Ketamine Mechanism of Action: Separating the Wheat from the Chaff

(R,S)-ketamine (ketamine) exerts rapid (within hours) and robust (>60% response) antidepressant effects in severely ill-depressed patients who have failed conventional treatments (Zarate et al, 2006). This clinical finding has been paradigm-shifting as there is now tremendous hope that very ill-depressed patients can be treated in a matter of hours, rather than many weeks or months required for standard therapies to take effect (if they do at all). However, although the therapeutic potential of ketamine has elicited tremendous excitement in the field, ketamine's use outside of a monitored clinic setting is limited due to its anesthetic actions at higher doses, abuse liability, ataxic effects, and capacity to produce changes in sensation and dissociation even when administered at sub-anesthetic antidepressant-effective doses. Ketamine's antidepressant action had been presumed to be via its anesthetic target, which is the inhibition of the NMDA glutamate receptor (Singh et al, 2014). In contrast, although published clinical studies to date have suggested modest antidepressant efficacy of some alternative NMDA receptor antagonists, thus far these drugs lack the robust rapid or sustained efficacy of ketamine, and in some cases (eg, memantine) they have been proven clinically ineffective (Newport et al, 2015). This suggests that it is unlikely ketamine exerts its antidepressant actions solely via inhibition of the NMDA receptor