In this lecture, Dr. Sapolsky discusses depression. He provides a history of the biological elements, touching on the role of neurotransmitters (epinephrine, dopamine and serotonin) in depression, and an overview of the psychological elements (and their tie-in to the biological).
Sapolsky opens by offering an unusual viewpoint - when it comes to human diseases, there are few disease out there that are bad as depression. It is crippling. It is pervasive. It wipes out any capacity for joy, hope or pleasure.Cancer victims will often express gratitude for their disease. It woke them up, gave them a new perspective, helped them rebuild important relationships and get to the meaning of life.
This is not depression.
Depression destroys perspective, undermines relationships, steals joy. Depression isn't a disease that you are grateful for having. It doesn't open doors; it closes them. And in this lecture Sapolsky will show that it's every bit as real as diabetes. You don't tell someone without insulin to just get over it, but this is exactly what happens with depression. Yet both diseases are characterized by hormones and chemical reactions that are way out of control.
Humans have an astonishing capacity to derive joy, hope and/or meaning from the most difficult of circumstances. What could be worse than a disease whose defining characteristic is the inability to feel pleasure?
(Here one should pause and set aside questions of mortality for a moment. Sapolsky's meaning is crystal clear when we think of the disease as it is - what's day to day life like with cancer, congestive heart failure, depression? It's within this context that it can be the worst experience imaginable. As for the mortality issue, people with cancer fear death; people with depression wish for it.)
Symptoms
Anhedonia - the absence of pleasure. This is where nothing brings joy or pleasure. Not good fortune, not a promotion, not an achievement.
Grief - sorrow. Loss. Hopelessness. Obsessing over actions that went wrong. Delusional thinking.
Guilt - blaming yourself for failures both perceived and real. Blaming yourself for blaming yourself. Blaming yourself for feeling sad and unable to do what you should be doing.
Self-injury - injuring oneself, be it cutting, suicide, or some other form of self-inflicted pain. Suicide is one of the top causes of death in teenagers.
Psychomotor retardation - everything is exhausting to do, to think, to move. Getting going is unbelievably hard. At a chemical level this likely has a lot to do with insufficient dopamine. Dopamine isn't so much the reward chemical as it is the chemical that motivates you to take an action that will lead to a reward. Doubt that the reward will happen and you get no dopamine.
As a side note he points out that the probability of suicide goes up when the psychomotor retardation alleviates. The person may then have enough oomph to kill herself.
Vegetative symptoms - here he again stresses that this is a real disease with biological underpinnings. There's a sense that everyone goes through hard times and feels sad and bounces back, so those that don't bounce back must be milking it for their own pleasure, or because they're weak or selfish. Here he's establishing that actual medical info, not people's common sense, establishes that it's a disease as real as diabetes. Why? The physiological data from people suffering a major depression demonstrates a strong stress response and does so even when the person is sleeping (and thus not able to be blamed for deliberately thinking sad thoughts).
Sleep changes - often wake up early. Remain in stress response during sleep. The sleep cycles are totally screwed up. This is not get over it. This is biology.
Loss of appetite is common.
Activation of stress response. Sympathetic nervous system gets fired up (adrenaline). Glucocorticoids pouring out. Outwardly the person looks lazy and tired and like nothing's going on. Inside the body is going through a massive stress response that is similar to what your body would be doing if you were fleeing an armed assailant. All the time.
Now on to the chemistry of it.
Neurons communicate with chemical messengers, neurotransmitters.
Norepinephrine - MAO inhibiters. After a neurotransmitter has been dumped into the synapse, it needs to be cleaned up. It can be recycled or flushed out of the body via the cerebrospinal fluid, bloodstream, urine, etc. MAOI drugs inhibit the activity of the enzyme that breaks down norepinephrine. Since it's just sitting there in the synapse, it goes ahead and pings the receptor a second and third time. Thus the theory is that if the person gets better, the problem was likely caused by too little norepinephrine.
In the late 1960's the tricyclics emerged. These do basically the same thing - they gum up the pump that removes the neurotransmitter. Further evidence comes from drugs that inhibit norepinephrine production. The side effect of these? Depression. The original theory was that it's related to the anhedonia in depression since it was believed to be part of the pleasure pathway. The theory is good, but the catch is that the neurotransmitter involved isn't norepinephrine, it's dopamine.
Dopamine is the neurotransmitter involved in the pleasure pathway. However, dopamine is not the reward; it's the feeling and belief that what you do will lead to a reward. Dopamine is what gets you to take the action that will lead to pleasure. Thus when there's a flood of dopamine, the brain is expecting a very good result and becomes happy.
SSRI drugs, such as Prozac, increase serotonin signalling/block reuptake of serotonin from the synapse.
The current thinking is this.
Dopamine -> Anhedonia. The absence of pleasure via the route of hopelessness. If you're hopeless, there's not a whole lot of this is going to be great let's do it signalling in your brain. Lack that, and you won't take action. And you won't get results, which confirms the original hopelessness.
Norepinephrine -> Psychomotor retardation. Norepinephrine is essentially a stimulant (which is why it would raise blood pressure). A deficit leads to a lack of stimulation and thus less movement and less energy directed toward movement (and toward feeling energized).
Serotonin -> The grief and guilt thing. The obsessive part of the actions is majorly implicated, as is seen by evidence that OCD can be alleviated with SSRI drugs.
The remaining symptoms result from the toxic mixture of combined deficits among these three key neurotransmitters.
Substance p is another neurotransmitter that tells us about the biological nature of depression. It's released when the body encounters pain (acute or chronic). Drugs that inhibit substance p signalling can relieve depression, again demonstrating that the body is using real pain pathways to experience psychic pain.
So what about neuroanatomy?
The triune brain theory. The back portion handles the day to day affairs - respiration, blood pressure, circulation. It's the so called reptilian brain and while it's absolutely vital for life, it doesn't have a whole lot to do with advanced emotions and thinking. Sitting atop the reptilian brain is the limbic system. This is the main section for emotions. And it talks to the other sections of the brain. To wit, it triggers responses in the body. Finally there's the cortex up top. This is the thinking center. And it's capable of triggering a full-on stress response in the rest of the brain and body through thoughts, which are simply neurotransmitters being dumped over and over again (especially when there's an obsessive quality to them). The more the thoughts happen, the stronger the pathway and the more effective the signalling. Thus a depression is, at some level, simply the cortex whispering endless sad thoughts to the rest of the brain. And once this starts, the biochemistry shifts until the cortex gets caught in its own trap and can't not think the thoughts because all the signalling is already repeating them endlessly.
(To understand what he's saying here, it helps to know that the human stress response is the same for all types of stressors. While the intensity and duration varies, the internal biochemistry is the same. So the brain interprets a stressful event, it release some stress hormones that float down to the adrenal glands which then pump out their own set of stress hormones and the body gets ready to fight off whatever challenges it. While the body will respond in different ways to heat or cold, this basic stress response is the same to all stressors. Add in that all stimulation runs through the brain and you can see that whether the pain is physical or psychic, the brain starts the cascade. So the brain is the reality center, the stress response is the same, and you end up having a physical stress response to a mental event and the response is every bit as real in your body as it would be if you'd just been assaulted).
He mentions snipping off the connection from the cortex to the rest of the brain. The takeaway here is that a candidate for this would be someone who has nothing to lose in the way of pleasure because there was no pleasure to begin with. Again, this is the biologic element of depression.
Thyroid hormones - metabolism, body temperature, energy levels. Some depressions are really hypothyroidism. Nutrition and hormone levels matter too.
Women are at about twice the risk of depression as men, and the worst times are after birth, menopause, and around the time of their period. This is also a time of hormones bouncing around like crazy. Additionally, women tend to ruminate more on emotionally upsetting things than men. Sapolsky jokes about men and how they "can't express their emotions." But of course there's a real truth in that which may be a big deal for depression - if it's at some level about the cortex expressing emotional thoughts to the rest of the brain, an incapacity to express those thoughts would be protective. A portion of the brain known as the reticular activating system helps focus the brain on the thoughts and stimuli you want it to see. For example, if you look around a room looking for brown colors, you'll see them more than green colors. Do the opposite and you'll see more green. It also applies to thinking processes. If you ask your brain to come up with five things you did well today, it will do so. Ask it to come up with five things you screwed up, and it will do that too. So these thinking processes are hardwired to direct the rest of the brain and the body. Start obsessively thinking things through in the wrong direction and the system can run amok all on its own.
Welcome to the party glucocorticoids. These are the stress hormones released by the adrenal glands. These indicate that the full on stress response is occurring. The more exposure to glucocorticoids, the greater the risk. It's possible these are the guys that turn ruminating thoughts into the derailed train of depression. Get yourself a massive stressor, add in the thoughts, and next thing you know they're throwing the system out of whack and you don't bounce back.
Have 4+ major depressions, and the cycle can just go on its own (remember the pathways).
In Cushing's, a boatload of these glucocorticoids are secreted. Common side effect of Cushing's? Depression. It's also seen when people have to be on immunosuppressant drugs (these are also the glucocorticoids) - common side effect? Depression.
But wait you say, how can the hydrocortisone I use to reduce swelling be the same guy triggering a massive stress response and suppressing my immune system? Read Why Zebras Don't Get Ulcers to find out...
Freud, mourning and melancholia. In mourning we bounce back, in melancholia we don't. Start off with mixed views, lose a loved one (person, goal, concept, dream). You focus on the love and sense of loss. In melancholia you cannot put the negative in the background. Instead it grows. And thankfully as this is going this is just when all those helpful people in your life will start criticizing you and telling you to get over it, thus compounding and increasing the negativity. So you have the grief, but you also have the guilt and loss that goes with losing the chance to make things right.
Depression is aggression turned inward.
And that gets internalized and fires up the pathway.
So what else is going on? What impacts the weight of the stressor?
Outlets for the stress - do you have a support system?
Control - do you feel like you can control it? (In the Zebras book, Sapolsky sums up this area by noting that it's good to have a feeling of control if the situation is bad but could have been worse, but debilitating if the situation is as bad as it gets. Control isn't always a win.)
Predictability - do you have a sense of control and timing?
Lack control and you learn to be helpless. You give up. You aren't able to accept that this thing is awful but it's not the whole world. Instead you globalize it and it becomes your whole world. Research in this area can be sad; rats who have learned to be helpless in one area (shocks they can't control) will no longer bother pressing the lever when moved to a box where hitting the lever stops the shocks. And people aren't any different.
Lose a parent (to death) when you're under 10 and your risk skyrockets.
Depression is a genetic disorder. It has some degree of heritability. 50% identical twins, 25% full sibling. So again we have the whole nature-nurture interaction. Have the bad gene (a serotonin one), add in major stressors and uh-oh. A 30 fold increase in the likelihood of depression at the extreme. Oh, and glucocorticoids regulate the expression of the gene.
So the wrap-up. Depression is a real disease. What it's not is a fake disease suffered by lazy whiners. Or at least it isn't that anymore than diabetes is. Or than congestive heart failure. Or cancer.
Why does this matter? Because in the world of psychiatric disorders talking about it is always taboo. People either view it as hyperbole and whining or shun it and don't want the subject to see the light of day. Sapolsky's point again and again is that depression is real and normal, the same way that diabetes is real and normal. It simply happens and doesn't reflect on the person anymore than juvenile diabetes does.
With that in mind, I encourage all viewers to next watch the last lecture in his Hum-Bio series. You'll never find a more eloquent examination of psychiatric diseases within a population and what it means to view the world as them and their diseases as compared to us and our individual differences.
This is not depression.
Depression destroys perspective, undermines relationships, steals joy. Depression isn't a disease that you are grateful for having. It doesn't open doors; it closes them. And in this lecture Sapolsky will show that it's every bit as real as diabetes. You don't tell someone without insulin to just get over it, but this is exactly what happens with depression. Yet both diseases are characterized by hormones and chemical reactions that are way out of control.
Humans have an astonishing capacity to derive joy, hope and/or meaning from the most difficult of circumstances. What could be worse than a disease whose defining characteristic is the inability to feel pleasure?
(Here one should pause and set aside questions of mortality for a moment. Sapolsky's meaning is crystal clear when we think of the disease as it is - what's day to day life like with cancer, congestive heart failure, depression? It's within this context that it can be the worst experience imaginable. As for the mortality issue, people with cancer fear death; people with depression wish for it.)
Symptoms
Anhedonia - the absence of pleasure. This is where nothing brings joy or pleasure. Not good fortune, not a promotion, not an achievement.
Grief - sorrow. Loss. Hopelessness. Obsessing over actions that went wrong. Delusional thinking.
Guilt - blaming yourself for failures both perceived and real. Blaming yourself for blaming yourself. Blaming yourself for feeling sad and unable to do what you should be doing.
Self-injury - injuring oneself, be it cutting, suicide, or some other form of self-inflicted pain. Suicide is one of the top causes of death in teenagers.
Psychomotor retardation - everything is exhausting to do, to think, to move. Getting going is unbelievably hard. At a chemical level this likely has a lot to do with insufficient dopamine. Dopamine isn't so much the reward chemical as it is the chemical that motivates you to take an action that will lead to a reward. Doubt that the reward will happen and you get no dopamine.
As a side note he points out that the probability of suicide goes up when the psychomotor retardation alleviates. The person may then have enough oomph to kill herself.
Vegetative symptoms - here he again stresses that this is a real disease with biological underpinnings. There's a sense that everyone goes through hard times and feels sad and bounces back, so those that don't bounce back must be milking it for their own pleasure, or because they're weak or selfish. Here he's establishing that actual medical info, not people's common sense, establishes that it's a disease as real as diabetes. Why? The physiological data from people suffering a major depression demonstrates a strong stress response and does so even when the person is sleeping (and thus not able to be blamed for deliberately thinking sad thoughts).
Sleep changes - often wake up early. Remain in stress response during sleep. The sleep cycles are totally screwed up. This is not get over it. This is biology.
Loss of appetite is common.
Activation of stress response. Sympathetic nervous system gets fired up (adrenaline). Glucocorticoids pouring out. Outwardly the person looks lazy and tired and like nothing's going on. Inside the body is going through a massive stress response that is similar to what your body would be doing if you were fleeing an armed assailant. All the time.
Now on to the chemistry of it.
Neurons communicate with chemical messengers, neurotransmitters.
Norepinephrine - MAO inhibiters. After a neurotransmitter has been dumped into the synapse, it needs to be cleaned up. It can be recycled or flushed out of the body via the cerebrospinal fluid, bloodstream, urine, etc. MAOI drugs inhibit the activity of the enzyme that breaks down norepinephrine. Since it's just sitting there in the synapse, it goes ahead and pings the receptor a second and third time. Thus the theory is that if the person gets better, the problem was likely caused by too little norepinephrine.
In the late 1960's the tricyclics emerged. These do basically the same thing - they gum up the pump that removes the neurotransmitter. Further evidence comes from drugs that inhibit norepinephrine production. The side effect of these? Depression. The original theory was that it's related to the anhedonia in depression since it was believed to be part of the pleasure pathway. The theory is good, but the catch is that the neurotransmitter involved isn't norepinephrine, it's dopamine.
Dopamine is the neurotransmitter involved in the pleasure pathway. However, dopamine is not the reward; it's the feeling and belief that what you do will lead to a reward. Dopamine is what gets you to take the action that will lead to pleasure. Thus when there's a flood of dopamine, the brain is expecting a very good result and becomes happy.
SSRI drugs, such as Prozac, increase serotonin signalling/block reuptake of serotonin from the synapse.
The current thinking is this.
Dopamine -> Anhedonia. The absence of pleasure via the route of hopelessness. If you're hopeless, there's not a whole lot of this is going to be great let's do it signalling in your brain. Lack that, and you won't take action. And you won't get results, which confirms the original hopelessness.
Norepinephrine -> Psychomotor retardation. Norepinephrine is essentially a stimulant (which is why it would raise blood pressure). A deficit leads to a lack of stimulation and thus less movement and less energy directed toward movement (and toward feeling energized).
Serotonin -> The grief and guilt thing. The obsessive part of the actions is majorly implicated, as is seen by evidence that OCD can be alleviated with SSRI drugs.
The remaining symptoms result from the toxic mixture of combined deficits among these three key neurotransmitters.
Substance p is another neurotransmitter that tells us about the biological nature of depression. It's released when the body encounters pain (acute or chronic). Drugs that inhibit substance p signalling can relieve depression, again demonstrating that the body is using real pain pathways to experience psychic pain.
So what about neuroanatomy?
The triune brain theory. The back portion handles the day to day affairs - respiration, blood pressure, circulation. It's the so called reptilian brain and while it's absolutely vital for life, it doesn't have a whole lot to do with advanced emotions and thinking. Sitting atop the reptilian brain is the limbic system. This is the main section for emotions. And it talks to the other sections of the brain. To wit, it triggers responses in the body. Finally there's the cortex up top. This is the thinking center. And it's capable of triggering a full-on stress response in the rest of the brain and body through thoughts, which are simply neurotransmitters being dumped over and over again (especially when there's an obsessive quality to them). The more the thoughts happen, the stronger the pathway and the more effective the signalling. Thus a depression is, at some level, simply the cortex whispering endless sad thoughts to the rest of the brain. And once this starts, the biochemistry shifts until the cortex gets caught in its own trap and can't not think the thoughts because all the signalling is already repeating them endlessly.
(To understand what he's saying here, it helps to know that the human stress response is the same for all types of stressors. While the intensity and duration varies, the internal biochemistry is the same. So the brain interprets a stressful event, it release some stress hormones that float down to the adrenal glands which then pump out their own set of stress hormones and the body gets ready to fight off whatever challenges it. While the body will respond in different ways to heat or cold, this basic stress response is the same to all stressors. Add in that all stimulation runs through the brain and you can see that whether the pain is physical or psychic, the brain starts the cascade. So the brain is the reality center, the stress response is the same, and you end up having a physical stress response to a mental event and the response is every bit as real in your body as it would be if you'd just been assaulted).
He mentions snipping off the connection from the cortex to the rest of the brain. The takeaway here is that a candidate for this would be someone who has nothing to lose in the way of pleasure because there was no pleasure to begin with. Again, this is the biologic element of depression.
Thyroid hormones - metabolism, body temperature, energy levels. Some depressions are really hypothyroidism. Nutrition and hormone levels matter too.
Women are at about twice the risk of depression as men, and the worst times are after birth, menopause, and around the time of their period. This is also a time of hormones bouncing around like crazy. Additionally, women tend to ruminate more on emotionally upsetting things than men. Sapolsky jokes about men and how they "can't express their emotions." But of course there's a real truth in that which may be a big deal for depression - if it's at some level about the cortex expressing emotional thoughts to the rest of the brain, an incapacity to express those thoughts would be protective. A portion of the brain known as the reticular activating system helps focus the brain on the thoughts and stimuli you want it to see. For example, if you look around a room looking for brown colors, you'll see them more than green colors. Do the opposite and you'll see more green. It also applies to thinking processes. If you ask your brain to come up with five things you did well today, it will do so. Ask it to come up with five things you screwed up, and it will do that too. So these thinking processes are hardwired to direct the rest of the brain and the body. Start obsessively thinking things through in the wrong direction and the system can run amok all on its own.
Welcome to the party glucocorticoids. These are the stress hormones released by the adrenal glands. These indicate that the full on stress response is occurring. The more exposure to glucocorticoids, the greater the risk. It's possible these are the guys that turn ruminating thoughts into the derailed train of depression. Get yourself a massive stressor, add in the thoughts, and next thing you know they're throwing the system out of whack and you don't bounce back.
Have 4+ major depressions, and the cycle can just go on its own (remember the pathways).
In Cushing's, a boatload of these glucocorticoids are secreted. Common side effect of Cushing's? Depression. It's also seen when people have to be on immunosuppressant drugs (these are also the glucocorticoids) - common side effect? Depression.
But wait you say, how can the hydrocortisone I use to reduce swelling be the same guy triggering a massive stress response and suppressing my immune system? Read Why Zebras Don't Get Ulcers to find out...
Freud, mourning and melancholia. In mourning we bounce back, in melancholia we don't. Start off with mixed views, lose a loved one (person, goal, concept, dream). You focus on the love and sense of loss. In melancholia you cannot put the negative in the background. Instead it grows. And thankfully as this is going this is just when all those helpful people in your life will start criticizing you and telling you to get over it, thus compounding and increasing the negativity. So you have the grief, but you also have the guilt and loss that goes with losing the chance to make things right.
Depression is aggression turned inward.
And that gets internalized and fires up the pathway.
So what else is going on? What impacts the weight of the stressor?
Outlets for the stress - do you have a support system?
Control - do you feel like you can control it? (In the Zebras book, Sapolsky sums up this area by noting that it's good to have a feeling of control if the situation is bad but could have been worse, but debilitating if the situation is as bad as it gets. Control isn't always a win.)
Predictability - do you have a sense of control and timing?
Lack control and you learn to be helpless. You give up. You aren't able to accept that this thing is awful but it's not the whole world. Instead you globalize it and it becomes your whole world. Research in this area can be sad; rats who have learned to be helpless in one area (shocks they can't control) will no longer bother pressing the lever when moved to a box where hitting the lever stops the shocks. And people aren't any different.
Lose a parent (to death) when you're under 10 and your risk skyrockets.
Depression is a genetic disorder. It has some degree of heritability. 50% identical twins, 25% full sibling. So again we have the whole nature-nurture interaction. Have the bad gene (a serotonin one), add in major stressors and uh-oh. A 30 fold increase in the likelihood of depression at the extreme. Oh, and glucocorticoids regulate the expression of the gene.
So the wrap-up. Depression is a real disease. What it's not is a fake disease suffered by lazy whiners. Or at least it isn't that anymore than diabetes is. Or than congestive heart failure. Or cancer.
Why does this matter? Because in the world of psychiatric disorders talking about it is always taboo. People either view it as hyperbole and whining or shun it and don't want the subject to see the light of day. Sapolsky's point again and again is that depression is real and normal, the same way that diabetes is real and normal. It simply happens and doesn't reflect on the person anymore than juvenile diabetes does.
With that in mind, I encourage all viewers to next watch the last lecture in his Hum-Bio series. You'll never find a more eloquent examination of psychiatric diseases within a population and what it means to view the world as them and their diseases as compared to us and our individual differences.
