Pioglitazone as an adjunct to CBT for cocaine relapse prevention

项目总结 最近的趋势显示，超过100万美国成年人患有可卡因使用障碍(CUD) 自2010年以来，与可卡因有关的死亡人数有所增加。对于长期吸食可卡因的人来说，大脑的显著变化 功能和结构为复发奠定了基础，不幸的是，复发仍然是最常见的结果 在治疗之后。对于物质使用障碍，认知行为疗法(CBT)可以说是最好的 有经验支持并被广泛使用的复发预防方法。被认为是认知控制 治疗，CBT旨在改善CUD患者严重受损的“自上而下”的执行控制功能 与旧病复发有关。越来越多的证据表明，CBT促进了大脑区域有意义的变化 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。 对于CBT，支持了旨在通过综合治疗改善效果的研究的呼吁。 拟议项目的目标是通过辅助使用来加强CBT的复发预防效果。 吡格列酮是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对PPAR途径的激活 赋予广谱抗炎和神经保护作用，防止对脑白质的侮辱 (Wm)。证据表明：(1)WM在CUD中的功能意义已得到很好的证实。 长期接触可卡因改变WM结构完整性；(2)WM改变损害患者的认知功能 (2)更好的WM完整性预示着更好的CUD治疗结果。在最近的一次概念证明审判中 我们发现，在一小部分非戒断性疾病患者中，PIO显著改善了脑WM完整性 丘德。与安慰剂相比，PIO治疗耐受性良好，并与减少可卡因渴望有关。 总而言之，这些发现提出了一种令人兴奋的可能性，即PIO可能通过改善CBT来增强对CBT的响应 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 近期戒毒患者在渴求突出的康复早期辅助性PIO， 复发风险很高，需要完整的认知控制才能积极维持戒酒。在5天内 住院戒毒，60名患有CUD的成年人将随机接受PIO或安慰剂治疗，然后是12人 接受数周的门诊CBT治疗，同时继续接受辅助研究药物治疗。具体的目标将 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)，并证明了将临床疗效(禁欲、功能健康)与机制联系起来的证据 订婚。预期结果将使PIO成为一种辅助治疗，可以与CBT结合起来 减少戒毒后的复发风险，从而达到NIDA评估使用 提高行为干预效果的药物。

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.