Hello and welcome. I'm Dr. Rob Cotez, Director of the Clinical and Research Program for Psychosis at Grady Health System and Associate Professor at Emory University School of Medicine. I'm so pleased that you're here joining us for today's SMI Advisor webinar, Some New Thoughts on Lithium. SMI Advisor, also known as the Clinical Support System for Serious Mental Illness, is an APA and SAMHSA initiative devoted to helping clinicians implement evidence-based care for those living with serious mental illness. Working with experts from across the SMI clinician community, our interdisciplinary effort has been designed to help you get the answers you need to care for your patients. Today's webinar has been designated for 1.5 AMA PRA Category 1 Credit IV positions, 1.5 Nursing Continuing Professional Development Contact hours, and 1.5 Continuing Pharmacy Education hours. Credit for participating in today's webinar will be available until December 19, 2023. All right. Slides from the presentation today are available to download in the webinar chat. Select a link to view. Captioning for today's presentation is also available. Click Show Captions at the bottom of your screen to enable. Click the arrow and select View Transcript to open captions in the side window. All right. We welcome your questions. Please feel free to submit them throughout the presentation by typing them into the question area found at the lower portion of your control panel. We'll reserve 10 to 15 minutes at the end of the presentation for Q&A. Now I'd like to introduce you to the faculty for today's webinar, Dr. Jonathan Meyer. Dr. Meyer is a Voluntary Clinical Professor of Psychiatry at UC San Diego and a Distinguished Fellow of the American Psychiatric Association. Dr. Meyer has teaching duties at UC San Diego and the Valboa Naval Medical Center in San Diego and has published extensively on psychopharmacology along with Dr. Stephen Stahl. He's the author of the Clozapine Handbook and also the author of the Clinical Use of Antipsychotic Plasma Levels, which was released in 2021, and also is the author with Dr. Stahl of the Lithium Handbook, which will be available shortly. Dr. Meyer, thank you for everything you've done. Great friend to SMI advisor and mentor for me, and I'll turn it over to you. Thank you so much, Rob, and thank you all for joining me on a Friday. So, I have no disclosures on this topic. Seemingly, lithium is made by a lot of people. So, most importantly, you're turning in today to really understand why you need to know how to use lithium. And it's become much different than it was a few years ago, simply because, as you'll learn, the most widely used mood stabilizer, Neeming Valproate, is now a drug we cannot give to half the population. If you're not sure which half, you'll find out. I'll tell you how to dose it, how to obtain levels, why once daily dosing is easier on the kidneys, how to manage some of the non-renal stuff, but most importantly, really focusing on the renal aspect, and then some of the newer data on the use of lithium in pregnancy and breastfeeding. This is perhaps the most important thing we've learned in the last 20 years. Yes, most antipsychotics have indications for acute mania, they have anti-manic properties, and some have antidepressant properties, but they don't do the same thing as lithium does on second messenger systems. A famous psychopharmacologist out of Denmark, Mullen scouted all the early work on lithium once they heard about that extraordinary experience from Australia. And he would publish this handbook from time to time until he passed away about 15 years ago. And I love this quote because it really shows you that we clinically can see the difference between lithium and antipsychotic. And I'll read the quote right here, an experienced patient who during previous manias at first tried what we used to call neuroleptic, and then lithium said that during treatment with the former, he felt as if the gas pedal and the brake were pressed down at the same time. With lithium, it was if the ignition had been switched off. So yes, in fact, antipsychotics have anti-manic properties, but they don't do the same thing as lithium does in managing the mood disorder. And we now have naturalistic evidence of this. So this diagram was much more complicated, and I've tried to simplify it to some of the monotherapy options. These are all bipolar I patients who had a history of mania followed over a period of time. What you can see is among the monotherapy options, people on lithium had the lowest failure rates. You think, well, why would people on lithium fail? Well, as we'll talk about lithium, although it has many anti-suicide properties, it's not a great antidepressant. You have to acknowledge the fact that if you have a history of mania, you're going to become depressed. Usually we often need separate agents for bipolar depression. That being said, who did the worst were people who are on monotherapy with the atypicals like elantipine or quetiapine or monotherapy with valproate. So naturalistically, yes, I understand elantipine has an indication for maintenance in bipolar I. People on atypical monotherapy tend to do quite poorly, and it's our job to educate them. Fine, you don't want blood tests. You're going to get some blood tests if you're on elantipine anyhow, or aripiprazole is another one indicated as monotherapy. But my best advice as a clinician is it's probably not going to work out well for you. You're probably going to end up needing a mood stabilizer. I alluded to at the beginning the fact that you can't give valproate to half the population. Well, now you know which half of the population. These are women of reproductive potential. In 2018, the European Medicines Agency essentially banned the use of valproate for women of reproductive potential, and it says, and I highlighted it, that these medicines must not be used in any woman or girl able to have children unless the conditions of a new pregnancy prevention program are met. This is not saying you can never use it, but it also is saying you can't just rely on someone who says, oh yeah, I'll use birth control. That is not sufficient, and the UK finally followed suit in this year, and they also banned it for both men and women under the age of 55. We'll get into the data for men in a second. It's a little bit thin, I'll say that, but they highlighted the fact again that if you were in the UK right now and you had a woman under the age of 55, we'll assume she has reproductive potential. If I wanted to put her on valproate for whatever reason, migraine, bipolar, seizures, whatever, I would have to have two independent consultants certify that she has no other option and she'd have to be enrolled in a pregnancy prevention program, which means she's going to have either an IUD or some very tight controls on her use of oral contraceptives to make sure she's really adherent, and this is the reason why, and I highlighted this in the red box. In case you don't pay attention to lectures, the red box is usually something really bad, and if you've never heard about this, well, you should be very mindful of this, and at the end of this lecture, you're probably going to go through in your mind who you have on valproate, who's a reproductive potential, because you need to have a discussion with them. The UK advisory, and if you download these slides, I give you the PDF link at the very bottom as the last reference. I'll quote it, high teratogenic potential, exposure of an unborn child to valproate in utero is associated with a high risk of congenital malformations, you probably heard about that, and neurodevelopmental disorders, 30 to 40 percent, which may lead to permanent disability. There's a name for this. It's called fetal valproate syndrome. You can't just simply give somebody valproate and trust that they're going to use effective contraception, and also, most importantly, the consent that you use for a woman reproductive potential must include the words fetal valproate syndrome and those rates of 30 to 40 percent. Not everybody gets the congenital malformations, but on average, there's an IQ loss of eight points, but it can be even more severe with higher levels of exposure, and this is why the UK said, look, we don't want to take care of these kids who are going to have a permanent disability with intellectual impairment. This is unacceptable. You have to use other options. For women, there's also other concerns, such as polycystic ovary syndrome, and I give you the summary literature up there from the review paper. In the UK, they did ban it for men under 55. There's a reversible impact on fertility. There also was a concern, I'm just going to allude to this, on what they call intergenerational problems, meaning they were worried that somehow it would do something to the germ line. I think that's a bit theoretical. I think the data on women are quite solid, and so now you know. You really cannot give valproate to women reproductive potential unless they have an IUD or some very reliable methods of birth control, and that consent form better have those words fetal valproate syndrome and those rates, so they know exactly what they're dealing with. Well, so you're thinking, I know about Lithia maybe has some issues with what we used to call Epstein's, but other cardiovascular malformations as well, so what can I do for somebody who really needs to be mood stabilized? Again, there are some people who simply cannot go for a trimester without a mood stabilizer. It is what it is. We recognize more than anything that if someone is bipolar and she's pregnant, just stopping the mood stabilizer is not necessarily the appropriate decision. These people have high recurrence risk for any mood episode, and their time spent ill will go up fivefold, so you just don't reflexively take people off. You have to understand what the person needs. There are women who say, you know, I didn't take my lithium for like six months last year. It was fine. Like, okay, well maybe you can skip it for a few months. On the other hand, I was giving a lecture and a woman came up to me in her mid-20s studying to be a psychiatric nurse practitioner. She said, you know, I'm bipolar 1. I don't take my lithium for a week and a half. I've become manic, and when I become manic, I become psychotic. What can I do? And I was fortunate that I knew the literature, and I also was able to refer her to the people at UCSD who have a great maternal and women's mental health program. This is just a little aside, the second bullet, or sub-bullet, about your GFR changes when you get pregnant. Your renal function actually improves significantly in the second trimester, so that if you keep people on with you, which you commonly will, who need it, you'll have to check levels throughout the pregnancy just to make sure, because they're going to start clearing it more rapidly. But the best data we have is this meta-analysis, which was published three years ago, and the findings really support the decisions of women whose psychiatric health and stability depends on lithium, not to stop it. So the number needed to harm for all cardiovascular malformations was 83. I mean, I would have to treat 83 women with lithium in their first trimester to get one additional cardiovascular anomaly. If they're on high dose lithium, maybe that number drops to 39, but for those who need to be on lithium, those are the numbers you have to talk to them about, and without scaring them unnecessarily, and then they come to a joint decision. If they understand those numbers, you have to translate to them to continue with lithium. Once you're after the first trimester, then you're home free anyhow. So when they deliver, it's nice if their lithium levels are below 0.64, but I wouldn't worry about this too much. It just really is an issue for reactivity and APGAR scores in that first 24-hour periods. If they need a higher level for stability, you run them where they need. This is the big thing, though, that also came out just in this past year. You can see this was published in 2022. They had 30 breastfeeding dyads, moms on lithium, kid breastfeeds, and they got lithium levels in the infant, which is always what we wanted. I could tell you the sum total of the world's literature before this paper was 39. So with this one paper, we increased the world's literature by almost 50%, and we almost doubled it, rather. What you can see is, if you look at the infant lithium data, is that the median levels are always extremely low. The only concern was really in those first few weeks up to a month. You can see, if you look at the range, there were a couple of outliers. One was 0.7, one was 1.2. How they typically managed these was they just reduced the proportion of breastfeeding. So rather than being 100%, maybe it went to a 75% plus 25% formula or 50-50. And they did that also, even if the lithium levels were kind of modest for the infant, but the infant just wasn't feeding well. They said, just reduce the proportion, but there was really no need to stop it. Once you got to after week four, meaning the start of the second month, there was no outliers. So the baby's renal function has matured, they clear the lithium, the levels are almost undetectable. I provide you some suggested monitoring. This is just a way to avoid having to stick the kid too often, but also do what we think is important, meaning just monitor renal parameters, TSH, and lithium levels periodically, just to see how things are going. But I think you can say, and this was the title of the article, lithium used during breastfeeding was safe in healthy full-term infants under strict monitoring. Okay. One other reason to consider lithium preferentially, now that you can't give valproa to half the population anyhow, is its neuroprotective value. This meta-analysis was published in 2020. It looks like the reference got cut off a little bit, but 2020. What it showed you was two important facts. The first one is that if you have bipolar one, a history of mania, your risk of dementia is increased threefold. And a lot of that has to do with the cardiometabolic comorbidities, which we see in bipolar disorder patients, but also recurrence of mania. And why do people get admitted to the hospital? It's usually for mania. And you can see here, every new episode leading to psychiatric admission increased the risk by 6%. Mania exerts a cognitive toll. And this is why people have three times higher rates of dementia compared to the general population. But here's the good news. Those people who remained on lithium for more than a few years had the risk of new onset dementia decreased by half, by 49%. So the old thing, the old saw is, well, to get an older, I'm going to take them off of lithium. It's the exact opposite. You want to preferentially know how to manage people on lithium as they get older, because you're going to preserve their brain. Think of this. What other drug do you give people, if it exists, that reduces somebody's dementia risk in the future by 50%? And we have mechanisms for that, which I'll allude to in a second. But here's a database study, which really shows you why we want to use lithium and not anticonvulsants in the older population. Medicaid database, huge number of people, 41,000 with bipolar disorder age 50 and above, who did not have a dementia diagnosis, an MCI diagnosis, were not on dementia meds or receiving dementia services in the prior year. And they excluded people with psychotic disorders simply because they may have higher rates of cognitive impairment anyhow. And they followed people kind of prospectively from the time point. And you can see mean age was 60, two-thirds white, predominantly female. Lots of follow-up here. 66,000 person years, mean exposure was 19 months. During that period, 1,500 were newly diagnosed. If you stayed on lithium for at least 10 months to a year, you've already reduced your dementia risk by 23%. So you see it as soon as a year of exposure. Again, it's the reason why we want to keep older individuals on lithium, because there was no benefit for any exposure to valproate, none whatsoever. Here's some mechanisms. I'm actually not going to get into this, but you'll have the slides. You can read this if you want to, but we think we have some biological mechanisms by which lithium might be neuroprotective. Okay, everyone's worried, I'm sure you are, about lithium and renal dysfunction. But I'm going to say one thing right here, and you can read the title. It's not always the lithium, it's the people themselves. I already alluded to the fact that bipolar disorder patients have three times higher rates of dementia. And why is that? Because a lot of it is a vascular component. High rates of diabetes, metabolic syndrome, hypertension, smoking. And all of those, surprisingly, are risk factors for chronic kidney disease. So yes, we used to prescribe lithium inappropriately in the past. We gave it multiple times per day, which you'll learn is not cool, causes more renal dysfunction. We ran people's trough levels too high as outpatients. Absolutely. So some of it was our fault. But some of it was the population who got lithium. It's what's called confounding bias, confounding by indication. Even if you do nothing to these people, they're going to get chronic kidney disease. Before we get into this, I think it's important. We're all medical providers here, I'm pretty sure. You have to know the vocabulary for talking to your colleagues about renal dysfunction and with your patients. We don't talk about lithium causing renal failure anymore because in the modern era, nobody should get renal failure due to lithium unless somebody is grossly mismanaging them. And you can see there's a definition for renal failure, which is a GFR less than 15. That should never happen. People will get renal dysfunction just because they're bipolar. And you have to know how to discuss this. You have to say, look, there's stages and the stages are based upon GFR. So if you ever want to email me about your lithium treated patient, I don't care what their creatinine is. What I want to know is their GFR. All decisions are made based upon GFR in the modern era. And I give you the stages on the left. Across the top are stages of albuminuria. Now lithium does not cause albuminuria. There's a problem up in the glomerulus. It's usually due to hypertension or diabetes. Shocking, I know. Why am I talking to you about this? Well, a lot of our patients have those comorbidities and I'm going to suggest there's probably need to monitor it proactively sometimes because people want to blame everything on lithium. PCP, oh, they have albuminuria. It's the lithium. And your job is to say, you know, before they were on lithium, for one thing, their diabetes wasn't well controlled. Not my fault. And they already had stage A2 albuminuria, which I checked before I started the lithium. So don't blame the lithium. I'm pretty sure it's their poorly managed diabetes. I'm just giving you the vocabulary because you're going to obtain an early morning urine albumin from time to time, especially when people have comorbidities to kind of see what's going on. But this is the best study, which really shows that it's the population and not the drug, which is the biggest risk factor for chronic kidney disease and end-stage renal disease. This comes from Denmark. And I'll say right now, this study was replicated very recently, published online in July in Sweden. So we think it's not unique to Denmark. They looked at rates of chronic kidney disease in the population, end-stage regional disease, and then specifically in the 10,000 people who had a bipolar disorder diagnosis. Okay. Very straightforward. They compared people who were on lithium or anticonvulsants. Well, just having bipolar disorder, you can already see three times higher rates of chronic kidney disease, depending on how they defined it, definite or possible, three times higher rates of end-stage chronic kidney disease. And I can tell you, most of these people were not on lithium, just having the bipolar diagnosis. So in this case, I don't want to say we blame the patient, but it's the population we're getting it. They have a risk for CKD and it's because of the medical comorbidities. But this is showing you that, hey, guess what? If you're on an anticonvulsant, it's almost the same risk as lithium. Surprise, surprise. It's the people. It's not necessarily the drug. Yes, in the past we use lithium inappropriately. It probably didn't help. And I'm sure we harm some people. But in the modern era, we now know how to dose lithium. A lot of the risk relates to who you're giving it to and not the lithium itself. Well, what's the independent effect of lithium? Now that we've understood this, folks have done analyses to try to parse out the medical comorbidity aspect from the lithium aspect. This is one of many studies where you had people on monotherapies of lithium, a couple of atypicals or valproate from Scotland. I give you the age range and the demographics there. Early 40s, about half were women. Median drug exposure for this analysis was, you can see, over three years for lithium, a little bit less for quetiapine, but very, very comparable overall for the various agents. People started with a nice baseline GFR. Lithium comparators were about the same. Once they adjusted, though, for age, the baseline GFR, medical comorbidities, and sadly, episodes where people got the lithium level a little high, they used 0.8 in this instance, and the use of various other drugs, mean annual GFR change for lithium was one milliliter per minute compared to 0.4, a difference that was not significant, and that attributable to lithium alone was only 0.24 mL per minute per year. Again, when you use lithium using modern principles, keep the trough levels modest, don't ever let them get above one specifically. Don't give lithium twice a day. You can manage the renal risk from lithium, and I'll show you some other ways to manage some of its side effects like polyuria, but lithium was not often the big issue. It's the people who get it, and the bad things we used to do way back in the day, giving lithium multiple times per day, and letting trough levels get above one as a 12-hour level. And this is what I'm alluding to. I trained with somebody who was from Scotland, and he already knew from European literature in the early 80s that maybe we shouldn't be giving lithium more than once per day. And admittedly, I suspect there's people who are attending who maybe have not heard this, but it's been known since the early 80s, and one of the first people who published this paper was Mullen Scow. He looked at two clinics, one who always gave lithium twice a day, one who gave it once a day at bedtime, and the once-a-day clinic had less polyuria. But the quality of that data was admittedly not really robust. This is the proof right here. Large retrospective study from a New England database. You can see they got 1,445 people who were on lithium with renal insufficiency defined as a GFR under 60 with the appropriate ICD code, and they matched them one to three with people who were on lithium, but who did not have renal insufficiency, and they were looking for demographic and other treatment-related factors which were associated with this. It's the perfect large case control study we never had. And there it is in black and white with a big red box around it. The odds ratio for having renal insufficiency was reduced on average by 20% for people who got once-daily dosing. And in this particular study, the median duration of exposure was under a year. So you can see with longer periods of time, that number is going to change drastically. But even within a year, just by giving people lithium once a day, you're already having a more favorable impact compared to multiple daily dosing. There was really never a reason to give lithium more than once a day. It was somewhat of a historical artifact because that's how they did it in the 50s and 60s, and when lithium was approved in 1970, that's what it said in the package insert. If you download the package inserts on lithium, it still says to give it two or three times a day because those package inserts have not changed in a half a century. But they are wrong. And this is the information you need to take back with you. You go through your patient pool on Monday and see, hmm, who's on lithium more than once a day because I need to change that. You really do. There's no value in giving it more than once a day. As I'll show you in the kinetic slides, the half-life in your brain is well over 28 hours. Don't do it anymore. If you have people on it, you now have the opportunity to change. Look, if you've never heard before, don't beat yourself up. A lot of people haven't, but this data set was published seven years ago, and really one of the reasons why I give lectures like this is because I want people to use lithium and I want them to know how to use it in the best manner possible. They also show that as you got to higher levels as outpatients, especially excursions, in this case above 1.2, there really was a renal hit. Other analyses have also showed that you really exert a greater renal toll when it goes above 1.0, and I think that is really the absolute maximum outpatient level for any human being. Take it all at night, you get a 12-hour level, it should never be above 1, and that's just really important because people are going to be on this drug for decades. Now I will say we do have a sense that the sweet spot for bipolar maintenance these days is 0.6 to 0.8. You can go up to 1. If you look at this level analysis in terms of risk of renal insufficiency, and they use as the comparator a level less than 0.6, that there was an effect of having higher levels. On the other hand, you have to treat their brain with a level that they need to keep them stable, but I think the rule of thumb is thou shalt never run anyone above 1.0 as an outpatient. Transientally on an inpatient, that's fine. You'll go up to 1.2, but if they need more than one mood stabilizer, you're going to have to add something else if the lithium is not sufficient. You always want to give the brain what it needs, but the starting spot for most people is 0.6 to 0.8, and that's what all the recommendations are in guidelines published in the last few years. It's important when you get levels, though, to try to get them around 12 hours. You can see within a couple of hours of that window, things are mostly linear, but every once in a while, I get calls from people, oh, I got this lithium level, and it's 0.3. What should I do? The first question I ask them is, well, what time was the level drawn? Like, oh, 3 in the afternoon. When did they take it? Oh, the night before. I don't know what to do with that. I really don't. So really try to educate people that take your lithium at night, get your levels about 12 hours later, and it'll really make life much easier for everybody. I just cannot interpret 18-hour and 24-hour levels. I just don't know what to do with it, because the curve becomes nonlinear. The other big issue with BID dosing, and you probably can appreciate this mathematically, if I take all my lithium at night, I get a 12-hour level. It's a 12-hour level on the entire dose, right? Well, if they're taking it twice a day, it's a level for 24 hours for half the dose, right? Because they took it the morning before, and that really distorts that level you're getting. So part of the issue for some people who are getting BID dosing is that actually they were being chronically overexposed to lithium, and the provider never knew that. So these three studies took people who were on identical doses, and they matched them from BID all to QHS, and they got 12-hour levels. They had one that was on TID, which we don't really see too much anymore. You can see, when people on the identical dose went from BID to once-nightly dosing, that 12-hour level went up on average 28%. And so often what happened was you had people say, well, but the level is fine. Her level is 0.81 on 600 BID. I'm like, hey, why don't you put it at all to 1,200 QHS and see what that level is? And then they realize, oh, I was giving her way too much. It's very important to educate people. You may inherit folks on your panels who have been on multiple daily dosing, and explain to them it's not necessary. It's a little bit harder on your kidneys, and you may actually be taking more than you need. Because sometimes people will be resistant and you wanting to reduce the dose, and you can say, look, if I match it all to QHS and a 12-hour level is 1 or above, we're going to have to shave down your dose a little bit. Not much. You know, you can go down by smaller increments than 300 of lithium carbonate. You know, you can go down by 150s. You can even use citrate. But you do really want to get it below 1, because it's going to be much easier on their kidneys. So this is the recommendations now for levels. I just went over this. You can download these. I don't have to read this word for word. Bipolar II people are a different kind of an animal. They often sometimes don't even need mood stabilization. Some of these people can even take traditional antidepressants. Not many, but some. But we tend to run them at a bit lower end. You know, usually maybe perhaps even 0.4 to 0.6 initially. You can always give them more. And when you use it for unipolar adjunct, the recommendation is 0.4 to 0.6. Again, always avoid BID dosing. If somebody is on BID and you have a level, you can just do the math. So somebody actually called me recently about a patient they inherited who had been discharged on BID dosing. It was actually TID, which is just silly. And I said, well, what's the level? And the level was like 0.8. I'm like, okay, well, we'll do the math right here. If it was 0.8, I know that level is going to be above 1. They're overexposed. So mash it all to QHS, repeat the level, and then you're going to end up lowering the dose. And we know that. But at least we could make a good guesstimate about what that 12-hour level would be on single QHS dosing and kind of anticipate the appropriate adjustments that needed to be made. And here's the kinetics of lithium. So lithium is available in a number of different formulations, usually dosed as milligrams of lithium carbonate. You can see there's increments of 150, 300, et cetera. There's also the citrate. And I give you the mathematical conversion because there'll be reasons you want the liquid because it just gives you much more dose flexibility. In case you didn't know, the active ingredient in lithium carbonate is lithium. See you learned something here. You're like, oh, I had no idea. I'm being facetious. But most people never had any idea of how much lithium was in 300 milligrams of lithium carbonate. It's 56 milligrams. The citrate is dosed in milliequivalents. How you get from milliequivalents of a salt to milligrams, assuming it's monovalent, meaning it's only one ion, like sodium or lithium, you multiply times the atomic weight, and the atomic weight of lithium is 7. So that's why 8 milliequivalents equals 56 milligrams of elemental lithium. Why do you want to know this? Well, you can buy lithium on the internet in the form of lithium orotate. And they sell it by the milligrams of lithium. Most of the tablets are 5 milligrams, which you can already see is like an 11th of a 300 milligram lithium carbonate. But they sell 10s, and there's even 20s. And there's cases of people becoming lithium toxic because folks pop these things like M&Ms. They're like, oh, man, I'm going to buy a day and take a bunch of this stuff. So you should kind of know what's out there and know that they're dosing it as milligrams of lithium and be able to make those mental conversions to lithium carbonate. Half-life peripherally is about 24 hours. Once you take it, the peripheral levels peak between 1 and 3 hours. Sustained release between 3 and 6 hours. But again, sustained release is always given at night, and we still get 12-hour levels because the 12-hour levels are almost exactly the same, whether it's standard lithium or some sustained release preparation. Food doesn't really alter the bioavailability. It does help with the kinetic zone when people are having problems such as nausea or cramping, which are not solved by being on a sustained release form, or even when they have diarrhea as well. But again, everything is given QHS. It's the way to go. And part of the issue also is that your CNS half-life is more than 28 hours. Why would you give it a drug more than once a day when the half-life in your brain might be as long as two days? You're like giving Zoloft twice a day. It just doesn't make sense. But again, it's a historical artifact. People were often taught that way. It's unfortunate. But now, you know, it's just not the way to go. On average, your brain level is about half of your peripheral level. But there may be an effect with age, which is seen in some imaging studies. And the point being, if somebody is complaining of a significant CNS side effect, maybe they're just getting more brain penetration than the average person for that level. And certainly if somebody says, you know, I was fine with lithium level 0.7 when I was 45, but now that I'm 60, you know, I don't feel as good. It may be that they're just getting a higher brain level. And maybe the consideration is, you know, maybe we should just dial back your lithium a little bit and see if you feel better. Because the hypothesis is you've gotten more brain penetration as you got older, and maybe less is better to keep you stable. Again, the only reason to use a sustained release form, which has a half-life in your brain of more than 28 hours, is if people have nausea. Nausea comes from rapid ion absorption in the jejunum and ileum. By smearing that out a little bit with sustained release, you do help treat that. Now, the opposite of that is diarrhea. That means they're delivering the lithium ion way too far south in the colon. And in those instances, if they're on a sustained release, you go back to standard lithium. If they're on standard lithium, usually the solution is give it with food, meaning at dinner. And it often solves the problem. Well, this is the biggie, and this is why you came here, to understand some of the renal issues. So this is a diagram of how lithium moves through the kidney. So proximally, it's an ion. It gets filtered just like sodium, and it gets reabsorbed with sodium, and it competes with sodium for reabsorption. So you can see on the left there, that little box, lithium will compete with sodium on the apical surface, okay, to go in through the sodium hydrogen exchanger 3, NHE3. So it competes with this. Since it competes with sodium, I think you can already understand, if sodium becomes sodium depleted, and the classic reason is, I had a lot of diarrhea, a lot of sweating, a lot of vomiting, and I didn't drink Pedialyte or take salt tablets. I just drank water, plain water. When they dilute themselves out, they become relatively hyponatremic, and then they preferentially reabsorb lithium. That's a big reason why people have trouble in those circumstances. What happens is, though, lithium competes with sodium for reabsorption, and then in the cell, lithium's not a good substrate for the sodium potassium pump, so it goes out through the other sodium hydrogen exchanger type 1. Seems to all work fine. You got enough of these cells where lithium doesn't build up. It gets out, and everything is hunky-dory. A lot of the drug-drug interactions have to do with proximal blood flow, non-steroidal assay inhibitors, ARBs, and we'll talk about that in a second. A little bit of lithium is absorbed in that thick ascending loop, and that's where drugs like furosemide work. The effect is not big for most people, unless you're older, and then there's an interaction which can make people lithium toxic. And then the big side of problems is absorption in the collecting duct, and we'll talk about that in detail in a section, but that's where lithium causes polyuria, that's where lithium gets into kidney tissues and causes all of its problems, but we have a way of preventing that, and I'll show you in a second. This is a diagram of what's called the principal cell, so I'll show you again. That distal collecting duct you can see on the right, there's cells that surround that duct which have to do with acid-base regulation and water and electrolytes. One of those groups of cells are called the principal cells, so you can see on the diagram the urine would be on the right, okay, so this cell is pointing to the right, and as lithium and sodium come down and water, water gets absorbed through those aquaporin channels, that's what it does. Sodium gets absorbed through this epithelial sodium channel, which we all call ENAC, so now that you know about ENAC, you're one of the few people in the world who will understand how lithium causes polyuria. The issue with ENAC is that not only it emits sodium, which is what it's designed to do, but sadly it emits lithium, and lithium has a much higher affinity for ENAC than does sodium, 1.6-fold. So the problem is, unlike proximally, where that sodium-hydrogen exchanger is kind of agnostic, lithium and sodium get emitted at kind of an equal rate, so it gives the cell enough time to get lithium out through that NHE1. In this case, lithium crowds inside the cell, and it overwhelms the capacity of the cell to get lithium out, because lithium is not a substrate for that sodium-potassium pump, and NHE1 is insufficient to handle that high intracellular lithium load. Well what happens? Lithium builds up in those cells, and it does all the things that lithium does, but in this case it causes problems, and these problems eventually cause vasopressin insensitivity, down-regulation of aquaporin channels, and eventually, if it's allowed to go on for years, the death of the cell. So the analogy I make is that lithium is your uninvited party guest. You didn't invite it to the party, but it crowds out all those nice sodiums who you invited. It gets inside, it builds up, it trashes your place, it drinks your beer, and you can't get it out the back door. Well, you're like, all right, I'm going to wise up. Next time, I'm going to hire myself a bouncer, and I'll tell you what that bouncer is in a second. Now I show this just for amusing purposes. I'm not even going to talk about this. Lithium does a lot of things on intracellular pathways which make it unique, contribute to its mood-stabilizing properties, to its neuroprotective properties. I didn't even talk about its anti-suicide properties just because of the sake of time. Lithium does many, many things. You can prescribe lithium and not understand any of this, but I just really want to make the point that its complexity is what gives it a different profile than an antimanic drug like an antipsychotic or even valproate. Here it is. You can read it at your leisure. Just accept it that lithium does some really wonderful things in the brain because of these multiplicity of actions. But this is what we're talking about, is that when lithium gets into these collecting duct principal cells through ENAC, you can see ENAC is drawn right up here. It is kind of small. Here's the urine stream. It causes all these problems because all those same pathways are impacted. You down-regulate aquaporin channels. One of the big things it does is inhibit this enzyme, GSK3-beta, and eventually you can see what it does. This is why people used to get fibrosis in the past because they didn't treat the problem. They just kind of let this process go unchecked and the patient complained. We have a way of preventing all of this, all of this, but the most important concept here is that if your patient complains of polyuria, pay attention. The downstream problem is the house burned down. You've got cell loss and tubular atrophy and fibrosis. Well, you don't want to wait until the house burns down to do something about it. Pay attention to the smoke. What's the smoke in this problem? What's the canary in the coal mine? It's the patient complaint that I'm peeing too much. You're going to ask people about that at every visit and there's ways to monitor that and there's ways to treat it. And by treating that, we maybe think you can prevent a lot of these downstream problems from ever occurring. Well, the question is, of course, is how do I, as a humble provider, monitor for polyuria? Well, when I trained, I was told, have the patient do a 24-hour urine. I don't know if any one of you have ever actually done a 24-hour urine collection. Maybe you could do it once, but you're certainly not going to do it repeatedly as we manage the problem. The way we manage GFR, I mean, intrinsic function is by measuring GFR. You all know about that. The way we can help monitor for polyuria is using two tools, one of which the patient can do if they'll do it, which is a 24-hour fluid intake record. All you do is ask the patient, hey, just record everything you drink for 24 hours, add it up. I try to have them do it in a couple of different days and average that. Some people will never do it and it's a problem. They'll just never do it and that's fine. But the better way and the more evidence-based way to do it in lieu of a 24-hour urine collection is the early morning urinose molality. Your urine is maximally concentrated in the morning. Before you drink water, your urinose molality is typically 850 millonosomes per kilogram or above. And if people are putting out dilute urine in the morning, they got a problem with concentration. So how do you do this for people? Well, the way you do this is one thing, you have to talk to them at every visit and ask them about this. If you want to nip this in the bud early, because patients don't like polyuria, and you can see on point number five, it was the third leading cause of somatic AEs, adverse effects that cause lithium discontinuation. People don't like it. But the way you help them manage it is that you have to have a supply of these cups in your office, like my clinician did who I visited for a different purpose. You give them the cup, you have them label it, they take it home, and your instruction is pee in the cup first thing in the morning. I'll put an order in the lab for an early morning or just a urinose molality, and you'll just drop it off at the lab whenever you have a chance. You have five days to do it at stable room temperature for five days. Very easy to do. There will be times when we have people with a lot of comorbidities, you'll also get an albumin to creatinine ratio, and it's also best done in an early morning specimen. So that's why it's good to know how to do an EMUO, get a supply of these cups in your office, give them to people, just save them a trip to the lab. Here's the cup, pee in it first thing in the morning, drop it off at the lab sometime in the next five days, and we'll see what your EMUO is. This is just a summary of just routine monitoring. There's nothing here to memorize. You can download the slides and read it. But early on, you get to monitor a little more frequently, then eventually you'll get to the six-month, and we'll just kind of track it from there. People with lower baseline renal function, of course, are always going to be monitored more often. We try to get the FIR if the patient will do it. We try to look at the EMUO. Some people will complain of polyuria very early on, and you want to track that more than anything. If people have comorbidities, the albumin-creatinine ratio, ACR, is helpful, mostly to document what the problem was even before they took lithium. And this is ongoing monitoring. It's very simple. Monitoring lithium is actually very easy. You talk to the patient, ask them about side effects. Are you especially peeing too much? And also skin and hair changes. The labs are lithium levels, TSH, and a serum calcium. You can get people to do the FIR. It's wonderful. If not, you'll hand them the cup, say, here, you know, go get, you know, pee in the morning and drop it off. You'll do an EMUO. Sometimes you'll need an ACR. Sometimes people have lower chronic kidney disease stages by GFR. You're just going to monitor more often, or if they have drops in the GFR, which are concerning. So how do you manage this? I've kind of illustrated the fact that this is a big problem, and it's very important to pay attention to it. This is the canary in the coal mine. This is the smoke. So how do you manage this? Well, we were fortunate that some group in Ireland got 79 people to not only do a 24-hour fluid intake, but also a 24-hour urine sample. And they did EMUOs as well. So if you look on the left, so by definition, Paul Urey is peeing more than three liters a day. That's the standard definition. Well, if you're peeing three liters a day, you're drinking probably at least three and a half. So you can see the problem with FIR, that you had some people with polyuria, seemingly you're drinking a liter and a half a day. It's impossible. So if people can't do the FIR, fine. You just ask them if they will, if they can't do it, they can't do it. But very few people who actually had polyuria were drinking more than three liters a day. So if you can get people to do it and you believe them, it can be somewhat helpful. But you can see some of these people were drinking, God, eight liters a day, seven liters a day. It's quite impressive. You can imagine they're spending all their time going to the bathroom. Some of these people will complain about incontinence because they're peeing so much. It's not that lithium makes you incontinent per se, but they're peeing so much, especially at night. Sometimes they just don't make it to the toilet. But the one test which was really helpful was EMUO. You can see everyone who had polyuria had EMUO less than 600. Now, polyuria, by definition, is you're putting out more than three liters. I can tell you, if every one of you all of a sudden started peeing 2.8 liters a day, you would not be happy. Now, you don't meet the clinical definition of polyuria, but you certainly have a problem and you would complain about it bitterly. But you can use the EMUO as sort of a proxy for the 24-hour urine collection because most people are just not gonna do it and they're not gonna do it on a repeated basis. And this just gives you tools to quantify the extent of the problem when people start to complain, you know, I'm kind of thirsty and peeing a lot. Well, how do you solve the problem? I already gave you the sense that lithium is the bad party gas. It crowds in through ENAC, and you should use that term among your colleagues. Lithium gets in through ENAC because it has a higher affinity for ENAC than does sodium, and you can't get it out the back door and it builds up and it trashes the place. Well, here's your bouncer, and your bouncer is amiloride. Amiloride is one of these old potassium-sparing diuretics. Its specific mechanism of action is as an ENAC inhibitor. That's all it does. We're so lucky it exists. You can use it in any human being, but it says it should not be combined with ACE inhibitors, ARBs, or other potassium-sparing diuretics. But if you have to, because you have an older patient, you can. So you don't have to be fearful of it, but you do have to monitor their potassium. That's the only thing you need to do. And you just let the PCP know, I'm putting them on amiloride because they have polyuria. This is a specific treatment for it. I will monitor their potassium so we know what is going on. Here's the standard dosing, you know, five a day for a week, and then you go up to five BID. The maximum is 10 twice a day, but you have to give it some time to work. So even if I block lithium from getting in, okay? So I'm blocking ENAC. Lithium's not getting in anymore. You have to allow time for lithium to eventually be cleared, which is very slow from NHE1. And then all those enzymes and processes have to be undone. This doesn't happen overnight. And it takes a number of weeks. So give people a good four to six weeks before you bother to recheck the EMUO or the FIR. Don't expect it to change overnight. But your eventual goal is, number one, the patient doesn't complain. I always like that when the patients don't complain. I would like to have the EMUO above 600 as well, because I know that's getting closer to normal. But number one is not having the patient complain, because if people complain, they're going to say, I don't want to take lithium anymore. And then what else do you have to offer them? In some instances, not a lot. What happens when the amyloride is not enough? And you'll run into this. And these are usually people who've been on lithium for years and no one ever treated the problem. They just got blown off. People ignored it. They didn't know how to manage it. So you put them up. What's happened is they've lost some of these principal cells. They've died. They've become fibrotic. And so what you do is you max out the amyloride, but we have another drug which we can add on top of it, which is cetazolamide. This is an old drug. It's a carbonic anhydrase inhibitor. If any of you took it, it's probably because you were climbing a mountain, which was really high, and you took it along just in case you got mountain sickness. What's interesting about this is it reduces urine volume by a different mechanism. It doesn't treat the issue the way amyloride does. Do not use it instead of amyloride. It does not block ENAC, but it will reduce urine volume, which is what the people will complain about. The interesting thing about amyloride is it actually lowers your lithium levels by about 31%. So if you put somebody on a cetazolamide in addition to the amyloride, just check their lithium levels, okay? But it really does work. There's extensive animal literature, human case series as well. It really is the tool which will help you manage this problem when max dose amyloride is not enough. Now, sadly, GFR will often go down. It's usually not your fault. It's the patient. Blame the patient. You're hypertensive, it's your fault. You're diabetic, it's your fault. But it's gonna happen. And at some point, when the GFR starts to get into stage 3a, you're gonna have to have the discussion that your lifetime on lithium may be shortened. And if it really gets to stage G3b, it's gonna be really tough to keep them on it because you've really lost a lot of your safety margin. So try to get them to manage their medical comorbidities as best you can, simply because that's often your enemy in keeping people on lithium because, of course, you'll be smart enough to know I'm only gonna give lithium once a day. The sweet spot is 0.6 to 0.8 as a 12-hour level. I'll never let them go above one. You know all those things, but if their A1c is always 12, it's gonna be a problem. Lastly, this looks terrible. Oh, I do all this stuff to start with him. You're doing all this stuff anyhow. You're gonna get a history. You're gonna get vitals and a BP. You're gonna have a chem panel. Probably they have all of this stuff at some point. The only extra thing is if they don't have a recent TSH, you get one, you don't need it on day one. You just wanna get it sooner than later. If you can't find a GFR, which is six months old, get one, all right? If they're pregnant, you're probably gonna have to get a pregnancy test or if they're reproductive age, rather, to get a pregnancy test. I suggest an ACR, albumin-creatinine ratio, only if you have people who have a lot of comorbidities, certainly if the GFR is no longer stage G1. EKG, not necessary, except in certain circumstances. They're older, they have cardiac risk factors, or they give you some of these histories which suggest they have what's called a channelopathy, Brugada syndrome. It's one of these weird things which have to do with these cardiac sodium channels and some of these people get sudden death. It's extremely rare to have this with lithium, but it's now in the package insert. Why would you suspect this? Person says, I have Brugada syndrome. All right, I've seen that once in my life. The person says, you know, I fainted a lot. That's serious, that's not normal. Or I have a lot of first degree relatives who have dropped dead at age below 45 and they all have cholesterol problems. I send them for an EKG. It's diagnosed by EKG. Most people are picked up who are asymptomatic and they have a characteristic EKG pattern which all the machines recognize. You can still use lithium in those circumstances, but it becomes a bit more complicated. You'll almost never see it, but you should have heard about it. And this is some optional stuff. It's not always necessary. Glucose and lipids, only because of the people who are getting it, has nothing to do with lithium as a fact that they're bipolar, schizoaffective bipolar. And a lot of this stuff has been ignored. The CBC is helpful because lithium raises neutrophil counts. It's kind of nice to know what the baseline is, because it's going to go up and at least you can advise the patient of that. And sometimes an EMUO. And this is just the ongoing monitoring. Very straightforward. You can read it as faster than I can say it. You'll download the slides. It's just periodic monitoring. You only get an EKG as an update if you have one at baseline. If you didn't have one at baseline, you don't have to get further ones. So there'll be some people who need an EKG. You'll get one initially after a few months and then periodically, usually once a year. Sometimes it depends on the local guidelines. How do you start lithium? So people often ask this. Gradual titration is what we often do for outpatients because you can manage the tolerability issues. The downside is it prolongs the time to therapeutic levels, but a lot of these people are not so ill that you have to get them therapeutic right away because they're not acutely manic. They might be on the edge of this. And that's why we do this. It's typically for outpatients where you want to make sure you can manage the adverse effects and you want to have good rapport with them. When do you get a level? Well, five half-lives to steady state is true for any oral drug. Lithium has a half-life peripherally of about 24 hours. So typically five days after a dose change, you can get a level or thereafter. You try not to stick people too often. So if somebody has super duper GFR, don't get them levels on these really low doses because you know it's going to be sub-therapeutic. So you just have to use your judgment there more than anything about just avoiding having to stick people too often, having to go to the lab too much. But these dose thresholds are just pure guesses about when to get labs. It really just depends on their GFR. Are they on medicines which kinetically interact with lithium? You know, things of that sort when you get the levels. But you know what the target levels are. Again, the sweet spot is 0.6 to 0.8 for most people. What about if you have sicker people, like people who are acutely manic? Well, there's a couple of methods. One's called the test dose method. I love this method. You give people 600 milligrams and you check their level 24 hours later. That output, that 24-hour level takes the sum of all the inputs, which is their age and their gender, which are baked into GFR. And if they're on kinetically interacting medications, it's all baked in. So Tom Cooper created this thing almost half a century ago. They initially based their dosing on TID dosing, which we never do, or BID dosing. We never do that. So I converted those to QHS dosing. Essentially, based upon that 24-hour level, you have to get the level at exactly 24 hours, which means they're going to be inpatients. We now know what their maintenance dose will be. And then of course, once you put them on that maintenance dose, which will always be QHS, you'll check their level again after five days. Very simple, very easy to do. The downside is, you know, for at least the first 24 hours, you know, it's going to take some time to get the level back. But often, some of these people are not the most easy to deal with, and they're going to refuse to take a lot of meds. Anyhow, if you get them to take one dose, you can get the level. Then maybe the atypical will help you until you can get them on the maintenance dose. Another method is loading. Most of you know that the loading dose for valproate or divalproate is 30 per kilo. Hey, guess what? It's the exact same for lithium. The difference is that we spread it out into three doses, because I give people large single doses, even though we're going to use a sustained release for loading the lithium, they're going to get some GI side effects. So if you split it up, you can get people on lithium, and you load them, and it gets them that much faster to steady state. If somebody's acutely manic, that's what we want to do. We don't want to send people out on atypical monotherapy. We really want them to be mood-stabilized, and most importantly, we want that lithium level to be therapeutic as soon as possible. Here's the study that did it. It's from a place where I trained up in Los Angeles. They had a sample size of 38. They based things on kratnin clearance, which is an old formula nobody uses anymore, but you can see no dropouts. No one had GI side effects by splitting it up. So you roughly split it up into three equal doses. The loading doses should be a sustained release preparation just to minimize GI side effects. You'll get their level the next morning, and then you'll put them on just whatever maintenance dose you think is going to be appropriate, and you can use standard lithium at that point because you're not giving people these large doses, but it shows you it can be done. It's very easy to do, and you don't have to do gradual titration on the inpatient unit. You have a couple of different ways to get people started on lithium to get them therapeutic faster, not prolong their time to effective treatment. Lastly, managing lithium-related adverse effects. Well, a big one is drug-drug interactions. As I said, most of these issues happen proximally with effects on renal blood flow. So you can see, you can use ACE inhibitors and ARBs with lithium. You're just going to reduce your dose by about a third because they increase lithium levels 36%. There's only one drug in that class of those two that you cannot use, which is lisinopril. Any other ACE inhibitor is fine. I don't care. It cannot be lisinopril. Lisinopril causes lithium toxicity in a way that the other agents don't because lisinopril is 100% renally cleared. So it'll tend to accumulate in people who might have subnormal renal function. You have somebody on lisinopril, just switch them to another ACE inhibitor. And again, your initial dosing will be reduced by a third. If the ACE inhibitors added onto lithium, somebody is now old enough that they need an antihypertensive or an ARB, they'll just reduce the lithium dose by a third and then just check it in a week. I gave you some guidance on nonsteroidals based upon how long they're gonna use them, what their baseline GFR is, and their baseline lithium level. Most of the time, it's not a big deal, but I give you some parameters if it really is somebody with subnormal renal function, a higher level, how to safely manage this. Carbonic and hydrous inhibitors are not commonly used. You guys might be the only one that actually uses this to manage polyuria where amiloride is not sufficient. It's gonna lower your lithium levels. The only other class of medicine which lowers lithium levels significantly are the SGLT2 inhibitors, and that's that box at the very bottom. Case report of it reducing levels as much as 63%. So you have people who are on those drugs for their diabetes, you should know that. If you're having trouble getting a lithium level and you're adding it to it, you know why. If the SGL2 drug is added to lithium, it's gonna drop your levels by two thirds and you're gonna have to make some adjustments. You can use thiazides with lithium. Again, you just have to lower the doses. Amiloride doesn't have as much of an effect as hydrochlorothiazide. You're gonna be checking things if they're on amiloride anyhow, but if you have somebody on a thiazide, you can use lithium, you just have to lower the dose of lithium a bit and just check levels a little more frequently. And lastly, the loop diuretics like furosemide, the classic one, most of the time the effect is not significant unless you're giving it to older patients. If you have somebody on furosemide and you add lithium or conversely, the wrong lithium, you add furosemide and you don't make some adjustments or monitor carefully, they will become toxic. And so we used to think furosemide wasn't a big deal. It's not for younger patients, but it is for older patients. And then lastly, some of the non-renal adverse effects. This is not exhaustive. That's why I wrote the book to cover that, but some of the more common things. Tremor, just like a central tremor, we can manage it with one of two ways. Possibly by lowering the level, possibly, but if you feel like that's not feasible, propranolol is the drug of choice. You just have to give enough of it. It's usually a BID drug until you get to 60. And then there's an extended release form for 60 milligrams and above. EKG changes are almost always benign. Do not get freaked out by these. These are not reason to discontinue lithium. The only one where it causes a problem, you have people with sinus node dysfunction. If they have bradycardia at therapeutic levels, they probably have a sinus node problem. That might be an instance where you're just going to have to interrupt their lithium until they get their pacemaker put in, which they're going to need anyhow, okay? Skin and hair are things you have to ask about at every visit. I can't regrow hair quickly. I can't treat acne quickly. If you ask at every visit, it gives you some time to treat it before the patient's fed up and says, I don't want to take this anymore. If they have hair loss, it's minoxidil. And the same strength for all human beings, male, female, whatever, 5%. The higher strengths can cause some scalp irritation. Just let them know. But you go to the pharmacy, go to, well, Rite Aid's now bankrupt, but go to the CVS and look around. There's a women's version, there's a men's version. You look at the ingredient, it's the same stuff, okay? Just different color cans. Just let them know. I can't regrow hair quickly. That's why I ask you at every visit because if you start to lose it, I want to get on top of it right away. And same with treating acne. Hypothyroidism, never a reason to stop lithium ever. I can treat hypothyroidism very easily. And hyperparathyroidism, we used to always have to treat with surgery, but we now have oral meds, which can adjust for that and maybe obviate the need of surgery. So again, the summary is, lithium is the gold standard for treating people with a history of mania, whether it's bipolar I or schizoaffective disorder, bipolar type. Antipsychotic monotherapy is insufficient. And that's your kind of marching orders to talk to people who are just on atypical monotherapy, especially if they've been doing poorly. Like this is not going to work out well for you. How can I talk you into getting on lithium? Because I know now how to use it. I know how to minimize some of those renal issues by giving it once a day, using modest levels. And guess what? I didn't talk about the anti-suicide properties because of the sake of time. It definitely has that. We can do that in the Q&A. I showed you the neuroprotective data, especially when you have older people. It's like, I can reduce your risk of dementia by 49%. How does that sound? We now know that we cannot use valproate at all in women of childbearing potential and what the numbers are for lithium. Those numbers needed to harm 83. I like those numbers a lot. If somebody really cannot do without lithium for the first trimester, even a number needed to harm a 39 in high dose lithium. And we think, and I'm going to use the word lithium, is safe during breastfeeding. You know how to use the levels now. And I've given you the tools, not only to understand how polyurea develops, lithium gets in through ENAC. And you're all going to know the word ENAC from now on what it means. Lithium gets in through ENAC 1.6 times more frequently than sodium. The way we monitor that is number one, ask the patient, are you peeing more? Number two, if they can do it, a 24 hour fluid intake record. If they can't, everyone gets an EMUO and you're going to give them the cup and give them the instructions. Pee in it first thing in the morning before you drink. And then I'll put the order in at the lab. You'll drop it off at the lab sometime within five days and we'll look at the EMUO. Monitor with GFR as I showed you. And most importantly, adjust the doses when there are kinetic interactions. It's not rocket science. You just have to make the appropriate adjustments. And most importantly, treat the polyurea. Take it seriously. If they complain about it, it's going to be a problem either for their kidneys or for their mental health, because they're going to say, I don't want to take lithium. I've now given you the secret, the keys to the kingdom, which is lithium gets in through ENAC, causes all its problems. I can stop that by giving amilorite, which is an ENAC antagonist. If that's not sufficient at maximum doses, then we also have acetamethylamide. So I want to thank you all for joining us right here. So we're going to go to the Q&A. So I'm going to pass it back to our moderator, Dr. Cotes, and I'll stop showing you some slides. Before that though, I think I'll just do this right here, that there is a mobile app. We really encourage you all to download it. You can see, you can download it at smiadvisor.org slash app. I'm going to leave this up here for a second. It has a number of tools there, not only to access content, but also to get answers to questions, including consultations, which are answered by smart people, such as our moderator, Dr. Cotes. There's also rating scales, which you can download, which are in the public domain. So again, go to smiadvisor.org, which you probably have heard about since you're here, slash app. At that point, I'm going to stop talking. So I'm going to pass it back to Dr. Cotes, and we'll see if you have some questions. So thank you all so much. There he is. Terrific. Thank you so much, Dr. Meyer. That was really, really wonderful. I'm already looking forward to re-watching that webinar and continuing to learn. I learned a lot from that. Really, really terrific. Couple questions. Yeah. One of the first questions that comes up is we know that bipolar disorder just sort of overall can be frequently misdiagnosed. I'm wondering if you have any clinical pearls on helping clinicians identify people who have maybe had a history of past manic episodes. Yeah, so there is a couple of tools which you can use. One of them is called the Rapid Mood Screener. So the Rapid Mood Screener was developed by Roger McIntyre, and the paper it was published in was three years ago. It was not behind a paywall. So if you just remember Rapid Mood Screener, it's only three words, Rapid Mood Screener. So that instrument was designed to help differentiate people who are bipolar I, specifically coming in for depression versus unipolar depressed. But the beauty is those last three screening questions, it's only six items, are questions with regards to mania. So those are great historical questions you can ask. And I think it's a really nice screening instrument. There was an older instrument called the MDQ, the Mood Disorder Questionnaire created by Bob Hirschfeld, who sadly passed away this past year. So the MDQ was created 20 years ago. It was 13 items, some of which were worded a little vaguely. And so Roger McIntyre and colleagues came up with the Rapid Mood Screener. It really is an improvement and a much easier to use instrument than the MDQ. So download it. The last three questions focus specifically on mania. The first three questions, though, I think are very useful because they're bipolar II people who also need to be mood stabilized. And this helps figure out who some of these people are. So they ask about, did you have onset of depression before the age of 18? Have you had six depressive episodes? It's worded a little differently. But the third question I love, and it's good for bipolar one or two. Have you ever had to stop or change your antidepressant because it made you highly irritable or hyper? So download that instrument. I think it gives you great screening questions. As we know, there are some bipolar two patients who can get away with that mood stabilization, but many of them need it. And we still think lithium is the preferred mood stabilizer for a number of reasons. You know, if you say, well, they're all fine on lamotrigine, I wouldn't disagree with that, but they are bipolar and they still can get the neuroprotective effects from lithium if they stay on it. So just something to think about. That's great. And something to think about for the app as well, the rapid mood screener. Absolutely, yes. I was, a couple of nice questions from the audience. One question is lithium immediate release leads to a higher C-max. Does that matter? And then the second part of that question is, if we block ENAC, more lithium stays in the urine, wouldn't that lead to more clearance? Yeah, so the first thing is, yes, standard release lithium has a bit higher C-max, but most people only would notice that if they took lithium during the day. There's a few people who get some CNS things at C-max, but those people who have nausea, meaning the upper GI lithium problem, that's why you would go to a sustained release because it's gonna lower that C-max and delay the T-max a little bit. So it kind of smears out that proximal absorption and that often helps with nausea. So when somebody complains of nausea, and I feel like I can't change the lithium dose, at least at that time, my first move is to go from standard lithium to sustained release all at night. If they still complain, then I have them take it with dinner and I do that also for people with diarrhea as well. And the second question is, will they waste more lithium on amyloride? It doesn't seem to be clinically significant, but guess what? You're gonna be monitoring their levels anyhow. And once you put them on amyloride, at some point you're gonna have a need to recheck their levels. But the clinical data don't seem to support that has a big impact on lithium, partly because your lithium concentrations in the urine are relatively modest. The big issue is lithium just gets into ENAC so readily that it overwhelms the capacity of those principal cells to kick it out the back door via the NHE1. Okay, sounds good. Next question, and I think that we're probably gonna get a couple of questions like this, is about lithium in older adults. Can you just, and I know that you spoke about it at various times during the talk. Can you talk a little bit about some considerations for lithium in older adults? Absolutely. As people get older, you know, their GFR may decrease. Can you just maybe summarize some of the main issues? So I think I very heavily made the point that the big advantage is neuroprotection you can reduce the rates of future dementia by 50%. So given that there's a huge, huge benefit, what's the risk? Everything, every decision is always made based upon GFR. There are people as they get older who have a lot of medical comorbidities and that's really gonna exert its toll on their GFR. It's not the lithium. And I think the biggest issue, the biggest risk for lithium toxicity, and there was this large study done out of the Kaiser in Colorado, where they looked at people who got admitted for lithium toxicity. The biggest factor, the odds ratio was like 30, was the addition of an interacting med. So your job is as people get older, of course, if they're already on the ACE inhibitor, makes just sure it's not less inappropriate, you've already made the appropriate adjustments. But your job as people get older, you say, if someone gives you a new medication, especially for your blood pressure or anything, you call me immediately. I mean, it's nice if the PCP would actually give you the time of day, but sometimes it's not the case. But the idea, the patient will call you up, oh, they put me on something for my stomach acid. You'll thank them, it's fine. Actually, there's an issue with that, which we'll get into in a second. But most importantly, they'll say, oh, I was just put on a thiazide or an ARB or an ACE inhibitor. You say, fine, thank you so much. I'm gonna lower your lithium dose by the appropriate amount, usually a third, and then I'll check your lithium level in about a week. And if they change your dose of the ACE inhibitor or ARB, just kind of let me know and we'll keep an eye on it. And that's really the most important thing is that this is what causes lithium toxicity. The other thing is as a GFR starts to get into stage 3a, G3a, which is 45 to 59 mLs per minute, you start having the discussions. But some people can hang out there for years. There's this wonderful case series out of Sweden, large sample size, where they had a bunch of older individuals who had mean GFR of 55, okay? And over the next eight years, they had no changes in their GFR along lithium. Why is that? They didn't have a lot of comorbidity. So don't get freaked out just because the GFR is below 60. It's often the context of what's going on. But look, you have to admit there's some people where the GFR is gonna drop, they have poorly controlled diabetes, they got other stuff going on, and there'll be a point where you're like, yeah, I just don't feel comfortable. And that's usually when you get into stage 3b, that 30 to 44 mL per minute range. You're like, I just don't feel comfortable here. And I understand it. You have to do what you can by prescribing lithium once a day, keeping levels modest to at least not make lithium the big contributor to that problem. One thing I wanted to say though, there are other drugs which cause nephrotoxicity, nonsteroidals you all know about, but here's one you've never heard of. And all of you write this down. The PPIs, the proton pump inhibitors like omeprazole, now have warnings on them about renal dysfunction. AstraZeneca just settled a multi-hundred million dollar lawsuit for omeprazole and estromeprazole for renal dysfunction. That whole class of medications is associated with long-term renal dysfunction. And in the Lithium Handbook, I talk about some of these medicines. So people are like, oh, that terrible lithium. It's the PPI. You know, I'm giving you lithium with a level of 0.65. It's the PPI which is causing the problem. And that's another point of education when you have people who come in, maybe you can talk to the primary care provider and say, hey, did you know it was a big lawsuit that just got settled for omeprazole, for renal dysfunction? Can we try something else? Because this is gonna be a problem for the patient, just independent of lithium use, but even more so because they're on lithium. Yeah, very interesting. And kind of while we're on the topic of drug-drug interactions, can you just say anything? I know you talked about it a little bit already, but about the SGL-2s and the sort of benefits risks with lithium. I mean, SGL-2s are very useful medications. I mean, they have indications for diabetes. I think they all have also indications for heart failure and mortality. So these are very useful medications, but they lower by their mechanism of action lithium levels. And the one cases I found, 63%. So what it's gonna mean is if they're on that medicine, you're gonna have to give them a lot more lithium because they're just gonna pee it out. They're just gonna clear it very, very rapidly because of the mechanism of action. So the most important thing is, anticipate it so the patient calls you up and say, I'm being put on one of these medicines. If that's what the PCP or the endocrinologist thinks is necessary for that patient, that's fine. You say, all right, let me explain to you what's gonna happen. Your lithium level is gonna drop by probably at least half, if not more. I'm gonna have to give you more lithium just to keep your level up. That usually is not a problem, but every once in a while, again, you have to give them enough of a single dose that it starts to bother their stomach. And then that's where you get into, well, maybe we'll switch you to a sustained release or we'll have you take it with dinner to help mitigate that. Sometimes people say, well, would you ever split up with the, if I have to, but it's always the most minimal dose. Meaning, if I need to give you 1,500 because you're just peeing it out and that's the dose you need to keep your level or you're just young and you have great GFR, you just, no matter what I do, with food, sustained release, you just can't tolerate 1,500. I'll say five. You take 1,200 at night and 300 at the morning because I really wanna minimize that distortion of the level, that 12-hour level by having half the dose and also minimize whatever renal hit you get from multiple daily dosing as best I can. All right. I wanted to ask you a little bit about lithium and its anti-suicide effects. Comment on that specifically in bipolar disorder and maybe any other conditions too outside of bipolar disorder. So the hard part is even though people with bipolar disorder have many fold increased risk for completed suicide, it's hard to do a study and look at differential rates of completed suicide because they're still relatively small. You know, you need literally thousands of people that you follow for long periods of time. No one can afford to do a study like that. We have retrospective data, which Ross Baldessaruni published now over 18 years ago, which seemed to indicate that kind of independent of your mood disorder diagnosis, that when lithium is used at therapeutic levels, it seemed to reduce the risk for completed suicide, not suicidal ideation, not parasuicidal acts, but completed suicide and serious attempts by five-fold. But that's all retrospective. And there's other analyses which show it also does it differentially compared to Valproate, including some within-person analyses that show that when people were on lithium, the risk of serious attempts and completed suicides was reduced in a way that it was not at all when they were on Valproate. So, but it's hard to prove this based upon the gold standard, double-blind placebo-controlled prospective trial. And the VA published a big one last year, and there was a lot of controversy where they didn't show an effect. Well, part of the issue is the anti-suicide effect is probably not instantaneous, okay? It's not like the anti-manic effect. You may need to be on it for a period of time, but it's also kind of like the neuroprotective properties, that as you look at the retrospective literature, that you may not just start to see really the big effect until you've been on it for more than a year, and maybe even a bit longer. The problem with the VA study is a lot of people weren't bipolar. Their median length of exposure was in months, not even a year. A lot of drinking, a lot of PTSD. They didn't show an effect, but it's just hard to know what to do with that. But I think the take-home message is we think there is an effect. You know, there's a lot of sources of data. If you have to weigh it on a scale, we'd say the weight of the evidence is that there's an anti-suicide effect. Could I ever show that in a double-blind placebo-controlled study? I don't think I can, and I think that's an honest statement. But I think we see it from enough sources of data we'd say we think there's something real there, but the effect is not instantaneous. So just assume, oh, I put you on lithium, and you'll be fine. What we do notice, though, is conversely, we take people off of lithium, the risk of suicide does go up quite significantly, quite quickly. If you ever need to stop lithium, for whatever reason, do not stop it all at once. Taper people off over a period of 15 to 30 days. Ross Ball-Disseriti also did those studies. Maybe it allows some intracellular adaptations, but if you can taper off over a month, people have a much more stable course, especially if they get another good stabilizer, than if you stop it instantaneously. And sort of as a follow-up to what you just said, is there any truth to this idea that if lithium is stopped, and then somebody comes back to it years later, is it less effective at that point? No, I cover that extensively in the book. There were some analyses that kind of suggested that, but then again, people did more rigorous studies. Lithium does not seem to lose efficacy when it's resumed. But again, you have somebody who's grossly unstable, are they gonna immediately become stable because they go back on lithium? And that's part of the issue, is you probably will be able to get them stable again, but it may not be easy. But what we've shown, and there's a lot of different ways you can look at this, is that if lithium was worked, other things may be insufficient, which is why they end up coming back to lithium. But it may take some time to get them stable again. Stability is not easily recaptured sometimes. And most of you know that if you deal with any form of severe mental illness. The psychosis was great on four of risperidone, and they stopped, and I'm having trouble getting them back on. Eventually they may get there on four of risperidone, but it may take them some time. And the same thing here, is that just may take some time for them to get back to where they were, but we don't think there's a loss of efficacy. Okay, thank you. I wanted to ask you a little bit about, again, this question between monotherapy and polypharmacy, when you're sort of meeting someone for the first time, say on an inpatient unit, somebody comes in, they're in the midst of a manic episode. How do you kind of think about whether to start an antipsychotic and a mood stabilizer, or antipsychotic monotherapy? Well, I always want to get them on the mood stabilizer. But as you all know, sometimes people who are manic are not the most reasonable individuals occasionally. So I don't have an injectable form of lithium. And often you're just forced into monotherapy initially. And sometimes you'd never have the legal authority, meaning an involuntary med order, to even try to compel them, however you best might do that, to take a mood stabilizer with lithium or divalpro-X at that point, assuming they're a candidate for VPA. And so you're just stuck with atypical monotherapy, but I really don't want to send people out on that, because I just know that this is not going to be the best outcome. And it doesn't matter if they're bipolar one or they're schizoaffective bipolar type, they need both agents early on. Eventually, if they're bipolar one, they might be able to stop the atypical for the upside protection, but they're almost always going to need a second drug for bipolar depression. Lithium has great anti-suicide properties. It's not a great acute antidepressant. So if you came to me and say, okay, I have this guy on Depakote and he's depressed, should I add lithium? I'd say not for that purpose. I would add one of those atypicals, which are indicated for bipolar depression. We have several of them now without big time metabolic issues like lumatepirone and criprazine and lorazodone. That's what I would do. So most people with bipolar one are going to need two drugs. Sometimes for the upside, at least usually one for the downside as well, because bipolar depression is not well-treated by lithium. Although it'll keep them alive, they may be depressed. And if they're schizoaffective bipolar type, they have to be on both drugs. They have to be on a mood stabilizer and atypical. So you just got to do the best you can. Look, there'll be times where you're like, I just can't force this person to take a mood stabilizer. They agreed to take the atypical. I don't have the legal authority. They're going to go on atypical monotherapy. All you can do is just document. Yeah, I'd put them on an LAI, to be honest. You know, an LAI, which is maybe indicated for bipolar one, like aripiprazole. And just say, look, you're probably going to need to take a mood stabilizer. And of course, as always, patients will do what they want to do. Right. A question on the so-called kindling hypothesis. Does the number of prior manic episodes predict poor response to lithium or other mood stabilizers? Not necessarily, no. Not necessarily. There are other independent factors. So people used to get, again, because of the perceived concerns about lithium safety, and in many instances, the lack of options. Before Dive Out Prolix was even around, there were no other options to lithium. So people often look for these ideal lithium, you know, responders and predictors. And they're not always going to be able to predict In the end, we kind of do this, but it's not as much of an importance, simply because a lot of those predictors are predictors of just poor response in general. And so the classic one, which I used to hear is, oh, I heard that if you're rapid cycling, you're a poor responder to lithium. You're a poor responder to everything. And Joe Calabrese did these studies, which show that these people do poorly on monotherapy of lithium or Dive Out Prolix. They're going to do poorly. And it's usually because, in addition to their substance use issues, they often get a lot of depressive breakthrough. That's the hallmark of rapid cycling, is that even if you're on a mood stabilizer, lithium or Dive Out Prolix, you're going to get frequent, short depressive episodes. And so they're going to need extra drugs to manage that. But lithium is no worse than Dive Out Prolix because they're both inadequate by themselves. So in the modern era, I think we would say lithium is the best drug. I can't give out probably to half the population anyhow. And I don't look at their prior history necessarily as a reason to avoid lithium. There's other considerations. It usually comes down to where the patient will go along with any blood levels of anything, and maybe baseline GFR and other considerations like that, medical ones. Next question. And I feel like we've had this conversation many times, you and I, about other things, but can you talk a little bit about sort of weight gain, other cardiometabolic side effects from lithium, and maybe about how to mitigate that? Yeah, so the nice thing, unlike many atypicals, lithium does not have cardiometabolic side effects. And I actually talk about a couple of studies. Admittedly, they're done in rats, which show that maybe lithium is a little bit cardioprotective. Don't get too excited about this, by the way. These are animal studies, but it does not have the lipid and glucose problems that you get with atypicals, period. Absolutely. The amount of weight gain, independently on lithium is quite modest. And you know how we know this is because lithium has been given to children and adolescents. It's indicated in the US down to the age of seven. Although some package inserts say 12, but the correct ones say seven. And those kids tend to be very sensitive to weight gain. If anyone treats children or adolescents or young adults with atypicals, you know they get weight gain on almost everything. And it's a big problem. Lithium is not associated with significant weight gain. I mean, there's measurable ones, but it's not the big problem. It's usually the other agents. And so in this day and age, I would say, I don't get too excited about that. I try to minimize the contribution of the other drug. So if they're bipolar one depressed, I would preferentially use lorazodone, for example, because it's generic now for their bipolar depression, as opposed to an old drug for bipolar depression, quetiapine, which causes a lot of weight gain, a lot of cardiometabolic effects. So you control what you can control. And, you know, people these days, if they start to gain weight, you know what we're going to give them and once you get to those magic numbers, they're all going to get Wegovy. Or maybe soon enough, they'll get Monjaro. And then that'll be the medicines which we'll use to manage their weight problems. All right. We have time for maybe one more question. I want to just follow up on something you mentioned earlier about substance use disorders. We all know that people with bipolar disorder are more frequently, are just more likely to use substances than those who don't have it. Anything you want to say about considerations with other substances that people may be using and might that affect lithium? Yeah, usually there's not much of a either kinetic or dynamic interaction with substances of abuse. The biggest issue with people who are substance users is that they're non-adherent. But I do want to say this before we close. In that study, which I alluded to, where people were their own controls, they looked at periods on lithium and periods on divalproate. And they looked at suicidality. The reduction of lithium in that study was roughly around 14% with no reduction in suicidal behavior and valproate. Most of those events occurred in people who were also duly diagnosed with substance use disorders. And the reduction in suicidality was the same in that population as it was in the non-substance users. And so if you can get people to stick with it, you might keep them alive. But there's always going to be an issue with them staying on it. So let me share my screen again, because I know you want to show them some more resources. So let me just get back to this real quickly here and so you can wrap up. All right, thanks so much, Dr. Meyer again. At SMI Advisor, we're really working on increasing our number of resources about lithium, which we feel like is a really key medication in the treatment of people with SMI. Oh, I know we weren't able to get to all the questions here today, but we have a mechanism for where you can ask more questions. And the way that you do that, access the course through SMI Advisor account, select the discussion tab, and then you can post questions or share ideas. You can also submit a consult through our consultation service at smiadvisor.org slash submit dash consult. All right. And we have more coming up on lithium. We have a virtual forum that Dr. Meyer is going to be hosting on demystifying lithium's renal effects. And this is, you know, stuff that sometimes it helps to hear again, to really kind of grasp it. So we're going to be talking more about lithium on November 1st from four to five Eastern. All right, next slide. So to claim credit for today, you need to just have met the requisite attendance threshold for your profession. After the webinar ends, please click continue to complete the program evaluation. The system then verifies your attendance for the credit claim. This might take up to an hour and can vary based on local, regional and national web traffic and the use of the Zoom platform. All right, so our next webinar is on October 27th as Dr. Saha will present addressing social needs and social determinants of health for people experiencing SMI. Again, this free webinar will be October 27th from 1230 to 1.30 PM Eastern on Friday. So thanks so much again for joining us and thanks to our presenter, Dr. Meyer. And we'll see you next time.

Dr. Jonathan Meyer

webinar

lithium

mood stabilizer

bipolar disorder

valproate

women of reproductive potential

neuroprotective properties

dementia

dosing

monitoring

renal dysfunction

polyuria