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This is an extract from a talk given by Professor Robert Sapolsky at a class of students a Stanford University back in 2009 with almost 6 Million views on youtube. Link to the actual talk (

As of May 2023 a report from the WHO (WORLD HEALTH ORGANIZATION) :

Globally, an estimated 5% of adults suffer from depression, this comes to around 400million people, roughly

An estimated 3.8% of the population experience depression, including 5% of adults (4% among men and 6% among women), and 5.7% of adults older than 60 years. Approximately 280 million people in the world have depression (1). Depression is about 50% more common among women than among men. Worldwide, more than 10% of pregnant women and women who have just given birth experience depression (2). More than 700 000 people die due to suicide every year. Suicide is the fourth leading cause of death in 15–29-year-olds.


15% of population will encounter a major depression event during a life time. A WORLDWIDE PANDEMIC

According to World health organization Depression is number 4th cause of disability and by 2025 will be number ONE After Obesity and Diabetes related disorders.

In this almost 1 hour class at the University, Sapolsky remarkably brings to consciousness the need to bring forth an integral or Wholistic viewpoint in order to asses property all the dynamics along with fully understanding what humanity will have to face sooner than later.

He strategically brings history and true cases from early this century encompassing 4 major areas of evaluation: BIOLOGICAL, CHEMISTRY, PSYCHOLOGICAL, HORMONAL AND HEREDITARY ones. In a further discussion, I will be bringing you the only factor that he fails to point out from the level of its importance and how this Global disorder is not evaluated from the Transpersonal and Spiritual level. Many Master doctors, scientist, psychologist, psychiatrist and so forth as Dr. Carl Gustav Jung, Dr. Rudolf Steiner, Allan Kardec, just to name a few predicted 150 years ago that this will be the illness of the future and the disease of the modern human being.




Semantic problem of misuse of the word DEPRESSED.


Minor sets of occurrences that brings you down and we way we are depressed.


The second occurrence has to to do with a MAJOR set back.. Death, loss of a loved one, injury, accident, unemployment, bankruptcy, lawsuit etc

A true sense of MALAISE for weeks, months, years... not being able to come out of the other end


A biochemical disorder with a generic component, and early experience influences, where someone can't appreciate sunsets

In comparison with other chronic disease like Cancer, like heart problems people come to a realization where they come to appreciation of family and friends support, saying I would have never been able to come out of this major event if it wasn't for such help, I would have would never reconciled with my family members, I would never have found my GOD on a completely weird level, I am almost glad this illness is happening to me.

We humans have this astonishing capacity to derive pleasure out of the most unlikely domains, what could possibly be worse than a diseases whose DEFINING SYMPTOM is the inability to feel pleasure?


It is about the inability to experience pleasure, loss of interest or satisfaction. Anhedonia is a It is the inability to experience pleasure, loss of interest or satisfaction. Anhedonia is a clear symptom of depression, and one of the main ones for the diagnosis of the disease[1].[1].


Hedonism is the belief that pleasure, or in other words the lack of pain, is the most important principle in determining the morality of any action.

Hedonism is a doctrine of philosophy that considers pleasure as the purpose or objective of life. Hedonists, therefore, live to enjoy pleasure, trying to avoid pain.It is a set of moral theories that emphasize that, in general, everything that man does is a means to achieve something else. Pleasure, on the other hand, is the only thing that is sought for itself.


Another Semantic Problem, it may become so severe that it actually takes on a delusional quality (example of the middle age successful guy who suffers from a heart attack.... Leading to a Major depression scenario, family congratulating him for doing to laps around the floor and he denies his accomplishment.


Depressives mutilating themselves at a high rate... SUICIDE, Risk of SUICIDE. In teenagers and early adults that along with accidents is a leading cause of death.


Psychomotor retardation is one of the main features of major depressive disorder (MDD) or, more simply, depression. Psychomotor retardation is the slowing down or hampering of your mental or physical activities. You typically see this in the form of slow thinking or slow body movements.


At this state the worrisome of SUICIDE is not significant they will not have the WILL nor energy to harm themselves.

The problem arises when they start to feel better, when they start to come out, then when they have the feeling of doing something catastrophic, that is when people are on suicide watches


we all get depressed at some point.. we feel lousy, we feel withdrawn, a sense of grief unable to take pleasure and we withdraw and THEN... WE GET BETTER.. We cope We heal, we deal with the things in life, what's the deal with you that you can't do that?




The bodies of MAJOR DEPRESSIVES work differently

  1. Trouble Sleeping (Waking up early)..

  2. Phases of sleeping in complete disorder

  3. (Carbohydrates decrease stress hormone release) Decrease appetite

  4. Activation of the stress response (classic stress hormones are highly elevated)

  5. Over Activating of the Sympathetic system. Adrenaline. Enormous internal body battle of all this going on internally. Increase metabolic rate, increased muscle tone

  6. Rhythmic patterns: Months of depression, debilitating, come out to the other end and year and a half later, the exact same patterns. Some MAJOR DEPRESSIVES only get their depression during the winter, something known as SEASONAL AFFECTIVE DISORDERS SAD's


We got 2 brain cells, two neurons, the way they talk to each other, they don't actually touch each other, they talk to each other, in order for a neuron to send a message to another one it needs to release a chemical messenger that goes floating in one area and does something to the other neuron, a chemical messenger called a NEURO TRANSMITTER.

By natural science law all neurons go from left to right, this is a cell that continues down this way, there is a state in the middle called a SYNAPSE, and what one is doing because is all excited, it has these little water balloons filled with NEUROTRANSMITTERS, Excitation signal comes along, dumps the neurotransmitters, they go floating across the synapse, bind to a receptor there and then suddenly, something changes in this neuron. That is how neurons talk to each other.

How many different types of neurotransmitters there are.. Probably hundreds and what will be pertinent here is in depression there is just a handful of them that seem to be implicated.

First Neurotransmitter something called NOREPINEPHRINE first got implicated in depression in the early 60's , what was the evidence? Around that time, the 1st generation of antidepressant drugs had been developed, something called MAO inhibitors. What do they do?.. so you got your neurotransmitters released, this neuron is excited, what do you have to do? It comes out, it does its thing with the receptors and then you have to clean up after yourself. You've dumped all the stuff in the SYNAPSE.. What do you do then? you got two options:

a. You can take the Neurotransmitter and you can be green in your orientation, you can recycle, you can take it back up and stick it back into one of these, you can do this recycling business , or you can be terrible and carbon footprint, you can throw out your neurotransmitter, There are like enzymes sitting around that break it up and flush it down the toilet.. What's the toilet? Out in to your cerebral spinal fluid, your bloodstream, your urine, whatever so:

A. Recycling or

B. Flush it out

So what do these MAO inhibitors do?

They inhibit the activity of the enzyme that that breaks down NOREPINEPHRINE, OK so what is the logic there? So you inhibit the activity of this enzyme, you don't break down norepinephrine, so is just floating around there, and for lack of anything else to do, it hits the receptor a second time, and a third time and a gazillionth time and suddenly, somebody's depression goes away. What's your theory have to be at that point? ohhh I bet there was not enough norepinephrine coming out, you find a means to increase the signaling, somebody gets better and now you hypothesize there is a problem with too little norepinephrine.

By the late 60's another class of antidepressants came in called tricyclic antidepressants, what do they do?.. essentially the same exact thing. what they do is they gum up this pump that recycles the stuff the norepinephrine doesn't get removed from synapse, has nothing to do, it hits the receptor, a second, third, tenth time, then the person feels better, oh, I think the problem in my theory is, too little norepinephrine coming out thus the NOREPINEPHRINE hypothesis.

More evidence of for it, there are classes of drugs that will decrease your norepinephrine release, but why do you want to do that? in some parts of the body, an excess of norepinephrine has something to do with high blood pressure. So you take a class of drugs, something called reserpine, and what it does is it disintegrates these things, and thus you don't dump as much norepinephrine. Major side effect of lowering somebody's blood pressure that way is that they fall into depression. So you take a depressive person. you find a way to boosting up their norepinephrine signaling they feel better. You take a normal person, you drive down their norepinephrine signaling they get depressed, there's got to be a problem here of too little norepinephrine. So that is incredible convincing. So at this point you got to say is, OK, great, that is convincing, that is irrefutable..


And people figure it out in the 50's... it's got something to do with this. Take a rat and take a certain part of the brain, you put an electrode down in there where you can stimulate the neurons, you can force them to talk to each other when otherwise they have nothing to say, stimulate this pathway and what you do you make a rat unbelievably happy!!! So of course the question is how do you tell when a rat is unbelievable happy? and what you do is you make it work in order to get stimulated there. It presses a lever and it presses a lever 25 times and it gets a little buzz there and it does another time and rats will work themselves out to death, they get stimulated in this area, is better than food, is better than sex, if they are addicted to a drug and going through withdrawal, is better than the drug and what you see is these mediates pure pleasure, and this was called the pleasure pathway in the 1950's.

So of course you look at it and then what you have to say is, oh!! do we have the same pathway? can I get a new one and a second one? shortly after that people went looking and saw the exact same thing in humans. And this would be during neurosurgery.. classical neurosurgery techniques, you don't anesthetize the person. the brain does not feel pain. Once you have anesthetized the skin and the skull, you get through there and you can actually keep somebody awake during surgery and they used to need to need to do that, because you put your little needle down on one part of the brain, the person flaps their arm.. and another part and they say the pledge of allegiance or whatever and then you look at you little roadmap and it says ok, go three neurons and make a left, people had to do that.

So it was around the early 60's that people started stimulating the same area in the human brain and it is unbelievable what you got, there were transcripts of some of these and you read it and the person is going on and say stuff like, oh!! that's great, that's kind of like sex but you know when you have this itch and finally you get to scratch it, and it's like getting back into bed and remember how in the fall you would go out and play in the leaves and mom would call you in and she made cookies and then.. and they just go on like this!!! it is like where can you sign up and have this happen? The same exact sort of these as in the rat.

it was around that time that people discovered that in this pathway it uses norepinephrine.. ahh so if you got a shortage of norepinephrine in that part of the brain, what have you just explained, that is the loss of pleasure (HEDONISMS)

So then one of the problems is that norepinephrine is useful in this pathway another neurotransmitter turned out to be even more important, a neurotransmitter called DOPAMINE. Cocaine works on dopamine systems so suddenly, norepinephrine is just a minor player in this "pleasure pathway" stuff. But the biggest problem came in the late 80's with the introduction of PROZAC.

PROZAC which is an SSRI, a Selective Serotonin Re-Uptake Inhibitor, what that does is work on. a completely different neurotransmitter system, this neurotransmitter called SEROTONIN, what that drug does is it does the same deal, it stops teh Re-uptake increased Serotonin Signaling so then what's your hypothesis? So you give somebody a PROZAC SSRI, they feel better I bet there was too little serotonin. So it was during this period where there was just endless tragic drive by shootings of norepinephrine people by the serotonin crown and the other way around, Huge controversy!! and of course. Some people suggested then that it had something to do with norepinephrine and serotonin and dopamine instead of only one of those .

The best evidence at this point, to be insanely simplistic is that dopamine has something to do with the ANHEDONIA, the absence of Dopamine.

The absence with Norepinephrine has something to do with the psychomotor retardation.

The absence of serotonin is this obsessive sense of grief.

(Here Professor Sapolsky brings back his arguments from the Chemical perspective to the Biological side.)

And interestingly, supporting that notion is you can have an obsessive sense of something else, you could have an obsessive need to keep utensils perfectly symmetrical and obsessively wash your hands eight hours a day, Obsessive Compulsive Disorder, that's helped by SSRI like PROZAC as well, whatever it is you are just perseverating over like mad, getting increasing serotonin signaling can help. So you have at least 3 different neurotransmitters relevant to pleasure, the psychomotor retardation, all of this, all sorts of other leads floating around the field.

There is a neurotransmitter called substance P, and what substance P is about is pain, like poke your finger and your spinal cord, there is neurons there are releasing substance P, talking to each other, is about PAIN, is about chronic pain syndrome, which about the whole body burns, everybody knew this, and then it was discovered that if you get a drug that decreases substance P signaling, sometimes depressives get better. What it does suggests it is just not a metaphor of depression as psychic pain, your body is using the same brain chemistry to feel this sort of pain of depression is just telling you, oh!, I just stubbed my toe.. Interesting similarities there.

Ok we got something about the NEUROCHEMISTRY, how about the NEUROANATOMY, the structure in the brain? and what you got here is this is the human brain.. and this formulation that came out during the 40's called the triune brain concept, which winds up being really really explanatory.

Down here at the bottom, you have got the really boring nuts and bolts parts of the brain, and as it was termed, this is the REPTILIAN part of the brain. Take a lizard, and it is basically the exact same stuff down there. What does this part of the brain do? like regulatory boring things, it measures your blood glucose levels, or f your blood pressure has dropped, it sends out a signal to tighten up your blood vessels, just total boring plumbing type issues.

Sitting on top if is is a much more interesting brain region called the LiMBIC system, Limbic system is about EMOTION. You don't see a big limbic system until you get to MAMMALS. Lizards are not famous for their emotional lives. Limbic system is much more about emotive stuff.. Fear and lust, and anger and rage and poignance and GOD knows what. What you got there is all sorts of ways where the limbic system talks to this part of the brain and what it does is rather than you being confused, ohh!! your body is getting cold, whatever, your are some hmm elk and there is a scary other elk there that's got your all upset and you start secreting stress hormones, that is your limbic system saying ohhh I do not like the smell of that guy talking down there all sort of means by which your emotional part of the brain all sort of means by which your emotional part of the brain can talk to stuff down there.

Then you got the really interesting area, up on top, THE CORTEX. Cortex, all sort of creatures out there have cortexes and we got more than anybody. It is this hugely expanded area in primates, we proportionally have the biggest one out there.

What does CORTEX do?

It makes you do your taxes, and does processing visual information and tells you that's punk rock and that's not Beethoven, and all sort of sensory stuff associative cortex things. But then there is an interesting part of the cortex that is very relevant to all of this. Ok suppose you finish the lecture, you go outside, unexpectedly, you are gored by an elephant.. What are you going to do? Your are going to activate your stress response, you may feel a sense of GRIEF at that point, you may kind of hunker down at that point, a little PSYCHOMOTOR RETARDATION.. APPETITE, there goes the dinner arrangements, sex may not be the most appealing thing under that context, You are having a stress response in response to the sort of insult that this part of the brain is thinking about.


So you think about whatever and suddenly your body does the exact same thing in as if you were gored by and elephant, you are having a stress response in response to the sort of insult that is part of the brain (left) is thinking about. And what is going on there is you get the feelings, the abstract sort of depressive stuff there, and this part of the brain is able to make the rest of the brain go along with it as if this was an elephant goring you.

On a certain, totally simplistic level, what depression is about is the cortex whispering on the rest of the brain, saying, this is as real as you were just physically assaulted by some sort of predator, whatever and you turn on the exact same thing. On a very simplistic level, what depression is the cortex having too many SAD thoughts and getting the rest of the brain to go along with it.

So how you come up with a very simplistic treatment for depression?

Which is get a pair of scissors and just kind of cut of here in the brain and separate that part of the brain form the rest of it (hahah).. And you are home free.. Ohh yeah right.. well.. certainly and advance in medicine, that is actually a medical procedure it is called a cingulotomy in the part of the cortex, is called an anterior cingulate, a cingulotomy or a cingulome bundle cut and what you do is you sever this pathway and people get less depressed at that point.

Ok, when does this happen? This is somewhere where someone where every type of medication and every type of therapy and electroshock interventions, all of that has been tried in every combination and they are still in the back ward of the state hospital slashing the wrists every three months, that when people try this, and the amazing thing with this desperate measure is people get less depressed at this point.

Ok, so at that point you may want to look at that and say "well!! anything else about these people when you have gone through there and just snipped away, Mind you, this is not a frontal lobotomy; Frontal Lobotomy is doing something very undefined up there, but instead, you are disconnecting here... (Professor shows that on a drawing on a chalk board) So... what else is up with somebody when you have just disconnected a part of their cortex from the rest of the brain?.. Insofar as the cortex can come up abstractly sad thoughts and get the rest of the brain to go along with it, maybe the cortex also comes up with abstractly pleasurable thoughts and gets the rest of the brain, but you just have wiped out somebody's ability to have abstract pleasure.. ABSOLUTELY.

So suddenly, you are off and running with a great philosophy, term paper, it is important that we have pain in order to have to have pleasure.. this is non sense. You get someone who is a candidate for this procedure, back in the state hospital there with writs scarred over and this is not somebody feeling a whole lot of abstract pleasure anyway. So what does this tell us? you come up with some ridiculously simplistic explanation that you make it impossible for the sad part of the brain to whisper sad thoughts to the rest of the brain, the best people in the field thinking about this can't come up with anything a lot more sophisticated that that.

So that tells you something about the brain structure with depression. Final bit of biology here.. HORMONES. What do hormones have to do with it? One very important domain of hormones.. You take somebody and they are having problems with a a class of hormones, THYROID hormones. What thyroid hormones are about is maintaining your metabolism, keeping your body warm enough, all that sort of stuff. If you have a sever shortage of thyroid hormone, lots of things happen including you fall into major DEPRESSION.. HYPOTHYROIDISM is associated with MAJOR DEPRESSION. There is an autoimmune disease called HASHIMOTO'S DISEASE, which involves problems with secreting thyroid hormone and that is a basic feature of it. And somebody comes in and you diagnose it, and you give them normal levels of Thyroid hormone and aways goes their depression; Lot of lessons with that.

The first one is best estimate are about 20% of major depressions are undiagnosed HYPOTHYROID SYNDROMES instead. The next one that demonstrates is you better when somebody is thinking about your psychiatric state you better have somebody there who's thinking about your nutrition, your hormone levels, your.... nothing about what's going on here (in the brain) is independent of the rest of the body, so a big role of your Thyroid hormones.

The next domain of hormones being relevant.. you take women and women have a higher incidence of MAJOR DEPRESSION than men do, approximately twice the rate, in addition women have their highest vulnerability to depression and suddenly at certain points in their reproductive life histories. After you have given birth, as post parturition depression; around the time of your period, around the time of your menopause, all of these scream BIOLOGY. So you look at why women have elevated rates of Depression and there is biology, there is all sort of other schools of thought that have gone into it, there are ones having more sociological framework, lack of control cause depression in society after society; women traditionally have less control no wonder why the fall into more depression. There is another school that focuses on a certain style of emotional differences, you see between genders, on the average women tend to ruminate more on emotionally upsetting things to focus in on more and this sounds totally stereotypical and when they do the studies, there is overlaps between individuals but nonetheless on the average what you see is these sort of studies where you get someone after they just had a fight with a close friend and what do women do? when they give a choice of a whole bunch of activities they choose to fill out questionnaires about how they met their friend and what the nature of the relationship is, and does the friend have a good marriage, all of that, you do it guys (men) and they fill out questionnaires about trivia questions about the civil war.. Ohhh my GOD!!! THEY CAN'T EXPRESS THEIR EMOTIONS!! No wonder why it is impossible and of course, again individual variations, this is highly stereotyping, but on the average though, women ruminate more on upsetting emotions than men do.

So that is solid science, but what is completely unsold science the speculation at that point that if you ruminate on bad feelings, you are more prone to a depression, so that is a whole emotional regulation argument. But you comeback to that business of women are most at risk for a depression in the two weeks after giving birth, around the period of their periods, menopause and that is all about hormones and by now there is a huge literature of having to do with the effects on all that stuff over there of ESTROGEN and PROGESTERONE and probably most importantly the ratio of estrogen to progesterone and what is going on around giving birth period? Levels of this stuff is just shooting around all over the place and the sense is something goes out of whack with the ratios there and everything about estrogen, progesterone and the ratio can change the number of receptors of these neurotransmitters, the extent to which you do this re-uptake pump, whatever depression is going on turn out is going to be on this nuts and bolts level, estrogen and progesterone can do something to it.

Final class of hormones that are relevant, a class of hormones released during stress, ok what is the most famous stress hormone on earth? ADRENALINE.. adrenaline is this vastly overrated hormone that I despise because theres is a much more important stress hormone out-there to which I have devoted the last 30 years of my life, class of stress hormones called GLUCOCORTICOIDS. They come out of your adrenal gland during stress. The human version is the HYDROCORTISONE also known as CORTISOL, all sorts of other species out there , you secrete these glucocorticoids when you are stressed.

You look at people with MAJOR DEPRESSION and about half of them have elevated levels of glucocorticoids through the roof. There is something out of whack with the regulation of the stress hormone during depression.. what's that about that? That's back to people with depression are not invertebrates sitting on their beds these are bodies undergoing massive stress responses. There is a huge emotional battle going on, all. of it inside their heads... So elevated stress hormone levels. What is very clear is you get exposed to a lot of glucocorticoids and you are more at risk now for depression. You can see this epidemiologically, you get people and statistically before their first major depressive episode, something awful stressful occurs, and that is where this happens and this is the subset of people who stay down there far longer. Have one of these first depressive episodes due to some stressful event, you come out of the other side eventually, you are no more at risk for depression than anybody else.

Along comes the second major stressor, and you fall into depression, you come out the other end, no more at risk than anyone else for depression, but somewhere around the fourth or fifth stress-induced depression something happens and things start cycling on their own there and you no longer need a major stressor to cause your to get depressed like that is when the clocks are often running, that is the transition.

Ok, so major stress can predispose you towards depression. More evidence, there is a disease called cushing's disease, where people secrete boatload of this glucocorticoid stuff, people with Cushings fall into depression. There is a whole bunch of diseases where people have to be treated with lots of glucocorticoids, they fall in to depression, What are glucocorticoids doing? a whole lot of them and your brain gets depleted of DOPAMINE and you are right back in this domain (ANHEDONIA, HEDONISM), that is probably the neurochemistry on how you get there.

Ok, so what do we get at this point?

We got something about brain chemistry and depression, we got something about the structure of the brain, we got something with hormones, you are a card carrying biological psychiatrist and that's all you need to know about the subject. And if that is all you know about the subject, you are going to be pitifully bad in making anybody get better because all of this knowledge winds up being effective for treating maybe 30%, 40% of the depressives. For the vast majority of people, the antidepressant drugs don't do a whole lot there, all you got there is modern cutting edge biology stuff and that is not enough

So the transition now is talking about the PSYCHOLOGY of DEPRESSION, because we better have that piece of the story or else you are absolutely useless. Starting off with, I make apologies here but I actually have to say a name of Sigmund Freud, because he winds up being very relevant to depression. Freud back when dealt with this puzzle of the difference between we all get depressed and come out the other end, and the subset of people who crash.

The turn of the century Vietnamese term for people who come out the other side, mourning, your mourn something and you recover, and another term for major depression, MELANCHOLIA, and Freud and this famous essay said, why is it that subset of us fall into it? What is the difference between mourning and melancholia!? and he came up with a really interesting model.

Ok, according to Freud, you have mixed feelings, ambivalence about everybody you love out there, you love them, you hate them, and you reject them, and all that Freudian Stuff. So in this Freudian view, you have lost a loved one, that can also be a loved concept, a loved goal, you have lost a loved one. What happens then is in most people, you were able to focus on the love and the sense of loss, then you mourn and you come our the other end. In Freud's view what Melancholia is about is the subset of people who can't put the negative feelings in the background, and instead you are awash in the love, and the hate, and the regret, and the pain, and the delight all of that and what a depression is, is this wallowing, this melancholic loss, and the ambivalences you have about the lost loved one .

It explains tons, no wonder you have the GRIEF, lose somebody and go through the mourning business, and only one thing is wrong, you have lost this loved one, lose somebody with melancholia, and two things have happened, you have lost the loved one and now you have lost the opportunity to ever make things better with them, no wonder you haver the guilt. You are sitting there saying thank GOD I am finally done with this person, they are never going to control my life... but how can I think such a thing like that? sudden, crippling guilt, all sort of other symptoms and out of this came this wonderful soundbite, depression is aggression turned inward, because you have you have nobody else to have these arguments with, this is the person who you have most loved, but most hated, you never said the things you needed to hear and pounding at the door to get them finally being able to tell them and now you have lost that opportunity forever and all you can do is internalize all of that aggression turned inward.

No wonder you are not feeling a whole lot of pleasure, no wonder you are secreting stress hormones, no wonder you are not getting out of bed, all that related with the psychomotor retardation stuff this really powerful soundbite of aggression turned inward; That's great.. but what isn't great is how in the hell you turned like Freudian ambivalent feelings into something into about neurochemistry? or what do estrogen progesterone ratios have todo with love hate ratios? it is great, it feels very intuitive, but you can't do modern science on it, which is a problem with the best parts of Freud.

Ok, instead you need to shift over to looking at experimental psychology and understanding what is the psychology of stress? What is it that makes psychological stressors stressful? an enormous amount of literature now shows that for the same external misery you feel more stressed, your turn on stress response, you are at most risk for a stress related disease if you don't have outlets for the frustration caused by the stressor, if you feel like you have no control over what's happening, you have no predictability as to when it's occurring and you don't have anybody's shoulder to cry on.

This is what psychological stress is about, and what a depression is, is pathological extremes of this, you fall into the cognitive psychology soundbite of what depression is, it is learned helplessness, it is learning to be helpless. Something bad happens to you, You a Rat, getting some shocks now and then, You a Human experience some loss and the logical thing you should do is learn, this is awful, when I am in this situation, there is not damn thing I can do about it, is awful, I feel terrible, but this is not the whole world, and what a major depression is about is you sit there, and you are that rat, and in this setting you get uncontrollable shocks, but put you in another setting and just by hitting the lever a couple of times you avoid the shocks and don't bother doing it because you have learned to be helpless, just like a human depression.

What depression, what learned helplessness is taking a circumstance where by any logic, again, you should be saying is, this is awful, but is not the whole world, and do this cognitive distortion and decide this is indeed the entire world and I have no control, I am always hopeless, this is the psychology of what depression is about. At that point, you don't have a whole lot of trouble seeing how you wind up here (Biological side) stress effects on some dopamine, all that sort of stuff.

Ok, so we have two extremely different viewpoints here, as to what depression is about... modern biological stuff, and this totally different world of psychology, loss, lack of control, one version of it, one of the most reliable findings in the whole epidemiology of depression is lose a parent to death when you are under 10 years of age and the rest of your life you are more at risk for MAJOR DEPRESSION. This makes perfects sense, what is a lot of what's going on during the first 10 years of life, you are learning about cause and effect, you are learning is this a world out there where I have any sort of efficacy where I nave any sort of control and you just have learned in the most big time, awful way, that there are things you can't control and sometimes they are awful and what just you have learned is that there are all sort of reasons where one can be helpless, and you are that much closer to the edge of this learned helpless cliff, for the rest of your life.

Extremely powerful model here of that. So you got all the biology stuff, you got this weird Freudian aggression turned inwards which just feel right but you can't do modern science on it, then you have this world, How do you begin to put this world and that world together? And the critical link turns out to be STRESS. Stress is the intersection of the two in a very interesting domain.

Ok, depression is a genetic disorder, What do I mean by that? Depression has some degree of heritability, depression tends to run in families, depression runs more reliably as you look at closer and closer relatives and then you look at identical twins and one of them has depression, the other has 50% chance. Full siblings. who are not identical twins, 25% chance, half sibling about 8%, Person of the street about 2%, 50% chance when they share the identical genes, What does that do? that tells you this is a disorder that has a genetic component. Wha t does that also tells you if you got 50% likelihood if you have all the genes in common, and you have 50% chance of NOT getting the depression, it tell you genes are important but they are not more important than any other component.

So genes and depression are not about inevitability, they are about vulnerability. So what is the vulnerability about? A few years ago, people discovered a particular gene that is really relevant to whether or not you get depression. What was exciting about that? There was a very clear finding, it has been replicated, what else is exciting about it? it made sense, this was not some weirdo gene having something todo with how your big toes functions, this was a gene having something to do with SEROTONIN, and this was a gene relative to this whole re-uptake pumping business of that (the chemical side of the brain), the main point of it is this gene comes in two different flavors, each one of us has one of the two versions and you immediately get this prediction, one of the version by all logic should should be predisposing to depression, one of them is the one that should get you in more trouble here.

So what does it look like when you go and study, first paper that reported this a few years ago, and this I suspect is going on to wind up being viewed as the most important paper in biological psychiatry for a quarter century this was this massive study where a bunch of researchers looked at 17,000 kids growing up in New Zealand following them year after year and looking at the genetic make up of these individuals and then asking in the early 20's, Who's got a problems with Major Depression? and asking this critical question, what doe it have to do with this gene? Does the version of that gene that gets you into trouble by all logic, is that going to set you up for more at risk for a depression if you got the bad version of the gene. And back comes to finding which is no, IT DOS NOT INCREASE YOUR RISK.

You look here (on the brain chemistry) and what's your likelihood of depression? and you have got the good version and it is likely you have got the bad version, and is this likely... IT DOES NOT MAKE A DIFFERENCE, unless something else is something else is going on, unless you have a history of exposure to major stressors, and what you are able to do is quantify how many major stressors somebody has had during their childhood, their development, and that involves parental divorce and a physical abuse and death of a family member, all that sort of thing and what you see is the folks who have the 'GOOD" version of the Gene, as you have more and more of a history of major stressors, the risk of depression goes up, absolutely!! Now you look at the people with the "BAD" version of the gene, and as you have more and more history of stress, your risk of depression does this (draws in the board an arrow going up) and when you look at the major history of stressors, a 30 folld difference in the likelihood .

This is not about genes control our brains, and genes control our behavior, this is a gene that is relevant to how readily we pick our selves up after life has dumped us on our rear ends, how readily we recover from stressors. What is the final piece of that story? We look at Glucocorticoids regulate the function of this gene, ALL the pieces fall into place there.. wonderfully logical and suddenly you have a way of taking this WHOLE WORLD of psychological components of stress and tying it into all that biochemistry, wonderfully INTEGRATED MODEL.

Ok, so in lots of ways this is where the field is at this point and what you should mostly have come through here amid, all this minutia and factoids and all of that it is the ROLE OF STRESS and the intersection of the biology and the psychological stuff and childhood as a very important time to imprint how vulnerable you are to depression for the rest of your life, but again the single thing I want to emphasize over and over implicit on everything on that left side of the board (the brain chemistry) there, which is this is not "OHH PULL YOURSELF TOGETHER" .. We all get depressed, this is as real as a biological disorder as is diabetes, and the thing I most want you guys to take off from here and in the context of a University setting is rife which major depression, the community of high achieving, type A individuals is rife with major depression is all around us, and amid it being all around us, there is this weird corrosive inhibition, embarrassment discomfort we have with the world of psychiatric diseases, one of the great things, if you are a researcher with a disease, one of the things you pray for is to have some powerful senator that have their loved one come down with your disease because they are going to set up a foundation and get special funding, and there is advocacy groups and all of that... NOT for psychiatric disorder, that is the one where people do not talk about it, and amid this screaming biology and this is a devastating disease and all of that, in any place.

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