Psychiatry & Psychotherapy Podcast - Why Lithium is a Good Option for Treating Bipolar, with Dr. Walter A. Brown

Episode Date: August 29, 2019

This week the Psychiatry and Psychotherapy Podcast is joined by Dr. Walter A. Brown, Clinical Professor Emeritus in the Department of Psychiatry and Human Behavior at Brown University, author of the brand new book "Lithium: A Doctor, a Drug, and a Breakthrough".  In order to capture the full experience of this week's episode, I've posted a transcript of my interview with Dr. Brown which you can access in the article link below. By listening to this episode, you can earn 0.75 Psychiatry CME Credits. Link to blog. Link to YouTube video. Engage in the dialogue on Dr. Puder's Instagram, Facebook, Twitter

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So welcome back to the podcast. This is Dr. David Puter. and today I am joined with Dr. Walter Brown from Brown University. He is a psychiatrist out there who recently wrote a book called Lithium. And I was looking through the list of new books on psychiatry coming out and I saw this book. And I'm very curious about the history of lithium and the history of psychiatry in general. So I thought I would have Dr. Walter Brown come on and tell us what he has learned through studying this topic. So welcome to the podcast. Nice to be here. So tell me a little bit about yourself and how you

got interested in this topic. Well, I've been a psychiatrist for more than 40 years, and a lot of my career has been, as a full-time academic, doing research into various features of biological psychiatry with a particular emphasis on the endocrine system as it applies to psychiatric illness and also psychopharmacology. And I also am interested in the history of psychiatry. And I came across lithium early in my residency training. I actually did my first year of residency training in 1969. And one of my first patients was some people. somebody who was a manic depressive that we know he called bipolar. And he was very difficult to manage.

And as I say in the introduction of my book, one of the things he was always trying to do was to leave the locked ward that he was on in a hospital in New Haven and go to Washington to meet with the president. And it was my job as a first year resident to stop him from doing that. And several times a week, a group of nurses and I would have to restrain him and he would be injected with a sedative. But none of that really helped the fundamental features of his illness. And at one point, as I was arriving at the hospital, I used to ride my bicycle to the hospital. I saw this man, who I referred to in the book is Mr. J, Mr. G, taken off across the parking lot and had to

for the train station. He intercepted him on my bike, brought him back to the ward, but the people in charge there felt that he was just too difficult to manage. And so he was transferred to the local state hospital for long-term care. And it was two years later that I saw him in one of the outpatient clinics, and he was doing fine. He was no longer hospitalized. He was no longer insisting on meeting the president. His periodic attacks of mania and depression had stopped. And I chatted with him briefly. He told me he was on this new drug, lithium. And clearly it had really changed his life. After that, I had, you know, like other psychiatrists of that era, many experiences with patients where they were taking off whatever stuff they were on to treat

their manic and depressive attacks and put on lithium, and many of them did very, very well. And I became curious as to how this drug was discovered and how it worked. So I started looking into it. At the same time, one of the things I do in the Department of Psychiatry at Brown is I teach a seminar on classical papers in psychiatry, papers that change the field. And I came across in the context of that teaching, John Cade's original report of the use of lithium in mania. And it was gripping for me because Cade was a essentially unknown young Australian psychiatrist working in 1948 when he did this study in a remote hospital outside of Melbourne. Australia. He had no grants. He had no collaborators. He had no formal research training.

And yet he managed to come up with what is arguably the most important discovery in psychiatry, certainly of the 20th century. And so I was curious as to how this guy who's still not a household name managed to come up with something so important, basically on his own. And so I looked into the history of his discovery and what happened afterward. And the more I learned about this, the more interesting the story became for me. And so I really decided to write it down. And what I started off doing was to write a biography of John K. Because there hadn't been one by that time. And I thought, given the importance of his discovery, it would be good to take a careful look at who this man was. But as I started to do research about lithium and how it developed, it really became clear that although Cade certainly was the first person to use lithium in mania and sparked a lot of other research, a good number of other researchers participated.

in the discovery and brought important elements to it and finally established lithium for its main effects, which are to prevent episodes of median depression. So the book became really more than just the story of one man. It became a story of the scientific process and the scientific discovery and try to look at what were the elements that went into finally getting lithium established. Yeah, and it was super interesting, and it's a great, a great story because it does give us that sort of glimpse into the scientific method and the errors of how we develop bias, how often charisma can get in the way of finding the truth. And so, Before we launch into it, tell me a little bit about the natural course of untreated bipolar,

pre-Lithium, pre-medications. Well, first of all, about probably untreated bipolar roughly 20% of the people with that illness will kill themselves. Suicide is very common in traumatic depressive illness, particularly during the depressive phase. So 20% of people are going to end up dead as a result. of the illness. The illness does not go away on its own. And so what the usual course is, is that the frequency of episodes of both mania and depression actually usually increases over time. So that people may start off by having, let's say, one episode of mania every two years, then it'll change to having one episode every 18 months and then one episode a year.

And these episodes are almost invariably followed or preceded by episodes of very, very severe depression. So that's the typical course, and that was the course of the illness before John Kate made his discovery. There really was no effective treatment. other than using electroconvulsive therapy to treat the depressive phase and sometimes the manic phase, but the alleviation of those symptoms didn't last very long using electroconvulsive treatment. Yeah, and so how genetic is bipolar in your estimation?

And what do we know about it at this point? And specifically I was reading about, you know, you looked at some of the Amish studies, and such, I think people would love to hear about that. Well, it's... We don't know what the genes are that underlie manic depressive illness, but I don't think there's any question at this point, but that it is a genetically based illness.

It runs in families, and there are probably several genes that underlie the disorder. How do we know that it's genetic? probably the family studies that were done over the last three or four decades have been the most important. And, you know, probably the acid test for heredity is the comparison of monosygotic and dysogotic and dysogotic twins and the concordance rates for the illness in the different concordance rates in those different kind of twins. concordance means the likelihood that if one twin has a disease, the other twin will also have it.

And for manic depressive illness, the concordance rate in identical twins, that is those who have the same genetic makeup, is about 60%. But the concordance rate in disigotic twins, that is those who don't share the same genes, they come from different eggs. the concordinated nose twins is closer to 10%. So that really tells us that genetics plays a big role and that the family environment, which is going to be roughly the same if you're a dyszygotic or a monosagotic twin, plays very little role in the expression of this illness.

And the relatives of manic-depressive patients have a 10 to 20-fold higher prevalence of manic depressive illness than the general population. So it's clearly genetically based. What was life like for people prior to lithium? How were they treated? And I think it would be interesting to talk a little bit about some of the specific examples of how people were treated like Rosemary Kennedy, the sister of President John Kennedy,

had a lobectomy. And when I read that in your book, it just broke my heart because, oh, you know, it's just so tragic that that had to happen. But tell me a little bit about what life was like and how these people were treated. Well, people with manic depressive illness

were treated the way other seriously mentally ill patients were treated up until the mid-20th century. And that is whatever was currently in use to treat the serious mentally ill was used for manic depressive. So, you know, in antiquity, way back when, there really were no treatments and people were cared for by their families and kept sometimes in horrendous circumstances. You know, if somebody was depressed, they were probably basically left alone until they got better. depression, even the kind of severe depression that is part and parcel of manic depressive illness, eventually in most people, goes away after a period of six months or so. But when people were at manic, which involves a lot of bizarre behavior, you know, rapid speech,

sexual excesses, physical violence, all kinds of things that create problems for society and their family. These people were sometimes locked in prisons. They were kept in cages in their family homes. And basically, there was nothing useful that could be done for them. Then, you know, through the Middle Ages, various kinds of potions. things we use to treat all kinds of mental illness, including compounds that contained opium, which would sometimes sedate people, but didn't really alleviate the fundamental symptoms of the illness. And then, you know, in the late 19th century, a number of physical treatments started to come into play. These included malarial treatment of tertiary syphilis.

people with tertiary syphilis or neurosyphilis, which is a horrendous attack on the brain, it's a degenerative brain disease, were made up a large proportion of the patients of asylums. And some of these people had symptoms of manic depressive illness, although they didn't have the classic symptoms that we later learned were characterized. So the people were treated finally with Malarial fever therapy, which killed a spirashy that caused the illness. Probably some of those people had manic depressive symptoms. And that was used at the turn of the century, the 20th century.

Other treatments of that era included insulin coma, which was used to treat manic depressive as well as schizophrenic patients, people were given doses of insulin that brought their blood sugar very low. They would go into a coma, sometimes that have seizures. And this went on for days or several days of the week sometimes. And this was a very dangerous treatment that was thought to be useful in both depression and schizophrenia, but on further study, it turned out really not to be terribly effective, but it was widely used for a number of years. Deep sleep

therapy, which was not dissimilar from its incommel, was also used in which people were given high doses of sedatives and put to sleep for weeks on end. And supposedly when they awoke, they would lose some of their psychotic

symptoms, but that didn't last very long. And finally, one of the most notorious treatments, that you have already alluded to was lobotomy, which was discovered by Moniz, a Portuguese neurologist in the 1930s. And this involved severing the frontal lobes from the rest of the brain using what it was essentially an ice pick stuck through the orbit of the eye. And this was a treatment that supposedly was useful both for severe depression and for severe obsessive-compulsive

symptoms. And it was certainly used in a good number of patients who were manic-depressive. We now call them bipolar. And again, after, you know, several decades, it was very widely used in the 1940s and early 1950s. both psychiatrists and neurologists finally concluded that it was not terribly useful that people really didn't know what they were doing to the brain when patients had this procedure and the procedure had a lot of awful side effects including intellectual impairment and socially

inappropriate behavior, as happened with, and as what happened with Rosemary Kennedy, she really became essentially a vegetable as a result of it. And that treatment finally was abandoned, although variants of it are still sometimes used today. The other big change over the years was in the role of asylums. Asylums really started out. in the Middle Ages as being really not very different from jails. And in fact, the kinds of people that were sent to the asylums of those days were both criminals and people who were mentally ill, anybody who was troubled to keep in society. But in the 19th century, a number of humanitarian changes were brought about in asylums

and patients were treated with so-called what they called moral treatment, which meant bringing them in, not chaining them up like they had been previously, giving people good food, a chance to work in gardens and so forth. And there was a feeling that a lot of patients actually recovered as a result of being in these pleasant environments. But on closer scrutiny, it was clear that this kind of so-called moral treatment really didn't accomplish that much. patients were not all that much better after it. So that was lordly abandoned. Tell me, why do you think poets have a higher rate of bipolar?

You mentioned 20 to 40 percent. And also writers, artists, composers, you said five to 15 times higher than the general population. So tell me a little bit about your reflections on that. Well, now from multiple studies conducted over a long, time that there is an association between certain kinds of creativity and maddie depressive illness and that is that you know people particularly poets but writers also composers have higher rates much higher rates of manic depressive illness than the general population the association seems clear but why it

I don't think anybody really knows. There's all kinds of speculation that the gene that puts people at risk for minding depressive illness may also separately have something to do with creativity. And in fact, family members of manic people with manic depressive illness who don't have the illness themselves often score high on measures of creativity. So it seems. like there may be some genetic connection between manic depressive illness and creativity. It's also been speculated that the experience of having these very intense moods somehow facilitates the poetic imagination and is somehow related to person's ability to perceive the world around them in the kind of special way that poets do so. But nobody really knows for sure what underlies

this association. So tell me about the story of John Cade, some of the highlights and some of the things that were kind of like those aha moments for you. Well, you know, one kind of kind of perception of what Cade did is that he just was lucky. You know, he sort of stumbled on something and really didn't put much thought into it. I think the story is more complicated than that. First of all, he was born into a family where the father was a psychiatrist. What had happened is that his father, when Cade was quite young, joined the Australian Expeditionary Force to fight in

the First World War. And he was overseas for a number of years assigned to an ambulance corps that was sort of like a mobile hospital. And when he returned from the First World War, this senior Cade was in rough shape. He was not the person

was before he left. He was shattered psychologically. He was unable to work really effectively as the general practitioner that he had been before he left for the war. And so he took a salary position with the Victoria of Australia Mental Health Service and he became a director of several mental hospitals. And in those days, the director and his family lived on the grounds of mental hospitals. So John Cade grew up really among severely mentally ill patients. And his son speculated that that sort of gave him a special empathy for these people and a kind of comfort with them and a desire to help them.

So Cade attended a very prestigious. secondary school called the Scotch Academy, and then went on to Melbourne University where he went to medical school. And at first he was, when he graduated from medical school, he was going to go into pediatrics, but decided to switch to psychiatry. And at that time, psychiatry training was not as formalized as it is now. So he worked for a couple of years in different psychiatric hospitals. And then like his father, he joined the army with the outbreak of the Second World War. And he was also assigned to an ambulance division, a mobile hospital. And he shipped out in 1940 to what was then called Malaya was a general medical officer in the army. He was not officially a

psychiatrist. And then in 1941, the Japanese invaded the Malayan Peninsula. And the war that ensued was a disaster for the British and Australian Commonwealth forces. Even though the Commonwealth forces outnumbered the Japanese two to one, the Japanese were battle-hardened and got much better leadership. Strategically, they did a lot better. The Commonwealth generals made a lot of errors. And finally, the Commonwealth forces retreated to Singapore, where they made a final last stand and were defeated,

and about 30,000 of these soldiers were imprisoned in the Changi Prisoner of War, camp, which became notorious. And Cade was among them. And he was imprisoned for three and a half years. During his imprisonment, he underwent severe malnutrition as at all the other prisoners, which was the major problem at Changi. The Japanese had not signed or not ratified the Geneva Convention, which stated that prisoners had to be fed to adequate diet. So these guys really were grossly underfed. But more to the point, Cade, because of his psychiatric experience, was put in charge of a 12-person psychiatric unit. And he was the only doctor there who did that. And there

he sort of cared for consultations on prisoners of war who developed psychiatric disturbance. This experience did a number of things for Cade. One is it convinced him that they needed to have better treatments for things like depression. And it also convinced him that a lot of mental illnesses had a biological basis because when he would do autopsies on some of the psychiatrically ill, he would find various kinds of brain abnormalities, including hemorrhages and tumors. And clearly the vitamin deficiency diseases that he was seeing sometimes had a psychiatric component. So when Cade returned home, He took a job at a psychiatric hospital run by the Victorian Mental Health Service,

and there he decided to start some research looking into the causes of manic depressive illness. He theorized that like thyroid disease, manic depressive illness resulted from both an excess and a deficit of some normal bodily substance. In the case of the thyroid, it's thyroid hormone. And he was going to look for the toxic substance in manic depressive patients that caused the illness. So, you know, at this point, things get a little difficult to follow logically. But he started doing some experiments with guinea pigs where he injected the urine of manic depressive of patients and basically judged the toxicity of the urine by how much it took to kill a guinea pig. It was, by his own ambition, a crude test of toxicity. And he found that, in fact, some of the

urine from manic patients seemed to be more toxic than the urine from people with other psychiatric diagnoses and healthy people. And he then began to look for the substance in urine that could be causing the mania. And in doing this, he went through various constituents of urine. And in the context of this, he began to eject the giddy pigs with uric acid and lithium salts, because lithium was very good at bringing uric acid into solution. So we started using lithium urate and lithium carbonate to examine the role of uric acid in this toxic urine. And when he injected animals with these lithium salts, he found that they became somewhat tranquilized. The rats, the guinea pigs, I'm sorry, would lie on their backs placidly just looking up.

at him and not running around and being startled like the way they usually were. And this somehow gave him the idea to go next door. His laboratory was really on the grounds of a psychiatric hospital and go to the ward where there are a bunch of severely manic patients and see what lithium would do for them. First, he took lithium in varying doses himself because there really wasn't much experience of the literature using lithium in the doses he planned to in humans. And he found that the lithium didn't hurt him, although his wife was not happy about the fact that he was experimenting on himself.

And then he started giving lithium to manic patients. And the first patient he gave it to had been manic for about five years, chronically manic. And within two weeks of getting lithium citrate was the combination he used, this man was able to leave the ward and ultimately went home and returned to a useful occupation. So that was, and K then went on to treat an additional nine patients, all of whom did remarkably well on lithium, better than they had on any other kind of treatment that was thrown at patients at the time. and he wrote up his results in the Australian Medical Journal, Medical Journal of Australia, and that was the beginning. That is truly, he sounds like such an amazing person.

I remember one of the quotes he had from one of the speeches about all the different types of science and sort of unique interests he had throughout his career, and he seemed like such an intelligent person. Well, the thing struck me most about how he operated was his capacity for sort of unfettered neutral observation. He was very interested in the natural world. And I point to several examples in the book. He was very interested in scat of animals.

He did his own research on birds and looking to see. see if the whiteback magpie or the blackback magpie were different species or varieties of one species. He pointed out to one of his sons that the fact that the gum empire caterpillar moth produced feces that were six-sided, meant they had a six-sided anus. He was always looking at things and examining them. And I think his ability to sort of see the unexpected was somewhat unusual. He certainly didn't expect to see the guinea pigs that he gave lithium to become tranquilized. And I think there aren't a lot of people who sort of trust unexpected observations.

As Yogi Berriss, he said, if I didn't believe it, I wouldn't have seen it. but Cade believe things that he saw for the first time. And I think that really facilitated his discovery, that cognitive characteristic. I want to jump ahead a little bit because we're kind of running out of time. And I think there's a lot more in the story that I'll leave people to read about how it kind of went from his discovery to not being widely adopted till much. later. Right. But I wanted to pick your brain a little bit on statistics that you mentioned that 50% of people with bipolar in European and Scandinavian countries receive lithium, but only 10% in the US. Yep. And I wanted to get your opinion on that and also your thoughts on why that might be the

case. Yeah, well, that, you know, it's hard to get highly reliable numbers on how many people are taking lithium because nobody's really tracking it. The pharmaceutical industry is not really interested in what's going on with lithium because they can't patent it, don't make any money from it. But the best that I could come up with if they're sort of coming through the literature was that 10% versus 50%. I think the major reason for that is that I think there are two reasons. One is that after the 1980s, lithium was approved the United States in 1970, after the 1980s, other drugs, particularly Depakote, came on the market that could also prevent episodes of maiden depression.

And the drug company that made that promoted it very aggressively. That was one thing. The second thing, so Deppocote was heavily. marketed and promoted. And to some extent took over lithium's role as the gold standard. The second thing is that lithium is, you know, does, can create serious side effects. I might say Debe got also a side effects. But in order to safely give lithium to somebody, it has to be given along with the measurement of lithium blood levels. And the reason for this is that the lithium blood level required for a treatment effect

or therapeutic effect is not very far below the lithium level that will give somebody serious toxic symptoms, which include, you know, tremors and other neurological symptoms, including coma. and people can die from a lithium overdose. So there's a little, you know, there's some complications in using lithium, particularly primarily, actually, having to monitor blood levels. But once blood levels are monitored, and it's not that hard a thing to do and doesn't need to be done once somebody is stable more than once or twice a year, it works perfectly well. And I think the third reason is that historically in this country,

lithium created trouble. And what happened is that in around 1949, lithium chloride, another salt of lithium, was promoted as a salt substitute for people on low sodium diets. So lithium chloride taste salty, but it doesn't create the problems with hypertension and kidney disease and so on that sodium chloride does. So people started using it a lot, and they were pouring it very liberally on their food, and a number of patients in about 1949 got toxic from the use of lithium the lithium salt substitute, some died, and the FDA banned lithium and banned its use and other substances. And people didn't forget about that. It was a real panic. It didn't last very long and about a year. You know, all the lithium was taken off the shelves of pharmacies and so on.

But people remember that salt substitute tobacco. And that may have had something to do with its slow uptake in the U.S. But I think the primary reason for the fact that lithium is somewhat underused here is the aggressive marketing of other drugs. Yeah, and I think that's why I get passionate about this for my audience, because I think there's no drug rep that's going to come to your office and promote lithium. Absolutely. And so I think that people who are looking at the science, who are looking at the data, who are trying to treat patients according to evidence-based medicine,

I think we've got to keep putting those principles out there. Right. What is your one big takeaway that you would want people to have, maybe about the history of lithium or about the scientific method? I think there are a couple. One is that it's important for whatever institutions are trying to promote innovative research should keep there a lookout for people who, who are imaginative like John Cade,

are careful observers, but who might not necessarily be inclined to write an extensive grant proposal. And sometimes the kind of people who are likely to make important breakthrough discoveries are not the kind of people that are necessarily getting funded in this country. There's a tremendous concern on the part of the psychiatric establishment and the research establishment in this country over the lack of real innovation, particularly in treatment.

You know, after Cade's discovery in 1949, in the following decade, all of the major types of drugs that we use today were discovered, the antidepressants, the antipsychotic drugs, all were discovered in that decade from 1950 to 1960. And since that time, there have been many new drugs, different drugs, have come on the market, but they really don't represent a change from those earlier drugs. And why don't we have more innovation? Why does the National Institute of Mental Health spends a gazillion dollars on all kinds of of research, but as the former director of the at IMH said, it hasn't really moved the needle

with respect to coming up with better treatments for the conditions that plague us. So I think we need to take a look at how we approach innovation. Yeah, that's, that makes me think, because, you know, grants, writing grants and doing research, you have to be very, very organized. Yep. But there's this other side of our, you know, human potential, which is, you know, people who are highly creative who often are more spontaneous, are high in openness and may not, they're almost like two different types of people, you know. So I kind of sense that dynamic going on as well because the type of person who rises up in research nowadays is you have to be highly organized, highly. almost obsessive with how detail-oriented you are. Does that make sense? Yes, absolutely.

The other takeaway, if I don't know if I'm out of time, is, and I think one of the things that I tried to convey in the book, is how different scientists learned from each other. And there was sort of like a web of information that was created about lithium. One, and I really, I document how, you know, after Cade's discovery, some other Australians looked at lithium, then a Dane named Mogadio went ahead and started doing some very important studies. People read his papers and then added more information. So it was, it's also an illustration.

of how scientific discoveries build on each other. Yeah. Yeah, I really appreciate that part of your book. And I think it's a great book because it really does show the scientific method. I think it also shows the danger of sort of a charismatic leader, or different charismatic leaders who before had ideas about what were the best treatments

for mental illness. and how they sort of utilized their charisma and their, you know, often good intentions, but not as scientific-minded as an open to internal critique probably as other people. I think that was a big takeaway that I had. And I really enjoyed our conversation. I would love some other time to dive into some of the pivotal papers. If you'd like to come back and talk about that, I think that would be a lot of fun.

Sure. And yeah, it's been so great having you. And if you have any questions about this episode, I post the episode on all my social medias. And I look forward to continuing this conversation with you maybe in the future. All right. Thank you. Thank you for such penetrating questions.

Have a good day. You too. Bye.