Three Approaches to Maintenance Therapy for Chronic Insomnia in Older Adults

 描述(申请人提供)：失眠在老年人中的普遍程度几乎是普通人群的两倍。这是一个重要的临床问题，因为失眠是一种 新发病和反复发作的精神疾病和内科疾病的危险因素。综上所述，失眠在老年人中的患病率和后果表明，失眠不应该不治疗。1)将DSM-5和ICSD-3中的失眠重新定义为一种障碍(相对于其他障碍的一种症状)，以及2)有针对性地治疗睡眠连续性障碍可能会对与失眠同时发生的内科和精神障碍产生临床益处，这一发现进一步强调了这一潜在的临床必要性。因此，目前的问题不是是否治疗，而是如何最好地治疗这种疾病，特别是在 老年人的背景。在现有的药物治疗中，研究得最好的策略是苯二氮卓类药物和苯二氮卓类受体激动剂(BZRAs)。在这两种情况下，治疗通常是通过夜间或间歇给药完成的。在夜间给药(QHS)的情况下，BZRA被发现在长达一年的时间内是安全和有效的。不太清楚的是，这种功效能否在数年或数十年内保持下去。在间歇给药(IDS)的情况下，减少使用策略被认为延长了药物治疗的有效性和安全性的“半衰期”，但代价是：在非药物治疗的夜晚几乎没有临床效果。为了解决这个问题，我们建议评估一种基于条件化和强化的行为原则的替代方法。具体地说，我们建议通过全量治疗(1个月)获得治疗反应，然后在非药物治疗的晚上使用安慰剂进行间歇剂量的维持治疗。仅从预期来看，这种方法应该比标准的间歇给药提供更好的临床结果。使这项研究在理论上有趣的是其基本概念：最初的治疗反应允许药物载体(胶囊)成为治疗反应(嗜睡和睡眠)的条件性刺激，并可以通过部分强化随着时间的推移(如果不是无限期的话)保持这种刺激。基于我们先前部分强化研究的结果，我们建议在三个阶段的研究中评估两种维持治疗的低频率方法。在第一阶段，所有受试者每晚服用唑吡坦，为期一个月，并评估治疗反应。在第二阶段，应答者被随机分成四种维持条件中的一种，为期三个月：夜间用药(QHS)；两种低频率部分强化条件中的一种(非药物夜晚每周1或3次有效剂量，使用安慰剂)；以及低频率入侵检测条件(每周1至3次有效剂量，不使用安慰剂)。第三阶段将是一个延长期，以评估这些办法的长期耐久性，超过9个月。这项研究的结果将是：复发率，复发潜伏期，平均睡眠连续性，以及治疗期间医学症状的数量和严重程度。这项研究的主要假设是，部分强化条件将产生与夜间剂量相似的结果，而优于入侵检测条件的结果。

 DESCRIPTION (provided by applicant): Insomnia is nearly twice as common among older adults as it is in the general population. This is of significant clinical concern as insomnia is a risk factor for new onset and recurrent psychiatric and medical illness. Taken together, the prevalence and consequences of insomnia in older adults suggests that insomnia should not go untreated. This potential clinical imperative is further underscored by 1) the reconceptualization of Insomnia within the DSM-5 and ICSD-3 as a disorder (vs. a symptom of other disorders) and 2) the findings that targeted treatment of sleep continuity disturbance may produce clinical gains for medical and psychiatric disorders that occur comorbidly with insomnia. Thus, at present, the question is not whether to treat but how to best treat the disorder in general, and specifically in the context of older adults. Of the available medical treatments, the best studied strategies are benzodiazepines and benzodiazepine receptor agonists (BZRAs). In both cases, treatment is typically accomplished with either nightly or intermittent dosing. In the case of nightly dosing (QHS), BZRAs have been found to be safe and efficacious for periods of up to a year. Less clear is whether such efficacy can be maintained over the course of years or decades. In the case of intermittent dosing (IDS), the reduced usage strategy is thought to extend the efficacy and safety "half-life" of pharmacotherapy, but at a cost: little or no clinical effects on non-medication nights. In order to address this issue, we propose to evaluate an alternative approach that is based on the behavioral principles of conditioning and reinforcement. Specifically, we propose to garner treatment responses with full dose treatment (1 month) and then conduct maintenance therapy using intermittent dosing with placebos on non-medication nights. This approach, by expectancy alone, should provide for better clinical outcomes than standard intermittent dosing. What makes the study theoretically interesting is the underlying concept: that the initial treatment response allows for the medication vehicle (the capsule) to become a conditioned stimulus for the therapeutic response (sleepiness and sleep) and that this can be maintained over time (if not indefinitely) with partial reinforcement. Building upon the findings from our prior investigation with partial reinforcement, we propose to assess two low frequency approaches to maintenance therapy in a three phase study. In Phase 1, all subjects receive zolpidem nightly for one month and are assessed for treatment response. In Phase 2, responders are randomized to one of four maintenance conditions for three months: Nightly medication use (QHS); one of two low frequency partial reinforcement conditions (1 or 3 active doses per week with placebos on non-medication nights); and a low frequency IDS condition (1 to 3 active doses per week, without placebos). Phase 3 will be an extension period to assess, over 9 months, the long-term durability of the approaches. The outcomes for the study will be: rate of relapse, latency to relapse, average sleep continuity, and number and severity of medical symptoms during treatment. The primary hypothesis for the study is that the partial reinforcement conditions will produce similar outcomes to nightly dosing and superior outcomes to the IDS condition.