Fig. 3. A simplified model of the ENCORE-D hypothesis. (A) During the development of depression, susceptible neuronal networks become gradually hyper- (red) or hypoactive (blue) under predisposing environmental conditions, and they retain that state at the expense of optimal network functionality. This may manifest as, for example, uncontrollable self-focused rumination, depressive thoughts, anhedonia, and cognitive dysfunctions. Rapid-acting antidepressants (i.e., ketamine represented in the figure) have excitatory effects that are 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. (B) Increased excitatory tone and synaptic strength are reflected in the homeostatic emergence of waking slow-wave activity (SWA) after the acute pharmacological or physiologic effects of the said intervention 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 subsequent slow-wave sleep (SWS), SWA is increased proportionally to the increase in cortical synaptic strength, and 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. However, if no further excitatory stimulus or other therapy is applied, susceptible neuronal networks may again gravitate toward their depressogenic state over the course of several sleep-wake cycles. Once depressogenic patterns of activity are re-established, symptoms of depression re-emerge.