Oxytocin Treatment of Alcohol Dependence: A Randomized, Placebo-Controlled Trial

描述（由申请人提供）：酒精依赖（AD）是世界范围内残疾、发病率和死亡率的主要原因。目前的治疗包括各种形式的心理社会治疗，最近还包括药物干预。然而，大多数AD患者没有接受治疗，很少接受药物治疗，部分原因是FDA批准的药物疗效不佳。人们普遍认为，需要开发具有更大有效性和/或新活性谱（例如抗焦虑特性）的AD新药。 许多最近的人类研究发现，鼻内注射催产素（OT）具有许多亲社会效应，并减少焦虑。临床试验测试高剂量鼻内OT长达8周，没有发现不良反应。 一些研究表明，OT可能是AD的有效治疗方法。动物实验表明，OT阻断对酒精的耐受性形成，并显着减少戒断症状。我们最近发表了一项随机、双盲、先导性研究的结果，该研究对接受药物脱毒治疗的酒精依赖受试者进行了CIWA评分驱动的PRN劳拉西泮治疗。BID鼻内OT在降低CIWA评分、完成解毒所需的劳拉西泮总量和焦虑指标方面比安慰剂显著更有效。我们的发现是OT治疗阻止人类酒精戒断的第一个证据。这具有临床重要性，因为使用苯二氮卓类药物进行酒精戒断的标准治疗是有效的，但与OT不同，可维持高水平的镇静催眠耐受性，这可能通过维持酒精渴望、焦虑加剧和科普压力的能力下降以及在复发时消耗大量酒精而增加复发的脆弱性。我们还发现，OT管理显着降低饮酒量和焦虑的P（酒精偏好）大鼠反复酒精剥夺结合压力，复发的动物模型。其他动物研究表明，OT具有强效抗焦虑作用。这一证据表明，OT治疗可能会减少酒精依赖患者的饮酒，减少焦虑，易受压力和酒精耐受性。 拟议的研究代表了具有OT专业知识的基础行为神经科学家（Cort Pedersen博士）和具有丰富临床试验经验的AD治疗专家（JC Garbutt博士）之间独特的转化合作。 我们提出了一个随机的，双盲的，安慰剂对照试验鼻内OT治疗50酒精依赖患者开始早期住院医疗戒毒和延长12周后出院，在此期间，受试者的饮酒将定期进行评估。该项目的总体目标是确定OT治疗在真实的世界重度饮酒者（在精神卫生中心寻求药物解毒的患者）样本中是否真正有效地减少戒断症状，并在门诊环境中减少饮酒。该项目有可能显着推进AD的药物治疗。此外，确认OT阻止酒精戒断并证明OT减少门诊患者的饮酒，焦虑和渴望将是转化研究的胜利，这将使CNS OT成为AD病理生理学研究的重要新前沿。

DESCRIPTION (provided by applicant): Alcohol dependence (AD) is a major cause of disability, morbidity and mortality world-wide. Current treatment involves various forms of psychosocial treatment and, more recently, pharmacological interventions. However, most patients with AD do not receive treatment and few receive medication, in part because of the modest efficacy of FDA- approved drugs. There is a general consensus that new medications for AD need to be developed that have greater effectiveness and/or new spectrums of activity, e.g. anxiolytic properties. Many recent human studies have found that intranasal administration of oxytocin (OT) has numerous prosocial effects and reduces anxiety. Clinical trials testing high dose intranasal OT for up to 8 weeks found no adverse effects. Several studies indicate that OT may be an effective treatment for AD. Animal experiments have shown that OT blocks tolerance formation to alcohol and markedly decreases withdrawal symptoms. We recently published the results of a randomized, double-blind pilot study in alcohol-dependent subjects undergoing medical detoxification with CIWA score-driven PRN lorazepam treatment. BID intranasal OT was dramatically more effective than placebo in decreasing CIWA scores, the total amount of lorazepam required to complete detoxification, and anxiety measures. Our findings are the first evidence that OT treatment blocks alcohol withdrawal in humans. This is of clinical importance as standard treatment of alcohol withdrawal with benzodiazepines is effective but, unlike OT, may maintain high levels of sedative- hypnotic tolerance that could increase vulnerability to relapse by sustaining alcohol craving, heightened anxiety and diminished ability to cope with stress as well as enabling consumption of large quantities of alcohol upon relapse. We also found that OT administration significantly decreased alcohol consumption and anxiety in P (alcohol-preferring) rats subjected to repeated alcohol deprivation combined with stress, an animal model of relapse. Other animal studies have shown that OT is potently anxiolytic. This evidence suggests that OT treatment may decrease drinking in alcohol- dependent patients by reducing anxiety, vulnerability to stress and perhaps alcohol tolerance. The proposed research represents a unique, translational collaboration between a basic behavioral neuroscientist with expertise in OT (Dr. Cort Pedersen) and an expert in the treatment of AD with extensive experience in conducting clinical trials (Dr. JC Garbutt). We propose a randomized, double-blind, placebo-controlled trial of intranasal OT treatment in 50 alcohol-dependent patients starting early during inpatient medical detoxification and extending for 12 weeks after discharge during which subjects' drinking will be assessed at regular intervals. The overall goal of the project is to determine whether OT treatment in a real world sample of heavy drinkers (patients seeking medical detoxification at a mental health center) is truly effective in decreasing withdrawal symptoms and, in the outpatient setting, reducing drinking. This project has potential to significantly advance the pharmacological treatment of AD. Also, confirming that OT blocks alcohol withdrawal and demonstrating that OT decreases drinking, anxiety, and craving in the outpatient setting would be a triumph of translational research that would establish CNS OT as an important new front for research on the pathophysiology of AD.