1 00:00:00,210 --> 00:00:07,020 Welcome to the Oxford University Psychology Podcast series. My name is Daniel Maun and I've got Professor Phil Cohen here with me today. 2 00:00:07,020 --> 00:00:14,940 Thank you for coming, Phil. Thanks for the invitation. It's really good to have you because you've done some really interesting work over the past, 3 00:00:14,940 --> 00:00:19,200 well, several years, really, and very engaged in psychopharmacology. 4 00:00:19,200 --> 00:00:25,050 And your particular area of interest is an antidepressant medication is basically the treatment of mood disorders, 5 00:00:25,050 --> 00:00:28,440 particularly depression doesn't respond well to other treatments. 6 00:00:28,440 --> 00:00:34,770 OK, and well, could you just begin by telling us what your main areas of interest are in that field, 7 00:00:34,770 --> 00:00:46,440 as is trying to understand how the medicines might work, try to understand what the underlying pathophysiology is of the condition, 8 00:00:46,440 --> 00:00:54,570 why some depressed people don't seem to recover as well as one would like, and then trying to come up with new treatments, 9 00:00:54,570 --> 00:01:00,870 maybe pharmacological in my particular case, that might be helpful in patients with that kind of problem. 10 00:01:00,870 --> 00:01:02,400 When you talk about depression. 11 00:01:02,400 --> 00:01:10,990 Do you see it as a unified entity or do you see depression as an umbrella diagnosis of which there are sort of many conditions within that? 12 00:01:10,990 --> 00:01:17,700 I think it must be like that, that it's a common condition. 13 00:01:17,700 --> 00:01:25,530 The features are fairly variable. And I suppose when when you're a psychiatrist, you tend to work in one particular area. 14 00:01:25,530 --> 00:01:33,090 So people who have quite severe depression, quite disabled by it, are not doing well with first line treatment. 15 00:01:33,090 --> 00:01:38,400 So you have that particular group in mind when you work as a psychiatrist. 16 00:01:38,400 --> 00:01:43,620 So you're working at the more severe end of the spectrum compared to perhaps what most people 17 00:01:43,620 --> 00:01:48,000 might have encountered in their daily life with people they know who might have been depressed. 18 00:01:48,000 --> 00:01:57,540 You you're thinking that the people you see are perhaps more functionally impaired or does it look different? 19 00:01:57,540 --> 00:02:03,420 Is the character or nature of the condition particularly different? Is there something you look at or. 20 00:02:03,420 --> 00:02:11,970 I think that that's that's right, because depression is very common and often treated very successfully in primary care. 21 00:02:11,970 --> 00:02:20,550 And so people would respond to psychological treatments, maybe FirstLine antidepressant medication, if that was necessary. 22 00:02:20,550 --> 00:02:27,930 So I'd say that the people that I would see in most psychiatrists, the depression would be unremitting. 23 00:02:27,930 --> 00:02:34,560 And that's a feature which causes a lot of distress for the patients, because if you're depressed, 24 00:02:34,560 --> 00:02:39,240 you often feel things aren't going to improve and this is confirmation of it. 25 00:02:39,240 --> 00:02:44,430 So it's severe, it's long standing and it seems very hard to shift. 26 00:02:44,430 --> 00:02:49,140 Certainly true. As you said, in those circumstances, it can be functionally disabling. 27 00:02:49,140 --> 00:02:59,760 So people who are often very capable, very accomplished, find that they can't work properly and their personal lives are extremely disrupted. 28 00:02:59,760 --> 00:03:06,750 We've had antidepressants for over 50 years now as a psychiatrist who been using them effectively in many cases, 29 00:03:06,750 --> 00:03:15,930 whereas the sort of the the front line not advancing area in antidepressants research at the moment, 30 00:03:15,930 --> 00:03:26,850 I think the main advances in my professional career have been the fact that more antidepressants are available and they're safe and better tolerated, 31 00:03:26,850 --> 00:03:30,870 but by themselves, they're not necessarily more effective than the older ones. 32 00:03:30,870 --> 00:03:36,300 So the failure to make more effective treatments has been a disappointment. 33 00:03:36,300 --> 00:03:43,440 On the other hand, because more drugs are available, you could usually find something that suits an individual. 34 00:03:43,440 --> 00:03:54,180 Moreover, it gives a chance for treatment combinations, and some patients with resistant depression seem to respond to that approach. 35 00:03:54,180 --> 00:04:06,060 So I think practically we're doing better, but individually we haven't really got a drug that's made a huge difference in terms of effectiveness. 36 00:04:06,060 --> 00:04:12,480 You've done some work into the effects of ketamine on people with with depression. 37 00:04:12,480 --> 00:04:20,370 I was wondering whether you could tell us a bit about that. Yes, that's an interesting development. 38 00:04:20,370 --> 00:04:26,940 And we started from observations made in the United States that intravenous ketamine, 39 00:04:26,940 --> 00:04:37,530 which is a widely used anaesthetic and has been used as a model for various psychiatric disorders when given to patients with acute depression, 40 00:04:37,530 --> 00:04:48,270 made them feel much better, essentially back to normal about an hour or two after the infusion of a sub anaesthetic dose, 41 00:04:48,270 --> 00:04:54,360 particularly intriguingly, in about half the patients, that effect persisted for a few days. 42 00:04:54,360 --> 00:04:59,250 So it was a striking effect because normally anti-depressants take a long time to work. 43 00:04:59,250 --> 00:05:06,630 Several weeks. They don't work that fast, therefore, and no one can imagine treatments that work quickly. 44 00:05:06,630 --> 00:05:14,790 For example, sleep deprivation sometimes use in that way. It's unusual for a quick acting effect to be sustained. 45 00:05:14,790 --> 00:05:22,800 Further, ketamine pharmacologically works in a very different way from our standard antidepressant treatment. 46 00:05:22,800 --> 00:05:28,070 It blocks a kind of glutamate receptor. 47 00:05:28,070 --> 00:05:35,220 So it's another neurotransmitter from the ones we normally think about in terms of antidepressant action. 48 00:05:35,220 --> 00:05:40,260 And therefore it may provide clues to a whole new class of anxiety depressants, 49 00:05:40,260 --> 00:05:47,090 which, as I was saying, we badly need to improve on what we're doing at the moment. 50 00:05:47,090 --> 00:05:51,690 That's really interesting. And have you seen any? Well, 51 00:05:51,690 --> 00:05:58,710 has there been any evidence suggesting that ketamine is potentially an effective 52 00:05:58,710 --> 00:06:03,390 antidepressant that has an effect that lasts longer than a few days before, 53 00:06:03,390 --> 00:06:10,890 tried various ways to extend the effects? They've tried giving courses of treatment and they've tried using orally 54 00:06:10,890 --> 00:06:20,310 administered glutamate like drugs in the hope of extending the effects of ketamine. 55 00:06:20,310 --> 00:06:25,050 My own experiences thus far, that's not been as successful as one would like. 56 00:06:25,050 --> 00:06:33,270 And so I was left with a tantalising position that you can get people out of severe depression for a for a few days or a week, 57 00:06:33,270 --> 00:06:38,550 but you're not confident you'll be able to sustain it. And that's a major problem. 58 00:06:38,550 --> 00:06:46,470 Thank you. And you've touched on on an issue in in in depression as a psychiatrist, 59 00:06:46,470 --> 00:06:54,540 which is that we have lots of drugs at our disposal now that we can use to help patients with that depression. 60 00:06:54,540 --> 00:07:00,060 But often there's there's not much difference in the in the efficacy or the effectiveness of that medication. 61 00:07:00,060 --> 00:07:04,380 There's often quite different side effect profiles. Yes. 62 00:07:04,380 --> 00:07:14,930 Is there is there anything you could advise people who are beginning to psychiatrists who are beginning treatment of somebody with depression? 63 00:07:14,930 --> 00:07:21,810 Were there any particular class of drugs you suggest to begin with? And what's your standard sort of approach? 64 00:07:21,810 --> 00:07:27,300 Well, I think for most of us now, the early stages of treatment are set by guidelines. 65 00:07:27,300 --> 00:07:37,380 So if you read something like the nice guidelines, it'll tell you what circumstances to think about medication and then what you might use first line. 66 00:07:37,380 --> 00:07:42,690 And so that's tackled very competently by GPS, usually for psychiatrists. 67 00:07:42,690 --> 00:07:44,670 As I said, you're a bit further down the line. 68 00:07:44,670 --> 00:07:51,060 People often tried a psychological treatment, perhaps a couple of the standard first line antidepressants, 69 00:07:51,060 --> 00:07:55,740 such as the SSRI locksmithing, drugs like that. 70 00:07:55,740 --> 00:08:00,840 And so we're then left in that position wondering what to do next. 71 00:08:00,840 --> 00:08:08,250 And I think you'd have to say that the treatment guidelines tend to be based on trials, 72 00:08:08,250 --> 00:08:12,870 evidence, and there's not a lot of evidence about next step treatments. 73 00:08:12,870 --> 00:08:23,040 So this is where your clinical experience and your knowledge of the patient becomes absolutely paramount. 74 00:08:23,040 --> 00:08:31,320 And what is it about the patient that helps you? What kind of things do you look for in a patient that helps you make those clinical decisions? 75 00:08:31,320 --> 00:08:36,600 I think there are a number of aspects, obviously, in any psychiatric consultation. 76 00:08:36,600 --> 00:08:45,990 One of the fascinating things is that you have to live in a sort of first person world trying to access the experience of the individual and also 77 00:08:45,990 --> 00:08:58,140 somehow synthesise that or fuse that with a third person scientific notion of what's going on perhaps at a neurochemical neuropsychological level. 78 00:08:58,140 --> 00:09:02,160 And that's one of the challenges, one of the excitements of doing psychiatry. 79 00:09:02,160 --> 00:09:08,880 So the first thing is to make a good emotional connexion with the patient, to really understand what their experiences are, 80 00:09:08,880 --> 00:09:17,490 to put this depression in the context of their life, and actually particularly helpful to get an idea of what's not right now. 81 00:09:17,490 --> 00:09:22,200 What would they be like if they were, well, how are things gone when they were? 82 00:09:22,200 --> 00:09:29,400 Well, that way you can't get a notion of how much it looks like an illness that somebody should be able to make a good recovery from. 83 00:09:29,400 --> 00:09:33,840 Often seeing a partner or friend is very helpful in that sort of situation. 84 00:09:33,840 --> 00:09:38,790 So that's the first thing, a really thorough assessment at a psychological level. 85 00:09:38,790 --> 00:09:49,530 Have you done any research on on this sort of level of clinical decision making on particular drugs that happen in particular circumstances? 86 00:09:49,530 --> 00:09:51,180 You've done some work with a. 87 00:09:51,180 --> 00:09:57,600 Medicine and and things like that with that lead you into making a decision in a particular circumstance with the patient. 88 00:09:57,600 --> 00:10:07,080 Well, that's been that's. Been a goal of many researchers and many research authorities to try and 89 00:10:07,080 --> 00:10:13,560 stratify patients to try and work out what treatments should you give someone, 90 00:10:13,560 --> 00:10:19,860 because there are many different drugs with slightly different pharmacological mechanisms. 91 00:10:19,860 --> 00:10:27,990 And often you just have to go through things in a careful empirical way. 92 00:10:27,990 --> 00:10:30,300 And that can take several weeks or months, 93 00:10:30,300 --> 00:10:36,150 which obviously is very disheartening to someone who's depressed anyway and is rather despairing about the future. 94 00:10:36,150 --> 00:10:40,890 If there was a way we could identify what to use, that will be fantastic. 95 00:10:40,890 --> 00:10:49,650 But at the moment, the current treatments we've got, the current investigations, brain imaging, Gene's clinical characteristics, 96 00:10:49,650 --> 00:10:55,170 not terribly helpful in trying to predict what someone's actually going to be helped by, 97 00:10:55,170 --> 00:11:01,710 but that's an area where there needs to be substantial progress. So in a sense, 98 00:11:01,710 --> 00:11:08,220 we are in a position where the crucial part of of of clinical decision making and a 99 00:11:08,220 --> 00:11:12,150 lot of the research that you've done over the years has really pointed to the fact 100 00:11:12,150 --> 00:11:20,790 that we need a an accurate and sort of personal engagement with the patient to 101 00:11:20,790 --> 00:11:25,590 really understand their situation and then to make decisions based based on that. 102 00:11:25,590 --> 00:11:39,930 Yeah, there are the old fashioned medications tricyclic antidepressants and the modern modern medications, serotonin based medications. 103 00:11:39,930 --> 00:11:46,560 Do you feel, looking back, that we've I know you said there's no there's no benefit in effectiveness, 104 00:11:46,560 --> 00:11:55,680 but do you think we've we've come a long way since then? I think the point of view of treating a broader range of people with depression, 105 00:11:55,680 --> 00:12:07,170 we probably have my own feeling is actually probably because I'm fairly elderly now that the tricyclics are still a little bit more effective, 106 00:12:07,170 --> 00:12:13,620 but they're hard to take and they're dangerous in overdose. So they're not easy to use over. 107 00:12:13,620 --> 00:12:19,050 The SSRI are effective for many patients in primary care. 108 00:12:19,050 --> 00:12:22,020 They're much easier to take. They're safer. 109 00:12:22,020 --> 00:12:35,010 And so that is a kind of useful, practical advance in treatment, even though they may not be any better than the older ones in terms of effectiveness. 110 00:12:35,010 --> 00:12:39,510 So we've talked a lot about the clinical aspects of how clinical decision making has changed. 111 00:12:39,510 --> 00:12:45,900 And in a sense, we have a lot more options for treating a lot a lot of different types of people. 112 00:12:45,900 --> 00:12:52,050 In what ways is the knowledge developed? We've we've we've grown rapidly in our ability to image the brain, 113 00:12:52,050 --> 00:12:57,400 our ability to understand all the different neurochemicals and the synaptic processes that are going on. 114 00:12:57,400 --> 00:13:06,320 What do you think are the really real advanced advances in not in knowledge about about your your work? 115 00:13:06,320 --> 00:13:11,550 I think we're much more sophisticated in our understanding of what the problem represents, 116 00:13:11,550 --> 00:13:16,530 even though sometimes that just makes you realise how little you actually do know. 117 00:13:16,530 --> 00:13:22,260 But it's certainly changed from when I was training in the sense people thought in terms of a single neurotransmitter 118 00:13:22,260 --> 00:13:29,870 causing depression to little serotonin to the adrenaline or a particular brain region causing depression. 119 00:13:29,870 --> 00:13:36,330 I think what we have now is a much more sophisticated understanding of the neural circuitry that underpins depression, 120 00:13:36,330 --> 00:13:42,150 the distributed circuitry that seems to somehow express emotional distress, 121 00:13:42,150 --> 00:13:49,650 and the way that the neurochemistry maps onto neuropsychology, what serotonin actually doing in terms of people's experience, 122 00:13:49,650 --> 00:13:56,370 how does boosting serotonin change neuropsychological processes that can lead people to feel better? 123 00:13:56,370 --> 00:14:02,850 So I think we've got a fuller understanding is easier to talk to people about what you think is going wrong. 124 00:14:02,850 --> 00:14:09,960 Unfortunately, it hasn't led to new pharmacological treatments yet because this is a distributed circuitry 125 00:14:09,960 --> 00:14:15,780 and more integrated understanding doesn't necessarily finger a particular molecule. 126 00:14:15,780 --> 00:14:24,270 I think in a way might be more helpful for improving psychological treatments because they probably do work more at a systems level. 127 00:14:24,270 --> 00:14:29,190 And perhaps understanding what's going wrong with the neuropsychological system might 128 00:14:29,190 --> 00:14:34,040 eventually lead to more targeted psychological treatments involving brain training. 129 00:14:34,040 --> 00:14:41,560 I could see that actually as being an outcome while we still struggle on to try and improve pharmacological treatment. 130 00:14:41,560 --> 00:14:48,540 Okay. There was a recent editorial by John Kerry's, amongst others in the BJP site, 131 00:14:48,540 --> 00:14:58,440 looking at how perhaps we need to change the way we think about classifying bipolar disorder based on their response to lithium therapy. 132 00:14:58,440 --> 00:15:05,760 Yes. And I wonder whether you. Do you think that the there is a case for that in depression, 133 00:15:05,760 --> 00:15:13,350 because some people that they they might they might argue whether they are depressed or not or they might 134 00:15:13,350 --> 00:15:19,410 there might be some discussion about whether that they they have a particular type of depression or not. 135 00:15:19,410 --> 00:15:26,550 And I wonder whether there would be a case for perhaps phenomenologically or or or 136 00:15:26,550 --> 00:15:33,330 diagnostically of the condition better because of their response to a particular antidepressant. 137 00:15:33,330 --> 00:15:41,250 Yes, I think that's a very interesting idea. We keep trying to stratify, to classify, to understand people, 138 00:15:41,250 --> 00:15:49,350 because if we can distinguish very different kinds of disorder under this umbrella depression, we probably will be able to improve treatment. 139 00:15:49,350 --> 00:15:59,100 And it's interesting that the conventional ways of doing it by various clinical presentations, by genes, family history hasn't been very successful. 140 00:15:59,100 --> 00:16:04,530 So doing it in terms of treatment response is very intriguing idea and seems to 141 00:16:04,530 --> 00:16:08,640 me at a practical level to fit in with what people might do clinically anyway. 142 00:16:08,640 --> 00:16:19,650 So I'm in favour of it. And just just before we go, Phil, could you tell us a bit about what your thoughts are about being an academic psychiatrist? 143 00:16:19,650 --> 00:16:22,830 And have you enjoyed your of you enjoyed your career? 144 00:16:22,830 --> 00:16:29,940 Oh, I think I've been enormously lucky because you're dealing with the most important and interesting problems. 145 00:16:29,940 --> 00:16:35,070 As I said, it's this combination of being able to engage in people's experience, 146 00:16:35,070 --> 00:16:46,410 to have the privilege of understanding someone's life history with them and at the same time fusing that with a third person scientific objective, 147 00:16:46,410 --> 00:16:51,390 trying to help them both at a personal level and through scientific approaches. 148 00:16:51,390 --> 00:16:56,460 I can't think of anything which would be more rewarding. Well, thank you very much. 149 00:16:56,460 --> 00:17:00,900 Thank you for coming. And thank you for tuning in to the Oxford University Psychiatry Focus series. 150 00:17:00,900 --> 00:17:03,112 We hope you listen to some more. Thank you.