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

研究背景：在世界范围内，酗酒是一个不断升级的问题。目前，英国约有9%的男性和4%的女性符合酒精依赖的标准，约有390万英国成年人。在全球范围内，酒精滥用约占所有死亡人数的4%和疾病负担的5%。据估计，英国国民保健服务每年因酗酒而造成的损失为27亿英镑，长期酗酒在身体和心理上的后果可能是严重的。对于酗酒者来说，彻底戒酒是恢复身心健康和生活质量的关键，但酒精依赖的治疗成功率很低。一半的酗酒者在戒毒后仅3个月就会恢复酗酒，这一数字在短短6个月后跃升至70%左右。由于NHS和英国经济的巨大负担以及越来越多的人依赖酒精，迫切需要新的酒精依赖治疗方法。我们的研究团队发现了初步证据，3剂麻醉药氯胺酮结合心理治疗可以将酒精的一年复发率降低40%以上。这种戏剧性的治疗效果以前从未在酒精依赖中观察到过。来自动物、健康人和抑郁症患者研究的证据表明，氯胺酮可能有助于促进脑细胞之间新连接的生长，我们知道酒精成瘾后这一过程会受损，这可能解释了显着的治疗效果。另一个可能的解释是，氯胺酮最近被发现是一种非常迅速的作用和令人印象深刻的抗抑郁药。我们知道抑郁症在酒精中毒中很普遍，并预示着复发，所以用氯胺酮治疗抑郁症可能会导致复发率的显著降低。然而，虽然支持数据来自对照实验室研究，我们的初步患者数据来自一个非对照的研究，这是至关重要的需要replicating.Aims和objectives的这个项目：我们的主要目的是评估氯胺酮辅助治疗是否是安全的，耐受性良好，有效地促进禁欲的样本96个最近脱毒的酗酒者与最低限度的轻度抑郁症。次要目的是检查单独使用氯胺酮是否与氯胺酮加心理治疗一样有效。我们将患者随机分为两组，一组接受每周3次氯胺酮或安慰剂（0.8mg/kg IV，45分钟）加心理治疗，另一组接受每周3次氯胺酮或安慰剂加心理教育对照。然后将对患者进行6个月的跟踪，并比较饮酒行为的变化。潜在的应用和好处：这些发现的应用是明确的：一个更有效的治疗臭名昭著的破坏性和耐药的酒精依赖性条件。如果这项小型研究的初步结果得到证实，这将为大规模临床试验提供基础。由于氯胺酮在英国的广泛医疗用途，这项工作可以很快在NHS中作为酒精依赖的新治疗方法推广。这将对国家的健康和财富产生巨大的影响，改善酒精依赖者的身心健康，为酒精依赖者的家人和亲人带来相关的好处，沿着减少NHS，法律的和警务费用，减少缺勤天数，更好的职业成就。如果氯胺酮辅助治疗确实对酒精中毒有效，它也可能被证明在其他成瘾中有应用，并为酒精中毒的共病抑郁症提供一种新的强大治疗方法。

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.