WEBVTT - Ep48 "Why do brains become depressed?" 0:00:05.160 --> 0:00:09.639 What is depression and why are brains so easily able 0:00:09.680 --> 0:00:14.640 to slip into it? Is depression detectable in animals? And 0:00:14.720 --> 0:00:17.000 when we look across the animal kingdom do we see 0:00:17.239 --> 0:00:21.079 options beyond fight or flight? And what does any of 0:00:21.120 --> 0:00:25.560 this have to do with measuring depression medications in city 0:00:25.600 --> 0:00:29.560 water supplies, or reward pathways in the brain, or the 0:00:29.600 --> 0:00:33.920 prevalence of tuberculosis or zapping the head with magnetic stimulation. 0:00:37.280 --> 0:00:39.879 Welcome to Inner Cosmos with me David Eagleman. 0:00:40.000 --> 0:00:42.960 I'm a neuroscientist and an author at Stanford and in 0:00:43.000 --> 0:00:47.199 these episodes we sail deeply into our three pound universe 0:00:47.520 --> 0:00:51.000 to understand why and how our lives look the way 0:00:51.000 --> 0:01:04.320 they do. Today's episode is about depression. We are going 0:01:04.360 --> 0:01:07.080 to dive into the science behind it and we'll see 0:01:07.360 --> 0:01:09.200 what new solutions are. 0:01:09.000 --> 0:01:12.760 On the horizon. So let me start by assuming way out. 0:01:13.360 --> 0:01:17.039 What fascinates me is not just what the brain can 0:01:17.080 --> 0:01:21.560 accomplish in terms of our normal functioning, but also one 0:01:21.640 --> 0:01:25.200 can't help but notice the fragility of the brain. 0:01:25.319 --> 0:01:28.160 I mean, just think about how easy it is to 0:01:28.280 --> 0:01:30.800 lose consciousness when you hit your head. 0:01:30.880 --> 0:01:35.160 Or think about what happens when you drink alcohol and 0:01:35.240 --> 0:01:39.000 your perception and your decision making changes, or you don't 0:01:39.040 --> 0:01:41.760 get enough sleep, and how you behave and how you 0:01:41.840 --> 0:01:44.960 decide these can become a little different. Or when you're 0:01:45.120 --> 0:01:48.840 angry and you act differently, or if you consume psychedelic 0:01:48.920 --> 0:01:53.480 drugs and your conscious experience changes entirely. What all this 0:01:53.760 --> 0:01:56.440 tells us, I think, is that it's very easy for 0:01:56.520 --> 0:02:00.680 the system to get knocked off its normal pathway. And 0:02:00.720 --> 0:02:03.919 what's clear is that the brain puts an enormous amount 0:02:03.960 --> 0:02:10.480 of effort into trying to stay operating in the normal range. Now, 0:02:10.520 --> 0:02:15.760 given this context, one area that's fascinating and of massive 0:02:15.880 --> 0:02:18.560 social importance is depression. 0:02:19.240 --> 0:02:21.120 This is a mood disorder. 0:02:21.160 --> 0:02:24.120 It affects how you feel, how you think, how you 0:02:24.440 --> 0:02:28.200 handle your daily tasks, how you eat and sleep. People 0:02:28.240 --> 0:02:40.359 with depression feel persistently sad. They often feel empty or anxious, pessimistic, hopeless, worthless, helpless, 0:02:40.800 --> 0:02:43.760 and they lose interest in the things that used to 0:02:43.800 --> 0:02:47.520 bring them joy. They're slowed down in all the aspects 0:02:47.560 --> 0:02:52.240 of their life, and often there are thoughts of suicide. Now, 0:02:52.400 --> 0:02:55.720 almost everyone has had someone in their life who has 0:02:55.720 --> 0:02:59.280 suffered depression at some point, whether that's recognized or not. 0:03:00.160 --> 0:03:05.120 And generally everyone's first intuition when they have a friend 0:03:05.240 --> 0:03:08.640 or a loved one who becomes depressed is to talk 0:03:08.680 --> 0:03:11.840 them out of it, to say, hey, things are okay, 0:03:12.440 --> 0:03:14.840 snap out of it, look at the bright side. And 0:03:14.880 --> 0:03:18.360 eventually you might be tempted to say, come on, just 0:03:18.600 --> 0:03:23.320 toughen up. But the important lesson from centuries of psychiatry 0:03:23.320 --> 0:03:26.800 and more recently neuroscience is that it's not so easy. 0:03:27.040 --> 0:03:30.680 It's a physical problem. And that's why we talk about 0:03:31.120 --> 0:03:35.160 mental illness nowadays exactly as we talk about a physical 0:03:35.480 --> 0:03:40.040 illness like COVID or a broken leg, and that understanding 0:03:40.520 --> 0:03:45.360 opens the door to different approaches, because a physical problem 0:03:45.920 --> 0:03:52.080 invites physical solutions. Now, my father was a psychiatrist, and 0:03:52.200 --> 0:03:55.720 he was always impressed that he could have a patient 0:03:56.080 --> 0:03:59.760 who would be suffering from clinical depression and would lose 0:03:59.800 --> 0:04:02.240 his job and maybe lose his spouse, and my father 0:04:02.320 --> 0:04:06.240 can make a prescription like let's say prozac, and that 0:04:06.400 --> 0:04:09.640 patient often could get out of bed again and then 0:04:09.680 --> 0:04:13.160 get his job back and win his spouse back. Now, 0:04:13.200 --> 0:04:15.720 how do we understand this, Well, it's an issue that 0:04:15.760 --> 0:04:18.120 I talk about a lot, which is that we are 0:04:18.240 --> 0:04:21.840 made up of small pieces and parts, And the thing 0:04:21.880 --> 0:04:25.520 to appreciate is that you are the sum total of 0:04:25.560 --> 0:04:26.679 all those pieces and parts. 0:04:26.720 --> 0:04:27.760 Whatever is going on. 0:04:28.160 --> 0:04:32.839 At this microscopic level is you and your mood and 0:04:32.880 --> 0:04:37.200 your behavior. Now, why would anybody think that crazy statement 0:04:37.279 --> 0:04:40.280 is true. Well, there are many things that we see 0:04:40.279 --> 0:04:43.360 in the clinics every day which teach us this lesson. 0:04:43.920 --> 0:04:46.960 People can get damage to their brains and they can 0:04:47.000 --> 0:04:50.440 no longer understand how to use a mirror, or they 0:04:50.480 --> 0:04:54.080 can no longer name furry animals, or they can no 0:04:54.160 --> 0:04:59.560 longer see colors, or understand speech, or understand music or 0:04:59.720 --> 0:05:02.480 any We have a million other things that we think 0:05:02.560 --> 0:05:05.400 should just come for free in the world. Now, what 0:05:05.480 --> 0:05:09.320 this exposes is that these are functions of the brain, 0:05:09.560 --> 0:05:12.200 and even if a little bit of the brain is damaged, 0:05:12.680 --> 0:05:16.800 then you can't perform that function anymore. Now, many of 0:05:16.839 --> 0:05:20.039 the sorts of brain damage that you'll read about in 0:05:20.160 --> 0:05:22.440 an exciting book about the brain, these are things that 0:05:22.880 --> 0:05:27.080 most people won't see in their lifetimes. They won't know 0:05:27.279 --> 0:05:30.560 any friend or relative who has these issues because they 0:05:30.600 --> 0:05:34.560 are rare things to happen, and they usually involve damage 0:05:34.560 --> 0:05:37.840 to a region of the brain from a tumor or 0:05:37.880 --> 0:05:41.159 a stroke or a traumatic brain injury, and those things 0:05:41.240 --> 0:05:44.919 represent big changes in the city of the brain, like 0:05:45.279 --> 0:05:48.400 an entire block of New York City falling in an earthquake. 0:05:49.320 --> 0:05:51.760 But there are much more subtle things that happen in 0:05:51.760 --> 0:05:54.480 the brain as well, and these are changes that have 0:05:54.560 --> 0:05:57.760 to do with the way the system runs, with its 0:05:58.080 --> 0:06:02.360 tens of billions of neurons and trillions of synaptic connections. 0:06:03.080 --> 0:06:06.240 So to return to the city analogy, imagine that instead 0:06:06.240 --> 0:06:09.480 of big damage that you can see, the city still 0:06:09.839 --> 0:06:13.200 looks the same, but parts of it are operating very 0:06:13.440 --> 0:06:18.960 subtly differently. So the playwrights have all quit, and the 0:06:19.000 --> 0:06:23.440 city planners have stopped planning, and the coffee shops are 0:06:23.440 --> 0:06:27.760 closing two hours earlier, and all of this stuff impedes 0:06:27.880 --> 0:06:32.119 the city's ability to thrive and be an active, well 0:06:32.200 --> 0:06:36.520 functioning place for innovation and tourism. But it's all very subtle, 0:06:37.240 --> 0:06:39.919 and if you looked at this from a drone flying 0:06:39.960 --> 0:06:42.640 over the city, you really wouldn't see much of a difference. 0:06:42.760 --> 0:06:47.159 It's small stuff that's happening at a small level, but 0:06:47.720 --> 0:06:52.520 it changes the way that the city operates. And again, 0:06:52.880 --> 0:06:56.520 who you are and how you see, the world comes 0:06:56.560 --> 0:06:59.760 from the way that the city of your brain is operating. 0:07:00.200 --> 0:07:03.120 In other words, the sum total of what's happening under 0:07:03.120 --> 0:07:07.000 the hood your biology. And I think the reason this 0:07:07.120 --> 0:07:11.400 is surprising is because we tend to think of ourselves 0:07:11.440 --> 0:07:15.360 as being removed from our biology. You are separate from 0:07:15.440 --> 0:07:21.080 it or able to ride above it. So if you've 0:07:21.160 --> 0:07:24.760 ever known someone with depression, or had depression yourself, you 0:07:24.800 --> 0:07:27.640 will know that you can't just say hey, come on, 0:07:27.880 --> 0:07:31.240 cheer up, snap out of it. That doesn't suffice to 0:07:31.520 --> 0:07:37.280 change the biology. And one of the most pervasive and 0:07:37.480 --> 0:07:41.960 societally important examples of these kind of subtle changes to 0:07:42.040 --> 0:07:46.200 the brain is with depression. And so for this episode, 0:07:46.600 --> 0:07:49.800 I decided to call my colleague Jonathan Downer, who is 0:07:50.120 --> 0:07:54.920 an incredibly insightful and empathic observer of the brain. He 0:07:54.960 --> 0:07:58.400 has an MD and specializes in psychiatry, and he also 0:07:58.440 --> 0:08:02.040 has a PhD in neurosci and one of his areas 0:08:02.040 --> 0:08:06.280 of expertise is depression. And as it turns out, Jonathan 0:08:06.280 --> 0:08:10.160 and I wrote a textbook together on cognitive neuroscience called 0:08:10.200 --> 0:08:13.560 Brain and Behavior, and this is the textbook used at 0:08:13.600 --> 0:08:17.400 Stanford and at universities worldwide. And the textbook covers a 0:08:17.400 --> 0:08:20.080 lot of ground, but for today, I just want to 0:08:20.200 --> 0:08:23.840 zoom in on depression. So I rang him up to 0:08:23.880 --> 0:08:26.559 get his perspective on this issue that is not only 0:08:27.000 --> 0:08:32.679 neuroscientifically important and fascinating, but also, unlike the strange deficits 0:08:32.679 --> 0:08:35.520 that you might see only in a textbook, you almost 0:08:35.559 --> 0:08:38.920 certainly know someone with depression, perhaps someone close to you, 0:08:39.080 --> 0:08:40.120 or perhaps yourself. 0:08:40.480 --> 0:08:43.640 It's a shockingly common challenge. 0:08:43.960 --> 0:08:52.079 So let's dive in to understand it. So, Jonathan, how 0:08:52.080 --> 0:08:54.600 did you get interested in studying depression? 0:08:55.800 --> 0:08:58.920 Well, it's a bit of an interesting story, David. You'd 0:08:58.920 --> 0:09:01.559 have to go back about years too. When I was 0:09:01.600 --> 0:09:04.880 a graduate student over at the Toronto Western Hospital. That 0:09:05.040 --> 0:09:08.120 is a hospital that has a i guess a major 0:09:08.240 --> 0:09:12.720 neurosurgical unit where they perform surgeries where they implant deep 0:09:12.720 --> 0:09:15.920 brain stimulators, which are a bit like brain pacemakers, into 0:09:15.920 --> 0:09:18.840 the brains of people with Parkinson's disease and other kinds 0:09:18.840 --> 0:09:22.400 of neurological disorders. And in a round two thousand and two, 0:09:22.520 --> 0:09:25.160 a patient came in who was a middle aged woman 0:09:25.240 --> 0:09:28.720 who had previously suffered from depression but no longer. She 0:09:28.840 --> 0:09:31.120 was coming in to have the deep brain stimulators implanted 0:09:31.240 --> 0:09:34.439 for her Parkinson's disease. They implanted the electrodes, one on 0:09:34.440 --> 0:09:37.320 one side and one on the other, and during the 0:09:37.320 --> 0:09:39.520 surgery they turned them on to make sure that they 0:09:39.559 --> 0:09:43.000 are succeeding in reducing the person's hand tremors or the 0:09:43.040 --> 0:09:45.880 other tremors in their body that they're trying to have treated. 0:09:46.600 --> 0:09:48.800 What was interesting is when they turned on the one 0:09:48.840 --> 0:09:52.200 on one side, the opposite hands started to reduce in 0:09:52.240 --> 0:09:54.240 its tremor and the tremor went away, which is exactly 0:09:54.320 --> 0:09:57.040 what they expected to happen. On the other side, there 0:09:57.080 --> 0:09:59.040 was something very strange happened as soon as they turned 0:09:59.080 --> 0:10:01.920 it on. Nothing Hahigh up into her tremor whatsoever, and 0:10:01.960 --> 0:10:08.840 instead she descended instantly into a deep despairing re experiencing 0:10:08.880 --> 0:10:11.920 of her depression. It kicked him within seconds, and she 0:10:12.000 --> 0:10:14.280 described it as a deep down, bad feeling in the 0:10:14.280 --> 0:10:17.360 pit of my stomach. I wanted to cry, but I couldn't. 0:10:18.040 --> 0:10:19.559 Someone could have come in to shoot me and I 0:10:19.559 --> 0:10:23.199 wouldn't have cared. I couldn't have cared less. No, immediately 0:10:23.240 --> 0:10:26.680 they turned the switch off again, and surprisingly, within seconds, 0:10:26.720 --> 0:10:29.920 the sadness lifted again and they found themselves in a 0:10:30.000 --> 0:10:33.320 very weird situation where every time they turned on this current, 0:10:33.480 --> 0:10:36.920 the person would descend immediately within a few seconds into sadness, 0:10:37.240 --> 0:10:39.320 and then every time they turned it off she would 0:10:39.440 --> 0:10:41.640 be able to emerge within a few seconds. Again, it 0:10:41.679 --> 0:10:43.920 was literally sadness the flip of the switch. 0:10:45.120 --> 0:10:45.400 Wow. 0:10:45.440 --> 0:10:48.679 And so that's what's got you started in researching that. 0:10:49.400 --> 0:10:50.400 So that's exactly it. 0:10:50.440 --> 0:10:53.760 So at the time I was doing my PhD using 0:10:53.760 --> 0:10:57.000 a technology called functional functional MRI, which I'm sure you've 0:10:57.000 --> 0:11:00.559 talked about on the podcast before, which is a way 0:11:00.600 --> 0:11:03.240 of using MRI scanners to look at the brain activity 0:11:03.400 --> 0:11:06.280 of people as various things happen. So the neuros versions 0:11:06.480 --> 0:11:09.120 wanted to understand what was going on, So we went 0:11:09.160 --> 0:11:11.720 down to where the functional MRIs were being done and 0:11:12.559 --> 0:11:14.599 they turned on and off one of the switches on 0:11:14.640 --> 0:11:16.720 the one side that affected the tremor, and they were 0:11:16.760 --> 0:11:19.400 able to show a particular brain pathway that was affected 0:11:19.600 --> 0:11:21.960 controlling the motor circuits of the brain, which was the 0:11:21.960 --> 0:11:25.319 intended effect. On the other hemisphere, though the electrode was 0:11:25.360 --> 0:11:27.600 just a few millimeters off and as a result, it 0:11:27.800 --> 0:11:30.840 landed on some other pathways that projected out to a 0:11:30.840 --> 0:11:33.520 completely different part of the front lobes, and every time 0:11:33.520 --> 0:11:35.679 they turned on and off this part of the frontal lobes, 0:11:35.720 --> 0:11:38.640 the person would instantly going out of the sadness. That 0:11:38.679 --> 0:11:40.400 was happy news of the patient because they were able 0:11:40.440 --> 0:11:43.360 to reposition the electrodes so that both electrodes did the 0:11:43.400 --> 0:11:47.120 appropriate thing. But it got us thinking about what this 0:11:47.160 --> 0:11:50.240 really meant about depression. All these theories at the time 0:11:50.320 --> 0:11:53.000 that depression might be a chemical imbalance or this or that, 0:11:53.520 --> 0:11:55.360 we really saw it very directly that there was a 0:11:55.440 --> 0:11:58.640 question of the activity of the brain and that within seconds, 0:11:58.920 --> 0:12:01.680 one pattern of activity the brain led to sadness, and 0:12:01.720 --> 0:12:04.120 within seconds, if that padding of activity could somehow be 0:12:04.160 --> 0:12:07.280 turned off, then the person's sadness would go away. And 0:12:07.360 --> 0:12:09.959 that really got us thinking about whether we might start 0:12:10.000 --> 0:12:12.719 being able to use things like brain stimulation to understand 0:12:13.240 --> 0:12:15.760 what depression was about in the brain, and maybe even 0:12:15.760 --> 0:12:17.560 to come up with a new generation of treatments that 0:12:17.600 --> 0:12:20.400 work better than the medications and therapy of the time. 0:12:20.720 --> 0:12:22.800 Okay, terrific, So we'll talk about that. 0:12:23.520 --> 0:12:26.720 Let's start with you, can you define depression clinical depression? 0:12:27.679 --> 0:12:27.959 Sure? 0:12:28.320 --> 0:12:31.280 So, there are standardized definitions of depression that involve a 0:12:31.320 --> 0:12:33.960 series of symptoms, the core of which is sad or 0:12:34.000 --> 0:12:36.880 depressed mood most of the day most days, and the 0:12:36.920 --> 0:12:39.480 second of which is a thing called anhedonia, which is 0:12:39.520 --> 0:12:42.559 the inability to enjoy things or experience pleasure, a loss 0:12:42.559 --> 0:12:44.760 of motivation, a loss of joy, a loss of the 0:12:44.800 --> 0:12:48.280 brain's reward functions. In addition to that, there are some 0:12:48.360 --> 0:12:51.200 standard symptoms that go along with that. Commonly, people will 0:12:51.280 --> 0:12:54.640 have disturbances in their sleep or appetite, trouble with concentration, 0:12:55.480 --> 0:12:58.080 They may have difficulty with their energy and fatigue levels, 0:12:58.760 --> 0:13:01.200 and there are thoughts that come along of self harm 0:13:01.200 --> 0:13:03.880 and suicide that there are obviously the most concerning parts 0:13:04.240 --> 0:13:07.640 about the depression. So that's the standard sort of diagnostic 0:13:07.679 --> 0:13:11.160 approach by which we determine whether somebody has been entering 0:13:11.200 --> 0:13:14.600 into a period of depression. It's unfortunately, really common. At 0:13:14.640 --> 0:13:17.320 any given time in North America, about five percent of 0:13:17.320 --> 0:13:20.600 people are in the middle of a depressive episode, and 0:13:20.760 --> 0:13:23.440 at least ten percent of people, perhaps more these days, 0:13:23.520 --> 0:13:25.800 are going to go through an episode of depression at 0:13:25.880 --> 0:13:29.280 some point in their lifetimes. Almost everybody will have somebody 0:13:29.400 --> 0:13:32.160 they know who has been through depression or is going 0:13:32.200 --> 0:13:34.200 through depression or will go through depression. 0:13:34.520 --> 0:13:36.040 So one of the things I want to talk about 0:13:36.080 --> 0:13:38.960 is why this happens, What it is about the wiring 0:13:39.040 --> 0:13:41.520 of the human brain that allows us to slip so 0:13:41.640 --> 0:13:43.960 easily into that mode. 0:13:44.640 --> 0:13:45.600 What are your thoughts on that. 0:13:46.440 --> 0:13:50.520 It's a really fascinating question, And I think to answer that, 0:13:50.600 --> 0:13:52.320 what we found is you can get a lot of 0:13:52.320 --> 0:13:54.800 the clue to that looking at evolution or a biology, 0:13:55.360 --> 0:13:57.640 because humans are not, by no means the only animals 0:13:57.640 --> 0:13:59.480 that can go into it a spare like syndrome, I 0:13:59.480 --> 0:14:01.920 mean depression. Most of us who have pets, and most 0:14:01.920 --> 0:14:05.240 of us of animals who have seen situations where animals 0:14:05.240 --> 0:14:07.520 can drop into a despair and stop eating and stop 0:14:07.559 --> 0:14:09.720 sleeping and do all the same things and don't enjoy 0:14:09.760 --> 0:14:12.600 the things they normally would. Something that looks a bit 0:14:12.640 --> 0:14:16.079 like depression is detectable in dogs and cats and elephants 0:14:16.200 --> 0:14:19.680 and zoo animals, and even in things like zebrafish, which 0:14:19.680 --> 0:14:23.600 are tiny little vertebrates. So evolution seems to have put 0:14:23.640 --> 0:14:26.720 a depression like mode there, you know, a very long 0:14:26.760 --> 0:14:28.920 time ago, and it's one of the oldest circuits in 0:14:28.960 --> 0:14:32.440 the brain. When we look at the circuitry that drives depression. 0:14:32.440 --> 0:14:35.160 What we find is it falls into a bigger category 0:14:35.240 --> 0:14:38.160 of circuits that help the brain to defend against threats. 0:14:38.920 --> 0:14:41.000 And in a nutshell, for every living thing, whether you're 0:14:41.000 --> 0:14:43.440 a fish or a raccoon or a human, there are 0:14:44.000 --> 0:14:46.080 sort of four main categories of things you can do 0:14:46.120 --> 0:14:47.840 if a threat comes along. So let's say you're a 0:14:47.840 --> 0:14:50.520 fish swimming along and a shark shows up. The first 0:14:50.520 --> 0:14:52.800 thing you can do is you can freeze and hope 0:14:52.800 --> 0:14:55.120 the shark doesn't see you, So that's freeze mode. If 0:14:55.120 --> 0:14:56.880 the shark sees you and starts chasing you, then you 0:14:56.920 --> 0:14:58.480 have to go beyond freeze. You have to go into 0:14:58.480 --> 0:15:01.000 this sort of the flight mode would be the escape mode, 0:15:01.880 --> 0:15:04.440 and if the shark corners you. We've all seen that. 0:15:04.440 --> 0:15:06.240 There are animals, you know, if you happen to get 0:15:06.240 --> 0:15:09.320 a possum or a raccoon in your garage, there usually 0:15:09.360 --> 0:15:11.160 will run away, But of course if they get cornered 0:15:11.160 --> 0:15:12.640 and they feel like there's no way out, they will 0:15:12.680 --> 0:15:15.760 fight very fiercely, and lots of animals do that. So 0:15:15.920 --> 0:15:18.920 there is this third mode called fight. But the brain 0:15:19.000 --> 0:15:21.840 needs a fourth mode to deal with situations that are unwinnable. 0:15:22.040 --> 0:15:25.640 Sometimes you've tried freezing, you've tried fleeing, you've tried fighting. 0:15:26.000 --> 0:15:27.720 But if at some point the brain decides you're not 0:15:27.760 --> 0:15:29.640 going to win this fight and there's no running away, 0:15:29.680 --> 0:15:32.239 there's no escaping, and you can't just ignore the problem, 0:15:32.600 --> 0:15:35.080 the brain taps into a fourth mode that I'll call fold. 0:15:35.400 --> 0:15:38.520 There's a passive threat defense mode where the instincts are 0:15:38.520 --> 0:15:41.440 all about losing your confidence, running home and hiding in 0:15:41.480 --> 0:15:43.720 your burrow and keeping your head down and hoping that 0:15:43.880 --> 0:15:47.440 something changes. This is the mode that is turned on 0:15:47.480 --> 0:15:49.960 when people are fighting off in illness or a major injury. 0:15:50.040 --> 0:15:51.720 So if they have surgery or if they're fighting off 0:15:51.720 --> 0:15:53.680 in illness. Some people will actually have a drop in 0:15:53.720 --> 0:15:55.960 their mood when they have an immunization as their immune 0:15:55.960 --> 0:15:59.080 system fires up to sort of to deal with the infection. 0:16:00.080 --> 0:16:02.480 In any situation where the brain decides that it needs 0:16:02.480 --> 0:16:06.240 to be hiding doubt in recovery and recovering and keeping 0:16:06.240 --> 0:16:08.800 its head down, it will go into this fold mode. 0:16:09.840 --> 0:16:12.160 Now that may be necessary to keep you out of 0:16:12.240 --> 0:16:15.160 danger until the threat goes away, or at least hopefully 0:16:15.200 --> 0:16:17.920 until the threat goes away. But the problem that comes 0:16:17.960 --> 0:16:20.840 up in depression is when this becomes a self perpetuating 0:16:20.880 --> 0:16:24.280 process and the circuits that drive fold mode, which is 0:16:24.320 --> 0:16:27.400 a normal and useful defense mechanism for the threats we 0:16:27.440 --> 0:16:30.040 can't win against. If those circuits get stuck in an 0:16:30.040 --> 0:16:32.560 infinite feedback loop and just keep going and going, then 0:16:32.560 --> 0:16:34.720 the person may still be stuck in depression weeks later, 0:16:34.960 --> 0:16:36.680 months later, maybe even years later. 0:16:37.640 --> 0:16:40.640 You once give me an example of falling off a 0:16:40.760 --> 0:16:42.800 ship in the middle of the night to illustrate this 0:16:42.880 --> 0:16:43.520 fold mode. 0:16:44.360 --> 0:16:46.400 Yeah, so I wanted to. That's actually a great point. 0:16:47.120 --> 0:16:50.920 So there are situations where we're we're going into this 0:16:51.000 --> 0:16:54.040 mode is really useful, and every once in a while 0:16:54.080 --> 0:16:56.000 we're reading the news about somebody who falls off the 0:16:56.000 --> 0:16:57.360 back of a ship in the middle of the night 0:16:57.400 --> 0:17:00.440 and then miraculously gets rescued in the morning. Now, if 0:17:00.440 --> 0:17:01.800 you or I fell off the back of a ship 0:17:01.800 --> 0:17:03.120 in the middle of the night, like a cruise ship 0:17:03.200 --> 0:17:05.520 or something, we'd probably swim after the ship for a 0:17:05.560 --> 0:17:08.199 while and scream for help and try and attract his attention. 0:17:08.280 --> 0:17:09.800 But if it was really clear that the ship was 0:17:09.840 --> 0:17:11.600 sailing away and no one could hear us, and we're 0:17:11.920 --> 0:17:14.520 stuck in the middle of the sea, I mean we're 0:17:14.560 --> 0:17:16.640 in a really bad situation. It's really risky, and this 0:17:16.680 --> 0:17:18.600 is probably not going to work out well. But our 0:17:18.640 --> 0:17:23.000 best chance of survival is actually to fold, to curl 0:17:23.040 --> 0:17:25.239 up into a ball and just wait and save your 0:17:25.320 --> 0:17:28.480 energy and hope that something about the situation changes, hope 0:17:28.520 --> 0:17:31.560 you get rescued. That mode is the same mode that 0:17:31.560 --> 0:17:34.119 we talk about when we talk about depression, and in fact, 0:17:34.800 --> 0:17:38.439 when pharmaceutical companies are developing new medications for depression, one 0:17:38.480 --> 0:17:40.560 of the ways that they'll do animal testing to see 0:17:40.560 --> 0:17:43.200 if the molecule helps depression is whether a thing called 0:17:43.200 --> 0:17:46.399 the forced swim test, and the forced swim test, the animal, 0:17:46.440 --> 0:17:49.640 like the mouse or whatever, is placed inside an air 0:17:50.040 --> 0:17:51.800 a little beaker where they have to swim around and 0:17:51.840 --> 0:17:54.240 there's nothing to stand on. Now, mice are quite good swimmers, 0:17:54.240 --> 0:17:56.200 and they're also quite good floaters, so they'll swim and 0:17:56.240 --> 0:17:59.000 swim around, and eventually, at some point they'll realize that 0:17:59.040 --> 0:18:00.760 they're not going to get out of this situation, and 0:18:00.760 --> 0:18:02.520 so they stop swimming around and they just give up 0:18:02.520 --> 0:18:05.800 and float. And at that point the experimenter will stop 0:18:05.800 --> 0:18:08.080 the stop watch and see how many minutes that took. 0:18:08.520 --> 0:18:11.760 What's interesting is that there are breeds of mice who 0:18:11.760 --> 0:18:13.680 are prone to depression and prone to this are giving 0:18:13.720 --> 0:18:18.000 up quickly, and most antidepressants, when the mice are on 0:18:18.040 --> 0:18:20.920 the antidepressant still actually swim for a lot longer before 0:18:21.000 --> 0:18:24.000 giving up. And so this forced swim tests, which is 0:18:24.040 --> 0:18:26.119 really a way of tapping into how long before the 0:18:26.160 --> 0:18:29.040 animal switches into this mode of folding and giving up 0:18:29.080 --> 0:18:33.560 and waiting for something to change. That approach is a 0:18:33.720 --> 0:18:36.240 long standing and standard way that people have searched for 0:18:36.880 --> 0:18:40.440 new antidepressant medications over the last several decades. 0:18:40.880 --> 0:18:41.760 Okay, terrific. 0:18:41.920 --> 0:18:46.240 And so when we look at depression in this country 0:18:46.640 --> 0:18:51.080 or around the world, what are the rates of depression? Like, 0:18:51.160 --> 0:18:52.920 are things going up or down? 0:18:54.000 --> 0:18:57.520 Yeah, so it's unfortunate that, I mean, the encouraging thing 0:18:57.560 --> 0:19:00.240 over the last few decades is that compared to say, 0:19:00.280 --> 0:19:02.760 the nineteen eighties and the nineteen nineties when I started 0:19:02.800 --> 0:19:05.600 doing brain imaging research, there's a lot less stigma around 0:19:05.640 --> 0:19:08.240 mental health than there was, and that that's certainly very encouraging. 0:19:08.520 --> 0:19:10.880 There are a lot more people seeking treatment than before, 0:19:11.320 --> 0:19:15.800 and people are seeking treatments with medications and with psychotherapy 0:19:15.960 --> 0:19:18.560 more more than ever. The problem is that this hasn't 0:19:18.640 --> 0:19:21.480 changed the numbers at all. So despite the fact that 0:19:21.520 --> 0:19:24.080 there's less stigma, despite the fact that people are coming 0:19:24.080 --> 0:19:27.080 forward and taking antidepressants, and that in fact, antidepressants are 0:19:27.080 --> 0:19:29.760 being used in sex quantities that they can be detected 0:19:29.880 --> 0:19:34.719 with spectroscopes in the water supplies of cities and so on, 0:19:34.800 --> 0:19:36.320 so they'll actually be able to go and they can 0:19:36.359 --> 0:19:40.960 detect trace amounts of all these medications in city water supplies. 0:19:41.680 --> 0:19:44.800 Despite all of this, the prevalence of depression and of 0:19:44.840 --> 0:19:48.520 suicidal acts and suicidality has not gone down at all, 0:19:48.920 --> 0:19:53.199 And in certain populations like younger folks under age twenty 0:19:53.240 --> 0:19:55.960 and in the early twenties, the numbers for depression, anxiety, 0:19:55.960 --> 0:19:59.040 and suicidality are going up rather than down. So we 0:19:59.119 --> 0:20:02.359 definitely need to put the search on to understand how 0:20:02.400 --> 0:20:04.600 depression works in the brain and really develop a new 0:20:04.680 --> 0:20:07.520 generation of treatments because what we're having right now is 0:20:07.520 --> 0:20:08.480 not moving the needle. 0:20:08.760 --> 0:20:10.600 Why do you suppose the numbers are going up? 0:20:12.080 --> 0:20:14.719 There are a lot of different possibilities for why that is. 0:20:15.680 --> 0:20:17.880 I think we could probably have a whole other podcast 0:20:18.000 --> 0:20:20.840 on what that is. In a nutshell, there are more 0:20:21.000 --> 0:20:23.480 there seem to be more situations where people feel like 0:20:23.520 --> 0:20:26.280 the fight is unwinnable. When I see that numbers for 0:20:26.320 --> 0:20:28.959 depression and suicidality going up, it's sort of an index 0:20:28.960 --> 0:20:31.320 of number of people who feel like they are losing 0:20:31.359 --> 0:20:34.000 it life and that there's no way out for them. 0:20:34.320 --> 0:20:36.600 So it is a bit of a barometer of social 0:20:36.600 --> 0:20:39.560 health in that way. Some people have also attributed to 0:20:39.920 --> 0:20:42.640 increased stressors around social media use and so on, and 0:20:42.680 --> 0:20:45.240 some people have even attributed to things like changes in 0:20:45.240 --> 0:20:48.120 the composition of the bacteria that live within our guts, 0:20:48.400 --> 0:20:51.240 some of which appear to have a protective effect against depressions. 0:20:51.280 --> 0:20:53.760 So there are a lot of theories out there, but 0:20:53.760 --> 0:20:55.800 I wouldn't say anyone has solved the mysteries of what 0:20:55.840 --> 0:20:58.640 it is. There are lots of people posing everything from 0:20:58.680 --> 0:21:03.919 social factors to psychological factors to biological factors like literally 0:21:03.960 --> 0:21:16.320 write down to the bacteria in a person's gut. 0:21:23.400 --> 0:21:26.280 So what do you think about the pharmaceutical treatments for depression? 0:21:27.000 --> 0:21:30.040 Are they are they useful? Are they neutral? 0:21:30.720 --> 0:21:32.760 Well, I would say that I can give you what 0:21:32.800 --> 0:21:35.360 the numbers say. So if a person comes into their 0:21:35.359 --> 0:21:38.240 family doctor with an episode of depression and they try 0:21:38.280 --> 0:21:41.320 an antidepressant. There was a famous study about fifteen years 0:21:41.359 --> 0:21:43.879 ago called star d Let out of the University of 0:21:43.960 --> 0:21:48.639 Texas Southwestern and they found that about two thirds of 0:21:48.680 --> 0:21:53.720 people could get to remission from depression after trying one 0:21:53.760 --> 0:21:57.320