Psychiatry & Psychotherapy Podcast - Lithium Indications, Mechanism, Monitoring, & Side Effects

Episode Date: September 5, 2019

Lithium is indicated for a number of things. Most clearly, as a mood stabilizer in bipolar spectrum disorders. It is unique among mood stabilizers in that it is very robustly anti-manic. The medication treats and prevents manic episodes from occurring, providing fairly robust prophylaxis against mood cycling. Lithium is also effective in treating bipolar depression, though not as effectively. Very few of the other mood stabilizers are effective for the depressed pole of bipolar illness. By listening to this episode, you can earn 1 Psychiatry CME Credits. Link to blog. Link to YouTube video.   Link to full article with details on up to date research and more: here Engage in the dialogue on Dr. Puder's Instagram, Facebook, Twitter    

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Hello, welcome back to the podcast. I am here today with Dr. Cummings, and today we are going to be talking about. lithium, what we consider our best mood stabilizer. Now, there is no drug companies coming to your door, banging on your doors telling you to prescribe lithium or take lithium because it is essentially a metal. You hear about it in lithium ion batteries, but in low doses, it can be very, very good for bipolar, bipolar depression, suicidality, anger, which is more of a impulsive anger. And in this episode, we are going to be going through the uses of it, the mechanisms. We're going to be talking about a lot of the nuance on levels and how to dose it.

We're going to be talking about how to use it in pregnancy, how after the first five weeks it is no longer a risk for Epstein anomaly. We're going to be talking about how to use it when there are kidney issues or issues with tremor or hypothyroidism. And finally, you know, I think we in the U.S. need to look at this more. You know, in Europe, there is 50% of people on bipolar who have bipolar who use it in the U.S. it's only 10%. So I think we need to look at it and become less fearful of it. And so we're hoping to do that in this episode. So Dr. Cummys, welcome to the show.

Thank you. I'm pleased to be back. And indeed, pleased to talk about lithium, despite its lack of use in the U.S., which is thought to be related to principally to people's fear of its narrow therapeutic index. Its toxicity is fairly close to the range in terms of plasma concentration at which the drug is therapeutic. Most of the drugs in psychiatry and in medicine in general have a therapeutic index of greater than 10, meaning the toxic level is an order of magnitude greater than the therapeutic level for most drugs. With lithium, the therapy. The therapeutic index is more on the order of two. So the range from therapeutic to toxic is small.

And I think for many clinicians, especially those not familiar with lithium and its use, that serves as a barrier to its prescription. Even though in 2014 there were some 2 million prescriptions for lithium in the U.S. that's far lower than the number of prescriptions in Europe. Yeah, so let's start with indications for lithium. Who would benefit? And, you know, this is building off of last week's podcast, which was kind of the history of lithium.

And so we're going to kind of jump into the modern use of it and what we know that it's good for. Mm-hmm. Now, lithium is indicated for a number of things. Most clearly, as a mood stabilizer in bipolar spectrum disorders. It's unique among the mood stabilizers in that it is very robustly anti-manic and is at least moderately antidepressant and also provides a fairly robust prophylaxis against mood cycling.

Most of the other mood stabilizers, are either anti-manic and only a very few things are effective for the depressed pole of bipolar illness. Lithium is also the best-tested drug for augmentation treatment of major depression that does not respond adequately to antidepressants alone. It also exerts an anti-suicide effect, which appears to be independent of its mood effects. It makes people less likely to commit suicide. And people with mood disorders,

it reduces the risk by almost fivefold. It also decreases violent behavior. And that's true in both mentally ill individuals and in the general population. There have been studies based on comparing areas that have water as a constituent of the natural water supply versus those that don't. invariably those with a little bit of lithium in the water have lower rates of suicide,

lower rates of homicide, and lower rates of violence in general than those areas with no lithium in the water supply. That's actually led the European Medication Council to propose perhaps adding very low doses of lithium as a nutritional additive to foods because the effect in non-mental ill people only requires a dose of about three milligrams a day. Lithium also has some unique uses. It is often used as a weak stimulant of colony stimulating factor in people who are taking chlopine and who hover just above the threshold where their monitoring has to be increased

to give them a little bit of a boost in their neutrophil count. And that's important because normally if someone is on lithium and you see that a little bit higher than normal neutrophils, it's not really an issue. No, it isn't. Lithium typically causes a mild leukocytosis. And many people, it doesn't extend beyond the upper end of the normal range. But compared to their baseline, their neutrophil count will be higher. And that's based on lithium causing an increased release. of endogenous colony stimulating factor. Yeah.

So lithium is used as a mood stabilizer, and does it both, it both treats manic episodes and prevents manic episodes from occurring. And also is effective, not as robustly, but is also effective in treating bipolar depression,

which is important because the number of things we have to treat bipolar depression are a meager lot. The antidepressants by and large do not treat bipolar depression and frequently serve only to increase mood instability, increase switches into mania or increased cycling rate. The things we have that will treat bipolar depression,

an interesting lot, they include lithium, Lomotrigine, also used as a mood stabilizer, but with no discernible benefit for the hypomanic or manic phase of the illness. Larazidone marketed as an antipsychotic, but also highly effective in bipolar depression. Quatyapine, by virtue of its metabolite, norquitapine, which is an neuropinecteatine, and then lastly, although fairly slim data for perhaps Pramapexel, dopamine agonist in bipolar depression. And then how does lithium as a mood stabilizer compare to antipsychotics and things like

Depico? Basically lithium is the best rounded, if you will, of the mood stabilizers being effective against both mood elevation and depression and also being prophylactic. It is the most effective mood stabilizer for classic type 1 bipolar illness. illness, illness in which the person becomes fully manic and fully depressed. It is less effective than valproic acid for rapid cycling bipolar illness or for type 2 bipolar illness, although that data is a bit mixed. In carbonazepine, the other classic mood stabilizer has largely fallen out of use because of all of its

risks and side effects. As well as it's all, carbonazepine is also a very potent hepatic inducer, so it will mess up the plasma concentrations of almost all other drugs. Coming back to this best tested for augmentation of depression, Dr. Bott, who's a colleague of mine here at Loma Linda at the VA, he's been working on a study,

a multi-site study, using lithium for depression in the VA setting. And he told me that they actually had to shut the study down because it was so much better at reducing suicidality than the placebo. And they were doing low-dose lithium. Indeed, lithium's effect on suicidality and its effect on depression is different than the effect it has on bipolar. illness. For most bipolar patients, not in an acute manic state, you're aiming for a plasma

concentration of between 0.6 and 1.0 millie equivalents or millimoles per liter. In acute mania, you may need plasma concentrations as high as 1.4 millimoles per liter or millie equivalents per liter. For suicidality, however, the plasma concentrations don't correlate very well with efficacy. In most studies, they aim for a plasma concentration of around 0.6, and that seems to be as effective as higher concentrations in terms of reducing depression when used as an augmenting agent or in reducing suicide risk. So what do you think about the use for reduction of violent behaviors. I know in previous episodes, we've talked about primary psychopathy. We've talked about predatory aggression versus more of the reactive, impulsive aggression. What type of violence

is lithium specifically helpful for? Lithium seems most helpful in terms of violence for those patients who are driven by impulsive violent behavior. Impulsive violence is characterized by an overly reactive limbic response to, at least what the person perceives as a threatening or insulting or objectionable action by someone or something. So it's an affectively driven violent response. And of course, lithium, I think, has been correctly described by many as a thymoleptic. It turns down the degree of affective intensity. in people in general, and certainly for people who are struggling to control angry impulses,

that may benefit them. Such individuals often have a deficit in sort of the top-down prefrontal inhibition of the limbic system. And lithium kind of turns down the temperature of the lithium of the limbic response, rather, and consequently makes it a little easier for the person to control their impulses. Now, you said the level, ideally for suicide is 0.6, but you also said in Europe they're looking at like three milligrams a day as like a nutritional amount.

Yes. A 3 milligram a day dose is probably like a couple orders of magnitude less than 0.6. Yes. So how do you make sense of those two things? Well, basically the 0.6 is from studies as an augmenting agent in major depressive disorder, the European studies and the Texas studies for groundwater lithium, if you will, those come from, those are general population studies in which the overall sample were not people with a mental illness.

It appears that people who are not mentally ill, that is they don't have a mood disorder are exquisitely sensitive to the effects of lithium in the brain. And that may simply be a way of saying that if you don't have as much pathology, then you don't need as much treatment. Now, you said it works on the limbic system. Are there any other brain circuits that it works on? Oh, there are a whole range of them. In fact, lithium does so many things.

That's one of the reasons we don't fully understand how it exerts its benefit. it desensitizes the auto receptors for serotonin and the raffane nuclei. So that increases serotonin secretion in the frontal and temporal lobes. That's thought to be one mechanism by which it's antidepressant, perhaps anti-suicide. It also directly inhibits the synthesis of guanine synthase kinase three beta. G-S-K-3-Beta, which is an important second messenger and modulator of ion channels in neurons, and that seems to have a benefit in terms of reducing mania and perhaps also producing mood stability. It also inhibits the formation of triphosphospho-inocytol, a very important second messenger in neurons in general,

and specifically in the limbic neurons. If you reduce trifosophonocytol, you decrease the intensity of neuronal firing rates. Lithium also, in addition to all of those things, promotes transcription factors for the fast response genes, FOS and Kreb, which indirectly then leads to an increase in a number of neurotrophic factors, including brain-derived neurotrophic factor and BCL-2 as well as others, as you can see from the number of things it does, including altering oxidative stress and mitochondria. There are a whole range of biological effects.

We're not absolutely certain which of those are critical to its benefits. Now, you've talked about lithium being neurotrophic. Yes. Do you think that's the BCL2 and the BDNF? That is what people at this point most suspect. And indeed, there have been now studies done in people suffering from Alzheimer's disease. And lithium appears to be able to provide some stabilization of neurons, decreasing apoptosis rates, neuronal death rates, in such patients.

producing increased dendritic arborization. So lithium actually is now beginning to be used in some clinical studies to perhaps improve cognition and behavioral control and people suffering from neurocognitive disorders, specifically Alzheimer's disease. I don't think anyone believes that lithium is capable of reversing the overall course of neurocognitive disorders, but it may be one of the few things that can at least transiently improve the person's cognition. This seems unique to me in psychiatric meds, the neurotrophic, meaning like, miracle growth for the brain of sorts. We've talked about that with clozapine, and we talked about that with lithium. Are there any other medications that cause this?

There are. Interestingly, a number of the second generation antipsychotics, things like aeroproprozole, partial dopamine agonist, olanzapine, also cause increases in neurotrophic factors in the brain. The first generation antipsychotics don't tend to have that effect as much. and in fact among them haloperidol appears to have none at all the antidepressants also typically cause an increase in neurotrophic factors so what we don't understand very well as yet is what the overall influence of increasing those factors has on the brain

although it's very clear when we treat people with mood disorder there is actually a thickening of the cortex in major depression or in bipolar depression when it's successfully treated. Those may be the results of boosting neurotrophic factors to higher levels. Also in depression people have a, when we talk about depression, people are most, of course, thinking about mood, sadness and hedonia. But you could also talk about it in terms of metabolic depression. the metabolic rate, if you do positron emission tomography on people with major depression, and compare them to themselves when they're euthymic, they undergo a 30 to 40 percent decline in neuronal metabolic rates.

And if you do anatomic studies, you find that there are things like hippocampal volume decreases, cortical thickness decreases. They are literally suffering from mostly a loss of dentistry, dendritic arborization and connection among neurons. Define dendritic arborization? If you look at the typical neuron, pyramidal neurons in the cortex are a good example. Out one end, you have an axon that exits from the neuron.

At the other end, you have a number of dendrites or spines, and on those you have little spikes. They're like the twigs on a bush. normally in a healthy, happy neuron, it looks kind of like a bush under the microscope with a number of spines and a fairly rich. In fact, we refer to it as arborization

because it looks like a plant. Yeah, it looks like a little tree branches coming out, right? Yeah. During illness like major depression, the main spines don't go away, if you will, the stems don't go away. but a lot of those little branching twigs just vanish. And then as the person recovers from the depression, those regrow. They come back.

And certainly the antidepressants and lithium seem to be able to promote that, and that's suspected to be a result of increased neurotrophic factors. Yeah. So we've talked, you know, a lot in this podcast we talk about the value of psychotherapy. and I think lithium and, you know, the treatment of bipolar, the treatment of schizophrenia, this is where I think as a psychiatrist you really have to lean into the medications. And so, you know, if you're listening to this and you're a therapist and you're, and you've gotten this far, you know, the reason why we care about this so much is because

when you get to the severe levels of, you know, mental health, patients are going to need more than psychotherapy. They're going to need these psychopharm options, and it's amazing that we have them. In many cases, what I often tell people in terms of the relationship between psychopharmacology and psychotherapy is the real job of the psychopharmacology is to improve the biology of the person's brain enough, essentially to make them available for other treatments, other treatments such as. psychotherapy, because indeed, in severe illness, often the person's so dysfunctional that they're not really able to engage very effectively in psychosocial treatments. And if we can improve the functional status of their brain, they can then begin to take advantage of psychotherapy, perhaps to address some of the issues that contributed to or led to

the mental illness. You know, the two fit together very well in terms of the more severe mental illnesses. Yeah, the one thing I would add to this is, at Patton, you have the benefit of being able to give patients whatever medication you want to give them, essentially, right? Yes. In the outpatient setting, you know, developing that therapeutic alliance with patients allows enough trust that they'll actually take the medications. Yes.

Well, and I think it's very important in discussing medications, including things like lithium, with patients, to point out that the medications are really a tool. I think it also goes a long way toward reassuring patients if you demonstrate essentially that you are knowledgeable about the medication and that you're not asking the person to blindly take any medication on an ongoing basis. If it doesn't work, then there's no point in continuing it.

If it causes intolerable side effects, there are generally alternatives. And most people, if you reassure them and explain to them the rationale for why you think the medication would benefit them, most people will at least give you a fair shot at seeing if the medication can be helpful. So now let's talk a little bit about levels and some of the nuance with levels. One of the things I want to throw out there right away is that the toxicity of lithium is most commonly due to medical issues that pop up that are not related to lithium. You know, if you have, for example, heart disease and then you get put on lysinepro

or you get put on, you know, something that increases the reabsorption of, you know, of lithium, the inability to excrete lithium, that's when the level jumps up. And so as we go into talking about the side effects, we want to really first talk about what are the ideal levels and how do we normally, under normal conditions, get to those levels and monitor those levels. Okay. In the typical individual, there are some baseline things to do before you start lithium. one is to check their thyroid status because lithium does tend to decrease the synthesis and release of thyroid hormone.

So you want to be sure that you're starting with a normal thyroid so that when you later monitor, you can find out if the person is having a decline in thyroid hormone. If they are, it's easy enough to replace. There's a synthetic levo-thyroxin is readily available. And frankly, your body doesn't care. whether the hormone came from the gland in your neck or out of a pill bottle. The other thing to check carefully, of course, is renal function. Lithium is more than 95% cleared through the lithium.

It's an ion, so it's not metabolized, not protein bound. But if you don't have kidneys, lithium is going to be very difficult. The measurement you want to make, the most sensitive measurement, is the person's estimated glimelular filtration rate. Basically, to give somebody lithium, you really want that to be above 50 milliliters for minute. Most of us, those who have healthy kidneys, will have a GFR greater than 100.

It does gradually decline with age, but even in the very elderly numbers in the 70s, are fairly typical. If you got good thyroid, good kidneys, then lithium is a reasonably safe medication to begin. Most people start at a fairly modest dose, 600 milligrams at bedtime, for example, and a young healthy person is a good place to start. That's not going to be therapeutic for most people.

It will, however, tell you if the person tolerates lithium. acute side effects can include tremor nausea, occasionally transient diarrhea. Most people, though, will tolerate it. If they do, then you can increase it up to 900 milligrams at bedtime and then measure a level after five days. That's when it will reach steady state. And you're aiming in most people with bipolar illness that is not

acute mania, a level somewhere between 0.6 and 1.0 millie equivalence per liter. In the severely manic person, you may need to push that up to 1.4 and then bring it back down as their mood stabilizes. You can load lithium, something that you don't see done much in the U.S., but has been done quite a bit in Europe for those who are hospitalized and ill, and you're trying to get the treatment on board quickly. Basically, you can give 30 milligrams per kilogram.

On day one, you give the extended release so you don't make the person throw up. You give it in three doses separated by two hours, usually 4 p.m., 6 p.m. 8 p.m. The next morning you measure a blood level. If it's under one, then they get 1,200 milligrams at night. If it's over 1, they get 900 milligrams at night. And then again, five days later, you find out what the steady state level is. Interestingly, when that was done, no side effects, no dropouts in the study that established that kind of lithium loading. I think we'll put that study in the resource library so that you guys can check that out.

Yeah, that was done by Dr. Cook et alice spelled K-O-O-K, I think Danish perhaps. Yeah, that's really interesting. I don't think a lot of people are doing that. You don't see it used too often. Where it makes sense clinically as if you're really needing to get the lithium on board and you're not wanting to gradually creep up on the level over one to two weeks

and you're trying to get it up to a therapeutic amount in one to two days. So I'm 100 kilograms, so that would be about 3,000 milligrams. So you'd be taking 1,000 milligrams of lithobid, a lithium extended release. 4 p.m. 8 p.m. the next morning you'd get a blood level drawn to see whether you're going to get the 900 milligram dose or the 1,200 milligram dose of the immediate release. You only use the extended release on the first day. The reason for that is the extended release is harder on the kidneys. You may also have noticed that I'm talking about giving lithium at bedtime all in one dose.

And that's also to spare the kidneys. The longer trough time you can give the kidneys, the happier the kidneys are in the long run. Yeah. And then you said after you load it, you actually check the dose in the morning, I mean the blood level in the morning. Yes. Well, presuming if you had your last loading dose at 8 p.m., you'd get the blood level about 8 a.m., 12 hours after the last dose. And that's, in some ways, that's purely by convention. The original and subsequent studies that established lithium's plasma concentration range, therapeutic range,

were all done based on 12 hours post-dose testing. That's one thing I was going to ask you because we have in the resource library like the different drug levels that are ideal for the different antipsychotics. Like clozapine, you know, you talk about less than a thousand. When are you measuring that? How many hours after the dose? Almost all drug studies. And again, there was nothing magic about the time period. I think it partially came out of the fact that by habit hospitals tend to, you know,

you get blood samples first thing in the morning. You know, if you've been in most hospitals, the venipuncturists are wandering around the halls very early. So most drug studies established their measurements based on a 12-hour post-dose time period, independent of the half-life of the drug. The reason that we still use that clinically, of course, is that if you're comparing your results to a table, say, that says, well, the optimal range is point. 6 to 1.0 for non-manic patients.

Well, what you're looking at, that range where they did the study, that was based on a 12-hour post-dose test. And for your data to be comparable to the table, you have to do it at the same time. Okay, so it's usually about 12 hours. Yes. Even though the brain half-life of lithium is, well, depending on age, somewhere between 24 and 36 hours. Which is why we wait four days to get a blood level. Yeah, because you're approaching for all drugs that are cleared by first order kinetics, meaning the rate of elimination is

proportional to the concentration. The time to steady state or the time to wash out is essentially five half-lives. Right. So if you want to get a blood level, you, and the drugs half-life is, let's say, two days. How many days would you have to wait to get a blood level? That's kind of accurate. If you wanted steady state, then you'd be looking at 10 days. If the drug has a half-life of, which many of our drugs do, have a half-life that is at least somewhere close to 24 hours,

then five days. you know the nice thing about the half-lives and the blood level o is as you get closer and closer to steady state the degree of change from one day to the next gets smaller and smaller so that if you're at least close to steady state you'll get a reasonable estimate of what the true blood level is okay an important point about that is something i want to emphasize for everyone's practice is if you really want to know if you're providing effective treatment, don't go by dose. Dose produces a whole range of concentrations depending on a variety of pharmacokinetic elements,

including absorption, distribution, elimination, metabolism. Measure the blood level. So let's say someone is past a couple week mark, and you have them on a stable dose, how often after that would you be checking the lithium and the renal labs and the thyroid labs? Typical recommendation is for,

like most drugs, if you're going to have problems, it usually occurs early. I can tell you that for the state hospital protocols, we recommend measuring the lithium weekly for the first four weeks, then monthly for the next two weeks, months, then quarterly out to a year, and then every six to 12 months after that. There are different

schedules. Some people don't measure that frequently. We often have people taking multiple medications, have medical illnesses. We have them in a hospital setting, so it's easy to get that many measurements. After the initial measurement, to be sure you're about where you want to be in many outpatient settings, you may then wait another month before you get another. other level. At the six and 12 month marks, you probably want to go back and also check renal function and thyroid function. What if you had someone who was bipolar who was a marathoner, would you do anything different for the period when they were going through the marathon? I would certainly take a while and educate them about the importance of avoiding dehydration,

becoming dehydrated will drive up lithium levels and can result in toxicity. Luckily, most serious runners are aware of the risks of dehydration because, of course, they can make themselves very ill if they get dehydrated, and they're very careful to take in an adequate amount of water while they're running. And that, you know, I basically just redouble that caution that if, If they're taking lithium, they need to avoid dehydration. Yeah, and also salt, right? Yeah, they need to replenish the salt as well.

They need to replenish the salt. Because the kidney can't really tell the difference between lithium and sodium, if you go on a low-salt diet or if you otherwise have wasted too much salt, sodium, the kidney will try to retain more sodium and it also will then retain more lithium and of course then lithium levels will go up. Yeah. So for every pound of weight, water weight, sweat it out, remember you're going to lose like, I don't know, I think it's about one gram of salt.

I don't know. Yes. Do you know the exact? Yeah, it's in that ballpark. About one gram of salt per pound of water lost. which means if people are exercising or if they're just in a hot environment, like Southern California in the summertime, they need to be careful if they're taking lithium to be sure that they maintain hydration.

What would you say about the use of lithium in pregnancy? Well, it depends on what part of pregnancy. The one teratogenic risk that we know of with lithium is, is Epstein's anomaly. This is a downward displacement of the tricuspid valve in the right ventricle of the heart. It's a serious anomaly. In the population as a whole, it occurs about one out of every 20,000 live birth. If somebody is taking a therapeutic amount of lithium, the probability increases from one out of 20,000 to about 1 in 2,000. Now, the risk is not. for the whole pregnancy, though. The risk occurs exclusively during the first five weeks of gestation.

The reason being is it's during the first five weeks that the heart's formed. After the heart is completed, then lithium can't cause a structural abnormality because that point is passed. So lithium often becomes the mood stabilizer of choice for the second and third trimesters of pregnancy. I think it's important because a lot of, you know, when women are planning to have children and they're on lithium or they have a history of bipolar, you know, how do we plan what is the best option? And then, you know, also to reduce your fear that if you're already past the first trimester, this will not increase the risk of Epstein anomaly. Yeah, indeed, you can't go back and, if you will, lithium doesn't go back and all, the structure of an already finished heart. And basically the heart is finished and starts beating during the fifth week of pregnancy.

And at that point, the risk from lithium is passed as a mood stabilizer. And the reason it's often then the one of choice is that many of the other drugs, which are mood stabilizers, are very teratogenic. Deppicoat, for example, doubles the risk. of autism in the offspring. It reduces IQ by almost a standard deviation and can also cause neural tube defects. Same thing can be said of most of the anti-epileptic agents. They cause either craniofacial defects or neural tube defects. So the anti-epileptics, which are used as mood stabilizers, are much less desirable than lithium. Many of the antipsychotics, however, though,

that exert mood stabilization also can be safe choices during pregnancy, things like aeropropyzole or olanzapine, although olanzapine has been associated in pregnant people, just as in non-pregnant people with excessive weight gain during pregnancy. Yeah, and then what about lactation? Like, are there any concerns for lithium and lactation? Interestingly, although if you look at a number of guidelines, it will say that lithium is contraindicated in breastfeeding. That, frankly, is an abundance of caution that's not supported by data.

Lithium enters breast milk very poorly. The concentration of lithium in breast milk is about 1% of the plasma concentration, which is probably too low a concentration to have any. substantial effect on the fetus and indeed in studies of people who were breastfed by mothers taking lithium there's been no demonstration of any adverse effect on the child what about people who have had like ruin wise and you know big parts of their intestines taken out does that going to change the dosing or the absorption it may lithium the immediate release is pretty well absorbed pretty

early in the small bowel. If someone, however, has lost a substantial amount of their absorptive surface, they may have a difficult time absorbing all of the dose. And that is worsened if they, of course, take an extended release formulation, because by definition it takes longer to absorb the ER formulation. The ER formulation is basically lithium embedded in wax. And as the wax melts in the GI tract, it releases the lithium. But if your GI tract is too short, well, basically the medication will go all the way through before it gets absorbed. Again, this is another point where blood levels can be very hopeful. You can estimate whether the absorption is adequate by simply measuring steady state blood level.

and I would add here just to consider in patients as you work them up and if they have a history of ruin why think about the medications that they're taking and if those are being absorbed because about probably 10 to 20 patients a year I see new patients get sent to me and they have ruin wise and they're on medications that are not dosed either the wrong medication or they're not dosed in the best way for someone who's had a portion of their GI track removed. Yeah, it's a very important point. And again, another flag to say, actually measure what's in the person's plasma so that you know if they're receiving adequate treatment. You know, basically treatment trials can fail for one of two reasons. Either it's a pharmacodynamic failure. The drug did not have the desired effect at the target organ, in this case, the brain, or

it's a pharmacokinetic failure, there was something wrong and enough of the drug never got to the brain. And of course, one of the elements of that can be a failure of absorption. Let's jump to side effects. I think probably

the biggest concern that I hear from primary care physicians, family physicians, people that take people off of lithium, is the renal side effects. Almost everybody. who takes lithium, even once a day, immediate release, will have a decrease in their urine concentrating capacity. And that's because in the distal renal tubule, lithium tends to accumulate in those cells and desensitizes the receptor for anti-diuretic hormone. In most patients,

they'll have about a 20% increase in urine output and they will need to increase their water intake by about 20% to stay in balance. Giving somebody multiple doses per day makes that worse because the lithium is good at getting into those cells. It's very slow at getting out of those cells. So the longer you can give the kidney between doses, the lower the concentration. of lithium will be in those distal renal tubular cells. Almost everyone who takes lithium chronically will show some greater decline in GFR over time than they would have had, were they not taking lithium? But only about 5% of lithium-treated patients after taking lithium for decades will

actually develop essentially renal failure. So lithium decreases anti-dioretic hormone and how it binds? Yeah, basically it makes the receptor for the hormone becomes insensitive to the presence of the hormone. So it's as if from the kidney standpoint, it's as if the hormone weren't present. Now, if it's a, if it is at its severe end, that's called nephrogenic diabetes insipidus, the person can't concentrate urine at all and they're not reabsorbing water and salt and, you know, they're flooding basically. They can't stay out of the bathroom because they're peeing all the time.

For the average person, though, the person who does not develop nephrogenic diabetes and syphidus, they'll still see an increase in urine output of about 20%. Yeah. So what are the treatments for this? other than, you know, if it's 20% drink more water, drink more, you know, salty foods, maybe. Well, the first treatment is, of course, to give the kidney as much trough time as possible, which means, except under very, very unusual circumstances, lithium should be given once a day, not divided.

The other things you can do is you can give, interestingly, the diuretic amelioride, will tend to block the absorption of lithium into the distal renal tubular cells and thereby decrease the tendency toward nephrogenic diabetes insipitous. The amelioride will raise lithium level, so you have to adjust if you start somebody on amelioride. Typical dose is to start at 5 milligrams a day and if necessary go up to 10 milligrams a day.

does that help at all with the chronic risk of having kidney failure? It doesn't seem to, and in part that may be a not completely accurate statement in the sense that the renal failure is such a rare outcome with lithium and takes so long a typical exposure in people who develop renal failures is on the order of three decades of exposure, that there haven't been any really good studies because you're trying to study something that happens rarely, and you've got to wait a long time for it to happen.

Okay. So are there any other treatments for sort of the chronic risk of kidney issues that you know? No, I think that's it. Basically, the other thing, of course, is monitoring. people don't develop rapid renal failure with lithium. So periodic measurement of renal function typically once a year is advisable. And you said if it goes below 50% that's when you have concern? Below 50 milliliters per minute, which is a GFR of less than 50.

You know, there are situations in which people are desperate and they may continue lithium. the risk really as with a declining GFR when you get into actual renal failure is that if the GFR declines steeply the lithium level is going to correspondingly increase rapidly and the person can become very toxic very quickly yeah okay and you mentioned tremor which is another issue that I commonly get from patients you know they get they go into the hospital for a manic episode they get treated. Now they're, you know, not up all night long, not trying to tell the president that they have the solution to the acute, tragic, non-existence that we're about to go into. And so now they're in my outpatient setting and they have this tremor.

Sometimes propanol is tried, low-dose propanol like 10 TID. Sometimes that helps a little bit. I don't know if you have any other. Is that, first tell me if that makes sense and then tell me your thoughts on. It does. Lithium, not lithium, lithium toxicity, somebody who's actually toxic, typically having a lithium level greater than 2, mili equivalence per liter. They may have coarse tremor, hyperreflexia, even myoclonic jerks. The typical person with an average lithium level may have a very fine, rapid tremor, especially if you have them extend to their hands. For some people, that doesn't bother them.

Other people, particularly if they work with their hands, they may be very bothered by that. The two principal treatments indeed have been beta blockers like propranol. Often the extended release propranol is easier for people to tolerate and you can push the dose higher more easily. the other thing that interestingly works, and this was a gift from the Swedes via Dr. Olson, who was studying rats and needed to make his rats more lithium tolerant, he discovered that giving them low doses of potassium increased their tolerance of lithium. and indeed both the increased urination and the tremor will respond to fairly low doses, 8 to 16 milli equivalents a day of potassium. That's really cool. So what kind of number needed to treat or, you know, how effective would that be?

It's fairly effective. Number needed to treat is estimated to be right around. four to five, which is in the range of acceptable. I mean, and particularly since, you know, everyone has potassium, it's one of our innate ions. Taking a small dose every day is not going to put the person at any risk. And if it works well, you know, they're home free with what amounts to a very small nutritional supplement. Okay, so then the third issue that can come up is hypothyroidism. So what is your approach if someone develops low thyroid function on lithium?

You know, if somebody is a lithium responder, you know, this drug is preventing mania, it's preventing suicide, is preventing depression, hypothyroidism should never be a reason to discontinue. you lithium in those patients. And that's because, frankly, we have an easy solution. We can replace thyroid hormone with exogenous synthetic thyroid hormone, generic name Levo thyroxin, taken once a day typically in the morning, and you can simply correct the person's thyroid level and make them euthymic.

In fact, one of the interesting uses of levothyroxin, one of the characteristics in people who are rapid cycling bipolar patients more than four episodes a year, if you give them a slightly greater than physiological amount of exogenous thyroid hormone, 80% of them will stop rapid cycling. That was research done by Peter Weibrow-E-D.L. when he was at UCLA. He got a group of rapid cyclers, gave them all 200 to 300 micrograms of lipothoroxin a day. And for comparison, a normal healthy thyroid gland produces about 150 micrograms of thyroid hormone a day. So he was roughly doubling in the highest doses, the amount of thyroid hormone the person had. and got an 80% response rate. Wow. That's really interesting.

People have known for a long time that there is an inverse relationship between thyroid hormone and mood instability. The lower the thyroid hormone, the more likely it is that a bipolar person will cycle. In the depressed population, being hypothyroid, of course, is one of the causes of depression

that typically we rule out when we see somebody who is newly depressed and we're wondering, well, is this typical garden variety major depressive disorder or are they depressed for medical reasons? How about the parathyroid? How often are issues seen there and what is your suggestion on both observing it and treating it? Luckily, lithium, although it will cause an increase in plasma calcium by increasing parathyroid hormone production in almost all patients, in the vast majority of them, is a very minor effect. About one per thousand lithium-treated patients will develop a clinically significant, elevation of plasma calcium and correspondingly a loss of mineralization of bone. They also may actually develop a parathyroid adenoma, which if that occurs and it becomes

independent of regulation, will need surgery. Monitoring for this, the recommendation is typically during the first year of lithium treatment, a measurement of plasma calcium at six months and at 12 months after that once a year. Okay. So are there any other side effects that you would think important to educate our audience on? The only other, and I've seen some clinicians who worry about this, because they remember something about lithium and the heart other than Epstein's anomaly, But sometimes they don't remember what it was.

The one circumstance in which you do not want to give somebody lithium is if they are suffering from sick sinus syndrome. That is if their AV node is failing to depolarize. And the reason being that at the sodium and calcium channels in the SAA node that lead to depolarization, lithium can compete with both of those ions and essentially partially block those ion channels, and that can lead to the SA node stopping, firing altogether, so there's no P-wave on the EKG. The person then also declines to a rate of ventricular rate that's being driven by the AV node, which for most people is not adequate because AV-node rates are to, typically in the 40s for heart rate.

Very good, very good. Okay, so as we bring this to a close, any final thoughts you'd like to put out there? I think in some ways we can end kind of where we started. I think people need to become familiar with lithium so that they become more comfortable with it. It is overall our best mood stabilizer still, and we are in the U.S. underutilizing it.

Excellent. All right. Thank you, Dr. Cummings for coming on. I really appreciate it. And I know a lot of our listeners really appreciate it. I get messages. And, you know, if you ever have a message of gratitude and you put it on either an iTunes review or an email, I forward that to Dr. Cummings. So, you know, there's a saying that gratitude is the oil of society. And I would say for us, it's more the gas that keeps us going. And we appreciate all your words. And I, you know, recently we got an iTunes review from someone who said, you know, that they really appreciated Dr. Cummings' wisdom and my interview with Dr. Cummings pulling out that wisdom.

And for a lot of the episodes, I would completely agree. So, Dr. Cummings, thanks for coming on. Oh, always in pleasure. Thank you for having me. I enjoyed it.