Cognitive-enhancing DA Medications for Cocaine Dependence

用于治疗可卡因依赖的认知增强 DA 药物

• 批准号: 8145588
• 负责人: SCOTT D LANE
• 金额: $ 37.74万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145588
• 关键词: Agonist; Attenuated; Behavior Therapy; Behavioral; Behavioral inhibition; Brain; Carbidopa; Chronic; Clinical; Clinical Trials; Cocaine; Cocaine Dependence; Cocaine Users; Cognitive; Cognitive Therapy; Cognitive deficits; Controlled Clinical Trials; Data; Decision Making; Development; Dopamine; Dopamine D2 Receptor; Dose; Double-Blind Method; Drops; Drug usage; Environment; Impaired cognition; Impairment; Intervention; Joints; Laboratories; Laboratory Research; Left; Levodopa; Link; Measurement; Measures; Mediating; Mediator of activation protein; Modeling; Motivation; Outcome; Parkinson Disease; Patient Self-Report; Patients; Performance; Peripheral; Pharmaceutical Preparations; Placebos; Preclinical Drug Evaluation; Principal Investigator; Process; Proxy; Psychopharmacology; Public Health; Randomized; Regimen; Relapse; Research; Rewards; Role; Severities; Sum; Synapses; System; Testing; Time; Translating; Treatment Efficacy; Treatment outcome; Urine; addiction; base; behavior measurement; cocaine use; cognitive function; decarboxylase inhibitor; dopamine system; evidence base; improved; innovation; neurobehavioral; neuropsychiatry; presynaptic; public health relevance; receptor; receptor function; remediation; response; ropinirole; success; therapy design; treatment effect; treatment response

DESCRIPTION (provided by applicant): Cocaine dependence has been linked closely to deficits in the dopamine (DA) brain system. Chronic cocaine users show impairments in cognitive processes known to be associated with DA (e.g., decision-making, behavioral inhibition, attentional bias). These cognitive impairments have been shown to predict higher drop-out rates, less efficacious therapy, and greater likelihood of relapse. Treatment medications aimed at bolstering cognitive functions via DA modulation might decrease drop-out and enhance clinical outcome. This project will examine the efficacy of DA enhancement therapy that targets cocaine use and cognitive deficits by combining two dopaminergic medications: levodopa and ropinirole. By enhancing presynaptic dopamine release (levodopa) and post-synaptic D2 receptor function (ropinirole), the combined regimen is expected to jointly target dopamine deficits associated with chronic cocaine use and cognitive functions. This dual-target approach is supported empirically by data showing the single medications to be safe and promising for cocaine treatment. Further, combination DA therapy has translated into broad efficacy for the treatment of Parkinson's disease and other neuropsychiatric conditions resulting from DA depletion. The proposed randomized, double-blind, double-dummy controlled clinical trial will compare the combination of levodopa/carbidopa plus ropinirole with levodopa/carbidopa only and placebo. Two-hundred treatment-seeking cocaine-dependent patients will receive 12 weeks of study medication along with evidence-based cognitive-behavioral therapy. It is hypothesized that the combination of levodopa/carbidopa plus ropinirole will improve treatment outcome (cocaine use, retention) and that a dose-response relationship will be supported: [levodopa/carbidopa + 4 mg/d ropinirole] > [levodopa/carbidopa + 2 mg/d ropinirole] > [levodopa/carbidopa + placebo] > [placebo + placebo]. Further, it is hypothesized that the effect of treatment (levodopa/carbidopa + ropinirole) on outcome (cocaine use, retention) will occur indirectly via improved performance on observed behavioral/cognitive measures of decision-making, behavioral inhibition, reward motivation, and attentional bias. The significance of this project lies in its potential to improve cocaine treatment success by combining medications that act simultaneously on dopamine. This project is innovative in testing a new pharmacological remediation approach and in identifying cognitive mechanisms by which DA medications may operate to change cocaine use, providing a potential neurobehavioral marker or proxy for severity of cocaine-related deficits and treatment-related improvement. The Co-Principal Investigators (Schmitz and Lane) have complementary and integrated expertise in clinical trial research, laboratory behavioral measurement, and psychopharmacology. The scientific environment of the UT-Houston Center for Neurobehavioral Research on Addictions (CNRA) will contribute to the success of the project. PUBLIC HEALTH RELEVANCE: Most cocaine dependent patients suffer from deficits in cognitive function that, if left untreated, predict poor outcome. The present study investigates a pharmacotherapeutic intervention designed to improve cocaine treatment success by combining medications that act simultaneously on dopamine, the brain system that is critically associated with chronic cocaine use and cognitive functions. Treatment with levodopa/carbidopa plus ropinirole (tested at two doses) will be compared to levodopa/carbidopa alone, and placebo. Measurement of performance on behavioral/cognitive measures of decision-making, behavioral inhibition, reward motivation, and attentional bias will be conducted at treatment entry and at repeated time points during the 12-week treatment. It is hypothesized that treatment with levodopa/carbidopa + ropinirole will produce superior outcomes in terms of reduced cocaine use and increased treatment retention and that these effects will occur indirectly via improved performance on observed cognitive mechanisms. There is a significant public health need to improve the outcome of treatments for cocaine dependence. This project responds to the current RFA-DA-10-006 by evaluating a pharmacotherapeutic intervention that may jointly improve cognitive functioning and attenuate drug use.

描述（由申请人提供）：可卡因依赖与多巴胺（DA）脑系统的缺陷密切相关。慢性可卡因使用者显示出已知与DA相关的认知过程的损伤（例如，决策，行为抑制，注意力偏差）。这些认知障碍已被证明预测较高的辍学率，疗效较差的治疗，复发的可能性较大。旨在通过DA调节增强认知功能的治疗药物可能会减少脱落并提高临床结局。该项目将研究DA增强疗法的疗效，该疗法通过结合两种多巴胺能药物：左旋多巴和罗匹尼罗来靶向可卡因使用和认知缺陷。通过增强突触前多巴胺释放（左旋多巴）和突触后D2受体功能（罗匹尼罗），该组合方案预计将共同针对与长期可卡因使用和认知功能相关的多巴胺缺陷。这种双靶点方法得到了经验数据的支持，这些数据表明单一药物对可卡因治疗是安全和有希望的。此外，组合DA疗法已转化为治疗帕金森病和由DA耗竭引起的其他神经精神病症的广泛功效。拟定的随机、双盲、双模拟对照临床试验将比较左旋多巴/卡比多巴加罗匹尼罗的组合与仅左旋多巴/卡比多巴和安慰剂。200名寻求治疗的可卡因依赖患者将接受为期12周的研究药物沿着循证认知行为治疗。假设左旋多巴/卡比多巴加罗匹尼罗的组合将改善治疗结果（可卡因使用、保留）并且将支持剂量-反应关系：[左旋多巴/卡比多巴+4 mg/d罗匹尼罗] > [左旋多巴/卡比多巴+2 mg/d罗匹尼罗]>[左旋多巴/卡比多巴+安慰剂] > [安慰剂+安慰剂]。此外，假设治疗（左旋多巴/卡比多巴+罗匹尼罗）对结果（可卡因使用、保留）的影响将通过改善观察到的决策、行为抑制、奖励动机和注意力偏差的行为/认知指标的表现间接发生。该项目的重要性在于，通过结合同时作用于多巴胺的药物，它有可能提高可卡因治疗的成功率。该项目在测试一种新的药理学补救方法和确定DA药物可能改变可卡因使用的认知机制方面具有创新性，为可卡因相关缺陷的严重程度和治疗相关改善提供了潜在的神经行为标志物或代理。共同主要研究者（Schmitz和Lane）在临床试验研究、实验室行为测量和精神药理学方面具有互补和综合的专业知识。UT休斯顿成瘾神经行为研究中心（CNRA）的科学环境将有助于该项目的成功。 公共卫生相关性：大多数可卡因依赖患者患有认知功能缺陷，如果不治疗，预测结果不佳。本研究调查了一种药物干预，旨在通过联合同时作用于多巴胺的药物来提高可卡因治疗的成功率，多巴胺是与慢性可卡因使用和认知功能密切相关的大脑系统。左旋多巴/卡比多巴加罗匹尼罗治疗（以两个剂量测试）将与单独的左旋多巴/卡比多巴和安慰剂进行比较。将在治疗开始时和12周治疗期间的重复时间点对决策、行为抑制、奖励动机和注意力偏差的行为/认知指标进行性能测量。据推测，左旋多巴/卡比多巴+罗匹尼罗治疗将在减少可卡因使用和增加治疗保留方面产生上级结局，并且这些作用将通过改善观察到的认知机制的表现间接发生。在改善可卡因依赖治疗的结果方面，公共卫生方面有着重大的需求。本项目通过评价可能共同改善认知功能和减少药物使用的药物干预来响应当前的RFA-DA-10-006。