Quetiapine for the treatment of Type A and Type B alcoholism

描述(申请人提供)：目前批准的治疗酒精依赖的药物并不是压倒性的有效。因此，研究人员继续寻找更好的药物来治疗这种严重的疾病。一种提高药物疗效的方法是针对治疗耐药亚群，如Babor所描述的B型酒精中毒。B型酗酒者的特点是较早出现酒精问题，依赖程度较高，治疗反应较差。相比之下，A型酗酒者的特点是出现问题的时间较晚，酒精依赖程度较轻，与酒精有关的问题较少，对治疗的反应也较好。我们进行了一项双盲、安慰剂对照的试点试验，包括61名酗酒者(32名A型和29名B型)服用奎硫平，每天400毫克，或安慰剂。在试验期间，服用奎硫平的患者保持戒酒的人数明显多于服用安慰剂的患者(31%对6%)。奎硫平在减少B型糖尿病患者饮酒方面明显更有效 病人。在A型患者中，奎硫平和安慰剂治疗的患者都显著减少了饮酒，因此没有检测到奎硫平的影响。经过进一步的分析，我们发现，对奎硫平有良好反应的最具预测性的特征是频繁大量饮酒，这是通过每天饮酒的平均数量和在试验前30天内饮酒至醉酒的较多天数来衡量的。在我们的试点试验中，A型患者很可能代表了不太严重的酗酒者亚群，这解释了为什么他们对安慰剂或奎硫平的反应同样好。奎硫平对经常酗酒的人可能更有效，因为与5-羟色胺能和多巴胺能神经传递相关的异常。非典型抗精神病药物针对多巴胺和5-羟色胺系统，并已显示出在减少酗酒者合并精神疾病的酒精使用方面的有效性。奎硫平是一种非典型的抗精神病药物，具有良好的副作用。拟议的为期5年的项目旨在证实和扩大我们关于奎硫平在双盲、安慰剂对照、13周的试验中用于治疗频繁酗酒者的初步结果。这项研究将对180名DSM-IV酒精依赖患者进行奎硫平(每天400毫克)和安慰剂的比较，这些患者是经常酗酒的人，根据参加试验前30天内平均每天饮酒超过12杯，并有15天或更长时间饮酒到醉酒来确定。主要的假设是，与安慰剂治疗的患者相比，奎硫平治疗的患者将有1)更多的戒酒天数和2)更少的酗酒天数，这是通过时间线随访来衡量的。将进行探索性分析，以进一步调查奎硫平/酒精亚型的其他可能相互作用

DESCRIPTION (provided by applicant): Currently approved medications for the treatment of alcohol dependence are not overwhelmingly effective. Therefore, researchers continue to look for better medications to treat this serious illness. One approach to improve medication efficacy is to target specific medications for treatment resistant subpopulations such as Type B alcoholism, as described by Babor. Type B alcoholics are characterized by an early onset of alcohol problems, greater severity of dependence, and a poor treatment response. In contrast, Type A alcoholics are characterized by a later onset of problem drinking, less severe alcohol dependence, fewer alcohol-related problems, and a better response to treatment. We conducted a double-blind, placebo-controlled, pilot trial, involving 61 alcoholics (32 type A and 29 Type B) treated with quetiapine, 400 mg daily, or placebo. Significantly more quetiapine-treated patients remained abstinent during the trial, compared to placebotreated patients (31% vs. 6%). Quetiapine was significantly more effective in reducing drinking in Type B patients. In Type A patients, both the quetiapine and placebo treated patients significantly reduced their drinking so no effect of quetiapine was detected. Upon further analysis, we found that the characteristic most highly predictive of a good response to quetiapine was frequent heavy drinking as measured by a high average number of drinks per drinking day and a greater number of days of drinking to intoxication in the 30 days prior to the trial. It is likely that the Type A patients in our pilot trial represented a less severely addicted subgroup of alcoholics and this explains why they responded equally well to placebo or quetiapine. Quetiapine may be more effective in frequent heavy drinkers because of associated abnormalities of serotonergic and dopaminergic neurotransmission. Atypical antipsychotics target both the dopamine and the serotonin systems and have shown efficacy in reducing alcohol use in alcoholics with comorbid psychiatric illness. Quetiapine is an atypical antipsychotic that has a favorable side effect profile. The proposed 5-year project is intended to confirm and extend our initial findings regarding quetiapine for the treatment of frequent heavy drinkers in a double-blind, placebo-controlled, 13-week trial. The study will compare quetiapine (400 mg daily) to placebo in 180 DSM-IV alcohol dependent patients who are frequent heavy drinkers as determined by averaging more than 12 drinks per drinking day and having 15 or more days of drinking to intoxication in the thirty days prior to entering the trial. The primary hypotheses are that quetiapine-treated patients will have 1) more abstinent days from alcohol and 2) fewer heavy drinking days compared to placebo-treated patients as measured by the timeline follow back. Exploratory analyses will be conducted to further investigate other possible quetiapine / alcohol subtype interactions