An article just published online in the latest issue of Nature indicates that a metabolite of (R, S)-ketamine, rather that the drug itself, is the responsible agent for it’s fast-acting anti-depressant effect.

Ketamine is known in popular media as a recreational drug, however it has long been known to have medicinal use. The drug is often administered as an anaesthetic agent for patients with traumatic injuries [1], but it has also long been known as an anti-depressant. Like so many anti-depressants, however the underlying mechanism of ketamine’s effects has alluded researchers for some time.

The ketamine molecule is made up of a pair of molecules, known as stereo-isomers. These isomers, known as R-ketamine and S-ketamine, are made up of identical atoms in the same structural shape as each other. However if we draw their chemical structures, they appear as a mirror image of each other. This slight structural difference means that the two isomers, acting separately, have differing effects on the body. Typically, the drug is composed of both isomers, although they can be synthesised separately. When ketamine is broken down by the body, these two isomers produce an array of different compounds. One of the group of compounds (or ‘metabolites’) produced are called hydroxynorketamines (HNKs), which, one of which is much more abundant when R-ketamine is broken down compared to S-ketamine. This HNK is the agent identified as acting on the brain to produce prolonged anti-depressant effects, even after a single dose.

ketamine
The R- and S-ketamine stereoisomers

The anti-depressant effects of ketamine were tested on mice. In the experiment by Zanos et al. [2], mice were injected with either R-ketamine or S-ketamine and were run through a number of standard behavioural experiments used to test anti-depressant effects of drugs in animals. In all three of these behavioural experiments, mice injected with R-ketamine performed better than mice injected with S-ketamine. When the blood plasma and brains of the R-ketamine mice were tested, a much higher amount of HNK was found in comparison with the S-ketamine group. Additionally, they found that female mice responded significantly better than male mice. Moreover, HNK produces none of the dissociative (dream-like, or hallucinogenic) effects that administering (R, S)-ketamine does; one of the main reasons that ketamine has not been used more frequently in treating depression to date. Most importantly for patients, when compared to a classic tricyclic antidepressant called Desipramine, the effects of R-ketamine were much longer lasting – even up to a week – after a single dose.

In summary, this is a very exciting finding and will lead to many new avenues of research. A fast-acting antidepressant would make huge differences in the lives of people suffering with chronic depression and the findings from the study suggest that ketamine is helpful in treating the third of patients that do not respond to other forms of treatment. I for one, will be watching these studies closely and will try to keep you up to date on the latest findings!

References

[1] Porter, K. “Ketamine in prehospital care.”Emergency medicine journal 21, no. 3 (2004): 351-354.

[2] Zanos, Panos, Ruin Moaddel, Patrick J Morris, Polymnia Georgiou, Jonathan Fischell, Greg I Elmer, and Todd D Gould, et al. 2016. “NMDAR inhibition-independent antidepressant actions of ketamine metabolites.” Nature [online only]  doi:10.1038/nature17998

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