Pioglitazone as an adjunct to CBT for cocaine relapse prevention

项目摘要 超过一百万美国成年人患有可卡因使用障碍（CUD），最近的趋势显示， 自2010年以来，与可卡因有关的死亡人数有所增加。对于慢性可卡因使用者，大脑的显著变化 功能和结构的改变为复发奠定了基础，不幸的是，复发仍然是最常见的结果 治疗后。对于物质使用障碍，认知行为疗法（CBT）可以说是最 经验支持和广泛使用的复发预防方法。被认为是一种认知控制 CBT旨在改善CUD中受损的“自上而下”执行控制功能， 与复发有关越来越多的证据表明，CBT促进了大脑区域的有意义的变化 与认知控制有关。尽管如此，许多认知障碍患者的反应并不理想 CBT，支持旨在改善综合治疗效果的研究的呼吁。 建议的项目的目标是加强预防复发的CBT与连续使用的效果 吡格列酮（PIO），一种过氧化物酶体增殖物激活受体γ（PPAR-γ）激动剂。不像 针对经典神经递质系统的传统药物，PIO激活PPAR通路 对脑白色物质的损伤具有广谱抗炎和神经保护作用 （WM）。工作记忆在CUD中的功能意义已被证实，证据表明：（1） 慢性可卡因暴露改变了WM结构的完整性;（2）WM的改变损害了认知功能， CUD;（2）更好的WM完整性预测更好的CUD治疗结果。在最近的一次概念验证试验中 我们发现，PIO显著改善了一小部分非禁欲患者的脑WM完整性， CUD。与安慰剂相比，PIO治疗耐受性良好，并与可卡因渴求减少相关。 总的来说，这些发现提出了令人兴奋的可能性，即PIO可能通过改善对CBT的反应， 神经结构和认知功能。 我们建议进行一项随机双盲临床试验，以评估CBT的疗效， 近期戒断的患者在恢复的早期阶段，当渴望突出时， 复发的风险很高，需要完整的认知控制来积极地维持禁欲。5天内 住院戒毒，60名成人CUD将随机接受PIO或安慰剂，随后12名 门诊CBT治疗周，同时继续接受连续的研究药物治疗。具体目标将 检查PIO对靶向改变机制（WM完整性、认知功能、可卡因）的影响 渴望），并证明临床疗效（禁欲，功能健康）与机制 订婚预期结果将确立PIO作为一种可与CBT整合的预防性治疗， 减少戒毒后复吸的风险，从而满足NIDA的战略优先事项， 药物治疗，以提高行为干预的效果。

PROJECT SUMMARY Over one million American adults suffer from cocaine use disorder (CUD) with recent trends showing an increase in cocaine-related deaths since 2010. For the chronic cocaine user, significant changes in brain function and structure set the stage for relapse that, unfortunately, continues to be the most common outcome following treatment. For substance use disorders, cognitive-behavioral therapy (CBT) is arguably the most empirically supported and widely used relapse prevention approach. Considered to be a cognitive control therapy, CBT aims to improve ‘top-down’ executive control functions that are impaired in CUD and strongly connected to relapse. Converging evidence suggests that CBT promotes meaningful changes in brain regions associated with cognitive control. Still, many patients with cognitive impairments show suboptimal response to CBT, bolstering the call for research aimed at improving effects with integrative treatments. The goal of the proposed project is to enhance the relapse-prevention effects of CBT with adjunctive use of pioglitazone (PIO), a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist. Unlike traditional medications that target classic neurotransmitter systems, PIO’s activation of the PPAR pathway confers broad spectrum anti-inflammatory and neuroprotective effects against insult to brain white matter (WM). The functional significance of WM in CUD has been well established by evidence showing that: (1) chronic cocaine exposure alters WM structural integrity; (2) WM alterations compromise cognitive function in CUD; and (2) better WM integrity predicts better CUD treatment outcome. In a recent proof of concept trial we found that PIO significantly improved brain WM integrity in a small sample of non-abstinent patients with CUD. Treatment with PIO was well-tolerated and associated with reduced cocaine craving relative to placebo. Collectively, these findings raise the exciting possibility that PIO may augment responding to CBT via improved neural structure and cognitive function. We are proposing a randomized double-blind clinical trial to evaluate the efficacy of CBT with adjunctive PIO in recently abstinent patients during the early phase of recovery when craving is prominent, relapse risk is high, and intact cognitive control is required to actively maintain abstinence. During 5-day inpatient detoxification, 60 adults with CUD will be randomized to receive PIO or placebo, followed by 12 weeks of outpatient CBT treatment while continuing to receive adjunctive study medication. Specific aims will examine the effects of PIO on targeted mechanisms of change (WM integrity, cognitive function, cocaine craving) and demonstrate evidence linking clinical efficacy (abstinence, functional health) with mechanism engagement. Expected results will establish PIO as an adjunctive treatment that can be integrated with CBT to reduce relapse risk following detoxification, thereby meeting NIDA’s strategic priority of evaluating the use of medications to improve the efficacy of behavioral interventions.