A pharmacologic strategy to bring about rapid (next day)

实现快速（第二天）的药理学策略

• 批准号: 7312925
• 负责人: HUSSEINI K MANJI
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7312925
• 关键词: pharmacologic; strategy; bring; about; rapid

Sleep deprivation is one of the only interventions that have consistently been demonstrated to produce rapid antidepressant effects. The mechanisms by which sleep deprivation brings about rapid antidepressant effects have not been elucidated. It is noteworthy; however, that recent genomic and proteomic studies have shown that acute sleep deprivation rapidly brings about an upregulation of several mediators of neuronal plasticity, most notably CREB and BDNF. Intriguingly, these very same molecules are upregulated by chronic antidepressants, and may underlie the delayed therapeutic effects of most antidepressants. Additional investigation of the regulation of CREB and BDNF by sleep deprivation has revealed that these changes are critically dependent upon the activation of the noradrenergic system. This is particularly noteworthy, since the locus coeruleus noradrenergic projection is quiescent only during rapid eye movement sleep (REM), when the target tissues display their greatest sensitivity; indeed, the temporal dissociation between the firing of the locus coeruleus noradrenergic neurons, and the sensitivity of its postsynaptic targets in the cortex may have considerable relevance for the antidepressant effects of sleep deprivation. In this context, biological rhythms have the capacity to temporally dissociate biochemical processes, and imposing a temporal coincidence on normally dissociated events can have striking and unexpected effects. Thus, it is our hypothesis that activating the normally quiescent noradrenergic system during REM sleep (i.e. when its postsynaptic target system displays its greatest sensitivity) will robustly upregulate CREB and BDNF, thereby bringing about a rapid antidepressant effect. We propose to activate the noradrenergic system during REM sleep by infusing an alpha-2 antagonist, yohimbine. Since it is our hypothesis that activating the noradrenergic system during REM sleep will bring about an antidepressant effect by a similar mechanism as sleep deprivation, we will ?enrich? our sample with sleep deprivation responders in this pilot study. Patients, ages 18 to 60 with a diagnosis of major depressive disorder, currently depressed without psychotic features will be recruited into this study. This experimental proof-of-concept study has two Study Phases. Study Phase I consists of total sleep deprivation. Responders to total sleep deprivation who subsequently relapse will enter Study Phase II. Study Phase II is a double-blind crossover administration of either intravenous yohimbine or saline solution during REM sleep. The specific aim of this study is to assess the efficacy of a single dose of intravenous yohimbine hydrochloride (0.125 mg/kg given over 3 minutes) compared with placebo in improving overall depressive symptomatology when administered during REM sleep. Our primary hypothesis is that the intravenous use of an antagonist in patients with major depression during REM sleep will activate the LC and thus increase noradrenergic activity during a time when the locus coeruleus is normally quiescent- namely REM sleep. If the hypothesis that the timing of the activation of the noradrenergic system is crucial in the antidepressant effect of sleep deprivation is correct then an acute antidepressant effect should be observed in patients despite minimal to no disruption of sleep.

睡眠剥夺是唯一被证明能产生快速抗抑郁效果的干预措施之一。睡眠剥夺带来快速抗抑郁作用的机制尚未阐明。值得注意的是；然而，最近的基因组和蛋白质组学研究表明，急性睡眠剥夺会迅速导致神经元可塑性的几种介质上调，尤其是 CREB ​​和 BDNF。有趣的是，这些完全相同的分子会被慢性抗抑郁药上调，并且可能是大多数抗抑郁药治疗效果延迟的原因。对睡眠剥夺对 CREB ​​和 BDNF 调节的进一步研究表明，这些变化严重依赖于去甲肾上腺素能系统的激活。这是特别值得注意的，因为蓝斑去甲肾上腺素能投射仅在快速眼动睡眠（REM）期间处于静止状态，此时目标组织表现出最大的敏感性；事实上，蓝斑去甲肾上腺素能神经元的放电与其皮质中突触后目标的敏感性之间的时间分离可能与睡眠剥夺的抗抑郁作用具有相当大的相关性。在这种情况下，生物节律具有暂时分离生化过程的能力，并且对正常分离的事件施加时间巧合可能会产生惊人的和意想不到的效果。因此，我们的假设是，在快速眼动睡眠期间（即当其突触后靶系统表现出最大敏感性时）激活通常静止的去甲肾上腺素能系统将强烈上调 CREB ​​和 BDNF，从而产生快速的抗抑郁作用。我们建议通过注入 α-2 拮抗剂育亨宾在快速眼动睡眠期间激活去甲肾上腺素能系统。由于我们的假设是，在快速眼动睡眠期间激活去甲肾上腺素能系统将通过与睡眠剥夺类似的机制带来抗抑郁作用，因此我们将“丰富”睡眠。我们在这项试点研究中对睡眠剥夺反应者进行了样本分析。 本研究将招募年龄在 18 岁至 60 岁之间、被诊断为重度抑郁症、目前处于抑郁状态但无精神病特征的患者。这项实验性概念验证研究有两个研究阶段。研究第一阶段包括完全剥夺睡眠。对完全睡眠剥夺做出反应但随后复发的患者将进入研究第二阶段。研究第二阶段是在快速眼动睡眠期间静脉注射育亨宾或盐水溶液的双盲交叉给药。 本研究的具体目的是评估在快速眼动睡眠期间服用单剂量静脉注射盐酸育亨宾（0.125 mg/kg，给药时间超过 3 分钟）与安慰剂相比，在改善整体抑郁症状方面的功效。 我们的主要假设是，在快速眼动睡眠期间，重度抑郁症患者静脉注射拮抗剂会激活 LC，从而在蓝斑通常处于静止状态（即快速眼动睡眠）期间增加去甲肾上腺素能活性。如果去甲肾上腺素能系统的激活时间对于睡眠剥夺的抗抑郁作用至关重要的假设是正确的，那么尽管对睡眠的干扰很小甚至没有干扰，但在患者中应该观察到急性抗抑郁作用。