Here, Dr. El-Mallakh and I review the side effect profile of lithium at high doses (900+ mg per day), which include thyroid, kidney, and toxicity risks. However, patients prefer lithium over other mood stabilizers, and because the majority of us are exposed to lithium at low levels regularly through our water supply and various foodstuffs (cereal, potatoes, tomatoes, etc.), lithium at lower doses is undoubtedly much better tolerated and safer. Dr. El-Mallakh gives us more information about how lithium's multiple mechanisms of action can contribute to its side effect profile as well.
Thanks for listening. For more social media content, check us out on all social media platforms @Renegadepsych. If you have any comments, questions or challenges to the information we've presented here, if you'd like to be a guest to the show, or if you have general comments, questions, or suggestions, email us at Renegadepsych@gmail.com and follow the link https://renegade-psych.podcastpage.io/ to our website for source material, transcripts, and additional links for my guests. If you feel passionate about our message and what we're trying to do, and you'd like to donate, you can also follow the link in the show notes to our website.
Disclaimer, this podcast is for informational purposes only. The information provided in this podcast and related materials are meant only to educate. This information is not intended as a substitute for professional medical advice. While I am a medical doctor and many of my guests have extensive medical training and experience, nothing stated in this podcast nor materials related to this podcast, including recommended websites, texts, graphics, images, or any other materials should be treated as a substitute for professional medical or psychological advice, diagnosis or treatment. All listeners should consult with a medical professional, licensed mental health provider or other healthcare provider if seeking medical advice, diagnosis, or treatment.
Ethan: Now we're going to talk a little bit about side effects of lithium. And before we start, I want to point out that the side effects we're going to discuss are in relation to higher doses of lithium, along the lines of 900 to 1800mg/day, doses most common in treating Bipolar 1 disorder. There is not the same evidence or association of side effects with low-dose lithium, 300 mg. or less. (And that is 300 milligrams of lithium carbonate.) And the reality is that lithium is present in so [00:01:00] much of our water supply at low doses, so we know that low-dose lithium is really well tolerated. There are significant and some potentially severe side effects at higher doses of lithium. So Dr. El Mallakh, tell us a little bit about the major and the most common side effects of higher doses of lithium.
Rif: There's 2 ways of thinking about the side effects of lithium. One is really what's dangerous and the other is what's burdensome. We'll start with burdensome because they're less important. The most common burdensome side effect with lithium is probably tremor. The way you identify that it's a lithium-related tremor is the intensity of the tremor will vary throughout the day. It's a reflection of blood levels of lithium, so it's dose-dependent, [00:02:00] dose administration dependent. It is to some degree dose-dependent, but it's also dependent on the timing. Patients are very much aware of tremor, but it's really because lithium is accumulating in the muscle. Actually have patients raise up their arm and if you've ever tried to carry something that was heavier than your muscles are capable, you can actually feel that muscle trembling.
Ethan: It should be worst after the lithium is absorbed and at its peak concentration?
Rif: And that's what usually happens. It's one of the ways that you differentiate lithium-related tremor from something called essential tremor. It is very much related to when you've taken the lithium. It peaks within an hour or 2 after taking the lithium. The tremor stays high for 2 or 3 or 4 hours, and then slowly gets better. The intensity is variable. The other common [00:03:00] nuisance side effect is GI side effect. People can get nauseated with lithium. People more frequently will have diarrhea. If you're having diarrhea, you probably want lithium to get into the body faster. If you're having nausea, you want lithium to get into the body slower. If somebody's nauseated, you use a slow release formulation, if somebody is having diarrhea, you give an immediate release formulation, so they're manageable and they're not particularly problematic.
Ethan: For the tremor, could you take the lithium at night?
Rif: Lithium has a half-life of 24 hours, absolutely can be given only once a day. We are scared of lithium and that's why we give it twice a day. But there's absolutely no good scientific reason. It's an emotional decision to give lithium twice a day. You give lithium at night. That way the patient sleeps through the side effects. For the more [00:04:00] important side effects, when we talk about the kidney, taking the lithium in a single dose tends to be healthier for the kidney. I always recommend to my patients, even if they're on reasonably high doses, that they take it just once a day.
Ethan: I've read some literature that say there's no reason to not just give it at night. The kidneys, they can recover each day, and then also reduce the incidence of tremor, or reduce the reporting of it (Rif: Right… yeah) because people will sleep through it, (and it’s not as public because you’re asleep).
Rif: And there are other nuisance side effects, but those are the main ones. The really important stuff are the effect of lithium on the thyroid and the kidney, and the effect on the thyroid is mediated by the fact that lithium inhibits the formation of enzymes and chemicals that live inside cells and are the product of the interaction between a neurotransmitter or an outside [00:05:00] chemical, a hormone, and the inside of a cell. Lithium inhibits Protein Kinase C, which is one of the 2nd messengers of thyroid hormone. Consequently, lithium creates thyroid resistance, so thyroid hormone is less potent because when it tries to transmit its message, the 2nd messenger is inhibited by lithium. More than half of patients will ultimately have some thyroid consequence. And it's pretty easy to treat. You just replace the thyroid, but you have to do it earlier. Psychiatrists are always in an argument with endocrinologists who wanna wait until the TSH, the Thyroid Stimulating Hormone is above 6 or 7 before they start doing anything. And psychiatrists, at least what I teach my students, is when [00:06:00] it goes above 2.5, which is still within the normal range, is when you start thinking about replacing thyroid. Because, if you don't replace thyroid, what ultimately happens is the thyroid gland will make up for it so you won't really be hypothyroid, you won't have symptoms of low thyroid, but your gland will get bigger and we call that a goiter, this big lump in your throat. In the olden days, when we didn't even know how to test for TSH, about 25-50% of the patients on lithium would develop goiters. We already know from old data that this is a problem and we need to address it early. But, that's easy to treat and it's fully reversible. If I was taking thyroid hormone because I'm taking lithium and I stopped taking lithium for whatever reason, you can wean me off of the thyroid hormone. You'd have to do it slowly, but it's fully reversible. It [00:07:00] doesn't hurt the tissue in any way. So a person can just come off their thyroid hormone. By and large, patients like being on thyroid hormone. And actually one of the interesting things in bipolar illness, if you make the patient a little bit hyperthyroid, they're actually more stable. When I start replacing thyroid in my lithium-treated patients, I always overdo it on purpose a little bit because it actually stabilizes their mood. Thyroid is one of the few treatments in treatment-resistant depression that actually works. Being a little bit on the high side reduces the risk of rapid cycling.
Ethan: I know a lot of patients worry about Chronic Kidney Disease (CKD). I was looking at a 2021 study by Van Alfin of 1,000 patients, followed for 16 years, all of which were on lithium. 118 or 11.8% [00:08:00] developed Chronic Kidney Disease, stage 3 (out of 5 total stages), and the median time for them to develop that was actually 41 years.
Rif: You're absolutely right. When you think about how likely it is to happen, how common it is, it is not as worrisome as you would think it would be but because dialysis is so burdensome, you don't really wanna get there. So, we have to continue to look out for reductions in kidney function. The thing to remember is that people who have a mood disorder independent of ever being exposed to lithium are unlucky enough to have twice the risk of developing chronic Kidney disease than the general population. So just having a mood disorder, and it could be other [00:09:00] medicines that we use, increases your risk for kidney disease. One of the most important things, particularly in good lithium responders, your patient is showing some reduction in their Kidney function and you want to know, is this really related to the lithium? Because if it isn't, is it really a good idea to stop (lithium)? And recently, over the last 20 years or so, one of the things that has been recognized is something called microcysts. People on long-term lithium will actually develop these very, very, very small cysts in the kidney. It's not PolyCystic Kidney Disease, which of course can also lead to renal failure, (in PCKD) these large cysts that develop ultimately deform the kidney. (With lithium), the kidney maintains its normal size and it's normal kidney shape.[00:10:00] The kidney is surrounded by this tough capsule that is sort of like our skull. It's unyielding. It's soft. You can bend it in a real organ, but it's unyielding. It won't allow the tissue inside to grow. Microcysts, we think they're caused by actually lithium having an anti-apoptotic effect. Apoptosis is programmed cell death. A normal phenomena that is necessary for us to continue to renew our bodies and lithium prevents old, tired cells from dying. By doing that to the cells that line the tubes inside the kidney, endothelial cells, extra cells will literally invaginate and form these minute cysts. So the cells just round up and form a ball, [00:11:00] and inside is a piece of the (kidney) tubule that doesn't do anything. It just sits there. These microcysts just take up more and more space inside this unyielding capsule of the kidney. And you get to the point where there's enough space that's lost to these microcysts that the normal tissue doesn't have enough space to function. By looking for these microcysts, you can determine if the loss of renal function is related to lithium. MRI can see down as small as 1millimeter/mm. These things can be smaller than 1mm, so they can be invisible. Or you can do an ultrasound of the kidney, which sees things that are maybe 2 or 3 mm. So it's a little bit harder to see how common they are, but you do an imaging study and if you don't have microcysts, now you have [00:12:00] this tough discussion with your patient about something that is hurting their kidney, that it's probably not related to the lithium, but lithium is probably not helpful either. Now if you do have microcysts, then you know that it's all caused by the lithium and it makes the decision easier.
Ethan: And I've heard another potentially contributing factor is lithium can cause dehydration. Dehydration can cause Acute Kidney Injury, and repeated insults of dehydration can contribute or cause chronic kidney disease as well.
Rif: Absolutely. And that's of course how people identified this in the first place. People would present with lithium toxicity, and their kidneys would be shut down. But almost always, it was pre-renal shutdown. You get dehydrated, your kidneys stop functioning cuz there isn't enough blood literally to flow through them. And so you come in with acute renal [00:13:00] failure, elevated lithium because you haven't been peeing out the lithium, and consequences of lithium toxicity. So that's how lithium attracted the attention of folks that are interested in kidney things that don't cause toxicity in that way, the anti-seizure medicines, Depakote, Lamotrigine, probably also cause Microcysts, but you don't really recognize that they can cause renal failure because you don't have this marker that became obvious with lithium early in its history. Generally, if you are developing renal disease and you're on an anti-seizure medicine, I don't say, Oh my God, we gotta stop that medicine because it hasn't really been identified, but I think it can for the same reason that lithium does… that it's anti-apoptotic.
Ethan: Tell us a little bit about lithium toxicity.
Rif: Remember that lithium [00:14:00] works, both its benefit and its harm are mediated by the intracellular fraction. The nuisance stuff is still mediated by intracellular, but is related to the extracellular concentration. The way that lithium works to control bipolar illness is it makes sure that cells that would fire too frequently are inhibited, literally picks out the fastest-firing cells and you actually get to inhibit cells that are abnormally active and you don't inhibit normal-firing neurons. So, if you get the lithium right at the right window, you don't inhibit normal brain function, but you inhibit abnormal brain function. As the level of lithium goes up, now you begin to inhibit normal cells as well, [00:15:00] and it's really quite interesting because the fastest normal neurons are the first ones to be inhibited as you're getting into toxicity. It turns out that our fastest neurons are neurons that coordinate things. And it's really easy to see dysfunction of neurons that coordinate movement. You begin to slur your words, walk like you're drunk, start getting blurry vision, transient blurry vision. Blurry vision that happens and then comes back, and then happens, and comes back. So that's an easy thing to identify, and being clumsier than your normal self is very easy for patients to realize. When the lithium levels are going up, and one of the things that I always do when I work with my patients on lithium, is educate them about that because they know that if that happens, they don't even need to call me. They simply skip a day's worth of lithium, [00:16:00] and that's enough to bring the levels down, make sure that the brain is working. And some patients will skip a day every week or every 2 weeks, that's all it needs for them to stay in that sweet spot. And you don't really wanna reduce the dose because you might get away from the therapeutic part of lithium. So educating patients is really important.
Ethan: I thought it was interesting that a 2023 Journal of Affective Disorders, 33,000 patient retrospective study on adherence, Lithium and Clozapine had the lowest non dispense rates from pharmacies. Again, we're, very fearful of these side effects. But according to that large study, it was the most tolerated based on the subjective view of the patient.
Rif: The more you know about what causes a disease, the closer you are to actually fixing a known abnormality. The more benign and more [00:17:00] effective your treatments are, you cause fewer side effects and you get better outcomes if you actually fix something that's wrong. Lithium literally fixes the most reproducible biologic abnormality in patients who have bipolar illness and are say manic or depressed, elevated intracellular sodium. Lithium is one of the very few treatments in psychiatry that actually fixes a known abnormality.
Ethan: The general public, when they watch an ad on television about Depakote, it makes them think, ‘Depakote's this great drug, lithium's not a great drug cuz I don't ever see an ad for it.’
Rif: People, definitely including physicians, probably respond it was easy to kick out Lithium because Depakote had people who were selling it to you and [00:18:00] Lithium didn't. Heck, you know, they even advertise that Depakote doesn't cause weight gain, but lithium does. Which is exactly the opposite of the truth.
Ethan: Yeah. The side effects, even in our education, they were way over-exaggerated compared to what you see clinically and then talking to people like you who have been doing this for a long time.
Rif: We're supposed to check lithium levels every 3 months. First of all, that's unnecessary; the changes that lithium causes are way slower. Measuring issues once a year is probably sufficient because that's the time course of these changes. I was just participating in a survey of what is the safest drug to use in a pregnant bipolar patient, or breastfeeding bipolar patient. And I said, lithium. And that is absolutely not legally, it's not what is taught, but it's absolutely the safest.
Ethan: Less than [00:19:00] 1% penetrance in breast milk. Yet it is somehow contraindicated in breastfeeding
Rif: The recommendations for pediatricians in terms of monitoring lithium were drafted in 1970 and have not been updated since. We're using really fear recommendations, still painted by the deaths that happened in the 1940s.