Reducing relapse in alcohol dependence with the NMDA receptor antagonist, ketamine

Lead Research Organisation: University of Exeter
Department Name: Psychology

Abstract

Context of the research:
Worldwide, alcohol abuse is an escalating problem. Nearly 9% of men and 4% of women in the UK today meet criteria for alcohol dependence - in all around 3.9 million British adults. Alcohol misuse globally accounts for roughly 4% of all deaths and 5% of the burden of disease. Costs to the NHS from alcohol abuse are estimated at £2.7 billion annually and consequences of prolonged alcohol abuse, both physically and psychologically, can be severe. For alcoholics, giving up drinking for good is key to allow recovery of physical and mental health as well as quality of life, but treatment for alcohol dependence has very low success rates. Half of all alcoholics will return to heavy drinking just 3 months after detoxification, a figure that jumps to around 70% after as little as 6 months. Due to the huge burden on the NHS and UK economy and the ever growing numbers of people dependent on alcohol, new treatments for alcohol dependence are urgently needed. Our research team have found preliminary evidence that 3 doses of the anaesthetic drug, ketamine, combined with psychological therapy can reduce one year relapse rates in alcohol by over 40%. Such a dramatic treatment effect has never been previously observed in alcohol dependence. Converging evidence from studies in animals, healthy humans as well as in humans with depression suggest that ketamine might be acting to promote the growth of new connections between brain cells, a process which we know to be impaired following alcohol addiction and which might explain the dramatic treatment effect. Another possible explanation is that ketamine has relatively recently been discovered to be a very rapid acting and impressive antidepressant. We know that depression is rife in alcoholism and predicts relapse, so treating depression with ketamine might account for this extraordinary reduction in relapse rates. However, while supporting data come from controlled laboratory studies, our preliminary patiet data come from an uncontrolled study which crucially needs replicating.
Aims and objectives of this project:
Our primary aim is to assess whether ketamine-assisted therapy is safe, well-tolerated and effective at promoting abstinence in a sample of 96 recently detoxified alcoholics with a minimum of mild depression. Secondary aims are to examine whether ketamine alone is as effective as ketamine plus psychotherapy. We will randomise people to receive either 3 weekly doses of ketamine or placebo (0.8mg/kg IV over 45 mins) plus psychological therapy or 3 weekly doses of ketamine or placebo plus a psychoeducational control. Patients will then be tracked for 6 months and changes in drinking behaviour compared.
Potential applications and Benefits:
The application of these findings is clear: a much more effective treatment for the notoriously destructive and treatment-resistant condition of alcohol dependence. If preliminary findings are confirmed in this small study, this would provide the basis for a large scale clinical trial. Due to the widespread medical use of ketamine in the UK, this work could then quickly be rolled out as a new treatment for alcohol dependence in the NHS. This would have a huge impact on the health and wealth of the nation, in terms of improved mental and physical health for those afflicted with alcohol dependence, and associated benefits for families and loved ones of the alcohol dependent individual, along with reduced NHS, legal and policing costs, less days absent from work, better vocational achievement. If ketamine-assisted therapy does emerge to be effective in alcoholism it may also prove to have applications in other addictions, and present a new and powerful treatment for co-morbid depression in alcoholism.

Technical Summary

Background: In the UK alone, nearly 9% of men and 4% of women today meet criteria for alcohol dependence - in all approximately 3.9 million British adults. Abstinence is key to allow recovery of physical and mental health as well as quality of life, but treatment for alcohol dependence is associated with high relapse rates of around 50% at 3 months, 70% at 6 months. Despite the huge burden on the NHS and UK economy, treating alcohol dependence and prolonging abstinence remains an unmet need.
Proposed solution: Our proposed solution is three isolated doses of ketamine in combination with psychological therapy. Our own preliminary data suggest that ketamine reduces alcohol use in hazardous drinkers; and that psychotherapy combined with three weekly doses of ketamine in recently detoxified alcoholics may reduce 12 month relapse rates in alcohol-dependence from 76% to 34%. Ketamine's antidepressant properties may contribute significantly to these effects, as depressive symptoms are a key contributor to relapse. Mechanistically, ketamine promotes the growth of new synapses in the brain which has been found to be impaired in chronic alcoholism.
Design: 96 recently detoxified alcoholics will be randomized to receive either 3 sessions ketamine (0.8 mg/kg IV over 45 minutes) or placebo plus manualised psychological therapy or ketamine and placebo alone, with a psychoeducation control. Patients will be assessed at 3 and 6 months on a range of psychological and biological variables. Primary endpoints will be % days abstinent at 3 and 6 months and relapse rates at 6 months. Secondary endpoints include depressive symptoms, craving and quality of life.
Application/exploitation: The findings would have broad application given the worldwide prevalence of alcoholism and associated medical, psychological and social problems. The success of this study would provide a very strong impetus for a large scale clinical trial.

Planned Impact

Policy Makers and Service Providers: Last year the Government released its 'Alcohol Strategy', vowing that they would "... radically reshape the approach to alcohol and reduce the number of people drinking to excess...", two key aims were cut the number of alcohol related deaths and to cut the number of people drinking above NHS guidelines, both of which this treatment may address. Access to a new highly effective treatment would have an impact on public service providers, such as the NHS, along with positive impacts on existing governmental strategies to target alcohol-related problems.

Wider community: Estimates suggest that roughly 3.9 million adults in the UK today show signs of alcohol dependence, these would be primary beneficiaries of the research, along with those in the social networks of these individuals, that is their families and friends. Alcohol related crime and violence is a key concern, with impacts on policing and the legal system. The probationary/legal system could be users of this research in terms of advocating more effective treatment orders.

Charitable Sector: A variety of charities e.g. Alcohol Concern; Addaction; Focus12 would benefit from knowledge of a more effective treatment for alcohol dependence.

Commerical Sector: Private healthcare and detoxification centres would benefit from access to a new treatment approach, along with possibly the pharmaceutical industry, who could use these data to inform drug development in addiction.

How would they benefit?
Service providers would benefit from having an swift and efficacious treatment that should improve treatment adherence, long-term outcomes and ultimately provide cost savings.

Service users would benefit from a shorter and more effective treatment that would be less stigmatising than being maintained on medication long-term. Benefits of no longer being dependent on alcohol for alcohol dependent individuals are considerable and wide-ranging. Physical health would improve, and risks of alcohol-related diseases such as cirrhosis of the liver would decrease. This treatment would also have a positive impact in terms of users' mental health (depression, anxiety) and improved cognitive function, as well as quality of life. Social benefits would also be seen, as alcohol dependence is a key factor in the breakdown of relationships and domestic violence. Benefits would be reflected economically, not only in a reduction in burden to the NHS but in more frequent and regular engagement in work activities, and a reduction in crime. Alcohol is also associated with considerable acute harms.


Potential to contribute to the nation's health and wealth: the marked prevalence of alcohol use makes it a public health issue and if successful this project will make a significant contribution to the nation's health. It will also have impact on wealth in terms of fewer days absent from education/work and this combined with improved neurocognitive function should enhance achievement and productivity. In 2012, 15,401 deaths in England and 1.24 million hospital admissions are attributable to alcohol consumption, therefore benefits would also acrue in a reduction in burden on the NHS and its workforce, in alcohol-related deaths and in other non-fatal acute harms.

Timescales for the benefits to be realized: the success of this project would lead to a large scale randomized clinical trial which, if also successful, would mean that benefits to the target population of alcohol dependent individuals could be realized within 5 years following completion of the present project.

What research and professional skills of staff working on the project will be gained? We anticipate a wide range of generic research skills will be acquired by the post-doc and RA as well as generic communication skills (via peer-reviewed articles, conference abstracts, oral presentations to a range of academic and non-academic audiences).

Publications

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Ivan Ezquerra-Romano I (2018) Ketamine for the treatment of addiction: Evidence and potential mechanisms. in Neuropharmacology

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Marsh B (2019) Shyness, alcohol use disorders and 'hangxiety': A naturalistic study of social drinkers in Personality and Individual Differences

 
Title Animations to explain mindfulness and relaxation to participants 
Description We engaged an animator to make some animations to accompany our therapy of relaxation and mindfulness to aid explanation to participants. 
Type Of Art Film/Video/Animation 
Year Produced 2016 
Impact We have had very good responses from participants and many enquiries from drug and psychology services to use our animations in their therapy packages 
 
Title Reflect 
Description Working with Sound UK and co-creating with peers to produce an installation exploring experiences of addiction 
Type Of Art Artistic/Creative Exhibition 
Year Produced 2019 
Impact In progress still however strong links with community and interest in research, media coverage, community organisations wanting to use installation approach in other communities i.e. translation. 
 
Description Training for local drug services in mindfulness and motivational interviewing provided as components of our trial therapy package
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact As a result of the psychological therapy training developed for our trial, when visiting local drug services and describing this therapy we identified a gap in the regional practice of practitioners in Dorset (EDP drug services) in that they were not providing best practise first line interventions. We arranged an initial training for the services in question, which has now formed a key part of their training packages.
 
Description Collaboration with local drug service 
Organisation Addaction
Country Unknown 
Sector Charity/Non Profit 
PI Contribution We worked together for the purposes of recruitment - but we have now co-created a project using a therapy as a result of this partnership.
Collaborator Contribution Addaction provided the staff time to refer patients for the trial
Impact The collaboration is multi-disciplinary involving psychiatrists, nurses, key-workers and psychologists. The outputs are a paper in prepartion.
Start Year 2016
 
Description UBC ketamine 
Organisation University of British Columbia
Country Canada 
Sector Academic/University 
PI Contribution We have been sharing best practise on ketamine therapy between our groups.
Collaborator Contribution They have also been sharing best practise of ketamine therapy with our group
Impact no outputs yet, ketamine systematic review underway
Start Year 2018
 
Title Relapse prevention CBT and mindfulness to accompany the administration of a drug treatment for addiction 
Description We have developed a new psychological therapy package to accompany the administration of psychotomimetic drugs in the treatment of addictions but which also functions as a brief, manualised stand-alone relapse prevention psychological therapy. We have combined all the leading psychological approaches in this package. We have conducted piloting and refining the study with patient involvement and further refine following the trial, before potentially seeking wider distribution. 
Type Therapeutic Intervention - Psychological/Behavioural
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2015
Development Status Under active development/distribution
Clinical Trial? Yes
Impact We have had positive patient reports on this therapy package, if implemented more widely there would be economic benefits. 
URL https://clinicaltrials.gov/show/NCT02649231
 
Description A series of talks to substance misuse services across London and the South West 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact South West: We spoke to local substance misuse services in Bristol (BDP and Avon and Wiltshire Partnership Trust) in addition to attending local meetings to talk to drug services in RISE services in Exeter, Newton Abbott, Tiverton, Okehampton, Barnstaple. We spoke to Addaction in Weston Super Mare, EDP in Weymouth, Bridport, Dorchester.
London: We spoke to CGL, Turning Point, Camden and Islington, Addaction, SLAM, and CNWL services.
Year(s) Of Engagement Activity 2016
 
Description Articles in 25 national and international newspapers July 2016 
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 Public/other audiences
Results and Impact Press release about the trial which sparked much interest in the media, many interviews and requests for TV broadcasts.
Year(s) Of Engagement Activity 2016
URL https://motherboard.vice.com/en_us/article/new-trials-are-using-ketamine-to-treat-alcohol-addiction
 
Description Articles in various newspapers about Dry january and the trial 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact A press release was prepared about dry january in order to draw attention to the trial and boost recruitment
Year(s) Of Engagement Activity 2017
 
Description BBC 1 TV programme 
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 Public/other audiences
Results and Impact This was a BBC 1 broadcast: The truth about alcohol. I spoke about the effects of alcohol on the body and the use of the SCRAM bracelets for alcohol monitoring that we are using in our current MRC funded trial.
Year(s) Of Engagement Activity 2016
 
Description Conference of addiction practitioners, expert panel debate 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Participated in a panel at UKSEAD - an international addiction conference for practitioners about novel approaches to addiction treatment.
Year(s) Of Engagement Activity 2016
 
Description Convened symposium at British Association for Psychopharmacology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Convened a symposium on the use of ketamine in the treatment of addiction and presented the trial and its design, as well as ethical recommendations developed as a paper in press
Year(s) Of Engagement Activity 2016
 
Description Organising Ketamine conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Helped Rupert McShane organise the first international conference on ketamine and related compounds in Oxford 21-23 March.
Year(s) Of Engagement Activity 2018
 
Description TV appearance about the trial 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact TV segment of the trial on the national news.
Year(s) Of Engagement Activity 2018