 I'm going to talk a little bit about clinical depression and then I'm going to tell you something about what I hope is an advance in understanding the circuits. You heard Sidney talk about the circuits of cognition. Well, I'm interested in the circuits of depression that mediate depression and how this might help us find new treatments. To start all this, I too want to thank the sponsors and especially St. John's. I'm going to mention them in terms of one of the vignettes and the Brain Behavior Research Foundation. It's a little self-interested. I was a founding member of the scientific council, but they are really doing an incredible job of finding young people. I'm saying that because my postdoc just is going to start her NARSAD Fellowship in July. And my number one collaborator here has one, so we're delighted with the support that we've gotten from you. Okay, let's move on. I hope I know how to do this. Let's see the next slide. Can I turn these? Maybe I can. Okay, I wanted to start with a couple of vignettes about the kinds of depression there are. And then we'll go into how serious a disorder it is in the United States. And then we're going to talk about how we might do better. But there are several types of depression, and the first patient I want to talk about was a melancholic depression. This was a patient who ended up being transferred from Stony Brook to St. John's, and it's how I got to know the nursing home. This was a woman from a very established family, and she was a very talented woman. She was a published poet, very involved in music in the city. And I got a call one day from one of the leading hospitals in the city saying that they would like to transfer her to Stony Brook. They felt that she had dementia, and they thought that we should try to find a placement out in Long Island. And she came out to Stony Brook, and I talked to her family and to her, and I decided that she didn't have dementia. She had a very severe case of melancholic depression. She wasn't eating, she wasn't speaking, she was just lying in bed. This was very, very unlike her, but those are cardinal symptoms. She would wake up early in the morning, but she would just lie there. She would do very little. So you have a person with a very low mood, very little energy, whose appetite goes down, whose weight goes down, and she stopped doing everything. She even stopped speaking. We treated her for depression, and she got up out of bed, went to St. John's, and started writing poetry again. And that's the melancholic depression, and that kind of depression we'll often have. I'm going to use each vignette to give a little bit of biology. We'll almost always have disturbances of what we call the HPA axis. The HPA axis is the hypothalamic pituitary axis. It's the fight or flight reaction. And what happens is when we're threatened, our body sends signals from the brain to the adrenal gland. We make cortisol and we also throw out some noradrenaline, and this is a protective response. Well, cortisol can be damaging if it's too high. And what happens in these patients is they often are running too high cortisol. Their diurnal variation is raised up, and this can lead to problems. It can actually lead to some atrophy in the hippocampus, we think. It can also lead to something called the metabolic syndrome, which is a serious problem and can lead to increased cardiovascular risk. And depression is tied in very tightly to increased cardiovascular risk. In fact, if you have a heart attack and get depressed, your chances of dying jump compared to having just the heart attack. If this is even worse, it could become catatonic. And at that point, the patients have something called waxy flexibility. You can put them in a position and they'll just hold it. Catatonic depression is very rare. But when you see it, it can be cured almost universally with electroconvulsive therapy. And I'm mentioning it because the expert and the person who found that was actually on Long Island. It was a man named Max Fink. And since it's so rare, we'll skip it. Atypical depression, you see instead of weight loss and retardation in movement, you see anxiety. And patients really get jumpy. Sometimes they will actually start eating too much, and instead of losing weight, they'll gain weight. And often they won't respond to antidepressants, but they may respond to earlier drugs called monoamine oxidase inhibitors. And that's monoamine oxidase inhibitors. We'll maybe get to that. I'm not sure. Then there is postpartum depression, and about 15 to 20 percent of women following delivery will experience a depression. Some of it very severe where they will fear that they can't take care of their child. They won't be able to take care of their child, and it's a serious problem. And then there's seasonal affective disorder. I want to tell a little story about this because it's a great way to cure a depression if you happen to have this. I saw a patient on Long Island who was a neurologist. And she came from Jamaica and she told me that, you know, every year around Thanksgiving, she started feeling really awful. And we talked a while, and it struck me that she had a light sensitive seasonal affective disorder. So since she was from Jamaica, I said, why don't you go back and visit your parents and see how you feel when you get down there. And she went down and she felt great. And so every fall she would make a trip to Jamaica, and she's been doing well ever since. She does have light treatment. We actually used light treatment and I probably won't get into that. But how serious a problem is depression in our society? Facts that aren't on this slide is in terms of disabilities. I was on a commission for the World Health Organization that looked at disabilities through psychiatric disease. And depression turned out to be the fourth highest disability in 2000 of all diseases. We're talking everything, cardiovascular cancer, everything. It's estimated that it may become the leading cause of disabilities by 2040 if it keeps going up. And one of the reasons is this epidemiology. 16 plus percent of people will have an episode of depression in their lives. That's almost one in five of us. Every 12 months, more than one in 20 of us will have depression and severe depression, 2% of the population. So it's a very common disorder. And our treatments are not great. In fact, they're not good in my feeling. If we give people sugar pills, about 30% of them will get better. If you have really good psychotherapy in 100 people, you might get up to 50 or 55%. With standard modern antidepressants, the newer ones, you might get to 2 thirds of the people. And in severe depression, where you can justify it with ECT, you might get 85%. But you still have 15% of patients who are resistant to most treatments. And that's a huge number in this country every year. And when you realize that the risk of suicide is increased dramatically in depression, you realize what a serious problem this is. This slide is aimed to give you the entire science of what we've studied about depression in one minute. Don't try to even remember it. It's totally a cartoon, and it's probably totally wrong, but it's going to give you a neat history. Initially, we thought depression was due to the fact that we had two little monomines. And in fact, every medication we use today as a primary antidepressant acts by increasing the concentration of these monomine substances, serotonin and noradrenaline and dopamine, some drugs, in the postsynaptic cleft. And where this came from is kind of neat. I'll probably go two minutes over time to tell this story, Sydney, too. It's a New York story. TB used to be a big problem, even older than I am. We had sanatoriums where we put people. And in New York, there was a TB sanatorium and a new anti-divercular drug came out. And the patients started getting really rambunctious. They started chasing the nurses, pinching the nurses, getting really active. These are guys with TB. What were they so happy about? Well, it turned out they were acting a little manic. And it turned out that this drug had monomine oxidase properties, and it increased the concentration of these amines. And that was one of the first clues that amines might play a role. And for a long time, people centered on this idea. And all of the drugs we have today come from this idea. The next idea was this hypothalamic stress axis. It was the idea that stress causes increased cortisol, which acts on CRH, which somehow changes something inside a cell. This is a big cell, and this is the nucleus in the DNA. And somehow that causes depression. And in these melancholic depressions, most of them have a distorted HPA axis, but there are other depressions which don't. No drug has yet been developed which really works using this. We're going to skip these guys because they're small. But a group at Yale moved us inside the cell. These are both receptors on the outside, and this one goes into the nucleus. These go through a series of steps, and they go into the nucleus, and they actually change gene expression. And they change gene expression. They change the expression of neurotrophins, most specifically a compound called BDNF, brain-derived neurotropic factor. And this changes something, either cells or synapses. And one of our ideas about five years ago was that maybe cells change, because even as old as I am, I am making new brain cells all the time in a little structure called the hippocampus, and there's another ventral stream that makes new cells. And it turns out that the antidepressants will increase the number of new cells in our brain. They increase the turnover, our heads don't burst, but they increase the rate of birth of these new cells. The rate of death also goes up. So one of the ideas was maybe we had a decrease in these cells, and that's why we had depression. I've thought that that idea was wrong, and maybe I don't have time to tell you now, but the evidence now pretty much is it's wrong. And one of the best pieces of evidence is that a class of drugs called benzodiazepines, which are very, very often used in anxiety. It's the valium class. If you take those drugs and antidepressants, you make no excess stem cells. You don't make new cells. So that's done clinically all the time, and it seems to me that rules this one out. So now the idea is that where nerves talk to each other, these synapses, and that's what we're going to talk about tonight. But that may be where the problem is. And how did I want to attack this problem is I wanted to use an animal model. But to use an animal model, I wanted it to have some bearing on depression. So I went to a theory of cognitive depression that Ted Beck developed about 40 years ago, and Ted and Zelligman, the man who really developed the model I'm going to use, and I have just been talking and with Helen Mayberg just wrote down some thoughts about depression. But the idea that Ted had was some event occurred, and then it was distorted in the brain. And the way it's distorted is typically seen in depressed patients who feel guilty about things, for example, that they have no reason to feel guilty about. There's a real distortion which changes how they feel. They feel bad about it. They feel anxious and depressed about it. That makes them behave worse, which makes their behavior maladaptive, and this cycle just spins them down into a hole. And the idea was, could you model this in animals? And the idea that Zelligman had was that you could model it in animals by doing something to the animal that was aversive, so it wasn't nice, and it was unpredictable and it was uncontrollable. That's how many of us feel sometimes in society. And if that happened that the animal would get this feeling of helplessness which ought to be akin to this cognitive dysfunction. And we use this complicated design, but the idea is this guy controls how much foot shock this guy gets. He also has a lever, but it doesn't do anything. This guy turns it off. And if you subject these animals to unpredictable, uncontrollable shock for a while, and you have a hundred of them, you'll get about five or six which are perfectly intact in every way you can measure. They're just like these guys or guys who never had anything done to them. They're all just fine. And you'll get about five or six who are really very helpless. You put them in a situation where all they have to do is walk across the floor to get away from the shock and they won't learn it, whereas these guys all learn it very quickly. And so we decided these helpless and non-helpless animals, that was a model that Zelligman suggested might have something to do with depression, and we used it and we modified it. What we did is we started breeding the helpless and the non-helpless over years and years, and we got to 30 generations. We have a line of rats that I consider my New York rats. They are definitely not helpless. And then we have another line of rats that are congenitally helpless. And that's the two we wanted to look at because we wanted to see them.