Robert Sapolsky: The Biology and Psychology of Depression

Hello, my name is Robert Spolski. I am a professor of

biology

, neurology, and neurosurgery at Stanford University. About 13 years ago I gave a talk at Stanford on the

biology

of

depression

, someone recorded it and Stanford uploaded it to YouTube and that produced some good news bad news good news in the year from 5 million views or more for this talk it is useful Bad news 5 million views or more telling you the magnitude of the problem that exists with

depression

now, of course, fortunately there have been some new advances in the field since 13 years ago and the purpose of this conference is a child of the conference 2010, is an update of the information, now I am going to argue that depression is one of the worst medical catastrophes that can overwhelm someone. and we will arrive at that argument and a considerable and detailed sense of what we are dealing with.

The World Health Organization sense that major depression is the first or second cause of medical disability on this planet. Millions of people, by best estimates, between 15 and 18% of people. will have a major depressive episode at some point, now the worst news is that about 80% of cases are never diagnosed and of those that are, about a third never respond to any medication, about a third do, but the effects secondary schools are intolerable and about a third receive help, in other words. We have enormous problems with oceans of people with this disease who are not being diagnosed or treated successfully.

About 80% of people have multiple rounds of depression and trying to impress to begin with is an important topic for us to be aware of. Now, one of the most reliable disturbing findings that exists is that with each passing decade the incidence of depression has increased. Well, that may not mean anything at all. There can be all kinds of confusion. Today, people are more likely to admit that they feel depressed than people. in the 1950s and therefore it artificially appears that there are more cases, all kinds of carefully controlled epidemiological studies showing that, cross-culturally, the incidence of the disease has been increasing over the decades.

The most informative place where it has been increasing is between adolescence and with each passing year, more teenagers are recruiting Roed into the cohort of people who struggle with depression throughout their lives just so that it is not purely a teenage issue. What we've also been seeing is an increase in the risks of depression over years and decades among older people. Now what you see is totally predictable who suffers from major depression. You see, just on a demographic level, low socioeconomic status is one of the biggest winners, so I'm going to try to make three points in this lecture, three incredibly important points and the first one is implicit in what I've been saying all along.

Depression is a medical illness. There's an incredibly toxic attraction to people who have no idea what it's like to say, "Oh, come on, we all get depressed and people come out the other side and pick themselves up and stop pampering themselves and not indulge." Saying that to someone with major depression is like sitting someone with diabetes down and saying, "Oh, come on, what is this? Stop treating yourself to this insulin thing. Come on, put up with the depression, as we'll see, it's such a disorder." biological as diabetes is. We will see a very different type of biology, however, we are talking about a medical disease.

The next critical point if you learn about this and everything you learn is the biology, the brain chemistry, the hormones, the genes and what connects to all of that. you will never be able to deal with this disease effectively and the two parts of this lecture reflect that point, learn all the biology and you have all those multicab terms under control and if you don't incorporate them with the

psychology

of depression you are not going to get anywhere now the Third point is why argue that this is one of the worst diseases and that it revolves around this totally strange thing that humans do?

You have terminal cancer. crippling heart disease, you've lost a limb, whatever and your life is obviously very limited and very competitive and interestingly people find positives in these things sometimes, this is when you realize how much it means family to you, this is where you realize that you have found your God, this is whatever it is that we are able to obtain satisfaction, pleasure, reward, satisfaction from the most terrible circumstances on Earth, ask anyone who has come out of the concentration camp feeling that, in some way, he was still stuck, is a person that we humans can make. in the best horrible situations we can see the positive side depression is a disease in which you can no longer see the positive side and what could be worse than that and if I had to define depression in a single sentence I would say that it is a Biochemical Disorder with genetic components whose main manifestation is that you lose the ability to be AED by rainbows and sub-sunsets, which makes you a pretty bad person now, just starting out before you start seeing the symptoms.

Some slang, yes, we all get depressed. Depressed in an everyday sense, some disappointment happens, something unrequited, whatever, and what you end up seeing usually comes out the other end and we heal, and what you see with the depression we're going to talk about today is not oh, hey. depressed state. After this discussion with a friend the next day I felt a little depressed, this is a major biological disease that destroys people's lives and once again one of the main causes of medical disability on this planet, unfortunately, what such a horrible day, I feel depressed and depressed. as a biological disorder use the same term, we are just talking about this huge medical evil here, okay, so let's start before we get into biology, what does the disease actually look like?

The defining symptom of depression is anhedonia and hedonism, the experience of pleasure Anil aned andonia the inability to experience pleasure and this is what the disease is about something wonderful happens you feel nothing it is just a flatness there is an emptying this is the symptom that makes This is one of the worst diseases we are going to encounter. How many more subtle things are happening besides the inability to feel pleasure? Additionally, people with major depression feel overwhelmed. Often, out of a sense of sorrow for things, the trauma simply reverberates over and over again. A feeling of guilt for imagined mistakes you made at some point. a feeling of guilt, one of the most pernicious versions is: I have been so lucky, I have been given so many gifts, I have been so privileged, all of this looks at me wasting my life, feeling sad and guilty as a result of there now being another realm of symptoms of depression and really informative, oh what is depression?

It's a disease of mood problems, it's also a disease of thinking cognition and that ends up being really informative in the lecture on cognition at the simplest level, like white bread, uh. depression involves cognitive problems people's focus goes out the window executive function working memory things like that that's the usual thing we're going to struggle with in the future is when someone is not good at remembering eight digit numbers or whatever Because their cognition is compromised by depression or it is because they are simply not motivated, why bother now? The area in which depression is problematic with cognition brings us to the work of one of the giants in the field, this guy, Aaron Beck, who frames depression as a disorder. of cognitive distortion not only of the negative mood not only of the absence of a positive mood but of depression as a cognitive distortion disorder.

What did Beck mean by this and his ideas became the backbone of what What is possibly the most effective type of psychotherapy for depression? Cognitive behavioral therapy CBT what? It is the cognitive distortion there, yes, something terrible happened to you, it is true, it is real. It is disturbing but that is not the end of the world and that is not your inevitable future and that is not the rest of your life and people with depression distortively overgeneralize the negative. in a world See how Beck turned it into a depressive triad a negative triad a depressive world worldview about yourself about the world and about the future so what does this look like when you see this in all kinds of cognitive realms you ask someone who remembers things, tell me? about this year of school when you were a kid or whatever and the depression you disproportionately generate you generate negative memories you give someone a lot of things to memorize and you disproportionately remember the negative ones you have a tendency to consolidate more negative memories you interpret things that happen around you you look at an image of an absolutely neutral face and you are asked to describe that person's mood and you have a bias in the direction of negativity your sensory processing even shows that where you look, you demonstrate it someone takes photographs and there is a negative with a kind of sad context, positive, wondering where your eyes go in a split second, which skews this negativity bias of memory retrieval, memory consolidation, interpretation of things that you are looking to get sensory information from this . permeating the illness now, another way to describe this cognitive deficit in depression is that people can't do reappraisal, you feel bad about something, you get a bad result on a test, whatever, and a very healthy response is to reappraise. saying "okay, maybe me." After all, I'm not that good at organic chemistry, maybe you'll start to re-evaluate that I wasn't that good that particular day, maybe it had something to do with me sleeping really badly, maybe what I need to keep in mind is that there are much more in life. than organic chemistry, you were changing your interpretation of the situation in a way to escape the negativity.

People with depression have enormous trouble reassessing a negative circumstance like that. Now it's kind of interesting in terms of people with depression having this more negative interpretation of the situation. In the world, this really amazing thing is that sometimes by having a more negative interinterpretation, they are more precise, they are more correct and this has led to commentary in the field. Sometimes people with depression are sadder but wiser because you look at your average. person and on average they are overly optimistic when you ask people what is the probability of this or this big thing or that kind of thing happening and you see that people with depression are much more accurate, well, wait a second, I was just talking about a few minutes ago about cognitive problems, distortions in depression, something terrible happened in the past and it distorts, and you decide that this has to be your future, you are distorting things, but here there are people with depression or being more precise that the average person is evaluating things. in the world around you when it is somewhat distant when it is somewhat emotionally distant people with depression are often sad but they are wiser in terms of having more accurate and realistic assessments about how the world really works well, so that's looking at a little cognition other The main characteristic of depression as a symptom is rumination, you ruminate like a cow ruminating, you ruminate, you can't stop the sad thoughts, you can't stop the negativity, you can't get out of this sad thing, it reminds you of that.

It is a sad thing and you are immersed in it. It's really interesting neurobiology. We're going to hear about a part of the brain called the dorsal lateral prefrontal cortex. What it really does well is help you control your thoughts and what you see is the dlpfc has to work especially hard in people with depression when you say, tell me about a happy childhood memory, it really has to work to overcome rumination, so Likewise, this part of the brain has to work very hard when you try to stop negative emotions. This and we're going to look at this part of the brain that atrophies and becomes less active in major depression.

This part of the brain has a lot to do with that hellish symptom of depression that you can't stop. the negative thoughts go on and on and they won't stop now another group of symptoms fall under this general term called psychomotor retardation going back to major depression is not, oh come on just stop pampering yourself major depression is a real illness The People with major depression, their bodies function differently, even when they're asleep, even when they're anesthetized. This is a real biological disorder and the psychomotor symptoms that you see in depression that sort of underline this, start to tell you what's going on. in the psychomotor, you slow down your sensory processing, everything is exhausting to do, think, say, getting up in the morning, brushing your teeth and figuring out where you left your car keys, everything is exhausting, overwhelming, which becomes a problem that we will come to this because you simply don't have the energy todo whatever or it's because you just don't have the motivation to bother.

Now, along with that come the so-called vegetative symptoms that the body is working on. In a different way, people with major depression have their sleep patterns interrupted or yes, big surprise, we all have problems falling asleep if we are depressed about something. With major depression people tend to wake up earlier than normal, they wake up early in the morning, plus you find someone when they are asleep. and you put on these EEG probes and what you will see is the structure, the architecture of sleep, we go through different stages and cycles of sleep, that is interrupted, the person is deeply asleep and their brain works differently at that point, which which you also see.

This appetite is altered in many of us when we are depressed in the everyday sense, that is the time to eat Cheetos or Oreos or whatever because the high fat and starch content can decrease the stress in us and people really understand how that works major depression the tendency is towards loss of appetite loss of pleasure in food part of the duckling part of the vegetative symptoms in the body there is a big surprise something else what goes down the tube is the libido interest in sex sexual excitement sexual repetitiveness motivation appetite all that like you're stuck in endless sad thoughts that won't stop sex is way down on your list okay what else is going on?

Of course, overcoming all of this is the real nightmare of major depression, which is suicide and self-harm, and major depression, because of this, is one of the deadliest illnesses on this planet. Statistics. Women with depression tend to attempt suicide much more frequently than men. Depression tends to succeed at this much more often than women. What is your classic profile of impulsive suicide? An older white man with little education and low socioeconomic status who has access to a gun. Now, something really interesting about depressive suicide is someone who is massively depressed. and they're in your ward in your psychiatric hospital and you're like, "Oh my God, they're so depressed and depression is associated with suicide, we really need to keep an eye on this person to make sure they don't do it, that's not when you worry." about suicide with someone with severe depression because it is someone who is paralyzed with his psychomotor skills.

It's not someone who is going to figure out how to shred the mattress to create a new source, something like that is not when people are most at risk, you take someone who is very deeply depressed and you start treating them with medications, whatever they end up with. that and they start to get better and in some cases the psychedelic energy returns, in some cases the person still feels the depression but they recover enough or become mobilized or active enough to go and kill themselves, this is when there is the danger of suicide. Now, another vegetative characteristic of depression, when you look at the psychomotor things, the person can't get out of bed, they're totally exhausted, you're thinking of them as if they were some kind of invertebrate that melts over the edge of the bed or something like that, you look at the heart rate, you look at the muscle tone, you look at the various hormones that happen there and what depression is about is a chronic activation of the neurochemistry of stress, of the awakening of vigilance and we're going to see a lot more about that.

If anything, psychomotor exhaustion comes from the fact that there's a battle going on inside your head and it's no wonder you don't have the energy to get up in the morning, much less get up and put on a happy face, okay? Another thing that underlines that we are talking about biology here is that there is more than one type of major depression, it comes in different flavors, a classic dichotomy that people argue about whether it is really valid or if it is all on a Continuum, that type of things is the difference. between reactive depression something bad happens, everyone feels bad and you know that most people get better in the following weeks, but some people fall into a major depression at that moment reactive depression versus endogenous depression someone falls into a depressive episode and not nothing bad has happened to you other versions of subtypes of depression there is a subtype called atypical depression that is simply dominated by psychomotor issues these are people who just do anything is overwhelming they are less concerned less with anhedonia, rumination all that and interestingly, atypical depression seems to have a lot of biochemistry in common with chronic fatigue syndrome, interesting and first indications now that there may be some similarities with variants of Long Hall covid, the type that still flattens you years later, so there is a typical depression and then there's psychotic depression, people who are so intensely delusional and we'll see what it is that they start thinking seriously disordered oh oh oh I know this big promotion I just got I'm going to get fired at some point that's cognitively distorted that's not delusional in the feeling of psychotic depression some people may remember this harrowing case: this woman, Andrea Yates, several years ago, who in a severe post-partition psychotic depression drowned her children and it took several trials for someone to discover that she It was about someone with a serious illness.

Why did she drown her children? She was a fundamentalist Christian and was raised in a school of thought that simply by being born her babies were almost doomed to go to hell at this time and drowning them would save them before they had the chance to become sinners. this is what psychotic depression looks like because this is absolutely what she believed when she did this and it is heartbreaking for everyone involved different subtypes of depression there are some that have rhythms there are rhythmic depressions where someone has two or three weeks of depression that They are type of disabling it goes away on its own it comes back later on its own and only cycles like that another version is people who have depressive episodes only at certain times of the year, which is called seasonal affective disorders and it is mainly people who fall into their annual depression every year, during the winter months, look at this, you have someone who something terrible happens to in July and they react with depression, they feel terrible.

It's very disturbing and you see that this is not all there is to life and you come out the other side and then comes January where everything is perfectly fine, but for the eighth year in a row they fall into major depression and need to be hospitalized and it turns out that this affective disorder Seasonally sad, these winter blues seem to have a lot to do with light exposure. hormone called melatonin relevant to that, what's the main point here? You take someone who has a different subtype of depression and is neurochemically different from someone with a different subtype.

You take someone with things that are terrible in the summer and they cope and things are great in the winter and they sink you're not looking at just one disease you're looking at a whole family of diseases in this case it's biological this is oh come on, stop to pamper yourself now an additional point in terms of the presentation of depression which It seems that depression very often goes hand in hand with an anxiety disorder. Now, what is anxiety? Hyperarousal. A physiological state of agitation. People with a severe anxiety disorder, particularly social anxiety, also have clinical depression. 50% of people with clinical depression also have a significant anxiety problem.

The two overlap in many interesting ways. One way this has been interpreted is that they are both anhedonia diseases it's not fun to have sad thoughts running through your head nonstop it's not fun to be anxious 247 what's the difference anxiety is anhedonia in a hyperaroused Vigilant State depression is anhedonia Without that now, some more clues about this come from the fact that most of the time, anxiety comes first, one interpretation of this is that you could think of anxiety as this hyper-aroused, frantic, urgent state, like a fire. forest, that anxiety is just little flames appearing everywhere and what depression is about is something that responds to what depression is.

This is a big, old, thick blanket that you throw on top of the fire to remove the air. Depression is an attempt to contain anxiety-related turmoil by simply flattening yourself out. That's a way of thinking about it that is metaphorical in many ways that that relates is another characteristic that you see with this transition of starting with anxiety leading to depression anxiety there is some disturbing challenge in many cases You're a rat, you're a human and they are shocking now and then whatever it is and what anxiety is about is that you are trying to cope with it you try to cope with it in 110 different ways at once, most of which are mutually contradictory you keep trying to cope with it when the challenge is over with this hectic attempt to give me some control Then I can make this challenge go away.

What depression is about then is when you have given up, the challenge is still there and you don't even bother, and we will see this transition in the Psychology section, it is actually about anxiety. Maladaptively trying to cope with depression is about you've learned to be helpless, you've learned to be desperate and in circumstances where you could cope and you could make things better, you don't even try or you stumble into doing it and it works. You don't even realize it worked, so this strong intertwining between depression and anxiety. I'm not going to talk today about the biology of anxiety.

Well, we've already gone and the symptoms, the comorbidities, all that, what is happening in the brain during major depression we start with what is the neurochemistry, the messengers of the brain and depression, for this we have to have the type of slide initial in which everyone who takes Neuroscience 101 is exposed to the image of synapses, you have two neurons, one neuron sends a projection to the other, the other has projections that come this way and the information flows from the first neuron to the second, the first neuron here, some exciting gossip and it gets excited, one cell's version of getting excited and in turn passes the excitement to the next neuron and line the gossip spreads now what you see in the diagram here actually this is just a green screen now, so I'm not sure if I'm pointing at the diagram or not, but in any case what you see is between those two NS, they don't actually touch, there's a space in the middle called a synapse , what that means is the excitation of the first neuron on the left, all the neurons go from left to right, the excitation that comes in this way cannot easily jump over the synapse and excite the next neuron, the excitation that is electrical has that translate into a different form of excitation the first neuron there releases a chemical messenger that floats across the synapse and binds to specialized receptors there and as a result this neuron has Now I heard the gossip about these chemical messengers that are released called neurotransmitters and very soon they will be very relevant to making sense of major depression, okay, a little bit of housekeeping stuff because that will be relevant and the first neuron is totally excited about any news. and it dumps a bunch of neurotransmitters into the synapse and they float around and interact with the receptors there and transmit the message and that's to mirror what happens to those neurotransmitters afterwards because they eventually get rid of these receptors and they're just floating around.

At synapses you have to clean up after yourself, and more generally there are two ways neurons do this. The first is that if they are ecologically minded, they recycle the neurotransmitter. That first neuron, the presynaptic neuron, has these specialized pumps that will get the neurotransmitter here that has done its job and pump it out again so you can reuse it or you can be a total waste and be left sitting in the synapse some enzyme that breaks down the neurotransmitter and you throw it away, what is the trash here? synapses and then to the brain in general and then to the cereal cerebrospinal fluid and to the blood and urine so that people can measure the levels of neurotransmitter breakdown products in their PD and get an idea of ​​what's going on up there.

Well, the first neuron to become excited releases neurotransmitters. that excites the next one or a twist in our story that can make the neuron here less excitable and an excitatory NE transmitter or an inhibitory neurotransmitter and then it gets cleaned up with reuptake or degradation, so with that in hand we now look at particular neurotransmitters. and the one that appears again and again is serotonin. 25 years ago people were talking about this and maybe serotonin would be the second or third neurotransmitter on the list. It is the number one neurotransmitter on the list. Serotonin because it is the most effective. class of antidepressant medications act on serotonin class of medications called selective serotonin reuptake inhibitor ssris the most famous is Prozac, but there is already a wide variety of them selective serotonin retic ssris what do they do thisneuron dumps serotonin into the synapse and normally it would be taken back, but what something like proac does is block the reuptake pump, what happens then there is no reuptake and the serotonin stays longer and, for lack of anything else to do , it hits the receptors a second time, a third time, and the hundredth time and people tend to feel less depressed at that time, so what is the only possible interpretation that arises if you add a drug that causes serotonin to remain in the synapse longer and makes the next neuron vibrate more frequently and does anyone feel better?

The problem was too little serotonin in the first place, and therefore the serotonin hypothesis dominating the entire field now is totally genius. What's one of the most interesting things about it is that serotonin is probably working in a part of your cortex that has a lot of serotonin. It has to do with blocking rumination, all that, so the serotonin hypothesis, the problem in depression is that there is very little of this selective SSRI neurotransmitter, which only acts in the serotonin system. That's not actually true, but we'll pretend for the moment that it blocks reuptake if the material stays in the synapse longer and buzzes here more and the person feels better, the only conclusion is that they didn't have enough serotonin there.

First of all, two problems naturally arise, the first is a crazy thing that affects everyone in the business because you add something like an SSRI and it does things for serotonin reuptake in minutes or hours and usually people don't If they don't I start to feel better over days or weeks, there is some kind of imbalance over time and there is a model that could explain it and it is so horrible and confusing that I have consigned it to one of the similar appendices in the back. They're dumb Russians if they want to learn about that, but that's one of the problems, the time course problem, the other problem reflects this story of serotonin, it used to seem like the second or third most important neurotransmitter and then it became seen. as the most important neurotransmitter there is a problem and then the temptation arose to decide that it is the only neurotransmitter relevant to this disease and what you see is all this controversy these days about the serotonin problems necessary and sufficient to explain depression because it is seen many people use Medications that affect the serotonin system don't actually work or when neurochemical problems are seen elsewhere, this has led to a somewhat anarchistic view that the whole serotonin story is meaningless in their Gib and all that. you know, it's not just one neurotransmitter which brings us to the second neurotransmitter that's relevant, something called neuropenphrine, neurop benine and depression has been on the scene for decades and decades, the first medications developed in the 1960s to treat depression.

They weren't working. at the serotonin synapses they were working at the neurop nephrin Sy synapse and what they were doing one of them blocked the neurop penin reuptake pump something called a tricyclic antidepressant another of them stopped the enzyme that breaks down nephrin from doing its job both resulted in nurr stays around longer and has more effect here and if the person starts to feel better, oh, I bet there isn't enough neuropenphrin either. The neuropen hypothesis and this started in the 1960s and dominated until people learned a lot more about serotonin, but the exact same logic happens there and what you see is that neuropen is probably more relevant in one part. of the brain, don't write this thing called Locust celus.

I can't spell it after decades of darkness, it's a part of the brain that has to do with arousal and vigilance and all that and you start to get stressed and you activate the system and you exhaust the neuropenphrine hypothesis, there's not enough stuff, you're short on neuropenphrine. and what happens instead is that you fall into psychomotor retardation there's a lot of evidence for that third neurotransmitter that used to be at the top of everyone's list it's interesting a neurotransmitter called dopamine everyone knows about dopamine dopamine is about pleasure is about reward it's about cocaine releasing dopamine all kinds of euphoric drugs that act on the dopamine synapses and what you see is whoa that's perfect dopamine rewards pleasure and you start to see some of the drugs that protect there , they block reuptake, they block degradation, oh, suddenly, a person does not have enough drug, that's where anhedonia comes from the loss of the capacity for pleasure because you don't have enough dopamine time to see a much more contemporary image than what what does dopamine do yes yes yes dopamine is about pleasure you take someone you take a person you take a monkey you take a rat and you give it a reward out of nowhere and the dopamine neurons that we are going to hear about release a lot of dopamine yes , it's about the rush of pleasure now you do something more subtle take that monkey rat person and you give him a training task you put him in a room and a light comes on and every time it comes on it means if you now press this lever 10 times you get a reward you've had a lot of practice that light comes on work reward signal work reward works perfectly fine so you put someone this kind of setup when dopamine is released if dopamine is just about work reward signal reward increase in dopamine that is not what you see once someone has learned this task when dopamine increases when the signal appears what happens when dopamine is discharged? these neurons when the signal goes on and the person or rat is sitting there saying yes, the lights just turn on.

I know how this works. I'm on top of this lever pressing a piece of cake. This is going to be an excellent dopamine, yes. It's even more about reward and pleasure, so it's about the anticipation of reward and pleasure and, surprisingly, you block the release of dopamine and don't press the lever. It's not just about the anticipation, it's about the work you're willing to do. at that point, to get that reward, it's about motivation, it's about goal-directed behavior and what you see is that during major depression there is a depletion in this relevant part of the brain that we're going to hear about and What you especially have is a loss of these sharp bursts of dopamine that arise, dopamine always has a certain undercurrent with this anticipation, but you lose the UPS, you don't lose the UPS, not of pleasure but of the anticipation of being willing to Work towards it and what you see is it's not so much about the pursuit of happiness, it's much more about the happiness of the pursuit of anticipation.

Okay, so we have those three neurotransmitters there and what you end up seeing is, you know, it's not just those three. I put up a slide. Here are some of the other neurotransmitters that have been implicated. Don't write it down because this graph will probably be obsolete when you're done with the selection. There are all kinds of players in this big surprise. It's not just serotonin. Sometimes it seems. like it's not even serotonin, it's not just these big three, there are all sorts of other relevant ones in recent years, one of those minor players has started to seem more relevant because again we have this time course problem if you increase serotonin . with one of those drugs if you do the same with neurop nephrine if you do the same with dopamine you are changing things in the synapses In minutes or hours and it takes people days or weeks to feel better, this imbalance and time is totally disconcerting and in In recent years a new medication has arrived, a new medication that has in some ways revolutionized many treatments for depression.

A medicine called ketamine. Ketamine is turning out to be an antidepressant. It's turning out to be one that works in a matter of minutes and people are just getting started. to learn about this and it's relevant to a neurotransmitter called glutamate, so suddenly glutamate comes on the scene as well. Well, we have all these players to broadly summarize what the problem with serotonin is. It's probably rumination because SSRIs work on another disease. that involves rumination obsessive compulsive disorder depression are you ruminating about sadness sadness sadness obsessive compulsive disorder are you ruminating Did I leave the oven on?

Did I leave the oven on? Do I need to have the utensils perfectly straight in both cases? Someone's feet just stuck in some sort of quick sand fly trap and ssris help with that too, so the serotonin part, to be totally simplistic, seems to have a lot to do with the rumination, the nurp part and effort seems to have something to do with psychomotor problems, the dopamine part seems to have something to do with anhedonia and glutamate, people are still discovering and so it's as clear as anyone can summarize all of this and it's terribly simplified, blah blah blah, this is where the people are.

In terms of studying neurochemistry, the most parsimonious thing in all of these cases is that there are a bunch of relevant neurotransmitters and for some reason you're depleted and some of the best medications out there tend to reverse that process, okay? is looking at the biology of depression from the point of view of the brain chemicals and neurons that communicate with each other. What about the actual structure of the brain? Where are your problems? Where are your problems in the brain? What particular brain regions have problems in major depression? and a conference. like this 13 years ago or earlier this now would be looking at this part of the brain and the evidence that something strange is happening there and then in this part of the brain this and where there has been tremendous progress is recognizing that that is not the most informative strategy what you want to understand is the circuits that connect different regions of the brain and that's where there have been some incredible ideas now to appreciate this we need to look at a classical model of how the brain works and again you take neuro 101 at any time in the last thousand years and you go to learn about this the Triune TR R IU NE the Triune model of brain function the three layers of brain function this was a guy Paul McAn Pioneer in G in the 60's who came up with the Triune model it is an unrelated model which neurons they actually project with and who by releasing neurotransmitters, it's just a way to conceptualize three layers of neuronal function, layer number one, what mle called the reptilian brain, that is, the parts of your reptilian brain and you. you go out and look at a lizard and it has basically identical parts there and it's the hypothalamus, the midbrain, the brainstem, what does the reptilian brain do?

The kind of thing reptilian brains do. You get high and you sweat, yes that's what reptiles do, but that's what we do, you're cold, you're shivering, you're hungry, your brain tells you to release hormones that generate appetite, you lose a lot of blood and the reptilian brain tighten your blood vessels to make sure you're there's no bleeding at all, what the reptilian brain is all about, it's just regulatory stuff, like little feedback loops, and on top of that is the second layer called the lymphatic system and you don't see much of it. lymphatic system until you get to mammals, what is the lipid system? about emotions and this is not surprising that reptiles are not famous for their emotional life, only when you get close to mammals do you have a part of the brain that is activated with sexual arousal, with fear, with anger, you take a type wild beast in their territory and some other big male wild beast shows up and is urinating all over the place in an action of Domination and Defiance and it's the Limic System that gets crazy, hot and bothered at that point, the third layer, of which you don't see much until you arrive. for primates, the cortex, the above that is about thinking, cognition, memory, evaluating information, doing or recording all that, so yes, we have this totally simplistic model, reptilian automatic regulation, emotion and thought and, for Of course, what one sees is that this is totally false. trichotomy or whatever in the sense that all these layers are talking to each other, for example, that scary Beast W shows up and urinates there and your domain is being threatened and all your emotions are going crazy in that limbic layer and one of the things that also happen is your heart starts beating faster, the lyrical emotional brain is telling the reptilian regulatory brain to change its function, you're just standing there looking at this guy, this barbarian at the gates and layer two tells him. tells layer one to activate, not because you're running. you walked up a flight of stairs, but because you were just emotionally aroused, layer two can talk to layer one, layer three can talk to layer one, now you just sit there and don't see that big scary wild beast appear that you're right there. before you go.

Sleep thinking about that boy and how disturbing he was and layer three activates the emotional lyrical system. Layer two makes your heart beat faster. This is just the means by which thought and memory can make your body function differently in all kinds of interesting ways. there is a lot of regulationtop down, plus there's a bottom up layer talking to layer two, just regulatory things that change your emotions, an example of this when people are hungry they tend to become less cooperative, less empathetic, they cheat more in the economic sphere. layer one wins or here's the news about circulating blood glucose levels influencing emotions there layer one influencing cortical judgment cognition kind of thing and the classic example of this is this amazing study from a few years ago who looked at a bunch of judges making decisions on parole boards, you give the guy good news, yeah, you were released, or bad news, you go back to jail, and over the course of hundreds and hundreds of judicial decisions in this system judicial, what was the greatest predictor of what a judge was going to decide? this person goes free goes back to jail how many hours had passed since the judge had eaten get someone right after a meal and you would have about a 60% chance of being released 3 to 4 hours later it has been reduced to zero wait a second, your blood glucose levels have to do with your requested reasoning, at which point you sit down with a judge and ask why they released this person but sent another to jail even though they both had done the same thing and you I'm not going to make them talk to you about blood glucose, they're going to go back to the freshman philosophy in a manual scam or something like layer one regulating layer three, by the way, as a footnote of page, here the judges, the study of the hungry judges has obtained a large amount. of media coverage, which is great because it's an incredibly interesting study, there have been some challenges, people say there's a flaw here, there's a confusion here, whatever, and for my money, the original authors have rejected each of those objections, this is a very solid study. finding that has now finally been replicated Layer two can talk to layer three emotions can talk to your cognitive brain, what is that about in an everyday life context?

That's why when you're frothing with excitement, you make terrible decisions. That's why when we're all emotionally freaked out about something, we do some stupid thing that we're going to do. regret it for the rest of our lives and we think it's brilliant at the moment when emotion marinates your supposedly nice and nocturnal rational cortex and why is this? In depression your cortex can sit there and say no, there's really no reason why this is going to go wrong in the future and here's why and that negative emotional bias is swelling up there and making you conclude that this was my past this is my present this is my overwhelming future there okay so we have this broad orientation here the Triune layers and again This is just the metaphor.

What we begin to see now are some of the circuits that are relevant. We start with our first circuit that is relevant to pleasure, anticipation and motivation, and all of that is very relevant. You'd better bet on both anhedonia and dopamine. a part of the brain called don't write this mesolimbic dopamine system and it consists again I guess where the slide shows consists of these two areas of the brain the vental tegmental area the nucleus acumina don't write this this is the part of the brain that drives the anticipation of all those things and so if there's a shortage of dopamine there or if the neurons there become less sensitive to dopamine, you're looking at loss of anticipation, loss of motivation, loss of pleasure and honesty.

Where does this come from? In depression you see hyperactivity of two inputs to the mesolimbic dopamine system, the first region of the brain, the amydala, the amydala is activated in response to unpleasant things, fear, threat, challenge, it drives aggression, all those stimuli. negatives activate the amydala and what you see is the The amydala input to the mesolimbic system is overactive in depression and what is the effect of that input tends to inhibit the dopamine system there, so that's bad news. One interesting thing is that you take someone, you put them in a brain scan and if it's someone without depression.

You show a picture of something scary and in a split second the amidala activates. You put someone with depression and a brain scan and it doesn't activate when you show them scary images. The amidala is activated when you show it sad images. It's reconfigured. to a different function until you think about it, if what the amydala is about is responding to scary things and you're really depressed, the scariest thing on Earth is anything that can come up that makes you even sad, so the nigala has simply been put there. Meanwhile, this other part of the body, the ACC, the anterior singular cortex, a totally cold brain area, what does it do?

It's about empathy, like this, you take someone, you put a brain scan and you prick their finger with a pin and all kinds of parts of the brain activate saying it was my finger, not my toe and that's it. kind of thing and the ACC also activates it encodes a representation of P now take someone, put them in the brain scanner and don't prick their finger with a needle, have them watch your loved one's finger move. It is pricked and the anterior singulate cortex is activated. These are neurons that literally can't distinguish between the pain that you were feeling and your own empathy for the pain and what people find is that the anterior singulate cortex tends to be overactive.

I have major depression and what it's also doing is feeding inhibitory signals that bring down the entire dopamine system, okay, so let's step back from modern science and turn this into some kind of idiotic metaphor for the previous singular in the cortex and it What's happening with depression is that ACC is like thinking all these sad thoughts. time and those are cognitions and somehow they send it to the lyrical system and turn it into sad emotional thoughts and they get the reptilian brain that the ACCC, feeling the pains of the world, is driving all kinds of things south, like this which this brings up. totally idiotic idea, so you have someone with depression and the ACC is too active, which is exactly what is shown, what would be a great solution: go in there and cut right below the ACC and make it impossible for him to speak with the lyrics. system and down the depression turned idiot Shazam and surprisingly it works desperate desperate final measure with the most severe depressions that have resisted all treatments imaginable is to make a singulo to cut the projections there so that metaphorically your ACC can't sink into bad thoughts and then make the rest of the brain work as if it were real in terms of real circuits, so that the ACC cannot deplete the mesolimbic system of dopamine and this procedure, which is a desperate Hail Mary, seems to work in about 50% of people. severe cases resistant to treatment, okay, so hold on, we'll notice one more thing in that diagram, both the ACC and the amydala interfering with the nezic dopamine system through the LH, a part of the brain I once knew for a long time time. end in the lateral habenula and when you activate it it inhibits the dopamine system and that's okay, that's part of the story and there's all kinds of evidence that it's overactive in depression and therefore it inhibits the dopamine system.

All that, what is the neurotransmitter that the lateral habenula has? you're using a lot of that GL glutamate neurotransmitter, where ketamine works in a matter of minutes as an antidepressant. This is the part of the circuit that is right near where you really want it to affect things, maybe that's why manipulate this and you feel better in a matter of minutes. or hours and worry about some of the others with slower acting medications and it takes days or months, suddenly lateral habenula and glutamate on the map and the terms to make sense of the circuit are okay, so that's the circuit that tells us something about loss of pleasure, loss of anticipation inhibition suppression exhaustion discouragement of this whole dopamine system down there in response to things like painful empathy negative stimuli Etc. now we move on to our second circuit and the second one is relevant to the room, the Sad thoughts won't go away and this has to do with a network in the brain called the default mode network.

You put someone in a brain scanner and watch. When you do this, this part of the brain activates and you do that to it and this part goes silent or whatever and MTH, things come out and the pain in the main feature is that you don't do anything to the person and there's everything kind of background activity, different parts of the brain just murmuring in the background all the time and this used to be seen. as background noise and when you analyzed your experiment you would have to subtract it as meaningless, irritating background noise until people figured out that it wasn't just background noise, this was the default mode Red that's always rumbling there, what's it doing ?

It's keeping your sense of self going, kind of autobiographical artwork, the default mode network is responding sensory, it's just this kind of background hum there and what you see is it's a default M pathway to get to the system. mesolympic dopamine and if what you're doing is daydreaming about your default network, which is one of the most important things, if you're sitting there daydreaming about sad things, this is another way to get to the mesolympic system, so what? where does rumination come from? this is just this resonant circuit and it goes over and over and all this kind of stuff, who talks to you during depression more than usual, the anterior singular, the amydala, the amydala through the anterior singular, lateral, all that, You access the circuit that way and that entangles you with reflective thoughts, that's what this is about now that takes us to our third circuit, which is the most important from the point of view of rumination, you have to Amal is too active and the ACC is too active and this default mode Network is too active for you to be ruminating on negative things.

Isn't there some part of the brain that can tell you to stop and that can tell you to slow down to stop it with all this negativity? And this is that part of the brain. I mentioned the frontal cortex earlier in the prefrontal cortex, a subarea called the dorsal lateral prefrontal cortex. What is it good for? It is good for breaking rumination. It's good for making your default mode of mumbling in the background suddenly stop when you're concentrating on things. the free frontal cortex the dlpfc is really good at blocking negative thoughts and counteracting positive thoughts and reevaluating all that and you better bet where we're going next the dlpfc is less active than normal in people with major depression and we see a lot of chronic depression serious and this dpfc even atrophies a little.

This is the part of the brain that tells you to do things like not steal money or not say outrageous things even if you're tempted and it doesn't block out all kinds of emotional things, it's the one that would normally say stop thoughts here stop negativity and stop thinking. weakens during depression two more circuits that are relevant one of them takes us back to that stress thing before and we hear a lot about stress when we get to the

psychology

section stress, you look at the body of someone with depression and there is a whole circuit brain that has to do with excitement, emergency, anxiety and all that.

These types of stress circuits are overactive in depression and we'll look at some of the tasks there, an additional part of the brain, okay, this is something in a part of the brain called the hypothalamus and it communicates with the lucus celus and the midbrain and everything. . Of course, this is the circuit by which being mired in major depression is a lot like being chronically stressed. Final circuit and this is one in which I confess that a part of the brain called the hippocampus I have spent my entire life studying the the hippocampus is a region of the brain that has something to do with memory, all of that is great and I spent years studying what it has I have to do with the hippocampus with depression and I have come to the conclusion that it is actually not one of the most interesting parts.

It's really involved in depression in all sorts of ways, but it's not central to anhedonia, psychomotor, rumination. You know, Benjamin Disraeli, the famous 19th century British political neurochemist, said that youth is about mistakes, old age is about regret, and now I regret wasting decades on it. hippocampus why even think about it in terms of stress and depression? with chronic depression, the hippocampus shrinks the neurons there, withers their synapses at one end, the neurons even die there, the hippocampus is not able to produce new neurons and all kinds of treatments for depression. We're supposed to focus on getting the hippocampus to grow new connections again, and hippocampal problems probably have something to do with why your working memory goes down the tubes with depression.

This is my confession here. I don't think the hippocampus is that important. As I am used to with all this, I have published it in a magazine called hippocampus, for the love of God, it is notcentral to the really important things, the anhedonia, the rumination that goes on and on, the thoughts that could stop the psychomotor exhaustion you have. something to do with cognitive problems, there are all kinds of people who will believe that I have now blasphemed before anyone else. Beyond any hope. Well, we just saw the neurochemistry, we just saw the neuroanatomy, the circuits where those neurotransmitters are. they're being relevant when this area talks to this one or this area doesn't talk to this one as much as it used to with all that extra bit of hormones in all those glands in your body that go into your brain and affect function.

So where are the hormones relevant to depression? One that's really important, but I'll go over it real quick because I don't actually find it very interesting. Oh, another confession: hormones related to the thyroid gland, thyroid hormones keep the metabolic rate high, all that and It turns out that there are many people who seem to have major depression, especially an atypical one dominated by psychomotor retardation, and the real problem It's that they have a hypothyroid disease of some kind and have too low a level. it levels out a thyroid hormone and there is some indication in the literature that that may have some antidepressant effects if someone is given replacement thyroid hormones.

What's most important about this. What goes wrong in depression is not just the psychiatrist's work. The work and what goes wrong in the thyroid gland is not just the job of the thyroidologist because you cannot take the pieces of this part of the body apart which is very, very relevant to your metabolic rate if you are running out of hormones and you are running. On a single cylinder, psychomotor depression, especially, is one of the consequences of the next hormone that is interesting and this is a hormone that I love more than any other on Earth because it is the main stress hormone that we have all heard of talk.

Adrenaline is garbage, it's Teflon. The reputation is very oversold. What's really interesting is a class of stress hormones called glucocorticoids. I have sung about glucocorticoids. They are so wonderful. Hormones that come out of your adrenal gland. Wait wait wait. Adrenaline comes out of your adrenal glands. Different kind of hormones. Hormone class. coming out of the adrenal gland glucocorticoids human version called cortisol hydrocortisone rodent version corticosterone all kinds of synthetic versions of the steroid hormone dexamethasone phyzone all that and there are real problems in the glucocorticoid stress system during depression. I've already heard about it, which is in many ways what happens in the brain.

Chronic depression is a picture of a chronic stress response at the hormonal level. The same as excess glucocorticoids in the bloodstream. An important finding in the early '60s was that it's a particular type, the glucocorticoid stress system has trouble shutting down once a stressor is over, it has trouble recovering, getting back to baseline, that seems to be its problem and we understand a little bit what it is and a classic clinical test, something called the dexamethasone suppression test DST dexamethasone a synthetic Luca cortico that they give it to you and this is a way to test if your system is resistant to shutting down after the end of stress.

Do you continue to secrete corticosteroids long after DST ends? The standard test for this, the DSTD, was invented in the early 60's and I remember my friends and I were very excited about the potential of the DST, we were all in kindergarten at the time because this could have been the Holy Grail of psychiatry, forget about talking. to the person just give me a blood test where I can diagnose this and then psychiatry could be another branch of medicine to beat the chest and not have to embarrass myself anymore, aha, the DST that will be the diagnostic test.

You give someone the DST and see if they continue to secrete glucocorticoids and that's how we're going to diagnose the disease, we'll never have to talk to someone with depression again and of course that turned out not to be specific enough, there are other psychiatric disorders in the that the problem is disappointed. that in first grade they had already accepted it, however, what you see with the glucorticoid system is the same as in the brain, your hormonal system suggests chronic depression, it is the chronic activation of the stress response. Now we move on to our final hormonal system and the That's probably the most interesting thing here for many people, which is the ovarian hormones.

The steroid hormones that come out of the ovaries, such as estrogen, progesterone, are very relevant to depression. How do you know that the first evidence comes only from demographic studies? Epidemiological studies. Women are about twice as likely. As men, if you have major depression, you are not twice as likely to have bolar disorder, manic depression, a totally different disorder that we're not talking about, but about two to three times the rate that men have. Cross-culturally, all types of societies are analyzed. Why are women so vulnerable to depression? Maybe they aren't. Maybe there is all kinds of confusion.

Perhaps women are more likely to help in a depressive state which turns out to be the case. Perhaps women are more likely to be able to do the same. Reflection on emotions is necessary to come out the other end, and reflection is part of what gets them there in the first place. We will see more about that, maybe there is something else going on and this has always been a confusion in the field. People who have major depression self-medicate because they have not been diagnosed, no one gives them medication and one way to deal very temporarily with their depression is with alcohol temporarily because afterwards it will be worse than before it started. higher rates of alcoholism perhaps many men who were classified as alcoholics what they are really doing is self-medicating a depressive disorder go into incredibly careful cross-cultural epidemiological studies and what you see is that women are two or three times more likely than men Men have major depressive disorder, okay, so how can you begin to explain this?

We can try to do this at a level of socialization of social behavior and you start to see sort of a very relevant first set of sex differences right from the start, a difference between men. Men tend to be at higher risk of depression in circumstances where they lack control over their lives. Women, on the other hand, are more likely, on average, when they lack social support. Women get more sense of self worth and self worth from their social connections than what their salary is in the corporation you see differences like that maybe that has something to do with it you see differences in other Kingdoms on average not all but on average women are more sensitive to social rejection than men and That's certainly relevant to a lot of this, there are other aspects and this is like one of the big ironic findings in the whole field of social support that we hear about social support being helpful in buffering depression. , what about marriage and what you see?

It's like married men are more resistant to depression than unmarried men, and then you see that married women have greater increases in depression than women who are not married, as has been said from a psychiatric point of view neurochemical. it's toxic for women and protective for men, okay, so all of these possible clues as to why there are different rates that have to do with social environments, then there's temperament, cognitive things, women on average are much more thoughtful than men, they are more likely to get caught. In negative affect loops, men on average are much more likely to use an avoidance strategy.

I do not want to think about that. I do not want to talk about that. He can't talk about his emotions and that's a constant sex difference in populations by sex on average, all that rumination brings you closer to the edge of getting stuck in the stagnation and quicksand of rumination, so that's a possibility, so it shows how much control you have in society and how much social support and how thoughtful. you're prone to anxiety because women also have much higher rates of anxiety, so all that, but then let's look at the biology because all those ovarian sex hormones are doing all kinds of interesting things in the brain, where does biology come in?

First of all, estrogen, estrogen makes some parts of the brain more sensitive to some of those stress hormones and this part of the brain don't write this, the locus celius that responds to stress or the transmitter called CR and CR can produce the locus cellus. Depression and estrogen make this area of ​​the Locus cerus relevant for psychomotor skills, making it more sensitive to this neurotransmitter. There is a lot of estrogen around and the same amount of CR is more depressogenic in this part of the brain. Maybe a drug could be produced that would block the effects here and people went and looked at all kinds of studies with rats and the conclusion is that no, there is actually a mistake in that literature which is that virtually all the studies were done in male rats, ooh, too bad, there's a little problem there.

They should have been done in female pathways because estrogen is very powerfully enhancing this pathway. Well, then estrogen does that. What are the things he does? Different antidepressant medications work to different degrees in different genders, depending on hormone levels. Things like that. We have some biology there, then we go and look at people's genes, we look at people with and without depression, women versus men, and what you see is that there are about 50 genes that go in opposite directions of activation, 25 of they are activated. are off, but they go in opposite directions depending on whether you're looking at a man with major depression or a woman, there are differences in gene regulation now, in many ways, what screams biology the most with sex differences is that it's only true time.

At times in life when women show higher rates of depression than men, what this immediately brings us to is the menstrual cycle and menes, menstruation and PMS lingo. What is clear now is that it is per menstrual, it is the moment just before and after, rather than just after and what one sees is most of what has been thought about premenstrual changes in mood and those things are myths in terms of the magnitude, the amount of mood swings there are are approximately the same as in men over the course of an average month or two. it's just that it's coupled to this time period and what you see are all kinds of suggestions that PMS, the average person has a certain degree of anhedonia and a certain degree of enlightenment and then you get severe perimental syndromes instead of just symptoms and these are people where everything is completely out of control with them all the time there have been all these great social anthropology theories about what menstruation is about and why people feel sad, so it's because you're in a culture that is tense about sex and if you go to any In the cool Polynesian culture you never see parmenstral mood swings, it's all over the planet and what really tells you that we're looking at biology here is that you look at a female baboon and her likelihood of social interactions decreases when she is menstruating and she becomes socially withdrawn.

At that moment she surely doesn't know if the spirit of her culture is to be like sex and bodies are beautiful or are tense and sinful. We are not the only species to show a permentral decline in the positive AFF effect now, then again. of life where you see a large increase in the incidence of depression in women a much higher rate where it shoots up in terms of comparison with the general state of Mal is after giving birth postpartum depression in the days weeks months after a subset of women fall into major depression at that time, what is happening there, the first thing is the mythical versions, it used to be said, and I said it in my sleep in my lectures, that the postpartum period is the time of life in the one to which humans are most at risk. for major depression that is probably not the case, the postpartum period is the time in life when humans are most vulnerable to their first episode of major depression, that seems to be the case and what postpartum depression looks like, all kinds of things in the brain. scanning and you hear your baby's voice and you don't secrete dopamine, you hear your child crying and you don't get changes in your pupils or your blood pressure, it's detachment, that's it, so what is postpartum depression?

There are clues that have to do with another hormone that comes out of the ovaries along with estrogen, progesta, progesterone that is secreted tons during pregnancy, it is progestational and what happens right at the time of delivery, these extremely high levels of progesterone plummet right after. At birth, they subside as thousand-fold changes in level in the bloodstream and there are someimportant indications that a subset of people who are vulnerable to postpartum depression, where this happens to them, birth and pregnancy after pregnancy, and this is what was happening. Sticking with Andrea Yates with her psychotic depression drowning her children, there is a lot of evidence to suggest that these are people who have a larger than average drop in progesterone or that their brains are more sensitive to a drop in progesterone and this has led to The newest medication for the treatment of depression was approved a month ago.

Right now it is August 2023. A medicine called Zora alone. No, I have to look it up because I had to write it. Oh, I just ruined everything. Oh, that. it's what's her name Zora n just Zora Nobody's okay this was news to me because I don't know much about the postpartum part of the story noron just neon just neuron just every was already up this was just on the news it's the The first antidepressant approved by the FDA for having specific effects for postpartum depression. It has a drug that works a little like progesterone in the brain and people are just starting to discover this.

More clues in terms of people with postpartum depression. You see all kinds of people who have normal progesterone levels but fall into the post par tradition and you see that they have variations in their estrogen-related genes, estrogen receptors, progesterone receptors, things like that that are different than most others. people, so there is genetic vulnerability. there over and over again what we're shouting here is biology biology and what you see is that every neurotransmitter system you can imagine dopamine serotonin nephrine glutamate is affected by estrogen and by progesterone and they are ways of tapping into every synapse relevant to the depression, other biological part, inflammation, people who have chronic inflammatory disorders or higher risk of depression, well, it's not surprising that you have some nasty chronic inflammatory disorder that you control, you compare them to people with some other chronic illness that is the same terrible and disturbing and is in inflammation. in itself puts people at higher risk of depression.

They are given drugs that mimic aspects of inflammation and this is done with some cancer patients and they catastrophically fall into major depression. The brains of people with depression are looked at postmortem and markers of chronic depression are seen. neuroinflammation and some interesting parts of the brain, so you have evidence that inflammation can increase the risk of depression and then you see that depression increases activation of the inflammatory system, you have a vicious cycle very similar to what you see with glucocorticoids and stress high levels of glucocorticoids you give someone a lot of artificial synthetic glucocorticoids for some disease they have a higher risk of depression you get a disease called cushion disease in which you secrete too many glucocorticoids you are at risk with glucocorticoids and stress can cause depression, depression activates the secretion of glucocorticoids, a circuit there on its own and what you get is that after a while you transition from major depressive episodes tend to come after periods of extreme stress that trigger this and what you start to see, oh, another major stressor and Sometime around the third or fourth major stressor that triggers a depressive episode, you start to see the system running on its own with its own internal endogenous rhythmic jargon for what happens there (this is called ignite ignite like kindling that you set on fire that explosion this is when the relationship between stress and depression suddenly ignites and takes off on its own now in the same way that you do see chronic inflammation can cause inflammation can cause depression and depression activates the inflammatory system once again, a loop there, you may be wondering this digression I just made about glucorticoids and turning on, that's because I suddenly remembered that I forgot to mention in the previous section, so record the last two minutes and we splice it back in there, but what we see is another example of a vicious cycle where the peripheral biological aspects of things are not good, which makes depression more likely, which produces more of that biological profile in your body, along with other things, your intestine. the bacteria in your gut has something to do with the risk of depression, people are doing all kinds of interesting things about that and for some reason I always fall asleep reading those P's, okay, what have we come to now, finishing the first of these two conferences we have?

Now you've learned about the neurochemistry of depression, the neuroanatomy, the circuits, the neuroendocrinology, and the neuroinflammatory aspects, and at this point you are a biological psychiatrist because you have all this knowledge about every contemporary part of the biology relevant to this disease. and at this point, if this is all you know, you're not going to get anywhere and actually make substantial progress in treating someone's depression, because what we've seen here is only half the story, the biological components, all the things I've gone over in this pair's next lecture on how it interacts with the psychological components of depression.

If you don't study the interactions between the two, you will never gain a fundamental understanding of this disease, so if you're still interested. In this pair of lectures, the next one looks at the psychological aspects of depression and, most importantly, how these two bodies of knowledge interact and a surprisingly interesting way of explaining what happens with depression, so maybe we'll all pick up after have a snack. Welcome to the second. Now part of this talk, one of the occupational hazards of professing things and lecturing is that you get through an entire lecture and then at 2 in the morning that night you suddenly remember, oh, I left out this or that in today's lecture. and I have been wrong. up and this is what we fear and of course after finishing the previous lecture and eating some cookies or whatever and saying oh no, I left out a whole section that I'll touch on very briefly here after going over everything before the neurochemistry, the neuroanatomy, neurological circuits. neuroendocrinology neuroimmunology all of that um I was going to briefly discuss what were the effective treatments these days that address the biology of what we just learned about depression and that's the variety of standard SSRIS medications like proac medications like Wellbutrin others that are pushing up serotonin signaling neopin phrina signaling dopamine signaling this Dr. that is only supposed to work in this system turns out to work a little in this one, people are still classifying you give people combinations of orchestrations of multiple drugs to try to address these three systems or ketamine and addressing that other neurotransmitter glutamate, so these drugs are there and they are miraculous when they work and as I pointed out at the beginning, about a third of people are resistant to treatment to any of the conventional drugs and the people who respond to anti-depressant drugs, about half of them have to be stopped because the side effects are intolerable, so yes, for drugs, it is limited, it is limited in how much they can do, they don't cure all the cases, not even remotely, then there's this whole realm of things like that. non-traditional antidepressants that people have been working on, those that block the stress response, those that block inflammation, those that affect how your gut works, those that replace thyroid hormone, and together, each of these people are totally enthusiastic about none of them.

They have had great success, but they all have some effects, they help a little, they help with this type of depression more than that type, all of that at this stage is still second level. What other treatments does someone who has resisted all receive? kind of medication that you've tried for their depression and they're really depressed like they're hospitalized because they're not working anymore and you get really desperate at this point and you look for the next line of defense against depression. depression ECT Electroconvulsive therapy electroshock therapy 18 seconds of its history is a treatment in which people's brains are shocked with electricity.

Scientists, doctors stumbled upon it purely by chance because it had antidepressant effects and during its heyday when people were so excited about it, they were using too much electricity and too many rounds and doing it to people they had no business doing it to. give them ECT and cause all kinds of brain damage and memory loss and a few years ago, PE people in Berkeley, on the other side of the B, for me, who believe in all kinds of nonsense and scoundrels that I deeply agree with agree, I even tried to have a referendum that would ban ECT within Berkeley.

ECT in its modern form you do a limited number of rounds you don't use much electricity I had a lot of professional investment to prove that ECT caused permanent brain damage and I couldn't find it, so what is it doing? Metaphor: Breaks the back of major, treatment-resistant depression. What is it doing in the brain when you hit someone with strong electrical pulses? What it does in the brain, no one is absolutely sure ECT has been around for about a century. Now it does things in the hippocampus, it causes the hippocampus to produce new neurons and that got me really excited.

That's the part of the story that knows it does everything for Each and every neurotransmitter that we've heard about is very effective for severe and desperate cases and we still don't really understand how it works and I have a close friend who is a psychiatrist who He said that every time he gets a patient who is severely depressed and he looks at them. and he says he's fine before finishing with the only thing that will help this person is ECT. They are very frustrated because they have to waste 6 months trying different medications that they know are not going to work until they can.

I conclude that the medications did not work, okay, let's try ECT. It's crazy how, on average, there are months of additional suffering before this can occur, amidst ECT having a horrible reputation. Jack Nicholson One Flew Over the Cuckoo's Nest, a history of abuse in its modern version is safe, it does not cause permanent brain damage. Dage in most cases, the vast majority of cases does not cause permanent memory loss and helps with severe depressions, although who knows what it is doing, one last area of ​​contemporary treatment and this is a realm encompassed by: you place a electrode in a part of the brain and stimulate it to become more active than it would otherwise be, like the mesolimbic dopamine system.

You do something called deep brain stimulation, which is one cutting-edge approach and another. one essentially does the same thing with magnetic waves on the surface of the skull, TMS transcranial magnetic stimulation and another, there's a nerve that enters the brain called the vagus nerve that stimulates there, these are exciting, these are some new approaches, tons and tons more. Work is needed once again within the framework that 15% of all people in the world will have disabling depression at some point and everything I just mentioned: conventional medications, new waves of medications, ECT, these brain stimulation, all that. and only about 20% of people are diagnosed for their depression and of those that don't work out in about a third of cases, we desperately need more treatments.

Well, this is where we should have ended the previous lecture and everything. these neurobiology things that you now know and if you're one of those people who decided you hated biology in ninth grade, you turned this lecture off after 10 minutes, you know all this stuff and my bottom line was if that's all you know and the bolt biology, you're not really going to understand this illness because you have to integrate it into the psychology of depression and a great way to frame this is that you're not going to understand how one part of the brain or a single neuron works. works or a single synapse works, you'll never really understand it if you don't consider it in the context of the entire brain and the person that brain is in and the society that person is in, because all those factors, psychological, cultural, etc., all of that impacts each of those synapses and that's where we'll see our integration between the biology of depression and its psychology, now the realm of depression psychology that people have been thinking about for a long time. and God help me not to mention his name Freud had some really interesting and moving things to say about depression in the midst of all the other problems it caused um, but Freud, a famous essay about his grief and melancholy, grief, you cry to someone who changes the century, viones term for what we would all call reactive depression something bad happens you get depressed for a while you recover Melancholy old vna term for what we would now call major chronic depression what is the difference betweenboth because that's the question that started when we all cry sometimes and a large percentage of Americans end up reaching the other extreme, we heal, what is it about the subset of us who, instead, fall into melancholy, fall into depression older and Freud's explanation was based on all kinds of forums and nonsense that are nevertheless right? we feel it intuitively so According to Freud we have loved object objects people we love ideas we love everything we have loved objects and Freud and inevitability we have mixed feelings about them we have a Love-Hate relationship with our loved object we are we have ambivalence about all of them, so in Freud's thinking, you lose a loved one, you lose a love object, someone has died, whatever it is that you really care about and the kind of Freudian requirement, you have mixed feelings towards them and you love and you hate and all that. , and most people when they are in this period of mourning their lost person, what they can do is let go of the negative feelings, the hate, all of that and just focus on the love and by focusing on the love in the that they can concentrate and then do that. how someone comes out the other end and is cured where does major depression come from where someone loses someone lost and instead falls into melancholy in Freud's vision these are people who are not able to let go of anger and hatred and the negativity and not being able to experience the pure love that you felt for them, instead the ambivalence continues and their view is that someone doesn't heal, that's where someone goes into major depression, in many ways that that feeling feels good, but it's very difficult to do modern biology about it and one of the really interesting ideas that Freud came up with about depression is that depression is anger turned inward and you've lost a loved one and you you loved them but you hated them and you're all this ambivalence and all that and you just lost the chance to tell them the things you wanted, to hear them say what you always wanted, all that and you love them and you're mad at them and all that. about it and you love it and ha and all this is happening inside you, no wonder you're chronically activating the stress response and it's hard to get out of bed in the morning.

Something about this Freudian formulation just feels right, but you still can't figure out what the love/hate ratio has to do with estrogen/progesterone ratios. It's hard to do modern biology, where we get the most information about the psychology of depression. Contemporary ideas are by looking at the role of stress now. We have already said stress many times here stress in the endocrine sense stress in the neurochemical sense all that stress in the psychological sense and when we start to see the first thing we see is the epidemiological evidence of important stressors at a rate much higher than expected.

They precede someone's first depressive episode, they come out the other end and are probably fine for the rest of their life, just like everyone else, they have a second big stress a week later, a decade later, who knows what , and they fall into a major depression you have a third major depression and it's around that point that it starts to work on its own when it kicks in when you're stuck in this vicious cycle and you no longer see a major stressor as the precipitant of the depression. . So that's one way to see where stress comes into play.

Stress is a major predisposing factor for major depression, especially stress in childhood, and all kinds of studies show things like early life loss, losing a parent to death when you were still a child and when. Studies show that for the rest of your life you are now at significantly increased risk of major depression. Stress can plunge you into depression. Stress can prime your brain now so that you will be a little more exposed for the rest of your life. Take a chance now, what's this about stress? Stressed because the lions are chasing you stressed because of the tornadoes.

All that we are mainly talking about is psychological stress and we have entered here into a very, very primate realm because primates are specialized and psychological stress. I spent 33 summers. studying wild baboons in East Africa trying to understand who had the best stress. It was great studying the responses and the healthiest bodies and what it had to do with this or that and the bad limits. They live in these big complex social groups and they get giant teas that the Lions mess with them maybe once a year and they just have to do it. they spend about three hours a day getting their daily calories looking for all of that and what that means is that the average fat moon has nine hours of free time every day to create psychological stress in another person bullying dominance interactions pity displacing aggression because you're in a bad mood it's all about psychological stress, just like we again, we have the westernized luxury of spending most of our days feeling stressed not by Tre Predators but by psychosocial factors and what you start to see then is that psychological stress is its own entity. like cutting off someone's arm, they're going to have a stress response, you know, starving someone, there's a stress response chasing them with a machete, any physical stressor.

Reptilian brain, all that stuff before you psychologically stress someone out and your brain and his body can do the same thing and this. They are our first steps into a lot of psychological stress that produces a disease of depression in which many parts of the brain and many hormones feel like you are chronically activating a stress response, so of course this leads us to what creates psychologically stressed. stressful What constitutes psychological stress for the same external reality? What are the mediators that make some of us more likely to become stressed? What is psychological stress? Some beautiful, elegant studies dating back half a century have shown exactly what the basic components of psychological stress are. lack of control stress, you take a rat that has been pressing a lever and gets rewarded and presses the lever and doesn't get a shock and is at the top of its game and suddenly the lever stops working, it has lost control and has a huge Same thing with college freshmen in Psych 101 who come and volunteer and they're doing a lever that makes it less likely that they'll get a mild shock and the lever stops working and they get a stress response. : loss of control, loss of feeling that you are the captain of your ship in any sense and what you see is that now you take people as volunteers and they get an electric shock from time to time and you tell them that by pressing this lever a shock is less likely, it doesn't really do anything, you still have exactly the same frequency, but because they feel they are in control, they have less of a stress response, the next basic component of psychological stress, loss of predictability, when a factor appears stressful, you are much more encouraged. the creek in terms of feeling stress, secreting stress hormones, etc., if you don't know when it's going to happen and you don't know how bad it's going to be and you don't know when it's going to end and therefore you really like it. deep studies where you take someone and you go shopping every once in a while, every time they get a shock, they activate the stress response, but then you give them predictive information 10 seconds before each shock, a little light goes on warning and they don't have as much of a stress response a sense of control a sense of predictability what are the other building blocks lack of exits you're at the bottom of a hierarchy and you were being abandoned left and right and what you see there is that You can't leave anyone else and you don't have outlets and you don't have social support and you don't have what that looks like in a baboon if you were a low-ranking baboon you lack control you lack predictability and you lack outlets because someone hits you because they're in a bad mood and you can't really go and tell someone else that you feel bad.

Could they prepare you? Nobody prepares you. No one will have sex with you. You can't hit anyone smaller because you. They are the smallest, and interestingly, many years of work on my part showed that if you are a low-ranking baboon in terms of stress hormones and physiology and all that, you are very much like a clinically depressed human, so the lack of outputs is implicit. in what I've been saying all this time, the lack of social support, having someone's shoulder to cry on or studies, something as direct and reductive as something, stress all the shocks from time to time, and you can take the hand from someone you know and trust, and we don't get as much of a stress response.

All of this feeds into all the things we heard from men before. Depression is disproportionately due to lack of control in women. It is disproportionately about a lack of social support. It is always one of the big four there is. them lack of control lack of predictability lack of outlets and lack of social support and the same external misery is much more likely to make you activate a stress response and the same external misery under those circumstances if it happens enough times over and over again and it's more likely to make you fall into major depression depression is a disease of chronic psychological stress and over the years it is enough and eventually it kicks in and the system works on its own where does this fit into the way we conceptualize stress psychological? this extremely powerful model of depression called learned helplessness and we go back to our scenario, you have the rat that gets shocked from time to time but it's pressing a lever and it's fine, it's preventing the shocks and it's great at efficacy and agency and all that and De Suddenly the lever stops working and the rat goes into an anxiety phase where what happens in its body is like if a human has an anxiety attack and all that and is trying to cope with it, he presses the lever 10 more times. than normal and he's pressing the lever with his feet and he's pressing the lever while wearing his lucky socks and everything and he's just trying to cope, trying to cope and the shocks keep coming and the liver doesn't do anything and finally the rat she gives up, she has become helpless. becoming hopeless and what many people consider the transition from anxiety that precedes depression is that transition into maddened maladaptive attempts at sort of coping and 24/7 vigilance and not recognizing when you're at risk. saved and all that until there's nothing I can do. to do about it and helplessness and what you see is that when an animal version of learned helplessness occurs there is a depletion of serotonin and dopamine and antidepressants could be protective and that is one of the paths to that, so What we see here is stress, a lot of stress.

Stress early in life, especially psychological stress, sets you up for forever greater vulnerability to major depression and we see what that is in terms of the cognitive psychological components of compensation, is this transition to why even bother me, it's useless, I'm helpless and this is where you get an idea of ​​the type of psychotherapy that is most likely to be successful with major depression CBT cognitive behavioral therapy what it is about is exactly what we were talking about before depression be a cognitive overgeneralization yes, that terrible thing happened to me when yes, I failed, yes I was abandoned yes, they didn't love me at all, but most of us cry and come out the other side, most of us can do a reevaluation, the Most of us would come out and say it was horrible, but that's not the whole world and that's not the rest of my life and you can build a wall around it and what we saw was, in many ways, stunning cognitive distortions.

If you decide reality when it has no walls and it just spreads out and this is inevitably your present and your future and all that. and this is the image of psychological stress reaching the point where you have learned to be helpless yes, I lacked control, then I lacked exits I lacked predictability I lacked support and this transition to overgeneralizing until becoming a globalized vision is a sort of the cognitive path to major depression and what cognitive behavioral therapy tries to do is break that path. Say yes, yes, that was horrible, no one is denying that why it's valid, it's appropriate that you feel devastated because you've been shaped by all of that. etc, etc, but did you realize that you did this the other day and that terrible result didn't happen?

It's not inevitable and try this, try this tomorrow, one where you're convinced it's going to be a disaster because it's been a while, try and maybe. it's not going to happen and little by little you start to learn the ways in which you were cognitively overgeneralizing and distorting and gradually the therapist was giving you the tools on what are the best ways to keep a wall around yourself and do the reassessment thatwas. so this is different now all that and this gives you a lot of insight into why early life stress sets you up for a higher risk of depression.

Forever. you can and cannot control in the outside world how much effectiveness you have, how much agency and if you spend your childhood stagnant and the lessons of you have no control, you have no outlets, you have no predictability, none of that if you spend being trained in childhood to be helpless. no wonder for the rest of your life and in many ways that explains one of the strongest predictors of major depression in childhood, low socioeconomic status, poverty, if you want to socially subordinate someone like no non-human primate could ever dream of. of inventing hierarchy and inventing unequal distribution and inventing poverty and poverty for children is a permanent and exhausting lesson in helplessness and that is one of the biggest predictors of falling into major depression later in life.

Okay, so how do we put all these pieces together? How do we get there? from psychological stress loss of control loss of predictability to your lateral habenula if you remember that term from before it starts doing something crazy what you see is stress, especially stress in the first years of life, when you secrete a lot of those glucocorticoids, they have all kinds of effects on the developing brain. a lot of stress in the first few years of life and you produce fewer dopamine neurons in your mesolyric dopamine system. As an adult, you are more vulnerable to anhedonia. a lot of stress in the first few years of life and your amydala will be larger and more hysterically hyperreactive and therefore more likely to access the default mode Red and you were just ruminating on the negativity and entering the meso liic system all that Early life a lot of what you're doing is learning how much control I have over the world learning how much control I have over the world translates into your igdal is going to work differently and your mesolimic system is going to work differently and we even know how that works. why this part of the brain gets bigger why this drive is going to slow down forever after this is where we all That psychological thing turns out to have exact parallels in all those practical aspects that biology was hearing about before we started to see signs of how they integrate.

The final piece that shows us how dramatically we can think about the biological and psychological intersection. Now, in the previous part of this lecture, we talked about hormones, we talked about neurotransmitters, we talked about brain structure B, we talked about all these things, one biological thing that we never got around to mentioning, you may have noticed is that we never talked about genes. What do genes do? It has to do with depression because it turns out that major depression is hereditary. The risk is much higher if you have another family member. If you look at adoption studies and depression risk transfers from birth parents who didn't raise you, regardless of the adoptee's depression status. parents too, what do genes have to do with that and right off the bat, genes do not cause depression, genes are not deterministic in that way in the same way that genes determine very few things, what genes do is interact with the environment. environment, in other words, in different environments the same gene works differently the same variant the same flavor ice cream flavor of this gene works differently and this is where we get a huge insight.

One way of saying that a gene has different effects in different environments is to say that its effects depend on context and one of the most important studies ever done in biological psychiatry showed a magnificent version of this. This has to do with a gene that encodes something five HT PP. What is this thing that codes for serotonin and the reuptake pump? Going back to the last lecture, remember liberation. serotonin and it buzzes there and you give someone ssris so this happens less, less reuptake and the person feels better oh you've increased serotonin, maybe you had a serotonin depletion and this is the gene that codes for that reuptake pump and enter different flavors different variants serotonin transporter gene and there is a version of resistance to depression and what you should immediately say is aha, people who have bad news.

The genetic variant should have higher rates of depression and this massive longitudinal study that followed thousands of people from childhood to early adulthood looked at the taste of this serotonin transporter gene, does its taste influence your likelihood of depression? If you have the bad vulnerability, you are more likely to have a history of major depression and the answer wasn't necessarily overall in the population which version you hadn't had. effect on your risk of depression and now it comes in context, dependence on interaction and environment, having the bad news version of that gene when you're just sitting there, having a perfectly mundane life doesn't increase your risk of depression, but If, on the other hand, you have a history of abuse during childhood adversity in childhood the more adversity there was in childhood the more bad news there wasThe version puts you at risk of depression, in other words, having the new bad version does not put you at greater risk of depression, puts you at greater risk if you suffered large amounts of childhood abuse in that environment, this variant prepares you for biology.

What we've learned about what this is telling you is that this is a way of coupling genes and harsh biological environments. Psychological stress. Lost of control. Predictability. Childhood adversity and harsh biology. where the Pieces of great importance come together, it turns out that Poca's corticosteroids affect this Gene and affect them differently depending on the flavor you have and therefore you can obtain permanent changes in the functioning of this if and only if you have glucorticoids due to Por All of this is a model of environmental genan interaction. Something important: this particular find has been embroiled in controversy.

All kinds of people say it's an artifact. It's not really true. This is how they analyze your data incorrectly. Other people replicate the wazu. I love this find. and I think it's absolutely legit and solid and all kinds of challenging, I think it's overdue and for my money, one of the biggest things that reinforces that this is real in the sense that monkeys come with multiple versions of this gene. . and monkeys have adult versions of depression and if you are a monkey with the same bad news version of this gene that some of us have, are you more at risk for depression only if you had an abusive mother during childhood, exactly the same interaction and My tendency is to show exactly the same thing in another primate and you are seeing the real thing happening there.

This is true whether this particular finding is robustly replicated or not. What you see is that now there are a lot of genes that have been involved genes involved in the stress response genes involved in the birth of new neurons and building the brain a lot of genes that come in different versions and, a priori, this version seems like it could be the bad news version, better, worse than this other version and in all cases the bad or bad version only manifests itself if it is combined with stress early in life, that kind of thing, so what we are reaching the end here is a model of vulnerability, biology, genes, genes, not so The genes of destiny are not inevitability, but potential genes, genes as vulnerabilities.

In this case, you have a genetic vulnerability towards depression and if life goes well from there, you will never have consequences, but if it is combined with a lot of stress, especially in the early stages of life, when you are arming your dopamine system and your frontal cortex and all that kind of stuff when you're building the system, a lot of stress early in life with childhood abuse and adversity and that's when that genetic variant will have effects forever. all the little pieces that we've seen here here is where the psychology of stress, especially psychological stress, especially psychological stress in the early stages of life, interacts with all the biology that we've seen here, so what have we come to in the end?

The same points that I emphasized from the beginning, that it is a biological disorder, we just spent two hours looking at its biology and how it interacts with psychology, this is biology, this is a real disease, someone with diabetes is not pampering themselves, the another subject. what came up through all of this is again the song and dance, you know, I can wear a lab coat and get through just thinking about this end of things, if all you're thinking about is the biological part, you're not going to understand what is happening. Also, if all you think about is the psychological part, blah blah, same exact thing, here you have to look at the interactions between biological vulnerabilities, environmental triggers, environments that teach you efficacy or coping strategies or give you skills for life to obtain social support. and things of that type the interaction between the two the most important point of these conferences these two is one that arises from their real biology is that you do not tell a diabetic to stop using insulin what you see here is major depression like any other psychiatric disorder that exists has a massive social stigma, being mentally ill has a massive stigma and we are terrified of receiving that label and we recoil from people with that label and we are only talking about the best estimates like 30% of human beings have some type of psychiatric disorder at some point or another, with depression and anxiety at the top of the list.

This is not about them and their illnesses, their mental illnesses, this is about all of us, our loved ones and the people that each of us encounters. Today, this is a pervasive feature of the human condition and if we are able with our human brain to know that one day we will die, if we are able to imagine horrible things happening to our loved ones, if we are able to do something that. It is no wonder that we are the species most vulnerable to depression and anxiety. There is a biological disease. If this is you, you are not alone.

If so, seek help because you have one of the deadliest diseases there is. If it is a loved one. Around you, take everything you've heard in these last two hours and do something to stop this from being a stigmatized mental illness problem and become the biology of what's wrong, and get them help because most People don't understand it, so, thank you. for your patience and good luck in facing some of life's challenges we approve of and address with primate markings for better or worse.