A pharmacologic strategy to bring about rapid (next day) antidepressants effects

剥夺睡眠是唯一一直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还没有被阐明。然而，值得注意的是，最近的基因组和蛋白质组研究表明，急性睡眠剥夺会迅速导致几种神经元可塑性介质的上调，最明显的是CREB和BDNF。有趣的是，这些非常相同的分子被慢性抗抑郁药上调，并可能是大多数抗抑郁药延迟疗效的基础。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系统的激活。这一点特别值得注意，因为只有在快速眼动睡眠(REM)期间，蓝斑去甲肾上腺素能投射才是静止的，此时靶组织表现出最高的敏感性；事实上，蓝斑去甲肾上腺素能神经元的放电与其在皮层的突触后靶点的敏感性之间的暂时分离可能与睡眠剥夺的抗抑郁效应有相当大的相关性。在这种背景下，生物节律具有暂时分离生化过程的能力，对正常分离的事件施加时间上的重合可能会产生惊人的和意想不到的影响。因此，我们的假设是，在REM睡眠期间(即当其突触后靶系统表现出最敏感的时候)激活通常静止的去甲肾上腺素系统将有力地上调CREB和BDNF，从而产生快速的抗抑郁作用。我们建议通过注射α-2拮抗剂育亨宾来激活REM睡眠中的去甲肾上腺素系统。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系统将通过与睡眠剥夺相似的机制产生抗抑郁效果，因此在这项初步研究中，我们将用睡眠剥夺反应者来丰富我们的样本。 年龄在18岁到60岁之间，被诊断为严重抑郁障碍的患者，目前没有精神病特征的抑郁症将被招募到这项研究中。这项实验性概念验证研究分为两个研究阶段。研究第一阶段包括完全剥夺睡眠。完全睡眠剥夺后复发的应答者将进入研究第二阶段。研究第二阶段是在REM睡眠期间双盲交叉注射育亨宾或生理盐水。 这项研究的具体目的是评估在快速眼动睡眠期间单次静脉注射盐酸育亨宾(0.125 mg/kg，持续3分钟)与安慰剂在改善总体抑郁症状方面的疗效。 我们的基本假设是，在REM睡眠期间，对重度抑郁症患者静脉使用拮抗剂将激活LC，从而在蓝斑正常静止的时间--即REM睡眠--增加去甲肾上腺素能活动。如果去甲肾上腺素系统的激活时机在睡眠剥夺的抗抑郁作用中起关键作用的假设是正确的，那么即使睡眠受到极小甚至没有干扰，患者也应该观察到急性抗抑郁效果。 该项目现在与MH002857-04项目高度集成，用于快速和持续的抗抑郁作用，在该项目中，我们发现谷氨酸能调节剂在4小时内导致快速抗抑郁作用，而不是标准抗抑郁药所发生的6周。预计本研究将于明年完成。本研究的目的之一是检测脑源性神经营养因子(BDNF)，它与现有抗抑郁药的作用机制有关，但BDNF的变化往往需要几周的时间才能增加，这与治疗的开始效果相一致。目前的项目收集了严重抑郁症患者的脑源性神经营养因子血浆水平，以确定在睡眠不足的情况下，这些水平是否会在几个小时内发生急剧变化，而不是几周；如果睡眠不足，脑源性神经营养因子的增加确实迅速增加，那么从理论上讲，这将导致抗抑郁药物行动的迅速开始。虽然我们还没有分析经历睡眠剥夺的重度抑郁症患者的BDNF水平，但另一项与此密切相关的研究(见上文MH002857-04)没有发现重度抑郁症患者在输注NMDA拮抗剂(氯胺酮)后4小时内BDNF水平没有变化，即使这些患者在这段时间内对氯胺酮有反应。这表明，开发快速增加BDNF的化合物可能不是获得快速抗抑郁反应的可行策略。脑源性神经营养因子可能与维持抗抑郁药物的反应更相关。然而，当我们在接下来的1-2年完成这项研究时，我们将能够确定快速启动的抗抑郁作用与睡眠剥夺是否与脑源性神经营养因子有关。

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. This project is now highly integrated with project MH002857-04 Glutamatergic Modulators for Rapid & Sustained Antidepressant Effect where we found that a glutamatergic modulator led to rapid antidepressant effects in 4 hours instead of 6 weeks as occurs with standard antidepressants. The present study is anticipated to be completed in the next year. One of the aims of this study is to examine brain derived neurotrophic factor (BDNF) which has been implicated in the mechanism of action of existing antidepressant but the change in BDNF often takes several weeks to increase which coincides with the therapeutic onset effect. The current project has collected BDNF plasma levels in patients with major depression to determine whether these could acutely change in a matter of hours instead of weeks with sleep deprivation; if an increase in BDNF does indeed rapidly increase with sleep deprivation then in theory that would result in a rapid onset of antidepressant action. While we have not yet analyzed BDNF levels in patients with major depression undergoing sleep deprivation, the other study which this is closely linked to (see above MH002857-04) did not find changes in BDNF in individuals with major depression within 4 hours of an infusion with an NMDA antagonist (ketamine) even though these patients responded to ketamine in that time frame. This suggests that developing compounds that increase BDNF rapidly may not be a feasible strategy to obtain rapid antidepressant response. BDNF might be more relevant for maintenance of antidepressant response. As we complete this study in the next 1-2 years, we will however, be able to determine whether the rapid-onset of antidepressant action with sleep deprivation is linked or not with BDNF.