What is it about?

ENCORE-D (Encoding, Consolidation and Renormalization in Depression) hypothesis takes elements from the Synaptic Homeostasis Hypothesis (SHY) of sleep and proposes the following mechanistic principles for rapid-acting antidepressants. 1. During the development of depression, susceptible neuronal networks become gradually hyper- or hypoactive under predisposing conditions, and they retain that state at the expense of optimal network functionality. This manifest e.g. as rumination, depressive thoughts, anhedonia, and cognitive dysfunctions. 2. Rapid-acting antidepressants produce prominent excitation in various brain networks that is reflected in the activity of local circuits, leading to increases in cortical synaptic strength and the re-emergence of global functional connectivity patterns. This breaks the recursive cycle of rumination and allows for the immediate relief of depressive symptoms (=rapid antidepressant effect). 3. Increased excitatory tone and synaptic strength are reflected in the homeostatic emergence of waking slow-wave activity (SWA) after the acute effects of the treatments have ceased. This phase is associated with the activation of several pathways implicated in synaptic plasticity and protein synthesis, and it contributes to the subacute consolidation of synaptic change. In line with the SHY, SWA is increased proportionally to the increase in cortical synaptic strength during subsequent slow-wave sleep (SWS), during which the global renormalization of synaptic strength takes place. During this period of renormalization, the increased activity of previously strengthened circuits offers protection from synaptic downscaling. Therefore, groups of synapses may maintain their relative potentiation, whereas others are relatively depotentiated (sustained antidepressant effect) 4. If no further treatment or other therapy is applied, susceptible neuronal networks may again gravitate toward their "abnormal" state over the course of several sleep-wake cycles (= symptoms of depression re-emerge).

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Why is it important?

Rapid antidepressant effects of ketamine are often explained with a pharmacologist mindset. This paper highlights the importance of complex intrinsic homeostatic mechanisms associated with synaptic plasticity and sleep in mediating rapid and sustained antidepressant effects.


It was a great pleasure to write this article with one of the most talented young neuropharmacologists I know (Samuel Kohtala). I hope this paper will receive attention among neuroscientists and clinicians working with depression and its treatment.

Tomi Rantamäki
Klassillis-filologinen yhdistys ry

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This page is a summary of: Encoding, Consolidation, and Renormalization in Depression: Synaptic Homeostasis, Plasticity, and Sleep Integrate Rapid Antidepressant Effects, Pharmacological Reviews, March 2020, American Society for Pharmacology & Experimental Therapeutics (ASPET),
DOI: 10.1124/pr.119.018697.
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