1 00:00:00,660 --> 00:00:07,470 Welcome to the Oxford University Psychiatry podcast series, I'm Daniel Morgan, and I have the pleasure of having Dr. Rupert McShane, 2 00:00:07,470 --> 00:00:14,670 who's a consultant psychiatrist and an honorary senior clinical clinical lecturer here at the Oxford Department. 3 00:00:14,670 --> 00:00:20,670 Good morning. And good morning. Thank you for agreeing to come and speak to me about your interesting research 4 00:00:20,670 --> 00:00:24,610 that you're doing into treatment resistant depression and using ketamine. 5 00:00:24,610 --> 00:00:32,130 And in these circumstances, which has received a lot of media attention and has had some interesting results. 6 00:00:32,130 --> 00:00:38,190 So perhaps we could start by learning a little bit about you and and your your 7 00:00:38,190 --> 00:00:44,520 role here in Oxford and then move on to think about this this use of ketamine. 8 00:00:44,520 --> 00:00:45,600 OK, thank you. 9 00:00:45,600 --> 00:01:00,390 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. 10 00:01:00,390 --> 00:01:04,800 That's electroconvulsive therapy, convulsive therapy to come back to that. 11 00:01:04,800 --> 00:01:10,590 But I've had sort of an interest, particularly in dementia as well. 12 00:01:10,590 --> 00:01:21,720 And and I look after the Cochrane Dementia and Cognitive Improvement Group, which does systematic reviews in dementia. 13 00:01:21,720 --> 00:01:29,070 And I've also got involved with the local clinical research network, 14 00:01:29,070 --> 00:01:33,730 which the aim of which really is fundamentally to recruit patients into clinical trials in dementia. 15 00:01:33,730 --> 00:01:39,150 So I've been interested in trials generally for for some time. 16 00:01:39,150 --> 00:01:49,050 But the the aspect of my job that has sort of taken off and has sort of gone off in 17 00:01:49,050 --> 00:01:54,450 a direction that I hadn't expected is the ECT and treatment resistant depression. 18 00:01:54,450 --> 00:02:00,840 So you sort of old old a consultant and you've got a specialist in sort of dementia and actual convulsive therapy. 19 00:02:00,840 --> 00:02:07,110 But you found that the recent research is more in the general population and treatment resistant depression, is that right? 20 00:02:07,110 --> 00:02:17,370 That's right. So so about about half of people who have ECT are elderly and the other half are under 65 and have 21 00:02:17,370 --> 00:02:21,420 by definition they're having ECT because they've got treatment resistant depression usually. 22 00:02:21,420 --> 00:02:30,540 Well, usually. And one day Phil Cameron said to me, you know, there's this sort of exciting new work about ketamine. 23 00:02:30,540 --> 00:02:35,100 Why don't we think about putting in a grant? So so we did that. 24 00:02:35,100 --> 00:02:42,510 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. 25 00:02:42,510 --> 00:02:48,300 And of course, that's when I said we were successful in getting that grant for advice. 26 00:02:48,300 --> 00:02:53,760 So Phil Collins, a professor here, and he's got a podcast mention of this ketamine study. 27 00:02:53,760 --> 00:02:58,800 Just just for those of you who might not be aware, what is a safety study? 28 00:02:58,800 --> 00:03:03,480 Well, so this is what it says on the tin, really. 29 00:03:03,480 --> 00:03:13,920 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. 30 00:03:13,920 --> 00:03:21,090 And we were also interested in the feasibility of whether you could give these ketamine infusions such an intravenous infusion that we were giving, 31 00:03:21,090 --> 00:03:24,720 whether we had to think about how well how you would give that. 32 00:03:24,720 --> 00:03:32,340 And the obvious place to do it was in the context of the C.T. suite while patients were having ECT. 33 00:03:32,340 --> 00:03:41,160 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. 34 00:03:41,160 --> 00:03:43,830 So it was making a virtue out of necessity, really. 35 00:03:43,830 --> 00:03:56,160 So we the patients who have had to come through to a recovery room and what we decided to do was to use one 36 00:03:56,160 --> 00:04:01,830 of the beds in one of the three beds in the recovery room for patients who were having ketamine infusions. 37 00:04:01,830 --> 00:04:07,680 And the anaesthetist would set up the infusion while he while we were treating the other people on the activist. 38 00:04:07,680 --> 00:04:11,280 Right. That's very helpful to understand the practical implications of this study. 39 00:04:11,280 --> 00:04:16,710 But I'm really interested in the fact that ketamine is actually a recreational drug 40 00:04:16,710 --> 00:04:24,240 and it's a fairly radical idea to be using ketamine in this particular situation. 41 00:04:24,240 --> 00:04:28,980 So what was the reasoning? Was the neurobiological basis for this use? 42 00:04:28,980 --> 00:04:35,100 So the original observation came from out of the basic science, actually, 43 00:04:35,100 --> 00:04:45,210 and the idea that depression may have at least part of its aetiology may be based in an abnormality of glutamate transmission. 44 00:04:45,210 --> 00:04:52,950 And ketamine is an antagonist, one of the glutamate receptors called the NMDA receptor. 45 00:04:52,950 --> 00:04:57,900 And interestingly, that's that's one of the receptors. It's particularly responsible for long term potentiation. 46 00:04:57,900 --> 00:05:07,550 In other words, the consolidation of memory. But so so the original observation actually was made about a decade ago, 47 00:05:07,550 --> 00:05:15,920 and then more recently a group at NIH in the States did a didn't ask to a small act, 48 00:05:15,920 --> 00:05:23,060 which really showed just what a dramatic effect ketamine could have in people with treatment resistant depression. 49 00:05:23,060 --> 00:05:30,200 And that was the reason that we decided it would be worth pursuing and getting some experience of that in this country. 50 00:05:30,200 --> 00:05:40,070 So it's got a sound neurobiological basis, but presumably some potential scepticism from from lots of quarters because of 51 00:05:40,070 --> 00:05:47,000 its recreational use or its potential psychedelic or hallucinogenic properties. 52 00:05:47,000 --> 00:05:52,370 Well, that's absolutely right. I mean, that the neurobiology is very exciting because recently it's been shown that ketamine 53 00:05:52,370 --> 00:06:03,500 can induce the very rapid outgrowth of dendritic the spines on the dendrites. 54 00:06:03,500 --> 00:06:08,120 So if you imagine a tree, this is the sort of terminal twigs that are, in fact, 55 00:06:08,120 --> 00:06:14,360 what made the connexions between neurones and they tend to retract in chronic depression. 56 00:06:14,360 --> 00:06:21,020 And in fact, perhaps, you know, might be the reason why you sometimes see brain volume loss in depression. 57 00:06:21,020 --> 00:06:34,400 But in the Petri dish, you can see the the neuronal cultures where the spines rapidly grow out again after with ketamine in 58 00:06:34,400 --> 00:06:39,800 a way that's dependent on a particular neurotrophic fact called brain derived neurotrophic factor. 59 00:06:39,800 --> 00:06:43,940 So the neurobiology of this is fairly rapidly being understood. 60 00:06:43,940 --> 00:06:56,570 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. 61 00:06:56,570 --> 00:07:00,710 So you talk about the recreational use of of ketamine, and you're absolutely right. 62 00:07:00,710 --> 00:07:10,130 That's that's a that's a key sort of obstacle when they ask. 63 00:07:10,130 --> 00:07:12,560 Well, it isn't actually as much of an obstacle as you'd think, 64 00:07:12,560 --> 00:07:21,170 because even even the committee that has recently rebadged the ketamine in terms of its controlled drug status, 65 00:07:21,170 --> 00:07:23,690 they said, you know, this shouldn't apply to medical research. 66 00:07:23,690 --> 00:07:27,410 So there's quite a wide recognition that, you know, ketamine, which is a very safe drug, 67 00:07:27,410 --> 00:07:32,030 it's the most widely used anaesthetic in the world with just about and very widely 68 00:07:32,030 --> 00:07:40,010 used in the Third World because it didn't have much by way of cardiovascular changes. 69 00:07:40,010 --> 00:07:45,830 So the recognition that it's safe, it's in fact some WHV drug list. 70 00:07:45,830 --> 00:07:53,300 So so, yes, there's a risk of diversion. But obviously, if you're giving it intravenously, that's not a risk. 71 00:07:53,300 --> 00:08:00,470 If you were going to give people oral ketamine, that would potentially become a risk, although, frankly, you know, 72 00:08:00,470 --> 00:08:07,710 one tends to see that if people are really benefiting from something, they'd rather not give their drug away to anybody else. 73 00:08:07,710 --> 00:08:13,520 But it isn't. But it is a risk. I think potentially the change in the situation, 74 00:08:13,520 --> 00:08:22,040 the clinical situation compared with anaesthesia is it is different because in anaesthesia you've got an unconscious patient, 75 00:08:22,040 --> 00:08:28,400 whereas you're dealing with patients who who have come in and their mood is low and they're struggling 76 00:08:28,400 --> 00:08:34,430 with day to day life and you're giving them a drug and they're experiencing potential hallucinations. 77 00:08:34,430 --> 00:08:37,860 And so, yeah, so there are side effects. And obviously it was a safety study. 78 00:08:37,860 --> 00:08:44,390 This is one of the things we want to look at and people get marked dissociative phenomena. 79 00:08:44,390 --> 00:08:48,470 So things look different, sound, sound a bit more metallic. 80 00:08:48,470 --> 00:08:57,140 People have some out of body experiences, really, and people feeling that they're detached from their body. 81 00:08:57,140 --> 00:09:02,780 And yes, as the dose goes higher than people might develop visual hallucinations. 82 00:09:02,780 --> 00:09:10,220 And certainly when people are coming around from ketamine, anaesthesia, they often have very pronounced visual hallucinations. 83 00:09:10,220 --> 00:09:15,760 The dose that you're right, that the dose that we're using is much lower than that is used anaesthetic. 84 00:09:15,760 --> 00:09:20,750 So the patients sometimes feel and do feel sleepy, have these experiences, 85 00:09:20,750 --> 00:09:26,750 but they're not they're not actually going to sleep and, you know, with the anaesthetic. 86 00:09:26,750 --> 00:09:36,860 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. 87 00:09:36,860 --> 00:09:46,050 Have you seen this? So. So what we wanted to do was to see whether if you gave ketamine infusion once a week, 88 00:09:46,050 --> 00:09:50,250 three weeks, you get any difference compared to giving it twice a week. 89 00:09:50,250 --> 00:09:56,090 Three weeks has a sort of fairly basic sort of design. 90 00:09:56,090 --> 00:09:59,710 And we just studied 12 patients in each group and. 91 00:09:59,710 --> 00:10:10,150 And essentially what we found, I mean, it was summarised, I thought, nicely by the Huffington Post headline that greeted our results, 92 00:10:10,150 --> 00:10:15,910 which was, you know, yet another trial shows that ketamine is an antidepressant. 93 00:10:15,910 --> 00:10:20,230 So, you know, that that just sort of says it. 94 00:10:20,230 --> 00:10:24,530 I mean, it is big news here in the U.K., but in the states, they are they've seen it all before. 95 00:10:24,530 --> 00:10:29,200 You know, it's nothing to do dramatic. But I have to say it was really dramatic. 96 00:10:29,200 --> 00:10:37,630 You know, some of the some of the cases, the speed of response, we found that some of them needed to infusion. 97 00:10:37,630 --> 00:10:42,040 It was quite interesting. They didn't respond to the first infusion or they had a sort of sense of something. 98 00:10:42,040 --> 00:10:50,440 But the second infusion, several patients who was at that point, that several patients really had a clearly very marked effect on their treatment. 99 00:10:50,440 --> 00:10:58,060 These people have been ill for many, many years, often were extremely disabled. 100 00:10:58,060 --> 00:11:04,330 And, you know, it was it was it was absolutely. 101 00:11:04,330 --> 00:11:11,860 And I was like Awakening's spine tingling that the Awakenings book by Oliver Sacks was right. 102 00:11:11,860 --> 00:11:17,260 Yeah. Wow. So this is very dramatic effect from from these ketamine infusions, actually. 103 00:11:17,260 --> 00:11:21,580 Did they did they report any problems with having the treatment? 104 00:11:21,580 --> 00:11:25,840 So so I mean, how you having said that, you know, there were some patients who responded dramatically. 105 00:11:25,840 --> 00:11:32,020 There were some who didn't respond at all. Right. So it was rather clear sort of dichotomy there. 106 00:11:32,020 --> 00:11:37,660 And we don't know how to predict who's going to respond and who isn't. 107 00:11:37,660 --> 00:11:44,440 There may be genetic determinants of that. There's a single nucleotide polymorphism that might predict that. 108 00:11:44,440 --> 00:11:54,380 And in fact, it's related to be DNF. So, so so some patients benefited, some didn't have. 109 00:11:54,380 --> 00:11:59,140 The duration of the response was very variable as well. 110 00:11:59,140 --> 00:12:01,100 And that was interesting. Unlikely. 111 00:12:01,100 --> 00:12:10,450 You know, and like all the other studies we've done that were done to that time, we kept people on their existing antidepressants. 112 00:12:10,450 --> 00:12:18,340 So that was another aspect of the safety study, is how what would happen if you gave ketamine on top of other antidepressants? 113 00:12:18,340 --> 00:12:23,140 And if anything, it seemed to prolong the response. But even then, you know, 114 00:12:23,140 --> 00:12:27,940 we have we had one patient who who's who had a few infusions and they had a response 115 00:12:27,940 --> 00:12:32,350 that lasted nine months before they relapsed at several that lasted for months. 116 00:12:32,350 --> 00:12:38,590 A couple that lasted one month is sort of this sort of thing. So about 30. 117 00:12:38,590 --> 00:12:44,080 So most people most people don't have prolonged benefit from from ketamine. 118 00:12:44,080 --> 00:12:52,360 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. 119 00:12:52,360 --> 00:13:01,300 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, 120 00:13:01,300 --> 00:13:10,900 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. 121 00:13:10,900 --> 00:13:18,610 So although it's dramatic, it's it's it's often quite short. 122 00:13:18,610 --> 00:13:23,140 But there is this group that has a much more prolonged response, and that's very interesting. 123 00:13:23,140 --> 00:13:28,360 Yeah. Is there some further research potentially being thought about or I mean, 124 00:13:28,360 --> 00:13:33,670 obviously this is, you know, how can you how could you how could you sustain the response? 125 00:13:33,670 --> 00:13:42,220 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. 126 00:13:42,220 --> 00:13:47,270 And we know that it's going to be a clinical, you know, life changing benefit for them. 127 00:13:47,270 --> 00:14:03,310 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. 128 00:14:03,310 --> 00:14:11,230 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, 129 00:14:11,230 --> 00:14:15,600 you can certainly understand the issues and understand particularly the the 130 00:14:15,600 --> 00:14:21,910 level of ignorance that we're at and that some of these things are by nature, 131 00:14:21,910 --> 00:14:27,360 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. 132 00:14:27,360 --> 00:14:36,160 So we've always been interested in in in other NMDA related drugs and in particular those that promote transmission through the AMP receptor, 133 00:14:36,160 --> 00:14:41,350 which is one of the other glutamate receptors. And at a neurobiological level, 134 00:14:41,350 --> 00:14:53,700 what seems to be seems to maintain the dendritic spine and growth is the is the movement for receptors from 135 00:14:53,700 --> 00:14:59,890 a sort of more peripheral position in the sign abs to a more central one that seems to be involved in the. 136 00:14:59,890 --> 00:15:07,150 Potentiation, consolidation of that of that synaptic transmission, so so we I mean, 137 00:15:07,150 --> 00:15:13,270 you know, it's one thing to have to move shampooer receptors around its finances. 138 00:15:13,270 --> 00:15:17,830 But, you know, we have all we have is drugs that we can give people and see what they do. 139 00:15:17,830 --> 00:15:31,330 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. 140 00:15:31,330 --> 00:15:35,240 But but of course, these are you know, we've done it in very small numbers of patients. 141 00:15:35,240 --> 00:15:43,420 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. 142 00:15:43,420 --> 00:15:51,880 And of course, you have this problem with the electroconvulsive therapy of rapid dramatic responses. 143 00:15:51,880 --> 00:16:02,780 The time limited responses and and the sort of therapeutic response to that has been to ensure adequate medication to the prolongs response. 144 00:16:02,780 --> 00:16:06,430 Yes, you are using that as a template for this sort of. 145 00:16:06,430 --> 00:16:13,840 Yeah, that's right. That's right. I mean, about 50 percent people who have ECT relapse into responded relapse within six months. 146 00:16:13,840 --> 00:16:22,850 So it's not great, but it's better than the alternative, which we can go with with psychological drug treatment. 147 00:16:22,850 --> 00:16:26,860 Rupert, it's been really interesting hearing about your study on ketamine. 148 00:16:26,860 --> 00:16:32,050 And it's I think there's a lot that you have yet to discover. 149 00:16:32,050 --> 00:16:36,040 And it's interesting to hear your your current thoughts on that on that area. 150 00:16:36,040 --> 00:16:39,370 But thank you for taking the time to speak to me today. Thank you. 151 00:16:39,370 --> 00:16:43,170 Yeah. It's it's it's incredibly exciting. I can't tell you how exciting it is, you know, 152 00:16:43,170 --> 00:16:48,840 this sort of thing that makes it worth really worth doing psychiatry and seeing people like this get better so dramatically. 153 00:16:48,840 --> 00:16:55,350 It's just incredible. I think it's a common fallacy about psychiatry is that not that you don't see patients getting better. 154 00:16:55,350 --> 00:16:59,560 Yeah, I mean, I'm very lucky in that this is really dramatic. But, yes, you're right. 155 00:16:59,560 --> 00:17:06,040 You know, there's nothing better than, you know, treating people with any sort of any sort of paradigm and then coming back. 156 00:17:06,040 --> 00:17:13,360 Grateful. Yes. Oh, thank you for that report. And thank you for tuning in to the Oxford University Psychiatry podcast series. 157 00:17:13,360 --> 00:17:16,042 Please do tune in again.