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

研究背景：在世界范围内，酒精滥用是一个日益严重的问题。如今，英国约有390万成年人，其中近9%的男性和4%的女性符合酒精依赖的标准。全球酒精滥用约占所有死亡人数的4%，占疾病负担的5%。据估计，英国国家医疗服务体系每年因酗酒而付出的费用高达27亿英镑，长期酗酒的后果，无论是身体上还是心理上，都可能是严重的。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，但治疗酒精依赖的成功率非常低。一半的酗酒者在戒毒后仅仅3个月就会重新酗酒，而这一数字在短短6个月后就会上升到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，迫切需要新的治疗酒精依赖的方法。我们的研究小组已经发现了初步证据，三剂量的麻醉药物氯胺酮，结合心理治疗，可以减少酒精一年的复发率超过40%。如此显著的治疗效果以前从未在酒精依赖中观察到过。对动物、健康人以及抑郁症患者的研究越来越多的证据表明，氯胺酮可能会促进脑细胞之间新连接的生长，我们知道这一过程在酒精成瘾后会受到损害，这可能解释了戏剧性的治疗效果。另一种可能的解释是，氯胺酮最近才被发现是一种作用非常迅速、令人印象深刻的抗抑郁药。我们知道抑郁症在酗酒中很普遍，并且预示着复发，所以用氯胺酮治疗抑郁症可能是复发率显著降低的原因。然而，虽然支持数据来自对照实验室研究，但我们的初步患者数据来自一项急需复制的非对照研究。该项目的目的和目标：我们的主要目的是评估氯胺酮辅助疗法是否安全，耐受性良好，并有效地促进96例最近解毒的酗酒者戒酒，并伴有轻度抑郁症。次要目的是检查氯胺酮单独使用是否与氯胺酮加心理治疗一样有效。我们将随机安排受试者接受每周3次剂量的氯胺酮或安慰剂（0.8mg/kg IV超过45分钟）加上心理治疗，或每周3次剂量的氯胺酮或安慰剂加上心理教育控制。然后对患者进行为期6个月的跟踪，比较他们饮酒行为的变化。潜在的应用和益处：这些发现的应用是明确的：对众所周知的破坏性和治疗难治性酒精依赖的更有效的治疗。如果这项小型研究的初步发现得到证实，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中作为一种治疗酒精依赖的新方法推广开来。这将对国家的健康和财富产生巨大影响，改善酒精依赖者的精神和身体健康，并为酒精依赖者的家人和亲人带来相关好处，同时减少NHS、法律和警务成本，减少缺勤天数，提高职业成就。如果氯胺酮辅助疗法确实对酒精中毒有效，它也可能被证明对其他成瘾有应用，并为酒精中毒共病抑郁症提供一种新的有力治疗方法。

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.