Valproate Efficacy in Cocaine-Bipolar Comorbidity

描述（由申请方提供）：本提案将测试一种有前景的药理学方法治疗共病可卡因依赖和双相情感障碍的疗效。我们提出了一项随机、双盲、安慰剂对照、12周的试验，以测试双丙戊酸钠、“丙戊酸盐”+替代治疗（TAU）与安慰剂+ TAU（TAU =碳酸锂+支持性心理社会治疗）相比，在可卡因依赖和双相情感障碍共病患者中减少可卡因使用和稳定情绪症状的疗效。该提案涉及NIDA治疗研究和开发司（DTRD）研究计划中确定的一个主要关注领域，即“治疗酒精和/或精神障碍和药物滥用共病的药物”。“双相情感障碍与可卡因和其他物质使用障碍（SUD）的相关率最高，而不是任何其他主要的严重精神综合征。这种合并症代表了一个主要的治疗挑战，并与严重残疾，发病率和自杀风险增加有关。非常少的研究旨在确定最佳的药物治疗，这些患者的治疗需求基本上仍未得到满足。我们最近结束的双盲、安慰剂对照丙戊酸盐治疗双相性酗酒者的研究仍然是迄今为止唯一一项针对任何双相性SUD合并症的试验。我们的研究显示，丙戊酸盐在减少重度饮酒方面优于安慰剂。有令人信服的理论和累积的临床证据表明，丙戊酸盐可有效减少重度受损人群中的可卡因使用。上述丙戊酸盐试验的次要分析显示，丙戊酸盐在减少可卡因使用（包括可卡因阳性尿液筛查）方面优于安慰剂。此外，我们的丙戊酸盐治疗伴可卡因依赖的双相情感障碍的开放标签初步研究结果也显示可卡因使用显著减少，沿着未经证实的情绪和功能。这些有希望的结果与一些测试丙戊酸盐在可卡因和其他SUD中的效用的开放标签研究的结果一致。有必要进行循证干预，以指导和告知这些高危患者的治疗选择。本研究的目的是：1）检查丙戊酸盐+TAU与安慰剂+TAU相比，在DSM-IV可卡因依赖和共病双相I型障碍患者中减少可卡因使用的疗效; 2）确定原发性与继发性可卡因依赖，双相亚型（抑郁与躁狂/混合型），以及额外SUD的存在缓和了治疗与可卡因使用结果之间的相关性; 3）评估药物依从性和情绪症状作为可卡因使用结果的介质的影响。

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.