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expert reaction to ketamine metabolite and depression in a mouse model

A study in mice published in the journal Nature has reported that a metabolite from the breakdown of ketamine is responsible for antidepressant effects of the drug.

These comments accompanied a briefing.


Dr James Stone, Clinical Senior Lecturer, King’s College London’s Institute of Psychiatry Psychology and Neuroscience and Honorary Senior Lecturer, Imperial College London, said:

“This is an exciting study that raises the possibility that (2R,6R)-hydroxynorketamine could be developed as an antidepressant. This paper predicts that it would have a similar very rapid onset of action and efficacy against treatment resistant depression to ketamine, but that it would lack some of the undesirable side effects such as perceptual distortion and addiction potential. Although these findings are very promising, clinical trials in patients with depression are required to determine whether (2R,6R)-hydroxynorketamine has antidepressant properties.”


Prof. Celia Morgan, Professor of Psychopharmacology, Department of Psychology, University of Exeter, said:

“Ketamine abuse is a concern for clinicians thinking of using repeated doses of ketamine in the treatment of depression. So these findings are exciting as they appear to demonstrate that the rapid anti-depressant effects of ketamine are possible by giving a metabolite of that drug that is free from abuse potential.

“The findings fit with an emerging profile that suggests it is ketamine’s longer term effects on a different receptor in the brain – called the AMPA receptor – that are important in reducing depression, and not its effects on the main receptor it works on, called the NMDA receptor. It also suggests, along with other work, that changes in an area of the brain important in memory called the hippocampus, which allow the brain to more readily form new connections, are important in producing rapid reduction of depression. Other findings from the paper are in contrast with those of previous work in mice, which had suggested that a pathway called mTOR was crucial to the anti-depressant effects of ketamine.

“These findings are in mice, so it still remains to be seen if they translate to humans. We also do not know the exact way in which this metabolite works, rather we know how it doesn’t work, so much work needs to be done before we get to the stage of testing such a drug in humans. But the findings represent a fascinating advance in understanding how ketamine has these life-changing effects in people with very severe depression.”


Prof. Bill Deakin, Professor of Psychiatry, University of Manchester, said:

“Great therapeutic optimism followed the surprising discovery in 2000 that severe depression can be helped within a day of a short intravenous infusion of the dissociative anaesthetic and club drug, ketamine. Since then progress towards the promised new era of rapidly acting antidepressants with new actions has pretty much stalled.

“This significant new study suggests that it’s not the well-known blocking action of ketamine itself on NMDA glutamate receptor function that matters, nor its dissociative effects, it’s the unexpected direct actions of a ketamine metabolite (HNK) that may mediate antidepressant effects via AMPA glutamate receptors. NMDA (N-methyl-D-aspartate) receptors and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors are different kinds of receptors that are activated by the neurotransmitter glutamate.

“Enhancing AMPA receptor function has been a target for antidepressant drug development for some time; what is novel is that ketamine may act in this way. This important conclusion, albeit from tightly logical experiments in mice, must remain tentative until HNK is shown to be effective in patients with depression without the dissociative effects of ketamine. Nevertheless, this is an exciting finding pointing to new fast treatments for depression.”


Dr Michael Bloomfield, Clinical Lecturer in Psychiatry, MRC Clinical Sciences Centre and UCL, said:

“Depression is a leading global cause of illness, affecting millions of people worldwide. Whilst common, the illness can blight people’s lives and severe forms of the illness can take people’s lives through suicide. Despite this, there is always hope and many people will benefit from combinations of psychological treatments and antidepressant medicines.  Whilst these treatments begin working as soon as they are started, it often takes weeks for patients to feel significantly better.  This delayed response to treatment is inconvenient at best, and at worst can be potentially fatal.  At the same time, not everyone will get better with the current commonly used treatments and some people with severe forms of the illness may need to have more intensive treatments including electroconvulsive therapy (ECT).

“Therefore, there has recently been enormous interest in studies that have found that the anaesthetic medicine ketamine appears to have a rapid antidepressant effect and that ketamine may be helpful in patients with a more severe illness that does not get better with current psychological therapies and medicines. This has in turn led scientists to a frantic search to understand how ketamine causes its antidepressant effects, since it probably works in a very different way to other medicines used to treat depression. This is important because understanding how ketamine works could potentially lead to a new generation of medicines to help patients with depression.

“Prevention is generally better than cure, and we must continue to tackle the many social and psychological causes of depression. Anyone who is worried about their own or a loved one’s mental health should speak with their doctor. For people who already have depression, a combination of existing medicines and learning new ways of thinking and behaving remain the most useful tools in the fight against this common, but potentially devastating illness.”


NMDAR inhibition-independent antidepressant actions of ketamine metabolites’ by Zanos et al. published in Nature on Wednesday 4th May. 


Declared interests

Prof. Morgan: I am Principal Investigator on a grant from the Medical Research Council investigating the reduction of relapse by combined ketamine and psychological therapy. I have consulted for the pharmaceutical company Janssen.

Prof. Deakin: “I carry out research on glutamate mechanisms of depressive illness and schizophrenia and their treatment. This is funded by the Medical Research Council, Innovate UK, Autifony and previously by AstraZeneca. I have share options in P1Vital ltd.”

All others: None received

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