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

睡眠剥夺是唯一的干预措施之一，一直被证明可以产生快速的抗抑郁作用。睡眠剥夺带来快速抗抑郁效果的机制尚未阐明。值得注意的是，然而，最近基因组学和蛋白质组学研究表明，急性睡眠剥夺迅速引起神经元可塑性的几种介质的上调，最显著的是CREB和BDNF。有趣的是，这些相同的分子被慢性抗抑郁药上调，并且可能是大多数抗抑郁药延迟治疗效果的基础。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能系统的激活。这一点尤其值得注意，因为蓝斑去甲肾上腺素能投射仅在快速眼动睡眠（REM）期间静止，此时靶组织显示出最大的敏感性;事实上，蓝斑去甲肾上腺素能神经元的放电与其在皮质中的突触后靶点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，生物节律有能力暂时分离生化过程，并强加一个时间上的巧合，正常分离的事件可以有惊人的和意想不到的效果。因此，我们的假设是，在REM睡眠期间激活正常静止的去甲肾上腺素能系统（即当其突触后靶系统显示出最大的敏感性时）将强烈上调CREB和BDNF，从而产生快速的抗抑郁作用。我们建议在REM睡眠期间通过注入α-2拮抗剂育亨宾来激活去甲肾上腺素能系统。由于我们的假设是，在REM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，因此我们将在这项试点研究中丰富睡眠剥夺反应者的样本。 本研究将招募年龄在18至60岁、诊断为重度抑郁症、目前抑郁但无精神病特征的患者。本实验性概念验证研究分为两个研究阶段。研究阶段I包括完全睡眠剥夺。完全睡眠剥夺的应答者随后复发，将进入研究II期。研究阶段II是在REM睡眠期间静脉注射育亨宾或生理盐水的双盲交叉给药。 本研究的具体目的是评估单次静脉注射盐酸育亨宾（0.125 mg/kg，3分钟内给药）与安慰剂相比，在REM睡眠期间给药时改善总体抑郁症的疗效。 我们的主要假设是，在REM睡眠期间静脉内使用拮抗剂会激活LC，从而在蓝斑正常静止时（即REM睡眠）增加去甲肾上腺素能活动。如果去甲肾上腺素能系统激活的时间在睡眠剥夺的抗抑郁作用中至关重要的假设是正确的，那么在患者中应该观察到急性抗抑郁作用，尽管睡眠中断很小或没有。 该项目现在与项目MH 002857 -04快速和持续抗抑郁作用的谷氨酸能调节剂高度整合，我们发现谷氨酸能调节剂在4小时内产生快速抗抑郁作用，而不是标准抗抑郁药的6周。目前的研究预计将在明年完成。本研究的目的之一是检查脑源性神经营养因子（BDNF），其与现有抗抑郁药的作用机制有关，但BDNF的变化通常需要数周才能增加，这与治疗起效一致。目前的项目收集了重度抑郁症患者的BDNF血浆水平，以确定这些水平是否会在睡眠剥夺的情况下在几小时而不是几周内发生急剧变化;如果BDNF的增加确实会随着睡眠剥夺而迅速增加，那么在理论上这将导致抗抑郁作用的快速起效。虽然我们尚未分析经历睡眠剥夺的重度抑郁症患者的BDNF水平，但与此密切相关的另一项研究（见上文MH 002857 -04）未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的变化，即使这些患者在该时间范围内对氯胺酮有反应。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。BDNF可能与抗抑郁反应的维持更相关。然而，当我们在未来1-2年内完成这项研究时，我们将能够确定睡眠剥夺是否与BDNF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.