What's the History of Lithium? How Does It Treat Bipolar Disorder? | Dr. Andrew Huberman
00:00:00.000 | [Silence]
00:00:04.080 | Discovery of lithium as a treatment for bipolar disorder
00:00:07.600 | is truly a miraculous story
00:00:09.400 | that I think everyone should know.
00:00:10.980 | The key player in this story is a physician
00:00:14.840 | by the last name Cade.
00:00:16.000 | He was an Australian physician
00:00:18.320 | and Cade has a very interesting story in his own right.
00:00:21.640 | Cade was an Australian psychiatrist
00:00:23.520 | or Australian psychiatrist who also was a soldier.
00:00:28.240 | And during World War II,
00:00:30.720 | after the fall of Singapore to Japan,
00:00:32.560 | he became a prisoner of war
00:00:34.760 | and he was a prisoner of war from 1942 until 1945.
00:00:39.000 | So he had some time for observation
00:00:41.240 | and during his imprisonment,
00:00:42.920 | he observed some of his fellow inmates
00:00:45.160 | as going through pretty wild vacillations
00:00:48.020 | in mood and energy,
00:00:49.680 | essentially going from manic episodes to depressed episodes
00:00:52.960 | or from manic to normal episodes.
00:00:55.240 | And for one reason or another,
00:00:58.320 | we don't know why,
00:00:59.240 | because I couldn't find any report
00:01:00.520 | as to why he hypothesized this,
00:01:02.480 | but he hypothesized that there was some buildup
00:01:05.060 | of some chemical in these people's brains
00:01:08.840 | that then they would urinate out
00:01:11.440 | and that urinating out of whatever chemical was in there
00:01:15.960 | would allow them to be more relaxed and not manic.
00:01:19.040 | In other words, Cade hypothesized
00:01:21.320 | that there's a buildup of a chemical
00:01:22.680 | in certain people's brains that makes them manic
00:01:24.680 | and they urinate that chemical out.
00:01:27.080 | So eventually he got out of this prison,
00:01:30.560 | as we mentioned, in 1945,
00:01:32.500 | and he started doing experiments
00:01:34.400 | in addition to seeing patients in his clinic.
00:01:37.320 | And what he did is he started to take urine
00:01:39.520 | from people who exhibited mania
00:01:42.000 | and urine from people who were not manic.
00:01:44.440 | And he took that urine and he would inject it
00:01:46.920 | into guinea pigs as an experimental model.
00:01:49.880 | And his general observation
00:01:52.440 | was that there was something in the urine
00:01:54.920 | that was indeed making the guinea pigs more manic
00:01:58.600 | if they were injected with urine from a manic patient.
00:02:03.120 | The exact measures that he was taking
00:02:04.840 | in these guinea pigs wasn't exactly clear.
00:02:06.720 | This is at a time or an era in science
00:02:09.620 | when you could just sort of report things
00:02:11.700 | a little bit more subjectively,
00:02:13.160 | although there were still numbers and statistics.
00:02:15.680 | It was a little bit more of like case studies
00:02:18.000 | and descriptions.
00:02:19.040 | But it turns out that even though
00:02:20.400 | that all seems a little bit loose,
00:02:21.720 | it led to some incredible and still important discoveries
00:02:25.380 | for psychiatric health.
00:02:27.120 | So what he figured out was that the urine
00:02:29.640 | from manic patients seemed to be more toxic
00:02:31.720 | for these guinea pigs.
00:02:33.280 | And he also knew that there are two toxic substances
00:02:36.860 | in urine, urea and uric acid.
00:02:40.240 | So he was able to separate the urea and uric acid
00:02:43.600 | from people with mania and patients that did not have mania.
00:02:48.040 | And he figured out that the urea was the same
00:02:51.240 | in both these mentally ill manic patients
00:02:54.280 | and the non-manic patients.
00:02:56.080 | So it did not seem that urea was the compound
00:02:59.640 | that was creating these manic episodes
00:03:02.120 | or related to manic episodes or held the toxicity.
00:03:06.280 | So instead he focused on the uric acid.
00:03:09.240 | Now, in order to put the uric acid into solution
00:03:12.960 | so that he could inject it into these guinea pigs,
00:03:15.240 | he had to try a number of different compounds
00:03:17.360 | in order to dilute it.
00:03:18.280 | It just so happens that,
00:03:19.920 | and you chemists will be familiar with this,
00:03:21.660 | but there's certain things
00:03:23.000 | that just don't go into solution easily.
00:03:24.640 | You put the powder in a vial,
00:03:26.600 | you add some water or a saline or another solution,
00:03:28.880 | you mix it up and the powder stays suspended in there.
00:03:31.240 | It just doesn't actually ever become a clear liquid
00:03:36.040 | that you can inject.
00:03:37.400 | So in order to try injecting different strengths
00:03:40.360 | of uric acid, he ended up using lithium
00:03:43.980 | to assist in the dilution and lithium worked.
00:03:47.200 | So what he basically was doing, again, for you chemists,
00:03:49.560 | is he was taking uric acid, he was adding lithium
00:03:53.000 | and making a solution of lithium urate, okay?
00:03:56.200 | This is a lot of details, but this is important
00:03:58.880 | because what he eventually found
00:04:00.960 | is that when he diluted the uric acid with lithium
00:04:04.960 | and created lithium urate,
00:04:06.320 | lithium urate could actually calm down these guinea pigs
00:04:10.600 | that were injected with the toxic urea.
00:04:13.840 | He also found that lithium urate
00:04:16.600 | had a generally calming effect on these guinea pigs.
00:04:20.320 | So now we're really off in crazy territory, right?
00:04:23.000 | We're talking about urine from patients
00:04:25.160 | that's separating out urea and uric acid.
00:04:28.360 | We're adding lithium to the uric acid.
00:04:30.480 | We're injecting this into guinea pigs.
00:04:32.080 | This is getting pretty wild and pretty weird,
00:04:34.200 | but this is medicine and from time to time,
00:04:36.800 | this is medicine and science.
00:04:38.440 | Cade was a good scientist
00:04:41.320 | in addition to being a good physician.
00:04:43.340 | And by good scientist,
00:04:44.980 | I mean that he did control experiments.
00:04:46.900 | Here he was injecting lithium urate into animals
00:04:51.820 | and seeing an effect,
00:04:53.060 | but he knew that that solution of lithium urate
00:04:56.140 | contained not just the uric acid,
00:04:58.940 | but it also contained lithium.
00:05:00.500 | And so he quite appropriately asked,
00:05:03.460 | maybe the lithium alone is having this calming effect
00:05:07.540 | on these guinea pigs.
00:05:09.020 | And indeed that was the case.
00:05:10.700 | When he did the proper control experiment
00:05:12.660 | and injected only lithium solution into these guinea pigs,
00:05:17.660 | they calm down.
00:05:18.940 | From there, he in sort of 1940 style medicine,
00:05:23.500 | this would not happen now.
00:05:25.260 | He very quickly moved from that animal model
00:05:27.460 | into human patients
00:05:29.020 | and started injecting human patients with lithium
00:05:32.060 | or providing lithium orally to those patients.
00:05:35.100 | And lo and behold,
00:05:36.740 | found an absolutely profound and positive effect
00:05:41.180 | of lithium in reducing symptoms of mania.
00:05:44.820 | And as all good physician scientists do,
00:05:47.460 | he wrote up his results
00:05:49.140 | and he wrote it up in a paper entitled
00:05:52.380 | "Lithium Salt and the Treatment of Psychotic Excitement."
00:05:55.820 | Okay, back then they didn't call it mania,
00:05:57.060 | they called it psychotic excitement.
00:05:59.320 | This is a paper that was published September 3rd, 1949
00:06:02.160 | in the Medical Journal of Australia.
00:06:04.080 | We will provide a link to this study
00:06:05.620 | is now a classic study in the field of psychiatry.
00:06:08.960 | It's a really wonderful paper to read
00:06:10.700 | and actually I encourage people,
00:06:12.700 | even if you're not a scientist or a clinician,
00:06:16.140 | to just take a quick look at the second page in this paper
00:06:19.060 | that we've made available to you,
00:06:21.220 | where he describes each of the various case studies
00:06:24.860 | or the individuals that he looked at.
00:06:27.020 | I'm not going to read these in detail now
00:06:28.620 | 'cause it would take a lot of unnecessary time,
00:06:30.560 | but things like case seven,
00:06:32.980 | MC aged 40 years old,
00:06:35.100 | suffering from manic recurrent mania.
00:06:37.060 | In this episode, he'd been excited,
00:06:38.260 | restless and violent for over two months
00:06:40.380 | and was interfering so often
00:06:41.420 | that he had to be confined to a single room during the day.
00:06:43.780 | Right, so this is very debilitating,
00:06:46.240 | what we now know to be bipolar depression.
00:06:48.340 | He commenced taking lithium citrate 20 grains,
00:06:51.780 | that's a measure of the amount of lithium,
00:06:53.820 | three times a day.
00:06:54.640 | In four days, he was distinctly quieter
00:06:57.180 | and by February 13th, 1949 appeared practically normal.
00:07:01.900 | He continued well and on February 20th, 1949,
00:07:04.380 | the dose of citrate was reduced to 10 grains,
00:07:06.540 | et cetera, et cetera.
00:07:07.380 | He left the hospital.
00:07:08.820 | There are numerous descriptions
00:07:10.740 | of this sort within this paper,
00:07:12.220 | including some descriptions of patients
00:07:13.780 | that did not see such success
00:07:16.300 | and including some descriptions of patients
00:07:18.680 | that suffered from some negative side effects.
00:07:21.660 | So that's important to point out as well,
00:07:23.460 | but it's an absolutely wonderful paper
00:07:25.720 | and it's an absolutely wonderful voyage
00:07:28.160 | into the history of psychiatry,
00:07:29.740 | right down to the discussion
00:07:31.020 | where in just three short paragraphs,
00:07:33.760 | Cade really lays out the case for why lithium
00:07:37.700 | is such an important discovery
00:07:39.420 | in the treatment of what at that time
00:07:41.420 | they were calling psychotic excitement
00:07:42.940 | and what we now know to be manic bipolar depression.
00:07:46.640 | [upbeat music]
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00:07:52.620 | you