#1233 Steven Hollon: A Clinical and Evolutionary Approach to Depression

00:00 Ricardo Lopes: Hello everyone. Welcome to a new episode of the Dissenter. I'm your host, as always, Ricardo Lobs, and today I'm joined by Doctor Steven Holland. He's the Gertrude Conway Vanderbilt Professor of Psychology at Vanderbilt University, and today we're going to talk about depression, particularly from an evolutionary perspective. So Doctor Holland, welcome to the show. It's a pleasure to

00:24 Steven Hollon: everyone. Thank you very much.

00:26 Ricardo Lopes: So let's start perhaps with exploring what depression really is because I mean, I wouldn't be surprised that even though we hear, we nowadays hear a lot about depression and other kinds of mental illness on the news. I mean, maybe many people out there are not really, don't really know exactly what we're talking about. So what is depression?

00:54 Steven Hollon: Yes, certainly, uh, depression, um. IS a uh uh conventionally considered a psychiatric disorder, and it's on a continuum ranging from normal sadness, you know, bad moods that everybody gets into, up to full-blown, very serious, uh, psychotic, uh, uh, uh, depressions that uh often will require hospitalization. Most folks will not, uh, have anything near that severe. Uh, BUT it is, uh, what, uh, the primary major diagnostic category, which is called, uh, major depressive disorder, is the single most common prevalent psychiatric disorder. And that, uh, you get about, uh, conventional wisdom says about, uh, maybe about 15% of all people are going to have one or more episodes in their lifetime, about twice as many women as men.

01:39 Ricardo Lopes: Uh, AND by the way, since you mentioned that, do we know at all why women are twice as much as men to suffer from depression?

01:49 Steven Hollon: Uh, NO, we don't. Um, WE, we, we don't know that. We know it's true. Uh, AND by the way, I'll be talking primarily about unipolar depression, which are those individuals that get depressed but never have a manic or hypomanic episode. Uh, THERE'S a very small percentage of people, about, uh, 1% of the population. Uh, IF you talk about, uh, uh, bipolar 1 or 2% of the population that have a really severe manic episode that usually requires institutionalization, uh, but that's, uh, the depressions in bipolar disorder are very similar to, to the depressions in unipolar disorder, but almost identical symptomatically. But bipolar disorder is highly heritable, about as heritable as the schizophrenia. Uh, IT'S, uh, far less prevalent, about 1 to 21 to 4% of the population can include the minor, the less severe bipolar 2. Uh, DISORDERS, and it is not, uh, uh, distributed unequally between the sexes. So there, uh, there are these tantalizing clues that something different is going on, uh, but again, we don't know exactly why that is.

02:46 Ricardo Lopes: And to what extent is depression genetic? Does it have a genetic component to it?

02:53 Steven Hollon: Uh, WELL, yeah, almost everything, uh, in, in human, uh, uh, functioning has some kind of genetic component, but it's not big in unipolar depression. It's about, uh, uh, 0.3 to 0.0.4, which I think in terms about 3 or 4% of the, 40% of the causal variants. Quite different from bipolar disorder where, which is, uh, goes about 0.7 to 0.8. So it's, it's far less heritable. And again, we don't, we don't fully understand that. If I circle back around to the why women are more likely to get depressed, uh, the, the other thing that, uh, stands out is that the, Incidence of depression takes off in early adolescence. It, it doesn't happen that often in childhood. If it, if it does, there's usually something situational, usually resolves and the situation resolves, uh, but starting from early adolescence on 1112, 13, uh, the incidence of depression goes up 2 to 3 times and twice as often, 2 to 3 times more often in women than in men because of when it. Starts in early adolescence. A lot of thought goes, maybe it has something to do with hormonal variation, the onset of menses. Uh, THAT'S also the time when, uh, uh, uh, males get the growth spurt and a little later and women don't. Uh, SO up until, uh, uh, elementary school, women generally do as well as men do in various kinds of pursuits and starting from adolescence on, um. They, uh, uh, they, they tend to get a, a drop in self-esteem and, uh, concern, interest in things like stem cells. So how much of that is biological, how much of that is cultural, uh, we don't know. Mhm.

04:17 Ricardo Lopes: And what are then the criteria to diagnose depression?

04:23 Steven Hollon: Yeah, um, you can find, uh, descriptions of depression that look very much like what we have now in our current, uh, nosologies, uh, back in in hieroglyphics on the walls of the pyramids. So it's been around a very long time. Uh. Criteria get get revised from time to time, but the general current criteria, and they're very similar to what we've been using for years, uh, you want to see it, uh, you don't want to see it, but you look for evidence of, uh, distress, uh, sadness, distress, etc. AND or anhedonia, which is an almost pervasive loss of interest. You need one of those two to get the diagnosis, and then there are usually about a half dozen other things that people look for. For a loss of interest, loss of motivation to do things. Uh, PEOPLE that used to love to play tennis stopped playing tennis. Uh, YOU get, uh, uh, oftentimes disruption in, uh, a couple of biological functions. Sleep becomes disturbed. Uh, FOR some people, it's having trouble falling asleep. For others, the classic pattern is waking up early in the morning, 34 in the morning, ruminating like crazy, and not being able to go back to sleep. It really tracks the, uh, uh, cortis. LEVELS, the, uh, for most people, the cortisol levels pick up around dawn. For somebody who's clinically depressed with melancholic depression, it, it starts a couple of hours earlier. Uh, LOSS of interest in food, in most instances for some people, uh, uh, there's a subtype called atypical depression. For some people, it's, it's almost like a case of the munchies. It's almost like they've been smoking marijuana. They snack and oftentimes a preference for carbohydrates and chocolate in particular. Um, LET'S see, we got, uh, food, uh, and a loss of interest in sex, uh, usually as well, those three kind of classic biologic things. Uh. Self-concept takes a, takes a plunge. Uh, PEOPLE don't think they can do things, uh, so they don't try. So there's a whole cluster of things, but it's usually the pervasive sadness or the loss of interest or both, uh, that defining the, the, uh, criteria.

06:13 Ricardo Lopes: And how long do people need to experience those kinds of symptoms before they get a diagnosis?

06:20 Steven Hollon: Yeah, that's, that's relatively arbitrary. The formal criterion, look for at least 2 weeks of, uh, that you meet criterion for, uh, uh, one or the other of those 2 key cardinal criterions, and then at least 4 or 5 of the others. I forget exactly how they set it up. It's kind of like a Chinese menu, menu in a Chinese restaurant. Uh, BUT they look for at least 2 weeks. Uh, MOST folks, uh, in their first episode don't pursue treatment unless it lasts long enough to become chronic. Um, BUT, uh, gee, the, uh, the, the work that I've done typically in outpatient psychiatric populations, uh, people might have been depressed for a couple of months, uh, or more, and usually in a 2nd or 3rd or subsequent episode before they think to seek, seek treatment. That may be changing now cause so much of the treatment nowadays is being done by primary care physicians. We have, uh, uh, some of the newer antidepressant medications, the Celexa. SEROTONIN reuptake inhibitors like Prozac and others are relatively safe and relatively effective. And because they're relatively safe, primary care physicians feel comfortable prescribing them. The older antidepressants that might work just a little better, uh, a little more problematic in terms of risk of, uh, of overdose and suicide or, or food, uh, uh, uh, things with food or over the counter medications that can produce complications, uh. Primary care physicians in the old days, nowadays wouldn't prescribed them, but SSRI's they're, they're comfortable prescribing. So there's been a real, uh, #1, increase in the number of people are getting treated, and 2, it's being half or more at the level of primary care.

07:51 Ricardo Lopes: Is it possible that that at least in some types of depression, people can get over the depressive period or phase without any medical help?

08:04 Steven Hollon: Yeah, depression is relatively unique. It's temporal and not situational. You think of people with phobias. They have to be in the situation where the thing is that they're afraid of for it to be a problem for them. In depression, it's temporal. When you get depressed, you get depressed most anywhere, most all of the time, but, uh, Unlike phobias, it goes away in time. We have, it's a phenomenon called spontaneous remission, and most people, particularly in our ancestral past, most people are going to get over depressions without any kind of treatment interventions. It may be several months, it might even be in a small number of cases, uh, several years, but almost all episodes of depression resolve spontaneously, and again, we don't know why.

08:41 Ricardo Lopes: Mhm. Yes, but, but still on that point, I mean, because, because of course we hear also now the, nowadays with the internet and social media, unfortunately, lots of misinformation very easily spread online and sometimes we hear things that are really not. Helpful and even might be harmful. I mean, does depression have anything to do at all with willpower? I mean, can people get over depression just because they want to, or?

09:14 Steven Hollon: Yeah, yeah, yeah, yeah, um. That is, it doesn't mean that you can't do things and learn to do things that get you out of a depression or keep them from coming back in the future. You can, but it's not a lack of willpower. Depression saps motivation. So almost the cardinal feature, it's, it, it makes it difficult for you to do the things you typically do, the things you typically enjoy, uh, and it's, it's almost the cardinal feature of the disorder. So I, I, you don't want to, uh, you don't want to hold anybody responsible for having difficulty getting things accomplished when they get depressed. Right. Like expecting somebody who has a bad case of the flu to get out of bed and then go back to business, they can, but it takes a huge amount of willpower to do it. It's not a lack of lack of willpower that causes it,

09:56 Ricardo Lopes: right? And, uh, of course, I'm going to ask you just in a bit, uh, how you approach depression from an evolutionary perspective, but how has depression been traditionally approached in psychology?

10:10 Steven Hollon: Yeah, um. Not, not typically all that well, uh, for in terms of psychological interventions, uh, most everything dates back to, uh, uh, Freud and, uh, some of the psychoanalytic psychodynamic, uh, therapies he developed, uh, might well work for other things. They're not particularly useful in the, in the treatment of depression. Um, AND it wasn't until the, uh, about the 1950s with the advent of the, uh, uh, antidepressant medications, most of them discovered accidentally that people were looking, uh, physicians looking for. Uh, MEDICATIONS or treat other things, but they noticed, uh, uh, almost by serendipity that it resolved depression. For example, some of the early trials, uh, uh, with the, uh, I think it was the, uh, uh, monoamine oxidase inhibitors were designed to see if they could relieve, uh, the buildup of fluid or tuberculosis. It didn't have, didn't help tuberculosis at all, but it helped the depression for people that are then locked away in, in asylums. Uh, SO we, we stumbled on medications that worked in the. Reducing uh uh symptoms of depression in the 50s, uh, by about the 1980s, 19, and they were, they were generally reasonably effective, but again, a tricyclic, one of the older standbys, uh you can overdose on two weeks of that. It's, it's like sending somebody who's suicidal home with a loaded gun, uh and the MAO and MAOI, MAO inhibitors, uh, um, you can, you, you, you can overdose with, uh, uh. What, what, not, not all the medi medication stuff so much, but the combinations with certain kinds of foodstuffs like soy sauce could put you in a hypertensive crisis. So, uh people other than uh psychiatrists were reluctant to prescribe. Nowadays with the SSRI's that came in in the uh late 80s, early 90s, the uh uh a lot of the treatment is, is passed over to primary care physicians.

11:58 Ricardo Lopes: Mhm. And so, uh, what does an evolutionary approach to depression bring to the table in terms of approaching it theoretically to under to understand better perhaps what it is and then I don't know if it has some also clinical applications we might talk about that,

12:17 Steven Hollon: right, it, it might have down the line, uh, let me say first, this is a very, very much a, a, a minority view. This is not something widely accepted in the field that would be considered quite controversial. Um, TO, however, that's within psychiatry or psychology, to an evolutionary biologist, uh, negative aspects like sadness, anger, anxiety, etc. uh, AREN'T disorders or diseases, those evolved adaptations that kept our ancestors alive in the past long enough to become our ancestors. They evolved because they served to function and what the, to an evolution of biologist, what that meant. As they kept, uh, they facilitated, uh, passing your genes on to subsequent generations, either yours or, or your, uh, uh, biological relatives. Uh, ONE of the biggest changes in evolutionary theory in the 20th century, uh, was moving beyond, uh, the notion of survival of the fittest to survival of the fittest gene line. And anything that you do that facilitates either you passing. Genes on or your biological relatives, uh, is going to be selected evolutionarily. It's going to give you a competitive advantage with other members of the species. The, uh, what, what passes for humor among, uh, evolutionary biologists, uh, fellow, I think, uh, Haldane once said, I wouldn't give my life for one brother, but I would for two brothers or 8 cousins because genetically, that's the break-even point. And, uh, And also, by the way, I don't want to uh uh sidetrack because all, by the way, might account for why suicide is probably baked into the species. Virtually any of us would sacrifice ourselves for children or grandchildren because they're younger, they're more likely to produce the gene line, and evolution is a cruel mistress. It selects winners and losers, and anything that works better is what then gets codified in the gene line and it's can be built in. Um, MANY people who become suicidal, not most people don't become suicidal mercifully, but many people who do get very concerned with being a burden on family, other kinds of members, or not having anything much to contribute, and, uh, it's, it's, it's always a tragedy. But for example, if you're a, uh, uh, First Nations, uh, uh. And what they used to call Inuits, Eskimos north of the Arctic Circle, 100 years ago, if it's a particularly harsh winter, it is not considered suicide for the grandparents to walk out in the snow and not come back, so the grandchildren have enough food to get the, the wintertime. It's, it's, it's something that's probably baked into our, uh, our psychological lives. Um, ALL of that being said, uh, the question then is if indeed it were an evolved adaptation, what function did it evolve to serve and. Excuse me. And for there, again, an evolutionary biologist, which I'm not, but I've been, uh, uh, hanging around with, uh, some, or at least one, what they would do is follow the energy. It's much like the investigative reporters in Watergate follow the money. The evolutionary biologists follow the energy, and when somebody gets depressed, um, the energy goes to the cortex. If you are Or, uh, uh, have an infection, the energy goes to the immune system. If you're starving, the energy goes to, uh, maintain the vital organs, the brain, the heart, etc. Neither send much energy to the cortex. If you get clinically depressed, the energy goes to the cortex, among other, uh, regions of the limbic and, uh, uh, the brain and, uh, limbic system and the, and the, uh, uh, limbic system as well. And basically, it makes you ruminate. And if depression makes you ruminate, uh, clinicians give rumination a bad name. They consider it something that's kind of working, endless, going over and over things, not getting anywhere. A regular non-medical dictionary, rumination just means thinking long and hard about a complex problem. And uh when you get depressed, energy gets uh uh directed to the cortex. It keeps you focused on the problem that you're trying to solve. It activates short-term memory, which is very energetically expensive, so that you can really think about things and hold it in, and uh you can make a pretty good case, I think, uh, for the brain being charged to spend its time trying to sort out what the problem was that was distressing you in the first place.

16:13 Ricardo Lopes: OK, but since we're tackling things from an evolutionary perspective here, are there any specific problems that are re evolutionarily relevant, uh, that would trigger, uh, depression or a depressive state then this

16:29 Steven Hollon: gets, uh, this becomes quite speculative. However, if we take a look at when depression really takes off in its incidence, that's early adolescence, uh, when, I mean, and when it takes off, particularly. Women relative to men, it, it increases in both gender and in both sexes, but especially women. Uh, THAT'S the time, uh, when you go, becomes, uh, reproductively active and in our, uh, evolutionary past, that would be the time that young primates, uh, could start to reproduce. That would be a time when young women, uh, female primates would be bothered by male primates. Males are bigger, stronger, uh, physically more aggressive when it comes to sex, and, uh, if you get ostracized from the troop. Um, YOU'RE going to die. You're either going to be picked off by predators or you're going to starve, so you have to stay in good graces with the, uh, uh, the, uh, social networks in the troop, and Males and females generally have somewhat separate uh social networks, so it means you've got to keep the grandmothers paying attention to your infants to get driven out, uh, uh, you're gonna, you're gonna starve or get picked off, and the evolutionary cost if you're a young female is twice as great as it is for males because you're losing both you and The infant, as opposed to just using the uh losing the male. For males, it's probably more tied up in uh uh dominance hierarchy and whether or not you're going to get a chance to uh to reproduce. Now, we don't know that for sure, uh, but it would match up very nicely with the time course.

17:52 Ricardo Lopes: Right. But then, uh, I mean, of course, as you said, this is a minority view, but, uh, since we are exploring it, um, if it is correct and if depression is an adaptation, is it still a disease?

18:11 Steven Hollon: No, no, no. Uh, FROM an evolutionary perspective and even uh within psychiatry, it's moving in that direction. It's not quite there yet. The notion is that a disease is when an adaptation breaks down. Not when a normal uh when amputation functions the way it was designed to function. For example, the uh uh a very small number of people are born with the hearts on the right side of their body. That's aberrant. That's not the way the, uh, body's designed, but it doesn't do anything to them or their uh uh life expectancy or the capacity to uh uh pass on their gene line. If your aorta uh ruptures, uh, you're gonna die very rapidly. That is a disease, the, a, a, uh, evolutionary plan, uh, that was structured, uh, uh, to keep you alive broke down, that would be considered a disease, but heart on the other side of the body, not a disease.

19:00 Ricardo Lopes: OK, so, but do you think that perhaps there, there would be some sort of evolutionary mismatch in the sense that maybe the kinds of societies, traditional society, societies we evolved in. Um, THERE would be, uh, space or it would be functional for people to go through a period of depression, uh, with the goal of solving those problems they would have to deal with that are relevant from an evolutionary perspective, but now that we live, or at least people who live in industrialized or post-industrial societies. I mean, they don't have enough time to deal with depression because they have to go work the next day or

19:48 Steven Hollon: yeah, yeah, it, it, it, it could be and there may well be changes, uh, at the same time, uh, you can take the, uh, I say, you can take the person out of New York and take New York out of the New Yorker. Uh, DEPRESSION across culturally shows up in virtually every culture in, in very similar kinds of ways, very similar kinds of, uh, Uh, uh, prevalences and incidence rates, uh, usually takes off in adolescence regardless of the culture. In, uh, Asian cultures, people describe it more in terms of, uh, fatigue and physical symptomatology rather than sadness, but all the other symptoms are there and they and it responds every bit as well. Uh, I look at the, uh, I look at the COVID, uh, uh, crisis, and when, uh, young adolescents couldn't go to school, they were spending more time on the internet, more time interacting with people. And we had increased incidence in, uh, uh, at least, uh, what appeared to be, uh, depressive episodes in, uh, teenagers, particularly teenage girls, because they were living and dying by whether or not they got liked by their friends and where things stand. So it's, uh, if there are things that are wired into the species, they're going to sometimes be aggravated by certain conditions, but by and large, the, uh, phenomenon we see in, in depression, both unipolar and much less common bipolar, seem to be relatively cross-cultural and cross-situational.

20:58 Ricardo Lopes: Mhm. Yeah, but, but I, I mean, perhaps the question I wanted to ask there was more, uh, so perhaps in more modern industrialized or post-industrial societies because, uh, the pace of life is, uh, faster. I mean, do, do you think that, do you think that perhaps it would make sense to, uh, treat, uh, depression or deal with depression as a Disorder or a disease because it is not, it is probably not a very um a behavior that is very well adapted to the

21:34 Steven Hollon: sense of society. It, it may well not be functional in current uh in current kinds of societies and again that may, uh, that would hold uh across uh, across genders. Uh, PARENT that can't get out of bed to, uh, make breakfast for the kids, that's not functional. And uh an individual goes on to work or doesn't go into work because they're too sad, too depressed, uh, that again, that's not functional. I wouldn't say that depression uh doesn't interfere with function, it clearly does, just that it's not a disease. It's a, uh, it's an adaptation that, uh, perhaps to biological, uh, a biologist, it's an adaptation that evolved to serve a purpose. Whether or not that purpose is still useful in current days, is a real question, and that's fair.

22:16 Ricardo Lopes: OK. So let's go back then to the um the more medical aspect of depression, the psychological aspect of it, uh uh from a clinical psychology perspective, of course. I mean, among people who suffer from depression, what percentage of them experience recurrent depression?

22:38 Steven Hollon: Um, CONVENTIONAL wisdom is maybe about 70, 80% of them. Uh, WHEN I gave you that guesstimate earlier about, uh, uh, that estimate of about 15, 16% of the population, twice as many women as, as men are gonna have one or more episodes of major depression. At some point in their lifetime, uh, the other part of the conventional wisdom and all of this based on retrospective epidemiological surveys was that about 70% to 80% of them are going to have more than one episode. It's going to be recurrent phenomena, and that's what conventional wisdom would hold. Um, IT turns out that if the way you get that kind of estimate is by interviewing people, maybe a whole range from adolescents on through, uh, uh, senescent, uh, people who are older forget earlier episodes. So it looks like, uh, younger people have. More episodes than older people and it looks like um the, the estimates are lower than what you get if you take a sample and follow them from birth on. Uh, THERE'S been a marvelous study, the Dunedin study that uh uh Tammy Moff and Ashley Caspi been following where people were picked up at birth in, uh, uh, New Zealand city. Uh, AND Dunedin and then followed every couple of years they get interviewed. They've been tracking the course. The sample now is up in their 40s, and the rates of depression in that sample are 3 to 5 times higher than what the retrospective epidemiological surveys would suggest. I have a good friend, colleague Ron Kessler, who's probably the best of the epidemiologists who conducted the retrospective surveys. I remember, uh, asking him one time, what do you think about it? He said, well, of course, they, uh, they don't miss episodes. We miss episodes because people don't remember. So it's understood among epidemiologists, that's a better way to estimate and estimate your estimates. And when you do that, uh, it's probably the case that anybody could get a unipolar depression if something bad enough happens to them. And indeed, uh, most of us would have a grief reaction if we lose somebody that we love dearly or a child. Uh, THAT'S virtually universal, um. Um, AND that's probably because the capacity to experience what would be severe enough to be labeled a clinical depression, uh, uh, is stamped into the, wired into the species. It could happen to virtually any of us.

24:51 Ricardo Lopes: And what is difficult to treat depression? I mean, why is it that some people, I mean, apparently never get over depression and even though they go through several different kinds of treatment. INCLUDING psychotherapy and medication, they seem to be resistant to everything.

25:13 Steven Hollon: Yeah, yeah, I, I don't think people know, uh, we're making great strides in the underlying biology, underlying psychological aspects. Uh, SOME things stand out as kind of quasi. Uh, RISK factors, the earlier the onset, the heavier the genetic load, uh, incidents of, uh, trauma, in pre-adolescence, particularly sexual abuse or emotional neglect and trauma, seem to be contributors, but we don't actually know for sure. And the one thing, uh, uh, That I, I would be, uh, not wild about the term, uh, treatment resistant. Uh, NO patient ever fails treatment. Treatments fail patients, and what that would mean is for an unfortunate smaller subset of the population, we don't know yet. We don't have tools at our disposal yet that can help lift them out of depression. Uh, THE wonder drug that people are, uh, really very excited about, uh, relatively, I'd say somewhat newer, is ketamine. Uh, WHICH, uh, uh, can, can get somebody who's, uh, seriously chronically depressed out of a depression within a matter of hours. The problem is, uh, if you take it too often, uh, uh, too, uh, repeatedly, it can, uh, drive a, uh, psychosis, and, uh, it, the effects generally fail, uh. Wash away pretty rapidly, but they're, we're hoping to move in the direction of being able to figure out exactly how to use that. It is, uh, it's more the, uh, MD MDA and MDA receptors, which is more glutenmatergic, which means it's downstream from the things that drive you to ruminate, uh, in the first place. So there may be something special there. We just haven't figured out how to use it yet.

26:44 Ricardo Lopes: Mhm. And what are the main treatments available for depression? So someone gets diagnosed with it, uh, I mean, what is available to

26:53 Steven Hollon: them? Yeah, got you. Uh, THERE are a couple of different things, and then I, one of the better aspects of depression, it's eminently treatable. Not only does it tend to go away on its own for most people, uh, but it's eminently treatable, uh. Let me start first with bipolar disorder. From bipolar disorder to bipolar 1, where a person has a truly psychotic level of manic or occasionally uh depressive episodes, you want to be on medications. You want to be on lithium and or a mood stabilizer. Uh, THERE'S nothing that we have psychologically. That offsets the onset of the next manic episode the way that lithium does. It's, it's a true wonder drug, but that's 1% of the population. If you have bipolar depression, which means you have, uh, you'll have occasional serious episodes of depression, but, uh, only hypomanic episodes, it just means more energy, uh. More, a little bit of grandiosity, but nothing that goes too far. Um, I'd, if I could sign up for that, I would, and actually I didn't have to. I'd probably have that. I'd probably be criterion, and I think that probably helps me write, do things, etc. AND, uh, a couple of, uh, uh pleasant episodes of depression back in my early twenties, but nothing since, so it You know, it's, uh, that people with with bipolar 2, particularly if it's only kind of chronically hypomanic tend to be overrepresented as, uh, heads of Fortune 500 companies, etc. It's, it might actually be a, be adapt adapted to have that extra, uh, drive, energy, etc. uh, FOR Unipolar depression, uh, you can treat it as reasonably with psycho, uh, non-psychotic unipolar depression is treated as reasonably as effective with psychological interventions as it is with medications. And the, uh, uh, the medications starting with the older MAOIs, the tricyclics, and now much more recently, the, uh, the SSRI's, uh, are generally effective for most people. They were generally, uh, reduce the, uh, uh, the symptoms of depression. Uh, PSYCHOTHERAPIES can do as as well readily those that are empirically supported. Uh, COGNITIVE, uh, therapy is the, uh, approach that I've been, I was trained in and, and stick closest to. Uh, NOT only seems to be as effective as medications on average, but has an enduring effect that medications don't have. If you stop taking, uh, uh, medications, oftentimes depression will come back and cognitive therapy, it's, uh, you, you cut risk for subsequent symptom return by about 50%. Interpersonal psychotherapy, uh, which Which is a very different approach to therapy. It's, it kind of grew out of psychodynamic approaches where they dropped uh attention to childhood events and they don't worry about creating a transference neurosis. It basically talk about relationships. Also seems to be quite effective, as effective as medications, as effective as cognitive therapy. Um, MORE purely behavioral interventions like behavioral activation also seem to be. Uh, uh, QUITE effective as, uh, not as intensively studied, it's often studied, but they seem to be about as effective as medications and may well have an enduring effect as well. They lend themselves particularly to shorter term, maybe digital kinds of interventions that you might do in, in global mental health, and, uh, so it's, it, it doesn't take quite as long there. Uh. By and large, uh, you kind of pick them and choose them. You get what you want, although in this country, what you typically get is the, uh, uh, whatever the person on the other side of the door that you go through offers. And if most of the treatments now being done in primary care, it used to be about 2/3 of the folks that were clinically depressed and got treated for it, got treated with psychotherapy. Nowadays, it's 2/3, maybe even more so get treated with medications. Most of those folks in, in primary care, not by psychiatrists.

30:25 Ricardo Lopes: Mhm. Uh, AND in focusing now on psychotherapy, I think that earlier you mentioned that, uh, approaches that are related to psychoanalysis, psychodynamic approaches do not seem to be very effective against depression, but I mean more broadly, what kinds of Of psychotherapeutic approaches.

30:48 Steven Hollon: Yeah, yeah, uh, let me just say that, uh, a quick word that I interpersonal psychotherapy, uh, where they have a number of things that help you focus on the relationship that's not that structured, it's not, uh, they wouldn't do things like homework, etc. BUT it again seems to be quite effective. It's not. Quite as uh easy to find outside of the uh major cities, but it's, uh, it, it, it seems to suggest that you don't have to attend to, uh, cognitions or behaviors to get somebody over depression. This works quite well as well, although we don't know whether or not it has an enduring effect. For cognitive behavior therapies, that's the, uh, the area that I'm most, uh, uh, done most of my work in, and in particular, uh, one version of the cognitive therapy. The original notion was that people get depressed because they come to believe unduly negative things about themselves, and they engage in, in, in biased information processing. From an evolutionary perspective, that's probably not the case. Uh, IT doesn't mean that. They don't believe things that aren't necessarily true, uh, but, um, if you induce sadness in somebody who's not depressed, they'll start, for example, with a social exclusion task, they'll start ruminating about what did they do wrong, and they'll, they'll end up producing things that, that not only feel sad, but they start producing the kinds of beliefs that somebody, uh, would come into therapy for uh clinical depression with. Uh, WHAT I've swung around to starting to think now is what we do in cognitive therapy is we help people ruminate more efficiently. Everyone, uh, some folks get stuck, uh, believing things, particularly, uh, things that are global, stable, and internal. Either I'm unlovable or I'm incompetent. Usually depression involves either love or work, score one for Freud, and what we help people do is to examine the accuracy of those beliefs, often running experiments to find out. Let's give you two examples. I had a client. Uh, YEARS ago, who had a sculptor, an artist who'd lost his job, probably no fault of his own in a small liberal arts college, uh, he came in convinced that what he had was a reality-based depression because he was out of work. He wasn't out of work, he was working as a handyman on a condominium complex, but he thought that was well beneath his level of training. What he hadn't done is apply for another job in academia since he lost his first job. And the reason was every time he started thinking about doing it, he got overwhelmed by the magnitude of the task, didn't think he was up to it, so he didn't start, and it was a relatively simple matter to get him to take a big task, break it down into small steps, like the first thing you want to do the first night when you get home is go out in the garage and look at which pieces of artwork you want to put to take pictures of. Then you get your camera, you get your film, you take the pictures. Within about 2 or 3 weeks, he had his portfolio put together. He was sending it around. And another young woman that I worked with, uh, uh, just under 30s who had, uh, a victim of a, of a traumatic sexual, uh, uh, event in her teens, uh, who came to believe as a consequence that she was unlovable, that no decent person would, that she was interested in would ever be interested in her. Uh, AND unfortunately what she then developed was a strategy where she would, uh, manipulate, uh, wheedle, uh, lie, etc. She wouldn't be herself in relationships, and that was what drove her partners away. It wasn't, she had a whole series now of relationships where she tore, tore the partner up. It wasn't because of anything I love about her, but the behavior she engaged in were problematic. Uh, FOR her, one of the key issues was to help her, uh, feel comfortable enough to with her current romantic partner, let him know what happened to her and see if he ran out of the room screaming. He didn't. Uh, IT turns out nobody else was concerned about that as, as she was, and she was able then to drop some of those, uh, protective strategies. Um, BOTH of those were people that had been depressed longer than typical in the episodes, and they had gotten stuck believing things about themselves that simply weren't true. Uh, IT meant running some experiments. The first, uh, the sculptor's case wasn't anything that scary about doing it, just had to help them pass. The, uh, uh, behavioral uh inhibition initiation. For the second lady, it was like terrifying. It's like telling somebody who's afraid they're going to jump off a bridge and they can run across the road, across the bridge, and they're not going to jump. So she had, she had run tested out herself that, uh, took a couple of months to get her to the point of doing that. But by and large, I think, uh, you can flip the, uh, uh, put the wheels on the other side for cognitive theory. It's not that these folks necessarily. Uh, GOT depressed because they believe inaccurate things about themselves, but in the midst of being depressed, thinking about a lot of different things, some of which are inaccurate, that they get stuck, you want to help them get past that point.

35:14 Ricardo Lopes: Mhm. So we talked about an evolutionary take or an evolutionary perspective on depression. Do you think that cognitive behavioral therapy can be combined with an evolutionary perspective to help facilitate the evolved functions of depression as you described earlier? Yeah,

35:35 Steven Hollon: yeah, yes, I, I, I think it can, although we're still kind of feeling our way. To that, and again, most of my colleagues who are cognitive behaviorists wouldn't uh buy into that. They would necessarily agree. Um, FOR example, uh, most people think of suicide as a paradox. Why would somebody take their own lives? Uh, AND I start talking with clients about my goodness, uh, it's probably stamped into the species. I'll talk about the, uh, uh, grandparents willing to sacrifice for the offspring, etc. ETC. It doesn't mean it's not a tragic, uh, tragic. WHEN it happens, and there's no way in which you're taking your own life is going to benefit other people that care about you. We refer to suicide as the gift that keeps on giving the the uh uh people, the families, etc. ARE horribly uh affected by an individual suicide, but it's not an aberration. It's something that's baked in and it's probably a mistake nowadays. It's probably something, if it ever served a purpose, it was, uh, uh, in the past. It's not likely to serve a purpose now, although, Uh, we're more likely to run into a burning building to save our children or grandchildren than we are to save somebody else's children or grandchildren. So again, it still affects what we do, but something that helps normalize the experience and suggests a pathway out of it is the, the way I think the evolutionary perspective starts to help you out.

36:47 Ricardo Lopes: Mhm. OK, so that's about psychotherapy. How about medication? I mean, what kind of medication do we have available for depression? You've already talked a little bit about that, but tell us more.

37:00 Steven Hollon: Yeah, well, again, I think for, if you've got a, uh, uh, Bipolar I with psychotic mania or depression, uh, I think lithium is a wonder drug, and I think the guy that uh first brought it, uh, uh, uncovered aca deserved the Nobel Prize that I think he got. Uh, OF course, pharmaceutical companies don't like it much because it's a natural salt, inorganic salt, which means they can't get patents on. So I don't make money on it, but I think it's, I think it's a wonder drug. And if I'm working with a client, which I've done rarely, who, uh, meet criterion for, uh, uh, bipolar one disorder, one of the main things I've tried to encourage them to do is, for God's sake, stay on the lithium. Don't, uh, don't come off a little high so, um, the, uh, The, uh, bipolar 2, nobody really quite knows how best to treat and probably you'd do the same thing you would for, uh, unipolar disorder. Although, again, if it were me, I wouldn't want to lose the energy. I wouldn't mind losing the occasional depressions, but I wouldn't want to lose the energy, so I'd, I'd buy into the, the hypomania. It's, uh, it's more adaptive than not. For unipolar depression, by far the garden variety version of things. Uh, MEDICATIONS we mentioned earlier, you've got the older monoamine oxidase inhibitors and the tricyclics, both pretty powerful, both pretty effective, but each have a downside in terms of some of the risks that they, they bring up. You have the newer, uh, uh, SSRIs, the selective serotonin reuptake inhibitors like Prozac, etc. YOU'VE seen the TV commercial, they got the, the, uh, the frowning face that bounces along that turns into a smiley face on Prozac. Uh, THESE medications do work most of the time for most people. The downside. Uh, AGAIN, from an, uh, an evolutionary biological perspective, the downside is that, uh, what they be able to do, uh, the, the conventional wisdom is that depression biologically is related to a deficit of serotonin, uh, in the brain. Uh, AND so you're trying to raise the serotonin levels. The older medications, MAOIs, tricyclics, um, and the newer SSRI's all increase the amount of serotonin in the synapse, so they'll, uh, they'll have that effect, and the general perception is that's why they work. Turns out they do that, but they do that only, uh, they, they do that for only for the first couple of weeks. And what then happens is it turns out there's not a deficit of serotonin, there's an excess, and what you're doing is driving an excess in the serotonin level so high that the underlying homeostatic regulatory mechanisms kick in and shut the system down. They suppress synthesis of serotonin pre-synaptically. They block sensitivity post-synaptically. So in effect, It's like you're tricking the nervous system to do something that it wasn't designed to do in a way that's gonna, may well, we don't know, but may well stay locked down as long as you stay on medications. The risk there is we know that the likelihood of the symptoms coming back. Uh, IF you stop medications, it's about 3 times higher, uh, uh, within the first, uh, uh, couple of months as it later on. We don't know exactly why that is, or at least we believe that's so we don't actually know if that's fully true and it may well be the case that with the medications. We're stopped, we're suppressing the symptoms, but we're keeping the episode going. So individuals stay in episode for as long as they stay on medications and they're at elevated risk when they come off. Uh, MY evolutionary biological colleague Paul Andrews, uh, did a very elegant, uh, look at meta-analysis, uh, uh, back in the uh uh teens where he predicted that the extent to which any given medication class suppressed the underlying uh. Suppress the underlying uh uh uh uh perturb the underlying neurotransmitter systems would predict how likely you were to relapse when you came off, and it turns out the, the data exactly conformed to that. If you get better on a pill placebo, it's about 20% that you're going to relapse after you stop. If you get better on an SSRI, it goes up to about 40%. Better on a tricyclic, which is both serotonin and norepinephrine, goes up to 50%. Get better on MAOI, which is norepinephrine, serotonin, and dopamine, it goes up to about 75%. That's a pretty elegant, uh, confirmation of a theory based on evolutionary biological notions. So the concern I would have for medications is, uh, uh, you pay me now, you pay me later, uh, they're going to suppress symptoms while you stay on, although. There's uh some uh evidence of what's called tachyphylaxis where you can break through for at least some individuals and become symptomatic again anyway. You may end up uh getting your clinical benefits because you're tricking the underlying nervous system of the brain in a way that is not natural for the brain.

41:28 Ricardo Lopes: Right, um, are there any, at least in the long term, I mean, if you use antidepressants long term, are there any side effects, any common side effects that you think people should be aware of, because sometimes I hear people complaining about, for example, sexual dysfunction or the fact that it's easier now for them to put on weight and things like that. I mean, is that true?

41:56 Steven Hollon: Well, it depends on the medication. And, and, uh, uh, for example, with the, uh, very common, uh, SSRI's, uh, one of the major side effects, uh, is, is, uh, sexual loss of interest in sexuality. Uh, WOMEN don't seem to mind, men seem to mind a lot, and in our clinical trials, if we're going to use SSRI as a compare one of the SSRI's as a comparator, we almost always, any, any male that access the internet would be worried about that. We'd have to also, uh, provide them with Viagra, uh, to, to carry things out. Um, THE, uh, Women can still function, men can't. It, it's a problem. Uh, Most of the serotonin in the body isn't in the brain, it's in the gut, and it regulates, uh, uh, uh, digestion, sexual interest as well. Uh, SO, uh, the side effects for the newer SSRIs are relatively minor, uh, if you consider loss of interest in sex relatively minor, consider some indigestion relatively minor, but you won't die as a consequence of taking the medications.

42:54 Ricardo Lopes: Mhm. Uh, AND so, I mean, at the end of the day, what do we know in terms of treatment? What is better? Is it psychotherapy, pharmacotherapy, or a combination of

43:07 Steven Hollon: both? Yeah, uh, again, we, we're kind of inching away to better understanding of how that works. In general, again, for bipolar disorder, bipolar one, I would start with medications and think of psych. Therapy is adjunctive. Uh, FOR unipolar disorder, non-psychotic unipolar disorder, uh, you can pick them and choose medications or, or psychotherapies. Uh, IT is probably the case that the combination works a little better than either one alone, um, and I would have, uh, uh, I would have said that, uh, 1015 years ago, maybe 2015, 20% increment in terms of the acute response, uh. But our most recent trial that I've done with colleagues suggests that if something like cognitive therapy has an enduring effect that cuts risk in the future, uh, doing it, uh, getting cognitive therapy in combination with medications cuts that out and uh eliminates that, and there's some you, you can begin to make a case for that might be if you understand the animal literature and, and the way the medications work. So, um. 1520 years ago, I would have said they can start on uh uh any of the psychotherapy, well, you can start on cognitive therapy or behavioral activation or uh interpersonal psychotherapy or you can start on medications, pick them and choose them, uh, or the combination. I would say, I wouldn't start the combination. I would start somebody on one of the, uh, empirically tested, known to be effective psychological interventions of cognitive. Uh, THERAPY, and behavioral activation, interpersonal psychotherapy, and only bring medications in if somebody isn't better within about 8 to 10, 8 to 10 to 12 weeks. Um, YOU can, you get a pretty, if somebody's going to respond, usually that happens pretty rapidly. And if that isn't happening, that that may be an individual that might benefit. There also are some, uh, there's also a reason to think that different people are just going to respond to different things. We're not sure about that, but the evidence is, is tipping in that direction. Very recent study out of Emory in Atlanta, uh, Bodie Dunlap and Helen Mayberg and Ed Craighead and others that uh People that didn't respond to cognitive therapy got switched over to medications. People that didn't respond to medications got switched over to cognitive therapy or the combination, and they did better among the non-responders. So in depression, if the first thing doesn't work over a reasonable period of time, either switch to something else or add something else, and I think that would hold us true from the medications. If I had my druthers, I would rather be over depression than. Than not, and even if that wiped out a long-term enduring effect, better to not be depressed than to be depressed. Although if I had my choice, I would choose something that would uh either cut the risk for future depressions, which cognitive behavioral interventions look like they do, or improve the quality of my relationships, which looks like interpersonal psychotherapy does.

45:51 Ricardo Lopes: Um, I mean, are, are there instances where someone, a patient might be, might be suffering from depression that is so severe that before they start psychotherapy, they have to be put on medication because maybe they won't even speak or something like that.

46:11 Steven Hollon: Yeah, yeah, yeah, that, that does happen. Um, YEAH, that's, uh, relatively rare within the, uh, uh, about 15, 6, 16% of the population that the epidemiological studies, uh, meet criteria for major depression, about, uh, uh, 10% of them might be so severe, we consider that almost a psychotic level of depression. They're probably going to get hospitalized at least initially to get things stabilized. And, uh, very often that you're going to start with either medications. The single most effective thing, uh, for the treatment of very severe depression is electroconvulsive therapy, ECT, and, uh, in the old days they had a reputation for being barbaric before we had the, uh, uh, muscle relaxants, people would break spines, break bones in, in the midst of the convulsions, uh, but that's pretty well handled, and, uh. My goodness, if I had a severe psychotic depression. Um, I wouldn't want to live in Berkeley, where the city fathers once outlawed the use of ECT. It's the fastest way to get back on your feet. Uh, UNFORTUNATELY, like, uh, like medications, if you stop doing the ECT, it, you can't do that often, that, uh, that many of that often. If you stop doing it, the depression will tend to come back. So what most of my psychiatric colleagues do is use ECT to get a really, really severe recalcitrant depression under control and then bring that, put medications on top or have other psychotherapists come in down the line.

47:31 Ricardo Lopes: So let me ask you this because I've heard this from some people and I'm not sure if that kind of claim should be taken seriously, scientifically. I mean, uh, is there any evidence that nowadays in the more developed industrialized society. The, uh, societies, there's an overdiagnosis of depression or, and, or an overprescription of antidepressant drugs.

48:04 Steven Hollon: Yeah, yeah, yeah, yeah. Again, this is, this is where my biases might show and where my good psychiatric colleagues might strongly disagree. I think more people are on medications than need to be. I think more people are kept on medications longer than need to be, uh, particularly since you have alternatives, uh, uh, psychological alternatives that don't have the, the medication downside. So I think er I think clearly the, the old prescription is going on. I'll also say that, uh, uh, uh, general practitioners are absolutely marvelous people. They have Worry about about 80 things every time you go to see them every year, 40 of which will kill you, and depression's not one of those. So if they do have a client, a patient that mentions being depressed or anxious, it's very reasonable for them to prescribe an SSRI. What they don't know how to do are the psychological interventions. So if most, most folks have a primary care physician, uh, most folks don't have a psychotherapist or psychiatrist. So if you're going to get treated for depression and or anxiety, it's, it's probably going to be a medication and uh. Um, NO great downside, uh, in the, in the short term. If there's a downside, it's in the long term, uh, but it's not grotesque. The older anti-anxiety medications, the, uh, minor tranquilizers, lithium, uh, uh, librium, Valium, etc. uh, WERE about as effective as, uh, alcohol and every bit as addictive. So, uh, we, it's better to have SSRI's than virtually any other thing we have for non-psychotic disorders, but again, I think the psychotherapies work at least as well or better.

49:32 Ricardo Lopes: Great. So I have one last question then. I mean, when is it exactly that depression ends and how does it end? I mean, are, is, is there any specific point at which uh doctors or clinical psychologists say, OK, so this person is cured of depression.

49:55 Steven Hollon: Yeah, no, there, there's no clear-cut boundary other than the symptoms are largely resolved. And, uh, um, they, uh, I've always been pretty open. I had at least 3 major episodes in my early twenties and, uh, in almost every case, I could, I could point to the time, the day, the night and the event when it went away. It just like it disappeared, like it cleared. But for other people, sometimes it's much more gradual phenomenon, so there's no clear demarcation. It's when the symptoms are largely resolved and, uh, and, uh, have gone away, you're back and doing things you would typically do, uh, that's a pretty good indication the depression's lifted.

50:29 Ricardo Lopes: Mhm. Great. So, Doctor Holland, uh, just before we go, where can people find your work on the internet?

50:39 Steven Hollon: Oh my, my goodness. Um, IF you go to, uh, uh, I have a website at Vanderbilt, uh, that some of my things will be on. If you go to Google Scholar, that'll list, a list of publications and usually there they'll have a, a, a link that lets you get right to the article. Uh, SHOUT out again to my, uh, uh, colleague, the evolutionary biologist Paul Andrews, who's really, uh, turned my own thinking, uh, around in the last 1015 years, and I would take a look at his stuff as well, especially his stuff.

51:08 Ricardo Lopes: Great. I will be leaving links to that in the description of the interview and, and thank you so much again for taking the time to come on the show. It's been a fascinating conversation.

51:18 Steven Hollon: Pleasure, pleasure, and I just say, uh, uh, if you're looking for future, uh, interviewees, Andrews. Be terrific. Uh, Daisy Single at the University of Toronto, who is a rising star in global mental health would be terrific. Vikram Patel, who's, uh, Daisy's, uh, uh, mentor at Harvard, would be terrific. So there, there's some really interesting people out there that are changing the way we think about things.

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