Proof-of-Concept Investigations

吸烟是一种有严重健康后遗症的成瘾行为，在世界范围内造成巨大的人力和经济损失。尽管近年来取得了重大进展，但有效的药物和行为戒烟干预措施仍然有限。初步数据表明，神经类固醇可能是戒烟的新药物，并在压力诱导的复发中发挥保护作用。因此，该项目将评估神经类固醇（孕烯诺酮，脱氢表雄酮，加那洛酮）和其他有希望的候选药物作为戒烟尼古丁替代疗法（NRT）的辅助治疗。候选治疗方法将在平行组设计中进行评估。在戒烟前使用尼古丁贴片治疗一周后，80名单独使用NRT治疗反应不足的受试者（使用与项目1：临床试验（PD: Rose）相同的标准，以过期空气中一氧化碳[CO]的减少作为指标）将被随机分配到四种条件之一，包括三种候选药物和安慰剂对照条件。治疗将在戒烟前和戒烟后分别持续一周和11周。使用我们提出的适应性治疗模型，NRT将在整个治疗期间持续进行，我们将尝试确定治疗干预措施，以证明对单独NRT反应不充分的吸烟者（约80%）增加NRT有效。尼古丁依赖的严重程度将使用费格斯特伦尼古丁依赖测试（FTND）进行跟踪，并通过在戒烟前每周间隔测量过期空气CO来评估自由吸烟的变化。戒烟前的实验将在基线、NRT第一周后和NRT加选定药物的第二周后举行。在每个疗程中，压力引起的渴望和吸烟行为也将使用节奏听觉系列加法测试（PASAT）进行评估。在为期两周的三次实验后，参与者将尝试戒烟。吸烟和戒烟将在戒烟后11周和6个月的随访中进行评估，并与戒烟前的生物和行为标志物（神经类固醇水平、压力诱导的渴望、过期空气CO等）相关。这些概念验证结果将用于指导项目1：临床试验（PD: Rose）中更广泛评估的治疗选择。

Cigarette smoking is an addicfion with major health sequelae, exacfing tremendous human and economic costs worldwide. Although significant progress has been achieved in recent years, effective pharmacologic and behavioral smoking cessation interventions remain limited. Preliminary data suggest that neurosteroids may represent novel agents for smoking cessation and play a protective role in stress-induced relapse. This project will hence evaluate neurosteroids (pregnenolone, DHEA, ganaxolone) and other promising candidates as adjunctive treatments to nicofine replacement therapy (NRT) in smoking cessation. Candidate treatments will be evaluated in a parallel-arm design. After one week of pre-cessation treatment with nicotine patch, 80 subjects who show an insufficient therapeutic response to NRT alone (using as an index the reduction in expired air carbon monoxide [CO], the same criterion as is used in Project 1: Clinical Trials (PD: Rose)) will be randomized to one of four conditions, comprising three candidate medicafions and a placebo control condition. Treatment will continue for one week pre-quit and 11 weeks post-quit. Using our proposed adaptive treatment model, NRT will be continued throughout the treatment period, and we will attempt to identify treatment intervenfions that will prove effective in augmenting NRT in smokers who do not respond adequately to NRT alone (approximately 80%). Nicotine dependence severity will be tracked using the FagerstrQm Test for Nicofine Dependence (FTND), and changes in ad lib smoking will be assessed by measuring expired air CO at weekly intervals pre-quit. Laboratory sessions pre-quit will be held at baseline, after the first week of NRT and after the second week of NRT plus selected agent. During each session, stress-induced craving and smoking behavior will also be assessed using the Paced Auditory Serial Addition Test (PASAT). After the three laboratory sessions conducted over the course of two weeks, participants will attempt to quit. Smoking and smoking abstinence will be assessed for 11 weeks after the quit date and at 6-month follow-up, and correlated with pre-cessation biological and behavioral markers (neurosteroid levels, stress-induced craving, expired air CO, others). These proof-of-concept findings will be used to guide the selection of treatments for more extensive evaluation in Project 1: Clinical Trials (PD: Rose).