In this section, we discuss the history of lithium's medicinal use, from Australian psychiatrist John Cade's discovery of its' superior effectiveness in manic-depressive illness, through the Lithium Chloride catastrophe and eventual FDA approval in the United States.
Ethan: Lithium has one of the coolest stories about its medical discovery of any substance. It took a lot of balls on the Australian psychiatrist, John Cade, who studied it. He served as a surgeon in World War 2, despite the fact that he was trained as a psychiatrist. He was actually captured by Japanese forces and was a Prisoner of War from February 1942 - September 1945. To me, it's incredible that he could go through that experience, and make one of the greatest discoveries, definitely in the field of psychiatry, of all-time. But, while he was there, he saw some of the other inmates that [00:01:00] would have this strange kind of vacillating behavior. We talked about Garrod and his work with lithium dissolving uric acid in Gout. Cade is a POW and he sees these other inmates, and has this thought that maybe their behavior’s related to a toxin affecting their brains because he noticed when they urinated, their symptoms would dissipate for a period of time. 4 years later, he first tests lithium on Guinea pigs and realizes that it tranquilizers them. Then, he takes the real leap of faith and takes lithium for himself, before he ever gives it to any patient, puts anybody in any sort of danger with a substance he doesn't know how it's gonna react or interact with them. He takes it himself, something I wish that, we still, as psychiatrists, had to do some of today.
Rif: I don't think it's good to take medicines you don't need to take.
Ethan: That's true.
Rif: But we do something similar. [00:02:00] We always test our medications in normal controls before we give it to patients.
Ethan: He's working in a veteran's hospital. He gives it to 10 patients. Many of them have been hospitalized for a long time, some of them years. A couple of case reports from his original paper:
-the first is of WB, a 51-year old who had been in a state of mania for 5 years. Cade describes him as: ‘restless, dirty, destructive, mischievous, and interfering, had long been regarded as the most troublesome patient in the ward. His response was highly gratifying.’ Cade describes that this patient ‘improved in three weeks. He was discharged in two months, was out of the hospital for six months, went back to work. And then he became non-compliant with his lithium. He was readmitted to the hospital, restarted on lithium, and he was back out again within a month.’ [00:03:00] Most of the other 10 patients had positive results.
-Patient 8 was WM, a 50 year old with recurrent mania since the age of 20. The current episode he was in had been going on for 2 months. Cade noticed that he was: ‘more quiet in 2 days. By 10 days, in he was working in the garden, and by two weeks he was ‘normal.’ This was in marked contrast to his condition a Fortnight before, when he had to be locked in a single room at night with a regular nocturnal hypnotic and was too restless to eat in the dining room owing to his unsettling effect on the other patients.’
-1 other quote about patient 9, WS, a 47-year old with recurrent manic episodes since the age of 25: ‘An acquaintance, who has known the patient for years, reports that he has never seen him as normal as at present.’ In a later 1996 book by The Royal Australian and New Zealand College of [00:04:00] Psychiatrists, there was a claim that, by 1985, Cade's discovery had saved the world an estimated 17.5 billion dollars.
Rif: I would believe that.
Ethan: By the 1950s and 1960s, Cade backed away from Lithium because he inadvertently made a patient toxic. But, the rest of the world started to study it in manic-depressive illness, bipolar disorder. What do you make of the discovery, and the mechanism of his discovery?
Rif: Yeah. He was motivated, had a lot of guts to him. But, he also was, if you will, naive, but that naiveté is actually 1 of the things that helped because even back then in the 1940s, the uric acid hypothesis had already been essentially thrown out. It was thrown out in the [00:05:00] 1920s medically, certainly even before that. So he did it for the wrong reasons. The other thing about Guinea pigs, he was probably giving the Guinea pigs a toxic dose of lithium because lithium is amazing in bipolar illness, but it doesn't slow people down that are normal or animals down that are normal until toxicity. So what kept him going was a false interpretation of the data. It was his naiveté that actually allowed for this to be taken to that paper. But, it was another person in Europe that was important in ultimately doing the research, and again, this is just sort of a random set of circumstances. So, there was a fellow who was from Denmark, Mogens Schou, [00:06:00] who had a brother who had bipolar illness. Mogans was himself a psychiatrist, and he had a brother who was horribly depressed when Cade's paper came out. You know, there was just nothing that could be done to help his brother. Mogans read Cade's paper and he knew his brother had manic-depression, as it was called then, bipolar illness now, and he got lithium and gave it to his brother and his brother just flowered. His depression got better. And that got Mogans Schou very interested in doing the initial research, introducing that research to Europe, if you will, because Cade's paper was published in Australian Journal. Mogans was really the force that brought it to Europe, publishing some of his relatively low-quality observations, actually in a European journal. By then, it was after World [00:07:00] War 2. Germany had been kicked out as the scientific leader of the world. At that time, America hadn't quite made it yet as a scientific leader in the world, especially in psychiatry. And so it was the British psychiatrists that did the Randomized, blinded studies to show that lithium is actually potent. So it was yet another set of almost random circumstances that were important to get lithium introduced.
Ethan: Very personal motivation.
Rif: Very personal motivation.
Ethan: It really doesn't sound like either of them had a whole lot to do with this long-lasting scientific pursuit. For Schou, it was more, ‘I need to try to help my brother in any way that I can, and maybe this'll help.’ It's important to point out that, at the time, there was no treatment for what we call bipolar mania now?
Rif: No. Just as Cade mentioned in his cases, just [00:08:00] hypnotics, putting somebody to sleep. There was some use of alcohol during prohibition in this country. You could actually get a prescription for booze. Alcohol was distilled for medical purposes and so you could actually get prescription for alcohol. And of course alcohol does, horribly speaking just because I don't want to encourage anybody to go out there and drink, but alcohol actually does work to…
Ethan: We have a disclaimer, don't worry, that we post before every episode…
Rif: That's good. Yeah, alcohol is very problematic…
Ethan: But, I like to use that as a comparison. It's similar to alcohol in the sense that if you have a drink of alcohol or you have 2 drinks of alcohol, it can act as an anxiolytic. But then, if you have 10 drinks of alcohol, all of a sudden it starts to become very toxic, and I'm not saying that alcohol reaches any degree of effectiveness as lithium, but in terms of the toxicity, I think it's a good [00:09:00] comparison to make.
Rif: It is. And, of course, it only takes about 2 weeks or so of regular alcohol consumption before alcohol itself becomes a problem, so alcohol dependence occurs very, very quickly. It becomes its own disease very, very quickly.
Ethan: Not to mention it's toxic to nearly every organ system that we have, especially our brains.
Rif: Right.
Ethan: That's really interesting about Schou because I kept seeing Schou's name come up in other people's research, but I didn't know the significance of that story. It's really interesting how pairing those two discoveries together, we've saved the world… 17 and a half billion dollars by 1985.
Rif: Yeah, way more than that now.
Ethan: A little bit of history about lithium's use in the United States: Between 1947 and 1949, cardiologists and some internists were actually touting the use of lithium chloride [00:10:00] over sodium chloride as a salt replacement, thinking that it would improve outcomes in heart failure and hypertension. The problem was, some good ol’ boys from, places probably where I'm from, Southern Kentucky, were putting a little too much salt on their meals, a little too frequently, over too long a period of time, and so several people died. Doctors and patients alike, both heard about this news at the same time, in the same way via the news media. There was this panic to get the word out for people to stop using lithium chloride. Lithium was then banned from 1948 until 1970 in the United States, either lithium or lithium chloride. It was taken out of 7-UP in 1948 as well. But I wonder how much of an impact that crisis had on this future demonization of lithium in the United States vs other countries around the world
Rif: Absolutely. You know, you had to wait a full [00:11:00] generation, 25 to 30 years, before they would really be comfortable prescribing lithium and, I don't know if it was actually banned necessarily, but the FDA certainly looked at things that contained lithium. You have to remember that lithium is naturally present in drinking water, particularly when it's well water, so you mentioned Lithia Springs, municipalities that have high concentrations of lithium in their water continue to sell lithiated drinking water. So, some of the items that you would have bought that would have high concentrations of lithium, they weren't necessarily banned by the FDA. They became, by virtue of the fear of lithium toxicity, they became [00:12:00] bad, if you will. But it was those very same municipalities that ultimately showed that lithium actually has other advantages, at small concentrations.
Ethan: I know the FDA put a ban on lithium-containing products in 1949, but maybe it was more for any product that was marketed as some sort of…
Rif: It was products where lithium was added, so if it contained natural amounts of lithium, the FDA couldn't control it. And things like 7-UP, there wasn't just 7-UP, there were a whole bunch of lemon-lime sodas that had lithium in them. 7-UP was the main one, and there were a lot of lookalikes.
Ethan: So that's why the suicide rate is so much higher now because we've taken all the lithium out of our water and substances…
Rif: That's actually one of the things that's been shown in these municipalities that have lithium [00:13:00] in the water. Not only do you have reduced suicide rates, you actually have reduced homicide rates. You're less likely to kill somebody if you're…
Ethan: Yeah. If you have a little bit of lithium in your system…
Rif: If you have a little bit of lithium in your system…
Ethan: So again, historical perspective… So, as that's going on in the US, in Denmark, Danish psychiatrist Erik Strömgren, following up on the work of Schou, does the 1st randomized control trial on Lithium in mania in 1952. He reports that it is ‘a good alternative to ECT,’ or ElectroConvulsive Therapy, which was the standard of care at the time. That requires a little bit of an aside too for our listeners. From the 1940s to the 1960s, we were still using insulin shock to induce convulsions. ECT, I think it was around at that point, but the mechanism of providing the shock, which was later made much, much safer - [00:14:00] anesthetized the patient and produced the same results without the patient having to consciously experience it. At this point, that's really like 1 of the only treatments that we had, which is why it's such a revolutionary treatment with lithium when Strömgren can show that it is as effective as ECT and a good alternative. A few years later, you've got the Coleman Electric Company creates a photometer that makes getting a blood level of lithium possible, to provide this therapeutic window, and then all of a sudden, lithium is approved all over the world, 1961 in France for bipolar mania, 1966 in England, ‘67 in Germany, 1970 in Italy. And here we are in the United States, with still this kind of bad taste in our mouths from the lithium chloride catastrophe.
There was a psychiatrist out of the University of Oregon [00:15:00] in 1960, his name was Paul Blakely. He wrote a piece in (the journal) ‘Psychiatric Opinion,’ and the title was, ‘FDA vs Physician: Does the Physician have a moral Obligation to Civil Disobedience?’ He basically encouraged providers to prescribe lithium, even though the FDA did not want people to prescribe it, and there was still fear of it because, he said, ‘it doesn't matter what the FDA wants, we have a moral obligation to do what's right for our patients.’ It still wasn't until 10 years later in 1970 that the United States became the 50th country to approve lithium for mania, and it took another 5 years for the US to approve lithium for mania prophylaxis, to prevent the onset of mania as opposed to the indication of using it in an already-manic patient.
Rif: You have to understand the system in America is based on [00:16:00] somebody making money. The FDA designs studies for companies that come to it and say, ‘I want to have an indication for this drug.’ What the FDA comes up with are based on what the FDA needs to show that something is safe and effective. So, it needs studies that do that, generally the person that pays for the studies is the person that's gonna benefit from them. And so, you have to have something that is patentable and lithium, as an element, is not patentable. You go to the FDA and say that you are gonna do these studies and you have to show to the FDA that lithium is safe. And this is after the FDA took lithium off the market [00:17:00] because it wasn't safe. You have to show that lithium is effective and you pay a few million dollars to do those studies, and then I come along and I say, ‘Oh, I have this pill that has lithium in it. I'm going to use your data showing that it's safe and effective to get my formulation approved.’ There's a big problem in this country that unless something is gonna make a lot of money, and unless something can be protected by a patent, people aren't gonna be interested in paying the money to get it approved. So there was this grassroots movement, people could go outside the United States to get lithium, but it was ultimately the NIMH, National Institutes of Mental Health, went to the FDA and said, ‘What do you need for us to get lithium reviewed by you [00:18:00] for approval,’ And the FDA treated the National Institutes of Mental Health as if they're a company and said, ‘This is what we need, design studies that do this, that, and the other thing.’ And the NIH ultimately then did those studies and submitted the data to the FDA for approval. So it was the National Institutes of Mental Health ended up then doing what industry would've done. Unless something is gonna make a lot of money, and can be protected by a patent, people aren't gonna be interested in paying the money to get it approved.