of Engagement Activity 2012
 
Description Hospital wards, service users 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Participation of wards in clinical trial. Ex-Service User on trial management committee

Not yet applicable
Year(s) Of Engagement Activity 2010,2011
 
Description RCP SCAN 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Health professionals
Results and Impact Talk to health professionals, and service users. Panel discussion with audience.

Much expressed interest from audience in the research.
Year(s) Of Engagement Activity 2008,2009,2010
 
Description Visits to drug and alcohol treatment teams 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact The research was presented to staff and team members across the five study sites. Staff are given the opportunity to ask questions and to give feedback on the trial.

These visits have helped to raise awareness about the trial and it's potential benefits for patients. They have also aided the referral and recruitment of participants.
Year(s) Of Engagement Activity 2009,2010,2011,2012