Ketamine is both an anesthetic and a psychosis-inducing (psychotomimetic) drug with significant potential for abuse. Over the last decade, investigators have shown that intravenously administered ketamine can lead to rapid improvement in depressive symptoms and suicidal ideation. Currently available antidepressants take several weeks before they start to work. In contrast, ketamine’s antidepressant effects are noticeable within hours after a single, sub-anesthetic dose and last for several days. However, little is known about the benefits and risks of long-term use of ketamine, and its psychotic and cognition-impairing side effects and potential for abuse make it ill-suited for widespread use as an antidepressant.

Ketamine blocks a specific brain receptor known as the NMDA glutamate receptor. It has been thought that this action is responsible for ketamine’s antidepressant effect. In a recent paper published in the journal Nature, Panos Zanos and colleagues described the results of a study that advances our understanding of the mechanisms underlying ketamine’s ability to relieve depressive symptoms. These investigators provided data from animal studies strongly suggesting that a metabolite of ketamine is responsible for its antidepressant effect. Furthermore, the mechanism of its action may not involve the NMDA receptor.  

Zanos and colleagues utilized mouse models of depression. There are several behavioral research paradigms that can be used with mice and rats that correlate with depressive symptoms in humans. Antidepressant drugs block these depressive-like behaviors in rodents. This is true for the classic antidepressants as well as for ketamine. These behavioral paradigms in animals are useful for testing the antidepressant properties of new drugs. 

Ketamine, which is sold as a mixture of R- and S-enantiomers in the United States, is broken down in the body to other chemicals. [Enantiomers are molecules that have identical physical and chemical properties but are mirror images of each other and rotate polarized light in opposite directions. Different enantiomers can have markedly different effects on protein interactions in the body.] Zanos’ group demonstrated that a very specific metabolite of ketamine is responsible for its rapidly acting antidepressant properties. This metabolite, (2S,6S;2R,6R)-hydroxynorketamine (HNK), demonstrates strong antidepressant-like properties in mice, and when its production from ketamine is blocked, the antidepressant effects of ketamine are diminished. Furthermore, the 2R,6R-HNK enantiomer was found to be a more potent antidepressant than the 2S,6S-HNK enantiomer. This is important because prior work had found that R-ketamine is more potent than S-ketamine in antidepressant assays while S-ketamine is more potent at blocking NMDA receptors. This finding raises the possibility that the antidepressant and NMDA receptor effects of ketamine can be untangled.

Two important characteristics of HNK are extremely exciting. First, the HNK enantiomers do not block NMDA receptors. Instead, they lead to sustained, enhanced synaptic transmission in the hippocampus mediated by another glutamate receptor known as the AMPA receptor. This enhancement of AMPA receptor-mediated transmission is thought to contribute to ketamine’s antidepressant effects. This is important because it suggests that AMPA receptors may be key mediators of rapid antidepressant actions. This finding should lead investigators to search for other substances that either directly stimulate AMPA receptors or enhance transmission via this receptor as potential new antidepressant medications.

The other important characteristic of HNK is that this chemical, particularly the 2R,6R-enantiomer, may not have the serious behavioral side effects associated with ketamine. It is known that ketamine can cause psychotic symptoms and is potentially addictive. Drugs that cause psychosis and are addictive have specific effects in a variety of animal models. In these animal models, ketamine has the effects that one would expect based on its known properties. (2S,6S;2R,6R)-HNK does not appear to have the same effects. Thus, it appears likely that it is a safer drug than ketamine.  

Although this work is very exciting, it is important to realize that results from mouse models do not always directly translate to humans. The data in these studies, however, strongly suggest that (2S,6S;2R,6R)-HNK is an active metabolite of ketamine that is responsible for the rapid antidepressant response. Furthermore, this metabolite may have a significantly more attractive safety profile.

It is likely that the results of this study will be of substantial interest to pharmaceutical companies. New medications based on increased understanding of the roles of various glutamate receptors will probably be developed. Clinical studies will be necessary to determine whether such drugs are both effective and safe.

This research is an interesting demonstration of the flow of science. Clinical observations and animal research involving the glutamate system were keys to the original proof-of-concept study demonstrating ketamine’s potential as an antidepressant. Further clinical studies have supported the rapid antidepressant effect of ketamine. Research involving animal models has advanced the understanding of ketamine’s influence on glutamate transmission. The study discussed in this post, utilizing animal models, strongly suggests that a metabolite of ketamine is the active antidepressant ingredient. Furthermore, this metabolite may not have the addictive or hallucinatory properties of the parent drug. Hopefully, further work will lead to the development of better and safer rapidly acting antidepressants.

This column was written by Eugene Rubin MD, PhD and Charles Zorumski, MD.

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