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

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 patient 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.

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.

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).