Valproate Efficacy in Cocaine-Bipolar Comorbidity

描述(由申请人提供)：这项提案将测试一种有前景的治疗可卡因依赖和双相情感障碍的药理学方法的有效性。我们提出了一项为期12周的随机、双盲、安慰剂对照试验，以测试双丙戊酸钠+常规治疗(TAU)与安慰剂+TAU(TAU=碳酸锂+支持性心理社会治疗)在减少可卡因使用和稳定合并可卡因依赖和双相情感障碍患者情绪症状方面的有效性。这项建议涉及NIDA治疗研究和开发部门(DTRD)研究计划中确定的一个主要感兴趣的领域，该计划是关于“治疗酒精和/或精神障碍和药物滥用的药物”。与任何其他严重的精神综合征相比，双相情感障碍与可卡因和其他物质使用障碍(SODS)的关联率最高。这种共病是一个主要的治疗挑战，与严重残疾、发病率和自杀风险增加有关。值得注意的是，旨在确定最佳药物治疗的研究很少，这些患者的治疗需求仍然基本上没有得到满足。我们最近结束的双相酒精中毒患者丙戊酸盐的双盲安慰剂对照研究仍然是迄今为止完成的唯一一项解决双相-SUD合并症的试验。我们的研究表明，丙戊酸盐在减少大量饮酒方面比安慰剂有显著优势。有令人信服的理论和不断积累的临床证据表明，丙戊酸盐可能在减少这一严重受损人群中的可卡因使用方面有效。对上述丙戊酸盐试验的二次分析表明，丙戊酸盐在减少可卡因使用方面比安慰剂有显著优势，包括可卡因阳性尿检。此外，我们的开放标签丙戊酸盐治疗双相情感障碍合并可卡因依赖的试点研究的结果也显示，可卡因的使用显著减少，以及未经改善的情绪和功能。这些有希望的发现与一些开放标签研究的结果一致，这些研究测试了丙戊酸盐在可卡因和其他肥皂中的效用。需要循证干预来指导和告知这些高危患者的治疗选择。本研究的目的是：1)比较丙戊酸盐+TAU与安慰剂+TAU在减少DSM-IV可卡因依赖及共病双相I障碍患者使用可卡因方面的疗效；2)确定原发性与继发性可卡因依赖、双相情感亚型(抑郁与躁狂/混合)以及额外肥皂液的存在是否缓和了治疗与可卡因使用结果之间的关联；3)评估服药依从性和情绪症状作为可卡因使用结果的中介因素的效果。

DESCRIPTION (provided by applicant): This proposal will test the efficacy of a promising pharmacological approach for the treatment of comorbid cocaine dependence and bipolar disorder. We propose a randomized, double blind, placebo-controlled, 12-week trial, to test the efficacy of Divalproex sodium, "valproate" + Treatment-As-Usual (TAU) compared to placebo+ TAU (TAU = lithium carbonate + supportive psychosocial treatment) in decreasing cocaine use and stabilizing mood symptoms among patients with comorbid cocaine dependence and bipolar disorder. This proposal addresses a major area of interest identified in NIDA's Division of Treatment Research and Development (DTRD) Research Programs on "Medications for the Treatment of Comorbid Alcohol and/or Mental Disorders and Drug Abuse." Bipolar disorder has the highest rate of association with cocaine and other substance use disorders (SUDs) than any other major severe psychiatric syndromes. This comorbidity represents a major treatment challenge and is associated with severe disability, morbidity, and heightened risk for suicide. Remarkably little research has been aimed at identifying optimal pharmacological treatments, and treatment needs for these patients remain substantially unmet. Our recently concluded double blind, placebo-controlled study of valproate in bipolar alcoholics remains the only trial completed to date addressing any bipolar-SUD comorbidity. Our work had shown a significant advantage for valproate over placebo on decreasing heavy drinking. There are compelling theoretical, and accruing clinical evidence suggesting that valproate may be effective in reducing cocaine use among this severely impaired population. A secondary analysis of the above mentioned valproate trial showed a significant advantage of valproate over placebo on decreasing cocaine use, including cocaine positive urine screens. Additionally, results from our open label pilot study of valproate for bipolar disorder with comorbid cocaine dependence, also showed a significant decrease in cocaine use, along with unproved mood and functioning. These promising findings are in agreement with findings of a number of open label studies testing the utility of valproate in cocaine and other SUDs. There is a need for evidence-based interventions to guide and inform treatment choices for these high-risk patients. The aims of this study are: 1) Examine the efficacy of valproate+TAU compared to placebo+TAU in decreasing cocaine use in patients with DSM-IV cocaine dependence and comorbid bipolar I disorder; 2) Determine whether primary vs. secondary cocaine dependence, bipolar subtype (depressed vs. manic/mixed), and the presence of additional SUDs moderate the association between treatment and cocaine use outcome; 3) Assess the effects of medication compliance and mood symptoms as mediators of cocaine use outcome.