A Better Ketamine

Peter Forster Major Depression, Psychobiology, Treatments of Depression

A better ketamine may be coming. That is the conclusion of NEJM Journal Watch Psychiatry reviewer Barbara Geller.

A common pathway to identifying new drugs, is looking at metabolites of a medication to see if there is one metabolite that works better than the active drug (desvenlafaxine – one of the metabolites of venlafaxine – may or may not be an example of the success of this approach).

Ketamine itself comes in two enantiomeric forms (escitalopram is the “S” enantiomer of citalopram), as do many organic molecules. Researchers have found that, though  the S-enantiomer is more potent at NMDA inhibition, the R-enantiomer has greater antidepressant action.

This has called into question the NMDA inhibition theory of how ketamine works as an antidepressant.

In this study, the authors go further and show that the metabolism of ketamine to hydroxynorketamine (HNK) is essential for antidepressant effects. And, beyond that, it is specifically the R-enantiomer of HNK that is the active agent.

HNK was found to have antidepressant action and to act via α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor pathways, rather than by NMDA receptor antagonism. Similar to other antidepressant agents, HNK was associated with elevated brain-derived neurotrophic factor (BDNF) at 24 hours. Prepulse inhibition with HNK was not altered…

A main adverse effect of ketamine is its psychotomimetic properties, but HNK, unlike ketamine, did not produce altered prepulse inhibition, which in humans is associated with schizophrenia. Thus, it is likely that HNK will not heighten the risk for psychotic behaviors in humans. A lesser adverse effect of ketamine in both mice and humans is abnormal motor symptoms, but these were not seen in mice given HNK in this study. If feasible, manufacturers are likely to bring HNK to market as soon as possible.


NEJM Journal Watch Psychiatry. Safer Ketamine May Be in the Offing.

Zanos P et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 2016 May 26; 533:481. (https://dx.doi.org/10.1038/nature17998)

For More Information

Ketamine for Depression Update

NMDA Receptor and Depression