Welcome to the Oxford University Psychiatry podcast series, I'm Daniel Morgan, and I have the pleasure of having Dr. Rupert McShane,
who's a consultant psychiatrist and an honorary senior clinical clinical lecturer here at the Oxford Department.
Good morning. And good morning. Thank you for agreeing to come and speak to me about your interesting research
that you're doing into treatment resistant depression and using ketamine.
And in these circumstances, which has received a lot of media attention and has had some interesting results.
So perhaps we could start by learning a little bit about you and and your your
role here in Oxford and then move on to think about this this use of ketamine.
OK, thank you.
Well, I'm an NHS consultant, actually, an old age psychiatrist by training and I have for well over 10 years now looked after the ECT service here.
That's electroconvulsive therapy, convulsive therapy to come back to that.
But I've had sort of an interest, particularly in dementia as well.
And and I look after the Cochrane Dementia and Cognitive Improvement Group, which does systematic reviews in dementia.
And I've also got involved with the local clinical research network,
which the aim of which really is fundamentally to recruit patients into clinical trials in dementia.
So I've been interested in trials generally for for some time.
But the the aspect of my job that has sort of taken off and has sort of gone off in
a direction that I hadn't expected is the ECT and treatment resistant depression.
So you sort of old old a consultant and you've got a specialist in sort of dementia and actual convulsive therapy.
But you found that the recent research is more in the general population and treatment resistant depression, is that right?
That's right. So so about about half of people who have ECT are elderly and the other half are under 65 and have
by definition they're having ECT because they've got treatment resistant depression usually.
Well, usually. And one day Phil Cameron said to me, you know, there's this sort of exciting new work about ketamine.
Why don't we think about putting in a grant? So so we did that.
And after a couple of failed attempts, my wife said to me, well, why don't you write it as a safety study, which I did.
And of course, that's when I said we were successful in getting that grant for advice.
So Phil Collins, a professor here, and he's got a podcast mention of this ketamine study.
Just just for those of you who might not be aware, what is a safety study?
Well, so this is what it says on the tin, really.
I mean, to you, you're trying you're giving patients a small, relatively small number of patients the drug to see how well it's tolerated.
And we were also interested in the feasibility of whether you could give these ketamine infusions such an intravenous infusion that we were giving,
whether we had to think about how well how you would give that.
And the obvious place to do it was in the context of the C.T. suite while patients were having ECT.
And the reason for that is that that's that's the only time that we have an anaesthetist around and the anaesthetist very used to using ketamine.
So it was making a virtue out of necessity, really.
So we the patients who have had to come through to a recovery room and what we decided to do was to use one
of the beds in one of the three beds in the recovery room for patients who were having ketamine infusions.
And the anaesthetist would set up the infusion while he while we were treating the other people on the activist.
Right. That's very helpful to understand the practical implications of this study.
But I'm really interested in the fact that ketamine is actually a recreational drug
and it's a fairly radical idea to be using ketamine in this particular situation.
So what was the reasoning? Was the neurobiological basis for this use?
So the original observation came from out of the basic science, actually,
and the idea that depression may have at least part of its aetiology may be based in an abnormality of glutamate transmission.
And ketamine is an antagonist, one of the glutamate receptors called the NMDA receptor.
And interestingly, that's that's one of the receptors. It's particularly responsible for long term potentiation.
In other words, the consolidation of memory. But so so the original observation actually was made about a decade ago,
and then more recently a group at NIH in the States did a didn't ask to a small act,
which really showed just what a dramatic effect ketamine could have in people with treatment resistant depression.
And that was the reason that we decided it would be worth pursuing and getting some experience of that in this country.
So it's got a sound neurobiological basis, but presumably some potential scepticism from from lots of quarters because of
its recreational use or its potential psychedelic or hallucinogenic properties.
Well, that's absolutely right. I mean, that the neurobiology is very exciting because recently it's been shown that ketamine
can induce the very rapid outgrowth of dendritic the spines on the dendrites.
So if you imagine a tree, this is the sort of terminal twigs that are, in fact,
what made the connexions between neurones and they tend to retract in chronic depression.
And in fact, perhaps, you know, might be the reason why you sometimes see brain volume loss in depression.
But in the Petri dish, you can see the the neuronal cultures where the spines rapidly grow out again after with ketamine in
a way that's dependent on a particular neurotrophic fact called brain derived neurotrophic factor.
So the neurobiology of this is fairly rapidly being understood.
The main problem that we've got is understanding how you can maintain the this outgrossed because and also how you can maintain the beneficial effect.
So you talk about the recreational use of of ketamine, and you're absolutely right.
That's that's a that's a key sort of obstacle when they ask.
Well, it isn't actually as much of an obstacle as you'd think,
because even even the committee that has recently rebadged the ketamine in terms of its controlled drug status,
they said, you know, this shouldn't apply to medical research.
So there's quite a wide recognition that, you know, ketamine, which is a very safe drug,
it's the most widely used anaesthetic in the world with just about and very widely
used in the Third World because it didn't have much by way of cardiovascular changes.
So the recognition that it's safe, it's in fact some WHV drug list.
So so, yes, there's a risk of diversion. But obviously, if you're giving it intravenously, that's not a risk.
If you were going to give people oral ketamine, that would potentially become a risk, although, frankly, you know,
one tends to see that if people are really benefiting from something, they'd rather not give their drug away to anybody else.
But it isn't. But it is a risk. I think potentially the change in the situation,
the clinical situation compared with anaesthesia is it is different because in anaesthesia you've got an unconscious patient,
whereas you're dealing with patients who who have come in and their mood is low and they're struggling
with day to day life and you're giving them a drug and they're experiencing potential hallucinations.
And so, yeah, so there are side effects. And obviously it was a safety study.
This is one of the things we want to look at and people get marked dissociative phenomena.
So things look different, sound, sound a bit more metallic.
People have some out of body experiences, really, and people feeling that they're detached from their body.
And yes, as the dose goes higher than people might develop visual hallucinations.
And certainly when people are coming around from ketamine, anaesthesia, they often have very pronounced visual hallucinations.
The dose that you're right, that the dose that we're using is much lower than that is used anaesthetic.
So the patients sometimes feel and do feel sleepy, have these experiences,
but they're not they're not actually going to sleep and, you know, with the anaesthetic.
So let's move on to the results. Tell us about what what what patients you've had through and and what's been there, their journeys and what results.
Have you seen this? So. So what we wanted to do was to see whether if you gave ketamine infusion once a week,
three weeks, you get any difference compared to giving it twice a week.
Three weeks has a sort of fairly basic sort of design.
And we just studied 12 patients in each group and.
And essentially what we found, I mean, it was summarised, I thought, nicely by the Huffington Post headline that greeted our results,
which was, you know, yet another trial shows that ketamine is an antidepressant.
So, you know, that that just sort of says it.
I mean, it is big news here in the U.K., but in the states, they are they've seen it all before.
You know, it's nothing to do dramatic. But I have to say it was really dramatic.
You know, some of the some of the cases, the speed of response, we found that some of them needed to infusion.
It was quite interesting. They didn't respond to the first infusion or they had a sort of sense of something.
But the second infusion, several patients who was at that point, that several patients really had a clearly very marked effect on their treatment.
These people have been ill for many, many years, often were extremely disabled.
And, you know, it was it was it was absolutely.
And I was like Awakening's spine tingling that the Awakenings book by Oliver Sacks was right.
Yeah. Wow. So this is very dramatic effect from from these ketamine infusions, actually.
Did they did they report any problems with having the treatment?
So so I mean, how you having said that, you know, there were some patients who responded dramatically.
There were some who didn't respond at all. Right. So it was rather clear sort of dichotomy there.
And we don't know how to predict who's going to respond and who isn't.
There may be genetic determinants of that. There's a single nucleotide polymorphism that might predict that.
And in fact, it's related to be DNF. So, so so some patients benefited, some didn't have.
The duration of the response was very variable as well.
And that was interesting. Unlikely.
You know, and like all the other studies we've done that were done to that time, we kept people on their existing antidepressants.
So that was another aspect of the safety study, is how what would happen if you gave ketamine on top of other antidepressants?
And if anything, it seemed to prolong the response. But even then, you know,
we have we had one patient who who's who had a few infusions and they had a response
that lasted nine months before they relapsed at several that lasted for months.
A couple that lasted one month is sort of this sort of thing. So about 30.
So most people most people don't have prolonged benefit from from ketamine.
And I think it's an absolutely key point is that, you know, an awful lot of work to do yet in working out how you can sustain the response.
But about about 30 percent of people will have a response that lasts at least three days and that sort of consonant with some of the other literature,
some of the other literature will sort of tends to refer to a 70 percent response rate that often often is based on what things look like in a day.
So although it's dramatic, it's it's it's often quite short.
But there is this group that has a much more prolonged response, and that's very interesting.
Yeah. Is there some further research potentially being thought about or I mean,
obviously this is, you know, how can you how could you how could you sustain the response?
And I mean, in a way, I'm in the sort of fortunate position in that because we've got these these patients who have had a definite benefit.
And we know that it's going to be a clinical, you know, life changing benefit for them.
It's it's not unreasonable to try for those individual patients to add in other drugs, which is one things might potentially sustain the response.
So this isn't done in a protocol driven way. This is done with the sort of experimental clinical experimentation with each patient that, you know,
you can certainly understand the issues and understand particularly the the
level of ignorance that we're at and that some of these things are by nature,
you know, a bit of a shot in the dark. But these are people who are very, very sick and what kind of medications, etc.
So we've always been interested in in in other NMDA related drugs and in particular those that promote transmission through the AMP receptor,
which is one of the other glutamate receptors. And at a neurobiological level,
what seems to be seems to maintain the dendritic spine and growth is the is the movement for receptors from
a sort of more peripheral position in the sign abs to a more central one that seems to be involved in the.
Potentiation, consolidation of that of that synaptic transmission, so so we I mean,
you know, it's one thing to have to move shampooer receptors around its finances.
But, you know, we have all we have is drugs that we can give people and see what they do.
So if we tried Memantine and Piracetam and I can proceed and various various NMDA and and glutamate related drug, none of them seem to have helped.
But but of course, these are you know, we've done it in very small numbers of patients.
Hard to know you wouldn't want to ride those drugs off, although there has been there have been negative trials of a in particular.
And of course, you have this problem with the electroconvulsive therapy of rapid dramatic responses.
The time limited responses and and the sort of therapeutic response to that has been to ensure adequate medication to the prolongs response.
Yes, you are using that as a template for this sort of.
Yeah, that's right. That's right. I mean, about 50 percent people who have ECT relapse into responded relapse within six months.
So it's not great, but it's better than the alternative, which we can go with with psychological drug treatment.
Rupert, it's been really interesting hearing about your study on ketamine.
And it's I think there's a lot that you have yet to discover.
And it's interesting to hear your your current thoughts on that on that area.
But thank you for taking the time to speak to me today. Thank you.
Yeah. It's it's it's incredibly exciting. I can't tell you how exciting it is, you know,
this sort of thing that makes it worth really worth doing psychiatry and seeing people like this get better so dramatically.
It's just incredible. I think it's a common fallacy about psychiatry is that not that you don't see patients getting better.
Yeah, I mean, I'm very lucky in that this is really dramatic. But, yes, you're right.
You know, there's nothing better than, you know, treating people with any sort of any sort of paradigm and then coming back.
Grateful. Yes. Oh, thank you for that report. And thank you for tuning in to the Oxford University Psychiatry podcast series.
Please do tune in again.