Valproate Efficacy in Cocaine-Bipolar Comorbidity

描述（由申请人提供）：本提案将测试一种有前景的药物治疗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、为期12周的试验，以测试双丙戊酸钠、“丙戊酸”+常规治疗（TAU）与安慰剂+ TAU （TAU =碳酸锂+支持性社会心理治疗）在减少可卡因使用和稳定可卡因依赖合并双相情感障碍患者情绪症状方面的疗效。该提案涉及NIDA治疗研究与开发部门（DTRD）研究项目“治疗共病酒精和/或精神障碍和药物滥用的药物”中确定的主要兴趣领域。双相情感障碍与可卡因和其他物质使用障碍（sud）的关联比任何其他主要的严重精神综合症都要高。这种合并症是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。值得注意的是，很少有研究旨在确定最佳的药物治疗，这些患者的治疗需求仍然基本上没有得到满足。我们最近完成的双盲、安慰剂对照丙戊酸治疗双相酗酒者的研究是迄今为止唯一完成的针对双相- sud合并症的试验。我们的研究显示丙戊酸在减少酗酒方面比安慰剂有显著的优势。有令人信服的理论和积累的临床证据表明丙戊酸盐可能有效地减少严重受损人群的可卡因使用。对上述丙戊酸试验的二次分析显示，丙戊酸在减少可卡因使用方面比安慰剂有显著优势，包括可卡因尿检呈阳性。此外，我们对丙戊酸钠治疗双相情感障碍合并可卡因依赖的开放标签试点研究结果也显示，可卡因使用显著减少，同时未经证实的情绪和功能也有所改善。这些有希望的发现与一些公开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sud中的效用。有必要采取循证干预措施，为这些高危患者的治疗选择提供指导和信息。本研究的目的是：1)比较丙戊酸+TAU与安慰剂+TAU在减少DSM-IV可卡因依赖和共病双相I型障碍患者可卡因使用方面的疗效；2)确定原发性与继发性可卡因依赖、双相亚型（抑郁型与躁狂型/混合型）以及额外sud的存在是否会缓和治疗与可卡因使用结果之间的关联；3)评估药物依从性和情绪症状对可卡因使用结果的影响。

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.