New Pharmacotherapy for Alcohol and Co-morbid Disorders

描述（由申请人提供）：我们提出一种治疗酒精和尼古丁同时依赖的新药物策略。酒精和尼古丁的强化作用都是通过皮质-中边缘多巴胺（CMDA）系统介导的，同时使用这两种药物可以增强它们的药理作用。我们提出了一种更好的方法，通过同时间接调节多巴胺释放及其功能表达来控制多巴胺（DA）的作用。在谷氨酸介导的兴奋性氨基酸通路的强直控制下，GABA的传出作用调节了DA在腹侧被盖区细胞体的释放和通过皮质-中边缘系统的强化作用的表达。因此，我们有理由假设，一种促进皮质-中边缘gaba能功能并抑制谷氨酸作用的药物，通过抑制中脑DA的释放及其从伏隔核到皮层的功能表达通路，从而减弱尼古丁和酒精的强化作用。我们最近的概念验证证明了这种新方法的前景，与安慰剂相比，托吡酯显著提高了酒精依赖吸烟者的戒烟率，降低了血清可替宁水平。托吡酯在酒精依赖个体中的一个重要临床作用似乎是它的抗戒断作用促进饮酒的逐渐减少。因此，由于托吡酯这种独特的抗戒断作用，我们建议在治疗酒精依赖个体时采用与吸烟者相同的方法，即设定一个目标戒断日期（TQD），之后可以测量任何一种药物的复发情况。我们建议进行一项为期18周的双盲临床试验，随访3个月，其中酒精依赖吸烟者将接受简短的行为依从性增强治疗（BBCET）和吸烟自助手册作为他们的心理社会治疗，并将随机接受安慰剂、高剂量托吡酯（高达250毫克/天）或低剂量托吡酯（高达125毫克/天），以防止重吸重酒。3个治疗组每组98人，总N为294人。TQD将在治疗第6周开始时进行。我们的主要目的是确定低剂量和高剂量托吡酯是否比安慰剂更有效地减少重度饮酒天数的百分比，并增加吸烟的持续戒断率，这是由TQD后和治疗最后4周的自我报告和CO监测相结合确定的。我们还将能够确定低剂量的托吡酯是否与高剂量的托吡酯一样有效，因此是否与较低的不良反应相关。我们的次要目的是测试托吡酯在TQD后和治疗的最后4周是否比安慰剂更有效地改善生活质量和减少渴望，以及这种改善是否会在随访阶段持续。

DESCRIPTION (provided by applicant): We propose a novel pharmacological strategy for treating alcohol and nicotine dependence concomitantly. The reinforcing effects of both alcohol and nicotine are mediated through the cortico-mesolimbic dopamine (CMDA) system, and the concomitant use of both drugs enhances their pharmacological effects. We propose a better approach to control dopamine (DA) effects by contemporaneous indirect modulation of DA release and its functional expression. Both DA release from its cell bodies in the ventral tegmental area and the expression of its reinforcing effects through the cortico-mesolimbic system are modulated by GABA efferents under the tonic control of glutamate-mediated excitatory amino acid pathways. Thus, it is reasonable to hypothesize that a medication that facilitates cortico-mesolimbic GABAergic function and inhibits glutamate action should diminish both nicotine's and alcohol's reinforcing effects by inhibiting the release of midbrain DA and its functional expression through pathways projecting from the nucleus accumbens to the cortex. The promise of this novel approach is exemplified by our recent proof-of-concept demonstration that topiramate compared with placebo significantly improved smoking abstinence rates and decreased serum cotinine levels among alcohol- dependent smokers. An important clinical effect of topiramate in alcohol-dependent individuals appears to be that its anti-withdrawal effects promote the gradual tapering of drinking. Hence, due to this unique anti- withdrawal effect of topiramate, we propose to adopt the same methodology for treating alcohol-dependent individuals, as is common practice with smokers, of setting a target quit date (TQD) after which relapse to either drug can be measured. We propose an 18-week, double-blind clinical trial with a 3-month follow-up, in which alcohol-dependent smokers will receive brief behavioral compliance enhancement treatment (BBCET) plus a smoking self-help manual as their psychosocial treatment, and will be randomized to receive placebo, high-dose topiramate (up to 250 mg/day), or low-dose topiramate (up to 125 mg/day) to prevent relapse to heavy drinking and smoking. Each of the 3 treatment arms shall contain 98 individuals, with a total N of 294. The TQD will occur at the beginning of the 6th week of treatment. Our primary objective is to determine whether both low- and high-dose topiramate will be more efficacious than placebo at reducing the percentage of heavy drinking days and increasing the continuous abstinence rate for smoking determined by a combination of self-report and CO monitoring after the TQD and in the last 4 weeks of treatment. We also will be able to determine whether a lower dose of topiramate is as efficacious as the higher dose and, therefore, is associated with a lower adverse profile. Our secondary objectives are to test whether topiramate will be more efficacious than placebo at improving quality of life and reducing craving after the TQD and in the last 4 weeks of treatment and whether this improvement will be sustained in the follow-up phase. PUBLIC HEALTH RELEVANCE: Smokers who are dependent on alcohol have perhaps the highest rate of preventable morbidity and mortality in the U.S. There is compelling evidence that promoting smoking cessation among those with alcohol dependence not only increases the likelihood of abstinence from smoking but also reduces drinking behavior. Few pharmacotherapy studies have sought medicines that are efficacious at treating both alcohol and nicotine dependence. We have provided evidence that topiramate, a facilitator of 3-aminobutyric acid (GABA) and an inhibitor of AMPA/kainate glutaminergic activity, not only decreased heavy drinking but also diminished nicotine consumption among a cohort of alcohol-dependent individuals who smoked. We now propose to test the efficacy of topiramate in a trial that focuses on treating alcohol-dependent smokers concomitantly. The uniqueness of the proposed trial is that it will include behavioral measures specifically focused to enhance smoking abstinence, address the treatment of both comorbid disorders equally in its general approach, and be directly comparable to the reporting of smoking cessation studies in its design by using a target quit date. This project supports NIAAA's mission to develop efficacious medications for the treatment of alcohol and nicotine dependence to prevent morbidity and deaths in society.