Discovery of lithium as a treatment for bipolar disorder is truly a miraculous story that I think everyone should know. The key player in this story is a physician by the last name Cade. He was an Australian physician and Cade has a very interesting story in his own right. Cade was an Australian psychiatrist or Australian psychiatrist who also was a soldier.

And during World War II, after the fall of Singapore to Japan, he became a prisoner of war and he was a prisoner of war from 1942 until 1945. So he had some time for observation and during his imprisonment, he observed some of his fellow inmates as going through pretty wild vacillations in mood and energy, essentially going from manic episodes to depressed episodes or from manic to normal episodes.

And for one reason or another, we don't know why, because I couldn't find any report as to why he hypothesized this, but he hypothesized that there was some buildup of some chemical in these people's brains that then they would urinate out and that urinating out of whatever chemical was in there would allow them to be more relaxed and not manic.

In other words, Cade hypothesized that there's a buildup of a chemical in certain people's brains that makes them manic and they urinate that chemical out. So eventually he got out of this prison, as we mentioned, in 1945, and he started doing experiments in addition to seeing patients in his clinic.

And what he did is he started to take urine from people who exhibited mania and urine from people who were not manic. And he took that urine and he would inject it into guinea pigs as an experimental model. And his general observation was that there was something in the urine that was indeed making the guinea pigs more manic if they were injected with urine from a manic patient.

The exact measures that he was taking in these guinea pigs wasn't exactly clear. This is at a time or an era in science when you could just sort of report things a little bit more subjectively, although there were still numbers and statistics. It was a little bit more of like case studies and descriptions.

But it turns out that even though that all seems a little bit loose, it led to some incredible and still important discoveries for psychiatric health. So what he figured out was that the urine from manic patients seemed to be more toxic for these guinea pigs. And he also knew that there are two toxic substances in urine, urea and uric acid.

So he was able to separate the urea and uric acid from people with mania and patients that did not have mania. And he figured out that the urea was the same in both these mentally ill manic patients and the non-manic patients. So it did not seem that urea was the compound that was creating these manic episodes or related to manic episodes or held the toxicity.

So instead he focused on the uric acid. Now, in order to put the uric acid into solution so that he could inject it into these guinea pigs, he had to try a number of different compounds in order to dilute it. It just so happens that, and you chemists will be familiar with this, but there's certain things that just don't go into solution easily.

You put the powder in a vial, you add some water or a saline or another solution, you mix it up and the powder stays suspended in there. It just doesn't actually ever become a clear liquid that you can inject. So in order to try injecting different strengths of uric acid, he ended up using lithium to assist in the dilution and lithium worked.

So what he basically was doing, again, for you chemists, is he was taking uric acid, he was adding lithium and making a solution of lithium urate, okay? This is a lot of details, but this is important because what he eventually found is that when he diluted the uric acid with lithium and created lithium urate, lithium urate could actually calm down these guinea pigs that were injected with the toxic urea.

He also found that lithium urate had a generally calming effect on these guinea pigs. So now we're really off in crazy territory, right? We're talking about urine from patients that's separating out urea and uric acid. We're adding lithium to the uric acid. We're injecting this into guinea pigs. This is getting pretty wild and pretty weird, but this is medicine and from time to time, this is medicine and science.

Cade was a good scientist in addition to being a good physician. And by good scientist, I mean that he did control experiments. Here he was injecting lithium urate into animals and seeing an effect, but he knew that that solution of lithium urate contained not just the uric acid, but it also contained lithium.

And so he quite appropriately asked, maybe the lithium alone is having this calming effect on these guinea pigs. And indeed that was the case. When he did the proper control experiment and injected only lithium solution into these guinea pigs, they calm down. From there, he in sort of 1940 style medicine, this would not happen now.

He very quickly moved from that animal model into human patients and started injecting human patients with lithium or providing lithium orally to those patients. And lo and behold, found an absolutely profound and positive effect of lithium in reducing symptoms of mania. And as all good physician scientists do, he wrote up his results and he wrote it up in a paper entitled "Lithium Salt and the Treatment of Psychotic Excitement." Okay, back then they didn't call it mania, they called it psychotic excitement.

This is a paper that was published September 3rd, 1949 in the Medical Journal of Australia. We will provide a link to this study is now a classic study in the field of psychiatry. It's a really wonderful paper to read and actually I encourage people, even if you're not a scientist or a clinician, to just take a quick look at the second page in this paper that we've made available to you, where he describes each of the various case studies or the individuals that he looked at.

I'm not going to read these in detail now 'cause it would take a lot of unnecessary time, but things like case seven, MC aged 40 years old, suffering from manic recurrent mania. In this episode, he'd been excited, restless and violent for over two months and was interfering so often that he had to be confined to a single room during the day.

Right, so this is very debilitating, what we now know to be bipolar depression. He commenced taking lithium citrate 20 grains, that's a measure of the amount of lithium, three times a day. In four days, he was distinctly quieter and by February 13th, 1949 appeared practically normal. He continued well and on February 20th, 1949, the dose of citrate was reduced to 10 grains, et cetera, et cetera.

He left the hospital. There are numerous descriptions of this sort within this paper, including some descriptions of patients that did not see such success and including some descriptions of patients that suffered from some negative side effects. So that's important to point out as well, but it's an absolutely wonderful paper and it's an absolutely wonderful voyage into the history of psychiatry, right down to the discussion where in just three short paragraphs, Cade really lays out the case for why lithium is such an important discovery in the treatment of what at that time they were calling psychotic excitement and what we now know to be manic bipolar depression.

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