Lithium is a natural element found in our environment all around us, in our water supply, in some of the food we eat, in the dirt we walk on, and it is BY FAR, one of the most useful medications in all of psychiatry, yet its' use has decreased precipitously over the last few decades, even in treatment of Bipolar Spectrum Illness, which some psychiatrists jokingly dub, 'Lithium-Deficiency Disorder.' In this segment, Dr. El-Mallakh and I talk about why it is the Greatest (Med) Of All Time, and also review factors influencing its' underutilization.
Ethan: So, I wanted to review a few of the earlier studies on why lithium is the best medicine for depression, whether that be bipolar depression or unipolar depression. A meta-analysis from 1971 that encompassed four studies, 116 patients with either acute mania or as a maintenance medication to prevent mania, they had an average response of 78% with lithium. In 1970, 84 either manic depressive patients or major depressive patients did a 5-month discontinuation study. Of those 84 patients, half of them on [00:01:00] lithium, half of the patients on placebo had a relapse, and zero of the patients on Lithium had a relapse. You had a 1971 study by Alec Coppin, a British psychiatrist, he did a double blinded lithium versus placebo in 65 recurrent affective disorder patients, and he had no lithium patients requiring ECT, while half of the placebo did. He was so moved by his results that he set up a lithium clinic, and he actually did a 10-year follow up. He found the rate of suicide in his lithium-treated patients was <1 in 1,000, compared to the accepted rate in the general population of 7 out of 1,000. This study was very well designed and you've got a medicine that has proven benefit to prevent the worst outcome that you can have in depression, which is suicide, loss of life. Basically, Coppin ran this study, keeping patients [00:02:00] on lithium versus placebo for two years, utilizing other psychiatrists in the field who were blinded, and were allowed to give other needed treatments. But the results of Alec Coppin’s 1st follow-up study and later follow-up studies are pretty astounding. He not only showed a huge reduction in the risk of suicide, he also showed the amount of other medications needed was much decreased, and that this suicide prevention was effective in both unipolar and bipolar disorder. Nassir Ghaemi, another world-renowned bipolar expert, gives us some details in his podcast about lithium and about why it is so important to use in suicidal patients. He talks about severe depression, stating about half of people with severe depression will have suicidal ideation, 10% of people with [00:03:00] severe depression will attempt suicide, and of those 10% who attempt, 10% will complete suicide. The risk (of suicide) in severe depression is 4-5% lifetime versus a fraction of a percent in the general population. And we're talking about 30 to 40,000 suicides per year in the United States alone.
You've got another, more recent 1999 meta-analysis in major depression with 19 randomized controlled trials in 865 patients with relapse rates of placebo of 74%, lithium of 29%, another 10-year follow up in youth showing that lithium outperformed other mood stabilizers with half the number of suicide attempts, and a 2023 Taiwanese study on mood stabilizers and the risk of all cause natural and suicide mortality [00:04:00] in bipolar disorder, comprising 26,000 patients showed a reduction of those risks with lithium, along with other mood stabilizers, but the reduction was greatest with lithium. Why is there not more current research on lithium. Why is lithium not approved for major depression or for unipolar depression or as an anti-suicide drug, which I use it all the time for patients who are suicidal.
Rif: It's an anti-suicide drug. The studies with unipolar depression are a little bit inconsistent. What happened in psychiatry is we've had this diagnostic inflation. In the 1960s, 1970s, the research criteria for, say bipolar illness, manic-depression, were relatively tight. Even what we called depression [00:05:00] was relatively rarefied. And then we went through this diagnostic inflation, really in the 1990s and 2000s, where we kept calling less severe things bipolar illness and less severe things depression. The patients today that we would diagnose with depression are absolutely not the patients that were in these studies. Know you had to need ECT to get the diagnosis of depression, which is probably more in line with what today we’d call bipolar illness. So, you know, I can be perfectly fine and I just don't like something and I come and tell you I'm depressed and now all of a sudden I meet that depression criteria, but there's no way I would've been called depressed in the 1970s. So we have actually changed what we call [00:06:00] depression, and in what we call depression now, lithium doesn't have these amazing numbers. These numbers are probably based on a population of patients that have very clear bipolar illness and again, in those days, manic depression actually referred to just a severe recurrent mood disorder. So you could actually have manic depression diagnosis and never have a manic episode. Today, of course, that's not the case. You have to have a manic episode to get the manic depression diagnosis. It is a different population of patients and in that population of patients that have this severe recurrent disease, you probably do get ion dysregulation, and so you probably do have a very lithium-responsive population. So we don't [00:07:00] have the massive utility of lithium because we have changed what we call depression, and we've changed it slowly and gradually over time. It's not like one big change in diagnostic criteria. It's a little bit of a change in diagnostic criteria and a huge change in what we accept for that category in the diagnostic criteria.
Ethan: I still wonder if there is an anti-suicide protective effect regardless of whether or not you have manic-depressive or bipolar illness or the pathologization of grief, for example, which, if you experience grief after losing a loved one for more than two weeks, and you meet 5/9 DSM criteria, then you've had a major depressive episode, right?
Rif: Yeah, so our threshold just keeps dropping and dropping.
Ethan: Yeah, but how would you reconcile that with [00:08:00] the lithium in the water supply in neighboring counties?
Rif: Very good question.
Ethan: Where you assume that at least if you have enough counties that they've tested this in, then you have a somewhat equal proportion of manic-depressive patients in both counties, yet you still see a reduction in suicidality and homicidality in the lithium (counties with) greater concentration.
Rif: The data regarding suicide is highly reproducible and it is related to the lithium concentration in the drinking water. So, the higher the lithium concentration in the drinking water, the more easy it is to show that there's a reduction in suicide. The easier it is to show something just means that the effect size is bigger. And in all of those situations, what those people are drinking, or consuming, is less than what we prescribe as physicians, much less. [00:09:00] You have to remember that you consume a fair amount of water in lots of forms. When you make your own coffee, you're consuming that lithium although nowadays of course, more and more people are drinking bottled water and so they don't get that effect. So, it's a little bit harder to show the effect in more recent years because of the increase in bottled water. And of course you remember that lithiated water tastes bad. People will actually go out of their way to not drink lithiated water.
Ethan: I don't remember that Lithiated water tastes bad after.
Rif: You remember because you, talked about lithium being used as salt substitute, right? So now imagine that you salt your drinking water before you drink it. Why am I drinking this horrible taste?
Ethan: So why does the NIMH, why would they not help to fund a study showing that lithium prevents suicide? Why Is that [00:10:00] not something in, you know, the first four years of medical school, I had to search out this information and this research on lithium preventing suicide, which is a very potent effect. And it's a very important thing in our field. That's one thing that really bothers me in lots of ways.
Rif: Lithium, you mentioned the numbers, so let me make it more overt. Lithium reduces the risk of suicide 7-fold. 7-fold is huge, from 7 in a 1000 to actually less than one in a thousand. It's just huge. But, sudden lithium discontinuation increases the suicide fold, a rebound effect about 22-fold. It's 3 times as big as the reduction. This is really important. Taking people off of lithium is something that you need to do extraordinarily carefully, but this stuff [00:11:00] is known and it's accepted, and you don't need to have another study to show it. What you do need is you need clinicians to adopt it, and that's actually a bigger problem. Why is lithium use declining? In the United States predominantly moreso than other countries, but also worldwide.
Ethan: You talked about that it's a naturally-occurring substance, so it can't be patented, it can't be commercialized. It's why you've never seen a Direct To Consumer Ad for lithium. You talked a little bit about the patent process. To add some numbers to lithium's far less-utilized in the United States, especially in the last few decades, from 1996 to 2006 the rate of lithium in bipolar disorder dropped from 38% to 14% according to one study. The study you mentioned earlier, Rhea et al, evaluated in [00:12:00] 1997, not just lithium, but other mood stabilizers, which is a really disturbing trend. Of all mood stabilizers used in bipolar disorder, they went from 62% in 1997 to 26% in 2016. Lithium saw a similar drop from 30% to 17%, and the usage of antipsychotics rose in that same time period from 12.4% to 51.4%, which to me, there's a very clear reason why this occurred. It's because the antipsychotics received the FDA approvals for bipolar mania, while they were still on patent right by each company. And therefore, in my mind, it's solely a marketing phenomenon that we've seen.
Rif: It's not solely a marketing phenomenon. Remember that psychiatrists, actually, not just psychiatrists, [00:13:00] all physicians, are scared from lithium. So there's a fear component and when you have something that, you look at a clinical study and it shows, it works for depression, it shows, it works for mania, you know that it works for say, anxiety, which is also common in a lot of patients with bipolar illness, all of the sudden you're sitting there going, ‘Why in the world am I giving this dangerous medicine, when I can give a safer, although it's not always.
Ethan: He put up quotations, by the way. You can't see that. But “safer”
Rif: And it's not safer. It's just that it kills people by a different way, by ways that we don't measure as psychiatrist, but if you think it's safer, then the calculus is easy and you don't prescribe lithium. There are true advantages to some aspects of the antipsychotics. For example, they work faster [00:14:00] than lithium. You know, lithium never really kicks in before two weeks. An antipsychotic kicks in within the first 3 days. And, psychiatric hospitalizations are unpleasant. I'm in the hospital and you say, ‘Okay, I can give you a drug that's gonna get you out of here in another 4 days, or a drug that's gonna get you out of here in another week and a half, which do you want?’ ‘Okay, gimme the drug that gets me out of here in four days. And, of course, your insurance wants the same thing. And that's the other thing, insurance drives some of the stuff. Even though some of these medicines are expensive, it reduces length of hospitalization. There are all sorts of finer sort of details that shouldn't be overlooked. It's really an important aspect for us to really be cognizant of the harm that antipsychotics actually do. And to be cognizant of the benefits [00:15:00] that lithium is actually associated with. But you're absolutely right, if we did the calculations correctly, we'd have a lot more people on lithium.