Lithium, the GOAT: What is Lithium?

Ethan: Lithium is a natural substance that has been around forever, found in salt mines and all throughout the world. Its primary indication is to treat bipolar mania, also has a lot of evidence as a maintenance medication to prevent bipolar depression, though it is not FDA approved for that. As far as I know, it's the only medicine that has really good proven data to reduce the risk of suicide. So, I just wanted to first give a little bit of historical background before any type of medical use. So in the 1800s, Cherokee Indians down in Georgia [00:01:00] were spending time in what was later dubbed Lithia Springs, as this sacred healing site. They were forcibly removed, and a hotel resort went up, and 1888 until today Lithia Springs is still used to bottle water for its high lithium and mineral content as a general health tonic. So it's something we've had an idea has had some benefit for a long time. But it is not this European phenomenon or European discovery necessarily. In 1847, it was first used as a gout treatment by a London internist, Alfred Baring Garod. The problem was he had to use really high doses of lithium and there is toxicity associated with it, so it wasn't a very reasonable or safe treatment for gout.

Rif: It definitely dissolves uric acid crystals in a test tube. It does not actually dissolve uric acid crystals in our body. And, like you said, it's the difference in concentration that you can achieve in the human [00:02:00] body and in a test tube. So it was, in a way, evidence-based but not clinical evidence.

Ethan: 1855, it was purified into its metallic form by Bunsen. So, he didn't just do the Bunsen Burner, he also purified lithium into metallic form. Lithium isotopes were banged together to create Tritium, which is used in Hydrogen Bombs. In 1929, shortly before the Wall Street crash, a new soft drink was unveiled. It was called Bib Label Lithiated Lemon Lime soda, quickly realized that name was too long and got shortened to 7-UP, and actually contained lithium as one of its components until 1948. We'll tell you why it got taken out in a little bit. It wasn't until 1894 that Danish psychiatrist Frederick Lang treated 35 patients with lithium carbonate as a prophylactic for depression. [00:03:00] To the general public, tell us, what is lithium?

Rif: Lithium and other mood stabilizers are the closest thing to actually fixing something that is actually broken in our patient's brains in psychiatry. So it's really important to use mood stabilizers in treating folks that have bipolar illness. Lithium is the most effective of those. But it is important to understand how difficult that is to use because the physiology that you're trying to fix keeps changing in persons with bipolar illness. The physiology is different when they're not manic or depressed. It's different again, when they're manic, and it's different yet again when they're depressed, and so it becomes really difficult to keep changing your dosage to [00:04:00] actually catch up with the physiology of the patient. It's very interesting when you look at the periodic table of elements, the first column is the alkaline earth metals, and the top one is hydrogen. And then the second one right after that with an atomic number of 3 is lithium. That entire column is mainly biologically active monovalent cations, so right below lithium is sodium and right below sodium is potassium. Not too far from that is calcium, which is a divalent cation, meaning loses 2 electrons. That column of elements is really important in terms of physiology, all of them, including lithium. But, lithium's importance in physiology really has to do with its relationship to sodium. Predominantly, it looks like sodium as [00:05:00] far as a lot of proteins in our bodies are concerned, and it ends up mimicking sodium in several ways. So it's an element that exists in nature. It comes into our bodies. We don't use it a lot because we just didn't evolve to use it. We evolved to use sodium, which is perhaps a little bit more common in waters on Earth.

Ethan: So essentially, when we talk about the electrons in the outer core of any element, that column has one extra electron that allows it to effectively interact with other substances, to break it down into very basic…

Rif: To form ionic bonds, specifically ionic bonds, and of course, ionic bonds are most common in water, aqueous solution because water is itself polar. It's the way it's structured, it has a [00:06:00] side that's negative and a side that's positive. And because of that, things that can lose electrons easily, like lithium or sodium or potassium or calcium or anything that's an ion in water, turns into an ion, so lithium will lose an electron and will go around with a positive charge.

Ethan: Can you talk a little bit about the, possible theories of how lithium exerts its benefit?

Rif: This is of course very fascinating because there are lots of theories, no absolute knowns. Part of that is related not so much to not knowing what lithium does, but not understanding what causes bipolar illness? Because if you're saying that something works for a specific disease in a specific way, what you really need to do is demonstrate that it reverses the pathology in that disease, not just [00:07:00] in terms of clinical symptoms, but really at a more biologic level. Since we don't understand how people get bipolar illness, we can never really say what the mechanism of action of lithium is. Having said that, studying what lithium does, has actually been used to understand what causes bipolar illness, reverse engineering, if you will. We know that Lithium works, so let's see what it actually does. There are really two sort-of categories that you can put the mechanism of action of lithium. One is, lithium is an ion and so maybe its mechanism of action is based on ionic actions. The other is, maybe lithium interferes with the physiology of the cells in some way, looking at the biochemical, [00:08:00] maybe gene-related actions of lithium. So, those are the two sort of major divisions. It is important again to restate that we don't really know what Lithium does, but we do know that lithium has to enter into cells and it's the intracellular fraction of lithium that actually makes a difference. We measure the amount of lithium outside, but that's not really how it works and inside cells, lithium accumulates based on several things. The major thing that makes lithium go into cells is how electrically active those cells are.

So, I mentioned lithium looks like sodium and actually interacts with biological [00:09:00] systems as if it is sodium, that is actually true in mammals for sure. Lithium moves across cell membranes as if it's sodium predominantly in how it gets into the cell. One of the reasons that Lithium works is, actually, once it gets into the cells, it gets stuck there. Lithium goes into the cell as if it's sodium, but the mechanisms that get sodium out distinguished lithium from sodium, and so lithium gets stuck inside the cells, and that's actually important for its mechanism of action. And it's non-ionic that you actually have to get lithium levels to increase inside electrically active cells, actually to a concentration that is greater than the concentration in the plasma overall. If you take the average intracellular [00:10:00] lithium concentration, it's about 7/10th of what it is outside the cells. But in electrically active tissue, it can be as high as 10 times greater than the extracellular concentration. So lithium is not at all distributed equally inside cells even within the cell. Its concentration is different in different parts of the cell. The greatest accumulation of intracellular lithium happens in nerve cells, which is nice because that's what we're targeting in terms of treating manic-depression, bipolar illness.

Right around the 1950s, when the initial clinical work was being done in Europe, predominantly, there was also [00:11:00] work being done to understand how neurons work. People have gotten Nobel Prizes for ultimately determining that the action potential, when a neuron is set to fire, is related to sodium moving into the cell and the sodium channels that move sodium from the outside to the inside. When a neuron fires, the same sodium channels transport lithium into the cell. That interesting sort of accident of nature, if you will, is one of the reasons that lithium works in bipolar illness, because nerve cells that are sick in a bipolar patients actually fire more readily than nerve cells in somebody who isn't sick, including bipolar patients when they're not sick. What that means [00:12:00] is that abnormally functioning nerve cells, in people say who are manic, and actually people that have bipolar depression (as well), accumulate more lithium than cells right next door. So you can have two cells sitting right next to each other, and one of them accumulated tremendous concentrations of intracellular lithium and the other not because it's not impacted by the disease. That accumulation of intracellular lithium is believed to do one of multiple things in the ion-regulatory realm. We know that when people are sick, when they're manic or when they have bipolar depression, we know their amount of intracellular sodium is high. And, when that happens the brain has all sorts of dysfunction and [00:13:00] lithium gets stuck there, it actually displaces intracellular sodium and normalizes the intracellular sodium concentration, literally the amount of increase in intracellular sodium that happens when people are sick is no longer there when they're treated with lithium. And I think that normalizes function of the neurons. So Lithium is really very potent at correcting the one clear abnormality that has been reported over and over and over again in people with bipolar illness. But, once you accumulate intracellular lithium, it also begins to interact with a lot of enzymes inside the cells, proteins inside the cells, maybe genes directly, and all of these different interactions which have been [00:14:00] documented in multiple experiments are shown to, again, normalize actions of things like second messengers, proteins that lead to cell death, activity of things that generate calcium, which is ultimately a huge effector inside nerve cells. So all of these things are normalized as well. So again, there’s sort of 2 main arms of how lithium works. One is ionic, one is all of these enzymes and proteins inside the cell, and the increase in intracellular concentration of lithium corrects both of those.

Ethan: So you've got some really excited nerve cells in the brain, especially in a manic patient, and to slow that firing rate down and see an improvement in symptoms. It might be a little counterintuitive for the depressed patient, but from more recent fMRI studies that I've seen on [00:15:00] depression, there is an excite-toxicity because, people who are depressed tend to sit and think and ruminate. They have that crosstalk between, you know, what we consider the conscious part of us or our frontal lobe and the more primitive brain or our lower brain, thalamus, hypothalamus hippocampus. That helped to explain to me why it has the effect it does in depression as well, that it can also slow down that crosstalk or that rumination that can lead to major depressive illness.

Rif: Absolutely. It is also important to understand that Bipolar depression is different than unipolar depression. Bipolar depression is not all that different at the cellular level than mania. As a matter of fact, when you look at what's happening at the cellular level in people that have bipolar illness, you [00:16:00] realize that depression is actually a more severe manifestation of mania. You know, this is something that happens in the brain all the time. The biphasic nature of how the brain works, when you take anything to an extreme, you get the opposite. When you take excitation to an extreme, you get the opposite, you get lack of excitation, and it happens clearly in bipolar illness. Bipolar depression, when you take that to the extreme, you get a condition called catatonia, both mania and depression together, where patients are in a state of excitement, but their activity is reduced. Lithium works for that condition as well.

Ethan: In terms of lithium not being able to get out of the cell, does that affect the blood concentration? Could you have more lithium exerting its action than you would be able to see on a blood draw?

Rif: Yeah, so this is important to know that when [00:17:00] we measure lithium levels in the bloodstream, we're really trying to infer what the intracellular concentrations are. It's not an absolute thing. Blood levels for lithium don't tell you 100% of the story. You have to really combine them with the clinical situation. They're not telling you how much lithium is inside neurons. There's actually, interestingly, an old blood test, which is unfortunate you can't actually do it anymore because clinicians, they've stopped using lithium, but they've stopped ordering this particular blood test. It's called lithium ratio. And the reason I say it's unfortunate that you can't do it anymore is lithium ratio is literally the intracellular concentration in red cells and the extracellular concentration in blood. And, red cells are [00:18:00] absolutely not electrically active. They're perhaps the most boring electrical activity cell in the entire body. But red cells will accumulate lithium because they do have sodium channels and lithium can get into the red cells and again, get stuck inside. But, the concentration of lithium in red cells is low. It's actually lower than the concentration in the plasma, because they're not electrically active. But folks that are likely to respond to lithium have higher intracellular concentrations of lithium than folks that don't respond to lithium.

Ethan: A stat that I always hear is a third of bipolar patients will have a super response, a third will have a significant response, and then a third will not have a clinically significant response.

Rif: Right.

Ethan: Would you say that that test is [00:19:00] relatively predictive or at least increases the accuracy of…

Rif: Yes. So, if you're between 0.4 and 0.6, you're in that middle third. If you're above 0.6, you're in that super responsive third. If you're below 0.4, you're in that non-responsive third.

Ethan: That would be nice to have.

Rif: And people have stopped ordering it. It's a difficult test to do because you have to centrifuge whole blood, then lyse the red cells, get rid of all the solids and the red cells, and then measure the lithium level.

Ethan: So, based on what you're telling me, if you have a patient in the hospital who's overtly manic and you treat 'em with lithium, and a month later they're much improved, they're out of the hospital and you see 'em in the outpatient setting, due to the fact that lithium is accumulating intracellularly without an effective way to get out of the cell, do you reduce that dose in a certain timeframe?

Rif: [00:20:00] Oh yeah, it's not just that lithium accumulates. The abnormal physiology that leads to mania or depression for that matter goes away, corrects itself, and consequently the concentration of lithium that you needed to correct that abnormal physiology is now too high inside the cells, and so patients can't tolerate lithium that we give them when they were acutely ill. And almost always, if we don't lower the dose, they'll stop it just like that fellow in Cade's report. This is really the difficult part of using lithium. But it's not just lithium, it's any mood stabilizer. You need to change the dose based on mood state, based on the physiology of your patient. And so, there's a lot of [00:21:00] education that goes with educating the patient when to alter their dose, either up or down, so you always need to lower it to avoid side effects and toxicity and increase it to actually reduce the symptoms of the illness. Most clinicians actually don't really understand that, and this is part of the problem regarding reductions in the use of lithium. It's because we don't use it correctly.