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.

Ketamine is rapidly metabolized in the liver via multiple cytochrome P450 isoforms to norketamine, dehydronorketamine, hydroxyketamines, and a number of hydroxynorketamines (HNKs) in a stereoselective manner (Adams et al, 1981; Desta et al, 2012). This presents the possibility that ketamine acts as a prodrug, whereby in vivo metabolic conversions result in the biologically active drug. We recently reported that the metabolism of ketamine is essential for its antidepressant actions in mice (Zanos et al, 2016). Specific HNK metabolites of ketamine, (2S,6S)-HNK and (2R,6R)-HNK, produced from (S)-ketamine or (R)-ketamine, respectively, do not bind to or functionally inhibit the NMDA receptor at antidepressant-relevant concentrations, but do exert antidepressant behavioral effects similar to that observed following administration of ketamine itself. Administration of the (2R,6R)-HNK enantiomer to mice fully reproduces the antidepressant (and anti-anhedonic) behavioral and biochemical actions of ketamine. (2R,6R)-HNK exerts unique electrophysiological actions that provide an explanation for ketamine's antidepressant efficacy (Zanos et al, 2016). Although the pharmacological target of these HNKs have not been identified yet, our data support a critical role of an acute increase in glutamatergic AMPA receptor activity, followed by a long-term upregulation of synaptic AMPA receptors, likely resulting in potentiation of excitatory synapses in mood-relevant brain regions. (2R,6R)-HNK exerts these effects without the sensory-dissociation, ataxia, and abuse liability of ketamine in animal tests. Overall, our findings, supported by pharmacokinetic and chemical validation, reveal that production of distinct metabolites of ketamine is necessary and sufficient to produce ketamine's antidepressant actions (Zanos et al, 2016).

Based on these data, we propose that ketamine, and individually (S)-ketamine and (R)-ketamine enantiomers, exert NMDA receptor inhibition-independent antidepressant actions via metabolism to their respective HNKs. Validation of the relevance of HNK metabolites to the clinical antidepressant actions of ketamine in humans will require human clinical trials, which are currently in preparation.

FUNDING AND DISCLOSURE

This work was supported by the U.S. National Institute of Health (NIH) grant MH107615 to TDG and the National Institute of Mental Health NIH intramural research program (CAZ). CAZ is listed as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro- and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain. CAZ, TDG, and PZ are listed as co-inventors on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. CAZ has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. TG and PZ have assigned their patent rights to the University of Maryland Baltimore but will share a percentage of any royalties that may be received by the University of Maryland Baltimore.