COMBINED PHARMACOTHERAPY IN DEPRESSED ALCOHOLICS

我们建议在一项双盲、安慰剂对照、随机、平行组试验中检验纳曲酮联合氟西汀与氟西汀单独治疗酒精中毒和伴发重度抑郁症患者的疗效。在美国，有近800万受影响的人，酗酒和重度抑郁症的合并症是一个重大的公共卫生问题。合并症的存在对治疗反应和结果有显著的负面影响，导致自杀风险增加和昂贵的住院精神科护理率增加。目前缺乏针对这三种双重疾病的有效药物治疗。在评估抗抑郁单药治疗抑郁症酗酒者的研究中，只获得了部分反应。我们之前对SSRI氟西汀的研究已经证明了迄今为止在严重抑郁的酗酒者中发表的积极结果。我们之前对SSRI氟西汀的研究已经证明了迄今为止发表的对严重抑郁的酗酒者最积极的结果。然而，在该研究中，氟西汀组仅显示出部分治疗效果，戒断率低，持续抑郁症状和酒精滥用。然而，我们最初和扩展的试点工作评估纳曲酮和氟西汀联合使用的有效性表明，酒精使用和抑郁症状显著减少，反应强劲。我们对这两种药物之间潜在相互作用的研究表明，纳曲酮不会增加大多数患者的氟西汀或去甲氟西汀血药浓度。我们提出的研究将建立在我们之前的工作和在这一复杂和高风险人群中进行药物疗效试验的既定记录的基础上，并发展必要的基础药理学方法来调查拟议的药物相互作用研究。我们提出的研究的及时性强调了这种合并症的高患病率，以及在临床实践中广泛但未经测试的联合用药治疗。因此，我们的研究将填补我们在临床高危人群治疗方面的一个重要空白。我们假设氟西汀和纳曲酮联合治疗将对合并重度抑郁症的酗酒者提供更好的治疗。氟西汀针对的是与酒精中毒相关的抑郁障碍和强迫性消费行为，而纳曲酮针对的是与病理性酒精使用相关的正强化效应和释放风险。我们要求5年的支持，以实现以下目标：1)比较纳曲酮加氟西汀与氟西汀加安慰剂在治疗伴有DSM-IV酒精依赖和单极重性抑郁症患者中的疗效；2)评估药物反应的具体预测因素；3)前瞻性评估持续抑郁症状对酒精使用的影响。106名急性抑郁症和积极饮酒的受试者将被随机分配，并在为期6个月的双盲研究和6个月的治疗后随访阶段进行前瞻性随访。

We propose to test the efficacy of the combination of naltrexone and fluoxetine versus fluoxetine alone in the treatment of patients with alcoholism and co-morbid major depression in a double-blind, placebo- controlled, randomized, parallel group trial. With nearly eight million affected individuals in the U.S., co-morbid alcoholism and major depressive disorder represent a significant public health problem. The presence of co-morbidity has a significant negative impact on treatment response and outcome, resulting in increased risk for suicide and increased rates of costly inpatient psychiatric care. Effective pharmacologic treatments addressing thee dual disorders are lacking. Only partial response has been obtained in studies evaluating anti- depressant monotherapy in depressed alcoholics. Our previous work with the SSRI fluoxetine has demonstrative the positive results published to date in severely depressed alcoholics. Our previous work with the SSRI fluoxetine has demonstrative the most positive results published to date in severely depressed alcoholics. The fluoxetine group in that study, however, displayed only a partial treatment response, with low abstinence rates and persistent depressive symptoms and alcohol abuse. However, our original and extended pilot work evaluating the usefulness of combined naltrexone and fluoxetine suggest a robust response, with a significant decrease in alcohol use and depressive symptoms. Our study of potential interactions between these two medications documents that naltrexone does not increase fluoxetine or norfluoxetine blood levels in most patients. Our proposed study will build on our previous work and established record both in conducting medication efficacy trials in this complex and high risk population, and in developing fundamental pharmacological methodologies necessary to investigate the proposed rug interaction studies. The timeliness of our proposed study is underscored by the high prevalence of this co-morbid condition and by the widely but untested use of the combined medication treatment in clinical practice. Thus, our study our will fill an important gap in our knowledge regarding the treatment of high risk clinical population. We hypothesize that combined fluoxetine and naltrexone treatment will offer enhanced treatment for alcoholics with co-morbid major depression. While the fluoxetine will target the depressive disorders in addition to the compulsive consumatory behavior related to alcoholism, the naltrexone will target the positive reinforcing effect and release risk related to pathological alcohol use. We request five years of support to achieve the following aims: 1) Examine the efficacy of naltrexone plus fluoxetine compared to fluoxetine and placebo in the treatment of patients with co- morbid DSM-IV alcohol dependence and unipolar major depression.; 2) Assess specific predictors of medication response; 3) Conduct a prospective assessment of the effect of persistent depressive symptoms on alcohol use. One hundred and six acutely depressed and actively drinking subjects will be randomized and prospectively followed during a 6 month double-blind study, and a 6-month post-treatment follow-up phase.