Laboratory of Neurotherapeutics, Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy (T.R., S.K.) and SleepWell Research Program, Faculty of Medicine (T.R., S.K.), University of Helsinki, Helsinki, Finland
Pharmacol Rev. 2020 Apr;72(2):439-465. doi: 10.1124/pr.119.018697.
Recent studies have strived to find an association between rapid antidepressant effects and a specific subset of pharmacological targets and molecular pathways. Here, we propose a broader hypothesis of encoding, consolidation, and renormalization in depression (ENCORE-D), which suggests that, fundamentally, rapid and sustained antidepressant effects rely on intrinsic homeostatic mechanisms evoked as a response to the acute pharmacological or physiologic effects triggered by the treatment. We review evidence that supports the notion that various treatments with a rapid onset of action, such as ketamine, electroconvulsive therapy, and sleep deprivation, share the ability to acutely excite cortical networks, which increases synaptic potentiation, alters patterns of functional connectivity, and ameliorates depressive symptoms. We proceed to examine how the initial effects are short-lived and, as such, require both consolidation during wake and maintenance throughout sleep to remain sustained. Here, we incorporate elements from the synaptic homeostasis hypothesis and theorize that the fundamental mechanisms of synaptic plasticity and sleep, particularly the homeostatic emergence of slow-wave electroencephalogram activity and the renormalization of synaptic strength, are at the center of sustained antidepressant effects. We conclude by discussing the various implications of the ENCORE-D hypothesis and offer several considerations for future experimental and clinical research. SIGNIFICANCE STATEMENT: Proposed molecular perspectives of rapid antidepressant effects fail to appreciate the temporal distribution of the effects of ketamine on cortical excitation and plasticity as well as the prolonged influence on depressive symptoms. The encoding, consolidation, and renormalization in depression hypothesis proposes that the lasting clinical effects can be best explained by adaptive functional and structural alterations in neural circuitries set in motion in response to the acute pharmacological effects of ketamine (i.e., changes evoked during the engagement of receptor targets such as -methyl-D-aspartate receptors) or other putative rapid-acting antidepressants. The present hypothesis opens a completely new avenue for conceptualizing and targeting brain mechanisms that are important for antidepressant effects wherein sleep and synaptic homeostasis are at the center stage.
最近的研究致力于寻找快速抗抑郁作用与特定药理学靶点和分子途径之间的关联。在这里，我们提出了一个更广泛的抑郁症编码、巩固和再正常化假说（ENCORE-D），该假说表明，从根本上讲，快速和持续的抗抑郁作用依赖于内在的稳态机制，这些机制是作为对治疗引发的急性药理学或生理效应的反应而被诱发的。我们回顾了支持以下观点的证据，即各种快速起效的治疗方法，如氯胺酮、电惊厥疗法和睡眠剥夺，都具有急性兴奋皮质网络的能力，从而增加突触增强，改变功能连接模式，并改善抑郁症状。接着，我们研究了最初的作用为什么是短暂的，因此，需要在清醒时巩固，在睡眠中维持，以保持持续。在这里，我们纳入了突触稳态假说的元素，并推测突触可塑性和睡眠的基本机制，特别是慢波脑电图活动的稳态出现和突触强度的再正常化，是持续抗抑郁作用的核心。最后，我们讨论了 ENCORE-D 假说的各种含义，并为未来的实验和临床研究提出了一些考虑因素。意义：快速抗抑郁作用的分子观点未能理解氯胺酮对皮质兴奋和可塑性的影响的时间分布，以及对抑郁症状的长期影响。抑郁症的编码、巩固和再正常化假说提出，持续的临床效果可以通过对氯胺酮（即，在受体靶点如 -甲基-D-天冬氨酸受体的参与过程中产生的变化）或其他潜在的快速作用抗抑郁药的急性药理学作用引起的神经回路中的适应性功能和结构改变来最好地解释。本假说为理解和靶向对抗抑郁作用很重要的大脑机制开辟了一个全新的途径，其中睡眠和突触稳态处于中心舞台。
