Fig. 4.

Emerging hypotheses of ketamine’s action. a The metabolism of ketamine to its hydroxynorketamine metabolites, and particularly (2R,6R)-hydroxynorketamine, is responsible for mediating the rapid antidepressant effects. b Ketamine disrupts neuronal homeostasis, which triggers self-correcting mechanisms. c Ketamine regulates both circadian and homeostatic processes of sleep to elicit antidepressant effects. d The hypothesis of encoding, consolidation and renormalization in depression (ENCORE-D) proposes that ketamine alters neural encoding of information, the consolidation of synaptic change, and the renormalization of synaptic strength during sleep to elicit acute and sustained antidepressant effects