 G'day, May 40 here. Welcome back to 40 University. Welcome to Medical School. I'm reading this terrific book, The Loss of Sadness, How Psychiatry Transform Normal Sorrow Into Depressive Disorder, by Alan V Horwitz, a sociologist of medicine, and Jerome C. Wakefield, a historian of medicine, and just a brief shot from this book. So perhaps the most popular and widespread theory about depression is that it's a chemical imbalance in the brain. I remember when I was basically bedridden by chronic fatigue syndrome between ages 21 and 27. I think the most common thing suggestion that I heard was maybe if you ate meat, you'd feel better, and that was right. I think in retrospect that was right. If I had just eaten meat, I probably would have turned things around. But then the second most common thing I heard was, well, it may be just the chemical imbalance in your brain and you should try psychiatric medication because it just corrects the chemical imbalance in your brain. Well, we don't really have much evidence for this thesis. What you usually hear about is specifically deficient amounts of the neurochemical serotonin, and that's what causes depression. So let's pray for Josh Randall suffering from super low serotonin levels right now. So then drug treatments, they target serotonin. The selective serotonin reuptake inhibitors, SSRIs, and these correct the chemical imbalance, and so this is the appropriate and the best way to treat depressive disorder. And this theory is just relentlessly promoted. Like pharmaceutical advertisements emphasize how correctable chemical imbalances cause depressive disorders. You've got public service messages that stress that depression stems from flaws in brain chemistry rather than in character. So don't be afraid to ask for pharmaceutical help. Then you've got mental health advocacy groups who share the message that depression is just a physical brain-based illness just like diabetes and asthma, man. So if you've got diabetes, you wouldn't turn down insulin, would you? Well, SSRIs are just like insulin for the depressed, right? What insulin is for the diabetic, SSRIs are for the depressed, right? That's what's pushed. And these messages are ubiquitous. Not only are they ubiquitous, they are all around. They are throughout. They are across our society. So there's this widespread impression that research has shown, like science has shown, guys, that chemical deficiencies are the cause of depressive disorders and drugs work because they correct these chemical deficiencies in the neurotransmission system. So you can separate depressive disorders, right? In DD, major depressive disorder, right? It's the most common psychiatric diagnosis from normal sadness. You just have to examine the levels of serotonin in the brain, bro, right? And where did this chemical deficiency theory of depression originate? With the good psychiatrist, your friend and mine, Joseph Scheidelkraut, he published this hypothesis in 1965 that low levels of amines were associated with the development of depressive disorder. And so we all know what amines are, right? It's an organic compound derived from ammonia, by replacement of one or more hydrogen atoms by organic groups. Boy, I'm so ashamed that I just cheated my way through chemistry. It was the only way I passed that class in high school. But I didn't call it cheating. I called it taking advantage of the surroundings. It shows my low levels of character. In some situations, I have low levels of character. So Dr. Joseph Scheidelkraut's hypothesis published in 1965. His paper is still one of the most frequently cited articles in the whole history of psychiatry. Now, he thought that norinephrine, not serotonin, was the neurochemical implicated in depressive disorder. So what is the evidence for the chemical deficiency hypothesis that stems from the purportive success of drug treatments, which raise levels of amines and alleviate depression symptoms a little better than just placebo effect? So Dr. Scheidelkraut recognized that even if the drugs are effective in treating the disorders, that does not necessarily imply that their mode of action involves correction of the underlying abnormality. But there are all these arguments relating to serotonin that rely on the premise that if we just enhance its transmission, we can improve depression. Because a deficiency in the serotonin system is responsible for the emergence of depression. But this theory has so many problems. So one is that SSRIs cause immediate changes in the levels of serotonin, but the resulting effects on depression, there are positive effects. They take a month or two to transpire. So you immediately get a boost in serotonin, but you don't feel any better for a month or two, if ever. So the impact of the drugs on depression might not result from the change in neurotransmitter levels that they create, but from another number of other processes associated with amine activity. So another problem with this theory is that drugs do not affect either serotonin or nephrin. So some drugs don't affect either. And these are the major amines involved in the chemical imbalance hypothesis. But these drugs still can alleviate depression just as much as the ones that do affect serotonin levels. So there are all these antidepressant drugs developed after SSRIs, but they don't boost serotonin. Now the third difficulty is that drugs use to treat depression work with equal effectiveness on other disorders, including anxiety, eating disorder, attention deficit disorder, substance abuse, personality disorders. And a whole host of other conditions that may or may not be comorbid with depression. So drugs are not correcting a specific neurochemical abnormality in the brain that underlies depression. So they're acting on general brain functions in ways that influence many different behavioral and emotional systems. So there's no theory that explains how a single abnormality in brain chemistry can be related to such a wide range of resulting problems. And only 25% of depressed patients actually have low levels of norenephrine or serotonin. Only 25%. Another problem is that these lower levels of serotonin among the 25% with depression do have these lower levels. These lower levels may very well be the consequences rather than the causes of depression. So there's no evidence that demonstrates that chemical imbalances precede and cause depression. So depression itself, as well as the drugs used to treat it, they will be responsible for these inferred deficiencies in serotonin levels. So most research participants with regard to psychiatric medication and depression have long histories of medication treatment. So it's impossible to know what their unmedicated brains look like before they begin using antidepressant drugs. And there's no adequate contextually grounded standard that exists for normal versus disordered levels of serotonin or other amines. We don't know what's an appropriate or proper or ordered level. So high or low levels of any neurochemical may not be abnormal in themselves. They may only relate, they may be contingent, meaning dependent upon a particular set of circumstances and to the way the brain is biologically designed to respond to those circumstances such as circumstances of loss, loss of income, loss of status, loss of a spouse, loss of connection, loss of community, loss of a job. So the brain mechanisms that underlie levels of serotonin and other neurochemicals probably biologically designed, evolutionarily developed to be responsive to a particular context. The brains of normal people who are experiencing serious loss, you'd expect them to show these same depleted levels of serotonin. And serotonin levels among primates vary substantially as a function of situation, situationism, situationism rules, social situation essentially determines or has a huge influence on your serotonin levels and your happiness and whether or not you are exhibiting symptoms of depression. So as you gain in status, you will behave in a more happy and confident manner. As you fall in status, you will behave in a more depressed manner. So gains and losses of social status correlate with rising and falling levels of serotonin. So low levels of serotonin in humans can reflect the emotions that normally accompany a recent negative change in social status rather than some major depressive disorder. So baboons living in the wild show highly elevated levels of glucocorticoid stress hormones after experiencing bereavement or loss of social status or other stressful events and these levels return to normal after the affected animals resume grooming behaviors with other members of their social network. So in many cases, these extreme levels of neurochemical imbalance do not indicate any disorder but instead show the way that normal brains respond to stressful situations. Also disorder states are associated not with extreme levels of neurochemicals alone but also with extreme levels that are inappropriate responses to an environmental context. So the sort of changes that you get in the brain result from depressive disorders basically the same as the responses in a normal person responding to stress. So the amount of serotonin or amine in response to some stressful event may well be adaptive to the situation in which it occurs. So the difference between what is a normal and abnormal neurochemicals lies not in the levels of the neurotransmitters per se but in fact the neurotransmitter level has escaped from the usual restraints and become chronic and removed from environmental circumstances. So statements that depression is a flaw in chemistry that it's a physical disease premature. It may be cognitive causes, psychodynamic, social, all sorts of other factors that may disrupt biologically designed sadness reactions that may or may not correlate with brain abnormalities. So the truth is it's not known how drugs alleviate the symptoms of mental disorders and it cannot be assumed they do so by correcting endogenous chemical deficiencies. One thing I find fascinating is how animals show all the same symptoms and behaviors of extreme sadness that human beings do and for similar reasons. So Charles Darwin noted that apes and humans show similar facial expressions in situations associated with sadness including elevated eyebrows, drooping eyelids, horizontal wrinkles across the forehead, outward extension and drawing down on the lips. So displays of sadness among apes like human responses include decreased locomotor activity, agitation, slouched or fetal like position, cessation of playing around and social withdrawal. It's pretty much the same among apes as among humans and lost situations that lead to depressive responses are similar in primates as they are in humans. So non-human primates react to separation from intimates, for example an infant monkey separated from its mother with physiological responses similar to those that correlate with sadness in humans including elevated levels of the stress hormone cortisol, like hormone impairments, impairments of the hypothalamic pituitary adrenal axis. Non-human primates that are separated from their sexual partners or peers show similar reactions to human beings, similar reactions of loss and symptoms of depression that develop after separation with primates and with humans these symptoms rapidly disappear when the situation of loss is resolved such as when an infant is reunited with its mother. Primates in environments that feature readily available mother substitutes rarely exhibit severe and enduring reactions to maternal separation. Any mum in a port, any partner's dorm. So usually our quote unquote major depressive disorder symptoms are transient sadness responses to separation or loss. They're just part of innate coping mechanisms among many species including humans and apes. Now prolonged separation, separations marked by profound isolation produce among apes, animals, humans, neuro anatomical changes that may permanently affect both human and non-human brain functioning. And this is essentially the triggering of genuine depressive disorder about humans and apes. So non-human primates share with human social hierarchies with high and low status positions. Situations of chronic social subordination lead to behaviour on brain reactions similar to normal depressive responses in humans. So subordinate non-human primates have higher levels than dominance of stress hormones and lower levels of blood serotonin that neurochemical link to depression among humans. The loss of rank among non-human primates in their social hierarchies triggers the production of the neurochemical correlates of depression. So there are all these similarities between primates, non-human primates and human primates. So we can see how normal depressive symptoms are frequently just a function of social situation. They are a function of situation. Situationism guys, it's so useful in understanding the world. The situation will determine our brain chemistry, our quote-unquote personality, right? The big five personality traits we're outgoing or introverted, conscientious, lacking conscientiousness, agreeable or disagreeable. Much of that simply reflects the situation. So non-human primates tend to possess strong and enduring hierarchical status relationships with one dominant male in each group. And the highest ranking males among non-human primates have serotonin levels that are twice as high as those of other males in the group. And when experimenters withdrew the dominant males from the group, their serotonin levels fell, right? So if you're the big man in a group, you're a big man on campus and you are pulled away from that group, your serotonin levels are going to fall. You're going to likely refuse food. You're going to show diminished activity. You're not going to want to play and you're going to appear to be depressed, whether you're an ape or a human. Now, the serotonin levels are previously dependent and low status monkeys who suddenly gain high status after removal of the previous dominant male apes. These previously low status monkeys rise, right? And they rise in status, they rise in serotonin levels. And they get the serotonin levels characteristic of dominant males. And similar results are obtained with female monkeys. So wild baboons living freely in East Africa, setting them shows a chronic social subordination is associated with high stress hormones consistent with depressive symptoms in humans. And when rank in status hierarchies changes, these physiological profiles change as well. So these physiological profiles, these brain chemistry profiles are heavily dependent upon social context on situation. So the behavioral and the neurochemical advantages of high rank are found only in stable dominant hierarchies. In unstable hierarchies in which the position of the dominant is precarious, high rank is not associated with fewer stress hormones. So humans have inherited from their primate ancestors a natural tendency to become sad in particular contexts of status and relationship loss. And this human tendency to become sad appears early in infancy. So way before the infant has ever learned culturally appropriate ways of expressing sadness. Infants and designs need strong attachment and they develop certain types of sadness responses as a coping mechanism when they are separated from their primary caregivers. So healthy infants who are separated from their mothers initially react by crying and other expressions of despair. They protest the separation. They search for their mothers. Their responses usually evoke sympathy from the mothers who respond by attending to the infant's needs. Now when the separations are prolonged, the infants start to withdraw. This is what happened to me when my mother was dying of cancer and I was put through foster care. Like the separation between me and my mother and me and my mother figures became prolonged. Now I withdrew. I became inactive. I became apathetic. I showed all the symptoms of an intense adult loss response. So prolonged separations from your caregiver and infants results in a state of attachment in which young children cease to respond to parental figures even after they are restored to their lives. So sadness naturally arises in infants, in non-human primates after the loss of close attachments. So we all will experience separation anxiety and grief when we lose intense loving relationships. So sadness that develops after the loss of these intense loving relationships is a normal pre-socialized aspect of human behavior and non-human behavior. When these losses are prolonged without any compensating remedies they can lead to responses that go way beyond normal sadness to become, you can call them depressive disorders or dysfunction. Bye-bye.