Ketamine: dream depression drug?

Around one in five people will have a severe episode of depression at some point in their life, but the current drug-based treatments we have can take weeks or months to work - if they work at all. More than a decade ago, scientists discovered that the animal anaesthetic ketamine had a powerful anti-depressive effect, but the side effects - including loss of sensation, paralysis, hallucinations and out-of-body feelings - have limited its use. That might be about to change, thanks to research from Todd Gould and his team at the University of Maryland, Baltimore, as he explained to Kat Arney...

Todd - The presumed mechanism whereby ketamine resorts to antidepressant actions has always been assumed to be via the same mechanisms whereby it exerts its side effects, which is inhibition of a receptor for the neurotransmitter glutamate - the NMDA receptor.

Kat - These are like the little gates on nerve cells that send signals between cells, isn't it?

Todd - Exactly.

Kat - What was the question that you were trying to figure out with this research? Where did you take this idea next?

Todd - What our evidence suggests is that it's not ketamine itself that exerting the anti-depressant activities - it's a breakdown product or metabolite of ketamine. This metabolite does not inhibit the NMDA subtype of the glutamate receptor. It does enhance activity of another type of glutamate receptor which is the AMPA receptor. The precise mechanism whereby it does this is not clear to us yet. We also showed that if we give only the hydroxyzine norketamine, we observe similar antidepressant effects we observe when we give ketamine itself.

Kat - What would be the advantages of giving this breakdown product of ketamine rather than ketamine itself?

Todd - So, ketamine has a number of side-effects. Some of them are related to its use as a club drug. What we show with this metabolite is that, to the extent possible using our animal models, that we don't have any of those side-effects. So we go up to pretty high doses - 40 times the antidepressant effective dose and we don't see side-effects.

We also looked at the capacity of ketamine versus hydroxyzine norketamine to be self-administered.

Kat - So if the mice keep wanting to take it, it's like they're addicted to it?

Todd - Yes. So, basically, mice press a lever to receive an intravenous injection of the drug, and mice will readily press a lever to receive ketamine. With hydroxyzine norketamine, they can occur less.

Kat - When can we get hold of this drug - what's the next step for it?

Todd - So, moving forward, we have a reasonable amount of confidence that hydroxyzine norketamine is safe, and the reason is that it's been in humans now for many decades - as a byproduct of getting ketamine you have hydroxyzine norketamine. So we know in very general term that hydroxyzine norketamine is quite safe for humans, but we still have to go through all the necessary regulatory steps - toxicology studies in model animals to prove that before we can move on to human clinical trials.

Kat - Do you think that there are other similar drugs that might be useful that you need to investigate in this way?

Todd - As a protocol, I tend to think when you give a drug, that that's all you're giving. And this is an example that when you're giving a drug, you're also giving all the metabolites of that drug and the majority of drugs are metabolised. It's important to us and to me and I think to the field that we need to consider more vigorously that the biologically active molecule may not be the drug itself that we're giving.