On Depression in the U.S.

• “There are all these great, made-for-TV-movie diseases out there. But when you want to come to basic meat and potatoes of human medical misery, there is nothing out there like depression.”
• 15% of us will have a major depression at some point in our lives
• WHO says depression is the #4 cause of disability on this planet, and by 2025 it’s going to be number 2 (after obesity and diabetes-related disorders)
• Semantic problem: we use the word depression for 3ish different things
  • Something minor goes badly (have to replace the transmission in your car) and you’re bummed for a few days
  • Some major misfortune/loss/setback happens, and you’re extremely impaired for weeks afterward. This is a reactive depression.
  • The subset of individuals who fall into the same sort of depressive state, but months later they’re still in it. This is a major depression, and is the focus here.
• “If I had to define major depression in one sentence, I would say it’s a biochemical disorder with a genetic component, and early experience influences, where somebody can’t appreciate sunsets.”
• Symptoms
  • Anhedonia, inability to feel pleasure
    • Even people with cancer or horrible chronic illness are able to feel pleasure, so depression is very unusual in this regard
  • Grief and/or Guilt
    • In major depression, this can take on an almost delusional quality
    • Example: late middle-aged guy, healthy, has a heart attack. Reality is, he’ll recover, but will have to make some lifestyle changes. Instead falls into a depression, envisioning himself as an old man. The hospital has a circular corridor, and he’s getting stronger (yesterday you made one loop, today you made two loops), and the guy says there’s an inner circuit whose circumference is less than half of the outer loop. This guy is the father of an acquaintance of mine, a structural engineer.
  • Self-injury
    • self-mutilation and risk of suicide
  • Psychomotor retardation
    • Everything is exhausting and overwhelming
    • When someone is so depressed they get admitted to the hospital, and are absolutely crippled with psychomotor retardation, they are not a possible suicide risk. Actually, when they start to get better and regain the energy to do something bad to themselves, that’s when they get put on suicide watch.
  • Vegetative symptoms: sleep, appetite, stress
    • Bodies of major depressives work differently, and this forms a large part of the evidence that major depression is as much a physical disorder as juvenile diabetes.
    • There’s a specific pattern in people with major depression: they wake up super early (4 or 5am) feeling tired. Sleep phases are totally disorderly and chaotic.
    • Although normal depression makes people eat more carbohyr
    • Most of us, what we do when we’re feeling kind of down is we eat more. Out of this general belief that when we’re feeling unloved, carbohydrates make us feel better. And bizarrely, there’s actually a brain chemistry of it, of carbohydrates decrease stress hormone release."
    • In major depression, you see decreased appetite.
    • You see a huge overactivity of certain stress hormones, in particular adrenaline
  • Another hint that major depression is biological: depression is rhythmic; it comes on in waves, or even at the same time every year
• The chemistry of it
  • For neurons to talk to each other, since they don’t touch, they need to release a chemical that’ll reach the other neuron. That’s a neurotransmitter.
  • There’s a space in-between called a synapse.
  • “Excitation signal comes along, dumps the neurotransmitters. They go floating across the synapse, bind to a receptor there, and then something changes in this other neuron.”
  • There are probably hundreds of neurotransmitters, and only a couple of them are implicated in depression
  • The first antidepressants (MAO inhibitors) had been developed
  • What’s the theory behind MAO inhibitors?
  • Okay, so a neuron’s just released a bunch of neurotransmitters, and the signal was received. What do you do with the rest? One option is to reabsorb and reuse the extras, another option is to leave them sitting around and wait for the body to degrade them and flush them out.
  • MAO inhibitors inhibit the enzyme that breaks down norepinephrine.
  • The theory there is that then the norepinephrine stays around longer, and the receptor gets activated more often, and depression goes away.
  • Observing this result, we hypothesized that depression can be caused by too little norepinephrine being released.
  • By the late ’60s, another class of antidepressants came out (the tricyclic antidepressants). They do almost the exact same thing. They gum up the pump that recycles noreprinephrine
  • More evidence for the hypothesis: other drugs that suppress norepinephrine release (e.g.reserpine, that lowers blood pressure) have depression as a side effect.
  • “So you take a depressed person, you find a way of boosting up their norepinephrine signalling. They feel better. You take a normal person, you drive down their norepinephrine signalling, they get depressed. There’s got to be a problem here of too little norepinephrine.”
  • Ok, but what does norepinephrine do? They found this out in the ’50s, it’s got something to do with the ability to feel pleasure
  • If you take a rat and put electrodes in the brain to forcibly stimulate these neuron pathways, and the rat becomes unbelievably happy.
  • “Rats will work themselves to death to get stimulated in this area. It is better than food, it is better than sex, if they’re addicted to a drug and going through withdrawal, it is better than the drug. And what you see is, this mediates pure pleasure. And this was called the pleasure pathway in the 1950s”
  • In the ’60s they did classical neurosurgery on humans to stimulate the same area (aka, just stick a needle in the brain), and indeed it also stimulates pure pleasure in humans.
  • [21:00] aaaIt is unbelievable what you got. There were transcripts of some of these, and you’re reading it and the person is going on. And they’re saying stuff like “Oh, that’s great. 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 oh, it’s like getting back into bed. And remember how like in the fall and you’d go out and play in the leaves and mom would call you in and she’d made cookies and then you’d get into your jammies with the feet on?” They just go on like this! It’s like, where can you sign up and have this happen?zzz
  • So it’s very convincing. Increasing norepinephrine increases pleasure, and less signalling less pleasure. It seems like this could be the cause for anhedonia.
  • Problems began to emerge.
  • If you take one of these drugs, signalling changes within the hour, but depressed people don’t start to get better for weeks.
  • It turns out another neurotransmitter is even more important in this pathway: dopamine.
  • Suddenly norepinephrine is just a minor player in the pleasure pathway.
  • In the ’80s, Prozac challenged the norepinephrine hypothesis most strongly
  • Prozac is an SSRI (Selective Serotonin Re-uptake Inhibitor), meaning it prevents serotonin from being recycled (thus increasing serotonin signalling)
  • The best evidence at this point, to be insanely simplistic, is that dopamine has something to do with the anhedonia, an absence of dopamine. The absence of norepinephrine has something to do with the psychomotor retardation. The absence of serotonin is this obsessive sense of grief. And interestingly, supporting that notion is, you can have an obsessive sense of something else. You could have an obsessive need to keep your utensils perfectly symmetrical and obsessively wash your hands eight hours a day. Obsessive-Compulsive Disorder, that’s helped by SSRIs like Prozac as well."
  • The substance P neurotransmitter is about pain. We found that if you give a drug that reduces substance P signalling, sometimes depressives get better.
  • Your body is using the same brain chemistry to feel the psychic pain of depression as it would for stubbing your toe.
• Neuroanatomy: the structure of the brain
  • The Triune Brain Concept, a formulation of brain structure from the 1940s.
    • At the bottom, there’s the reptilian part of the brain (called so because it’s basically the same in lizards). It does boring regulatory stuff, like measuring blood-glucose and blood-pressure, and activating responses when these are in imbalance
    • On top of that, the limbic system, which is about emotion. Lizards don’t really have one, but it tends to be larger in mammals.
    • Up on top, the cortex. Everyone’s got them, but it’s way bigger in primates with ours the largest relative to body size
  • Suppose after the lecture you’re unexpectedly gored by an elephant. You’ll activate a stress response. And a lot of the effects of a stress response will be similar to those of depression.
  • “On a certain, totally simplistic level, what depression is about is the cortex whispering in the ear of the rest of your brain saying this is as real as if you were physically assaulted by some sort of predator or whatever, and you just turn on the same sort of thing.”
  • If that’s how you think about depression, you could just cut out the part of the brain that triggers this stress response. That’d be a cingulotomy or cingulome bundle cut, where you sever the pathway between the anterior cingulate and the rest of the brain
  • This is something you would only do when every single type of medicine and intervention doesn’t work and the person is still in hospital and a risk to themselves. It will make them less depressed.
  • What else happens when you do this to them? Insofar as the cortex can come up with abstractly sad thoughts, and get the rest of the brain to go along with it, it also wipes out their ability to experience abstract pleasure.
• [31:20] Hormones
  • Thyroid hormones are about maintaining metabolism and body temperature
    • Hypothyroidism (severe shortage of thyroid hormone) is associated with major depression
    • If you can correct their thyroid shortage, it’ll go away.
    • “Best estimates are about 20% of major depressions are undiagnosed hypothyroid syndromes instead.”
  • Sex Hormones
    • Women have a higher incidence of major depression than men, nearly twice the rate.
    • Women have highest vulnerability at specific points of their reproductive life: post-parturition depression (just after giving birth), around the time of your period, around the time of menopause
    • This timing suggests biological factors
    • The sense is that something goes out of whack in the ratios between estrogen and progesterone, and that has some effect on brain signalling (changes the number of receptors, changes re-uptake, or something like that)
  • Stress hormones
    • “Adrenaline is this vastly overrated hormone that I despise because there’s a much more important stress hormone out there to which I’ve devoted the last 30 years of my life, a class called glucocorticoids”
    • Glucocorticoids come out of your adrenal gland during stress, the human version is hydrocortisone (aka cortisol)
    • About half of people with major depression have elevated levels of glucocorticoids, suggesting it’s being poorly regulated
    • What’s very clear is that if you get exposed to a lot of glucocorticoids, you become more at risk for depression.
    • You can see this epidemiologically: if someone experiences a depressive episode due to some external stressful event, they have no more risk of major depression than anyone else. Sometime around the 5th or 6th stress-induced depressive episode, something happens and things starts cycling on your own, and you no longer need a major stressor to experience periodic depressive episodes.
    • Cushing’s diseases, where people secrete lots of glucocorticoids, have very high incidence of depression. Similar with people undergoing medical treatments that increase glucocorticoids, they take on more risk of depression.
    • A whole lot of glucocorticoids
• [38:15] All of the biological stuff above is effective at treating 30-40% of depressives
• So the psychology of depression also matters hugely
• Sigmund Freud tried to investigate the difference between people who come out of a depressive episode (people who experienced “mourning”) versus those who get stuck in it (“melancholia”)
  • His model: you have ambivalent feelings about everyone. If you lost someone or something you loved, and you’re able to focus on your love instead of on your loss. But melancholia is that the ambivalence sticks in your mind and you can never resolve the conflict in your head about how you feel.
  • “And out of this came this wonderful soundbite–depression is aggression turned inward–because you’ve got nobody else out there to have these arguments with. This is the person who you have most loved, but most hated. And you never said the things you need them to hear and you’re pounding at the door to get, to finally be able to tell them. And now you’ve lost that opportunity forever. And all you can do is internalize all of that–aggression turned inward.”
  • “It’s great, it feels very intuitive. But you can’t do modern science on it, which is the probem with the best parts of Freud.”
• Experimental psychology
  • You’re more at risk for a stress-related disease if you don’t have outlets for the frustration, if you feel like you have no control over what’s happening, if you feel like you have no predictability about what’s happening, or if you have nobody’s shoulder to cry on.
  • [42:55] “And what a depression is, is pathological extremes of this. You fall into the cognitive psychology soundbite of what a depression is, it’s learned helplessness.”
  • “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’m in this situation, there’s not a damn thing I can do about it. It’s awful and I feel terrible. But this is not the whole world. And what a major depression is about is you sit there and you’re 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. You don’t bother doing it, because you’ve learned to be helpless, just like a human depression. What depression, what learned helplessness is, is taking a circumstance where, by any logic, again, you should be saying this is awful, but it 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 helpless, I am always hopeless. This is the psychology of what a depression is all about.”
  • “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 for the rest of your life you are more at risk for a major depression. This makes perfect sense. What is a lot of what’s going on during your first 10 years of life? You are learning about cause and effect. You’re learning, is this a world out there where I have any sort of efficacy, where I have any sort of control. And you have just learned in the most big time, awful way there are things you can’t control, and sometimes they are awful. And what have you just learned? There’s all sorts of reasons where one can be helpless. And you’re that much closer to this edge of this learned helplessness cliff for the rest of your life.”
• How do you combine these worlds of psychological and biological explanations?
  • The critical link turns out to be stress
  • Depression is a genetic disorder, meaning that it has some degree of heritability and tends to run in families
  • The closer in the family tree, the more similar your odds of depression: if a person has depression, there’s a 50% chance an identical twin would also have it, 25% chance a non-identical twin or other sibling would have it, 8% chance for half-siblings, 2% for a random person off the street
  • What’s it tell you that a genetically identical individual has a 50% chance of having depression? It tells you that there is a genetic component.
  • What’s it tell you that a genetically identical individual has only a 50% chance of having depression? It tells you that genes are important but not more important than any other component.
  • There is a particular gene really relevant to whether or not you get depression, and it’s been replicated. And what’s good, is that it fits into our existing knowledge: it’s a gene whose other functions relate to the serotonin re-uptake pump.
  • So the hypothesis is, everyone’s got some version of that gene, some of us have the bad one, some of us have the good one.
  • Massive study looked at 17,000 kids growing up in New Zealand, and their genetic makeup, and checking in their 20s who has a problem with major depression.
  • Back comes the finding that neither variant of the gene is sufficient to predict depression
  • But, if you take the subset who have a history of exposure to major stressors during childhood development (death in the family, parental separation, physical abuse), what you see is this. People with the good variant have higher incidence of depression than those without trauma. But those with the bad variant of the gene have a 30x likelihood of having major depression than those with the good variant.
  • aaaThis is not about “oh, genes control our brains, and genes control our behavior.” This is a gene that is relevant to how readily we pick ourselves up after life has dumped us on our rear ends, how readily we recover from stressors.zzz
  • The final piece of the story: glucocorticoids regulate the function of this gene.