20.1 Lithium: Beyond its' Psychiatric Use with Janusz Rybakowski, MD

[00:00:00] Just after this, we did some study for 10 years with patients studying lithium in the 70s and in 80s.

[00:00:08] Then we found that both groups of patients had the percentage of lithium responded on one-third.

[00:00:16] So, in one-third of bipolar patients, monotherapy with lithium can just make them completely healthy, provided the lithium will be given them.

[00:00:31] Somebody get this guy some help!

[00:00:41] Disclaimer, this podcast is for informational purposes only. The information provided in this podcast and related materials are meant only to educate.

[00:00:46] This information is not intended as a substitute for professional medical advice. While I am a medical doctor and many of my guests have extensive medical training and experience,

[00:00:52] nothing stated in this podcast nor materials related to this podcast, including recommended websites, texts, graphics, images, or any other materials,

[00:00:58] should be treated as a substitute for professional, medical, or psychological advice, diagnosis, or treatment.

[00:01:01] All listeners should consult with a medical professional, licensed mental health provider, or other healthcare provider

[00:01:05] if seeking medical advice, diagnosis, or treatment.

[00:01:08] So, today I'm very excited. I have on Yanis Rybikowski, a psychiatrist and absolute pioneer in lithium research.

[00:01:17] ResearchGate lists you as having 867 publications with over 20,000 citations, nearly 150,000 reads of articles on clinical psychiatry,

[00:01:32] research, and you are currently a professor of psychiatry at Poznan University in Poland, where you were the head of the adult psychiatry department for over 20 years,

[00:01:45] former chairman of psychiatry, and at the clinical academy,

[00:01:56] you've authored several books and book chapters, including The Faces of Manic Depressive Illness,

[00:02:02] and I appreciate your refusal to update to the less scientific term of bipolar disorder,

[00:02:09] lithium, the amazing drug in psychiatry, as well as lithium therapy, a personal tale of the recent decade,

[00:02:15] and you recently sent me an article about the outcomes of three patients on ultra-long lithium therapy for 50 years.

[00:02:24] You have received multiple Lifetime Achievement Awards via the European Bipolar Forum in 2012

[00:02:31] from the World Federation of the Societies of Biological Psychiatry in 2015,

[00:02:37] and maybe most proudly, or at least most relevant to lithium's history,

[00:02:42] the Mogen Scowl Scientific Award from the International Society of Bipolar Disorders.

[00:02:48] There's a laundry list of other awards and recognitions that you've received that I don't have time to reel off here,

[00:02:54] but on a more personal note, this podcast is all about trying to bring on actual experts in the field of psychiatry

[00:03:03] that have been recognized by others in the field as being most knowledgeable and most experienced in the uncertain field that is psychiatry.

[00:03:14] When I sought you out, I wouldn't have been surprised if you told me that you were too busy to do this interview.

[00:03:21] You're kind of a big deal in psychiatry and mood disorders, and I'm just a small fish in a small pond.

[00:03:27] Now, you not only agreed and were flexible on the time that we met,

[00:03:33] but you also sent me your PowerPoint from the American Psychiatric Association's 2024 Annual Conference

[00:03:40] titled,

[00:03:41] The Benefits of Long-Term Lithium Treatment Besides Prevention of Mood Recurrences,

[00:03:46] revealing so many of the ancillary benefits of long-term lithium treatment.

[00:03:51] I appreciate the prompt response and the passing on of good clinical information tremendously.

[00:03:57] And maybe my favorite part about doing this podcast, besides changing the world, of course,

[00:04:04] is that I get to learn how some of the best in the field critically think about what we treat,

[00:04:11] how we treat, what is known versus what remains uncertain.

[00:04:15] And I feel like it makes me such a better clinician.

[00:04:19] So, without further ado, thank you so much for your time and being here.

[00:04:24] And how are you doing today?

[00:04:27] I'm doing fine.

[00:04:28] Thank you very much.

[00:04:29] Okay, good.

[00:04:30] I'm the only dean of this podcast.

[00:04:33] So, if it's okay with you, before we get to any clinical issues,

[00:04:38] I'd like to do some rapid-fire questions with my guests

[00:04:41] to get a little bit more information about Giannis, the human being.

[00:04:48] Where were you born and raised?

[00:04:51] Well, I was born in some place in Krotosyn.

[00:04:55] And then after having 70 years, I came to Poznan to study medicine.

[00:05:02] So, Giannis, what did your parents do growing up?

[00:05:06] My father was not working,

[00:05:09] but my father was an accountant in some factory in Poznan, a milk factory in Poznan.

[00:05:15] When you were young, what did you want to be when you grew up?

[00:05:20] Well, I was kind of a good student during my, you know,

[00:05:27] both preliminary and high school.

[00:05:29] I got a very good grade on all subjects.

[00:05:32] And I was kind of fascinated by scientific discoveries, especially biological ones.

[00:05:41] However, as for studying medicine, it was a suggestion of my father,

[00:05:47] who was fond of efficacy of doctor, but not psychiatrists,

[00:05:51] just for surgeons, gynecologists in his family.

[00:05:54] So, when I decided to specialize in psychiatry and told it to my father,

[00:06:00] he was kind of disappointed that he had the biggest esteem for surgeons and gynecologists.

[00:06:09] My father is a surgeon,

[00:06:11] and I felt a similar feeling that he was disappointed that I went into psychiatry

[00:06:17] instead of one of the surgical fields.

[00:06:20] I see.

[00:06:22] So, when or if you get tired or burned out from your clinical work,

[00:06:27] what do you do to unwind or what do you do for fun?

[00:06:31] Well, I like reading.

[00:06:35] Also, I like music.

[00:06:39] I like playing piano.

[00:06:42] And I used to play piano in some band also.

[00:06:47] But now it's mostly kind of social situation.

[00:06:51] I do it.

[00:06:52] And, of course, the repertoire is concerned.

[00:06:56] It's mostly pop and jazz music.

[00:06:58] So, I like to play the jazz standards and piano with some improvisation also.

[00:07:06] That's really interesting.

[00:07:07] Maybe I'll get to hear you play sometime.

[00:07:10] Yeah.

[00:07:11] So, what are the biggest influences that you've had in terms of teaching you

[00:07:16] how best to interact with people and then down the road to interact with your patients?

[00:07:22] Well, generally, you know, having such a scientific career, I think that the biggest gratification for me was seeing the patients now.

[00:07:32] Clinical practice in psychiatry is very gratifying.

[00:07:37] And what is very nice is that the developments which are on some scientific component,

[00:07:45] they can be, you know, implemented in clinical practice right away.

[00:07:49] How many patients do you think you've seen in your lifetime?

[00:07:54] There were thousands of them.

[00:07:57] Definitely thousands of them.

[00:08:00] Now, when I have my private practice still,

[00:08:03] so I'm trying not to have the new patients,

[00:08:11] but still I'm seeing about 100 patients a month.

[00:08:17] Okay.

[00:08:18] Okay.

[00:08:18] I can imagine you've seen thousands and thousands of patients throughout the course of your career.

[00:08:24] You know, I graduated from the medical faculty of Poznan University of Medical Sciences 55 years ago.

[00:08:33] During my study, I was interested in biochemistry, neurophysiology,

[00:08:41] and then it makes me to choose psychiatry as a specialty, of course.

[00:08:49] And then I started my adventure with lithium very shortly thereafter.

[00:08:54] This was after a suggestion of some senior psychiatrist from my department,

[00:08:58] and it further transpired that I became a fruitful topic of my both scientific and clinical career.

[00:09:08] During this more than half a century of my career,

[00:09:13] I was witnessing both developments in psychiatry, especially in psychopharmacology,

[00:09:19] and also, of course, of lithium, which was the leitmotiv of my clinical experimental research.

[00:09:25] So now I'm kind of, you know, senior psychiatrist

[00:09:30] and witnessing more than half a century of the development of psychiatry, psychopharmacology.

[00:09:38] I was the chairman of or head of the Department of Adult Psychiatry for 22 years.

[00:09:45] I'm professor emeritus for eight years now,

[00:09:48] and my successor on the Department of Adult Psychiatry in Poznan is my son, Philip.

[00:09:57] So I have only one son, and I have a grandfather of four grandchildren now.

[00:10:05] And one of my grandchildren, Zofia, is also a third-year student of medicine.

[00:10:11] Oh, that must make you very, very proud.

[00:10:14] Before we start talking about lithium, my first medicine question actually comes from my wife.

[00:10:21] I asked her this morning, what question would you want to ask Giannis?

[00:10:26] Now, she's not a clinician, but a physical therapist.

[00:10:30] But she wants to know, how does the healthcare system in Poland differ from ours in the United States?

[00:10:39] The organization of the health system is generally free of charge.

[00:10:45] As far as I know, the free of charge in the United States is not the veteran administration system, right?

[00:10:51] Correct.

[00:10:53] Certain types of government insurance will be essentially free of charge.

[00:10:57] Yeah.

[00:10:58] But, of course, there is also a good, you know, private practice system.

[00:11:04] And not all patients, because there are sometimes long queues to the specialists.

[00:11:11] So some patients, which can allow, can go to the private system.

[00:11:20] As far as psychiatry is concerned, we have a pretty good, you know, both ambulatory and stationary system.

[00:11:31] And we didn't do such a mistake as it was performed in the United States to de-institualization of psychiatric beds.

[00:11:42] We still have a sufficient number of psychiatric beds to do to hospitalize patients.

[00:11:51] More than 80% of U.S. medical graduates end up specializing.

[00:11:57] So we have one of the lowest rates of people coming out of medical school that go into primary care,

[00:12:04] that kind of organize the person's entire, you know, health history.

[00:12:09] And so everybody in the United States essentially is specialists.

[00:12:13] And I think that is one of the big differences that I've seen in terms of how our health care system operates differently.

[00:12:21] There's just not enough good primary care physicians who manage all of the patient's care.

[00:12:27] But anyway, I want to talk a little bit more about lithium, what I consider to be the greatest drug in psychiatry.

[00:12:34] And I'll tell you that throughout my residency training, there was a building discontent with the patient outcomes I was seeing with SSRIs.

[00:12:46] In which place it was?

[00:12:48] Louisville, Kentucky is where I trained.

[00:12:50] Oh, I see. I see. I see.

[00:12:52] But I was seeing patients have okay or bad outcomes with SSRIs supposedly clinically indicated for nearly every psychiatric condition.

[00:13:03] And the patients for whom they worked initially would often report diminishing returns over time.

[00:13:11] And other patients felt that that class of medications actually made them worse, the SSRIs.

[00:13:17] Towards the end of my training and into my clinical years, I started to use more lithium, including low doses for unipolar depression prophylaxis that had failed to respond to other antidepressants.

[00:13:31] It really revitalized my love and my passion for what I do because I started to see people, not everybody, but some patients have a massive response to just a little bit of lithium.

[00:13:47] And most of those responses have stayed over time to where I don't think that they are just a placebo response at this point.

[00:13:56] I'm curious to hear about how you first learned about lithium, both theoretically or academically, as well as your initial clinical responses that you saw when prescribing it.

[00:14:10] It was in the beginning of the 70s.

[00:14:12] I started to see people, both of them.

[00:14:14] I started to estimate lithium in serum, urine and red blood cells.

[00:14:17] And then the effect of lithium and electrolyte metabolism was the topic of my doctoral dissertation.

[00:14:25] And then we were in Poland, the first to describe antidepressant effect of lithium.

[00:14:33] When I was in Bitgosz, we were the first in Poland to describe the lithium augmentation of the depressant because I think that lithium augmentation of the depressant is, you know, underestimated value.

[00:14:46] And then, of course, now we have four patients described.

[00:14:50] First was described in Brazilian Journal of Psychiatry.

[00:14:53] The second was in International Journal of Vipel and so forth.

[00:14:56] So, for patients which are excellent, decent responded after 50 years.

[00:15:02] But as far as this dose and the concentration of lithium is concerned, but for our patients which are on prophylaxis lithium, the mean serum lithium level is 0.65.

[00:15:17] So, it's not very high.

[00:15:20] So, it's not very high.

[00:15:20] And I think that this concentration is connected with kind of lower detrimental effect on kidney.

[00:15:31] And, of course, we have very few patients with unipolar depression which are on lithium prophylactis, but there is not low dose.

[00:15:41] It's just, you know, regular dose between 0.5 and 0.8.

[00:15:45] I think that the good range of lithium concentration.

[00:15:50] As far as the lower dose, you mean below 0.5?

[00:15:56] Yes.

[00:15:56] Such low dose can be, in some patients, even efficient and probably even very low dose in patients with some kidney failure.

[00:16:06] So, instead of discontinuing lithium, just giving lithium very small doses.

[00:16:14] I think it would be better than discontinue lithium and replace, especially in extra emission response, replace with another would stabilize it because this usually doesn't work.

[00:16:26] So, I trained with Riff El-Malik who taught me a lot about lithium.

[00:16:33] One of the things that he taught me is that mechanistically one way in which he believes that it works is by getting into the nucleus of the neuron, which sees it as sodium and allows lithium to enter into the nucleus.

[00:16:50] But then it doesn't have a great way to get out because the export sodium pump recognizes that lithium is not sodium.

[00:16:59] So, to me, that makes me wonder if even these really low doses, 150 or 300 of lithium carbonate, if they're given enough time, if they may work in a similar fashion, even at a blood level significantly lower than 0.6.

[00:17:18] So, what do you make of that?

[00:17:21] Yeah.

[00:17:21] Well, just incidentally, I wrote the articles and a book of El-Malik.

[00:17:28] He was in this, in Kentucky, in Louisville.

[00:17:32] Yes.

[00:17:33] I was in 76, 77 at University of Pennsylvania in Philadelphia, and we were one of the first to determine the lithium transport across red blood cells.

[00:17:44] It was so-called lithium-sodium-sodium countertransport system.

[00:17:48] I was working there with Alan Fraser, who was for the long time chief of pharmacology in San Antonio, in Texas, but now it's probably Professor Emeritus.

[00:18:02] I was really interested in the mechanism of lithium by the influence of membrane electrode metabolism.

[00:18:09] So, the name of El-Malik is for me, you know, rings a bell.

[00:18:15] He also, on that topic, he told me that there used to be a lithium blood test involving how much it accumulated inside of red blood cells that would help to predict lithium responsiveness.

[00:18:30] Can you expand on that a little bit?

[00:18:32] Yes, yes.

[00:18:34] Generally, we were estimating lithium in red blood cells, which is something like 0.4, 0.5 of the serum lithium levels.

[00:18:44] And there was a claim that the lithium-sodium in the country transport system is deficient in bipolarization, so they have a higher lithium ratio.

[00:18:54] But I think that this research was not further developed.

[00:19:01] There was a period, I think, seven to eight, when there were several places.

[00:19:06] For example, in USA, there was also, in Chicago, my friend, Shane Pandey, who was also doing this on this lithium concentration in red blood cells.

[00:19:23] But there must be something also with this lithium-sodium concentration transfer, which may be deficient and the cellular level is higher.

[00:19:31] The other guest that I've had on, and person that I have a lot of respect for, a psychiatrist, is Nasir Ghami, who I'm sure you're familiar with his ACTA psychiatra work on when and how to use lithium,

[00:19:45] which offered some kind of unique recommendations in terms of what other literature is out there.

[00:19:51] And he actually recommended, especially in unipolar depression, to titrate lithium to its clinical efficacy, regardless of what the blood level that was found was.

[00:20:05] So those are the couple of major sources for, and again, what I'm seeing clinically, for why I wonder if even using these really low 150 milligram, 300 milligram doses,

[00:20:19] over a long enough period of time, can still operate as a prophylactic once it's given time to accumulate in those neurons.

[00:20:28] But in this unipolar depression, you mean using lithium as monotherapy or are augmenting antidepressants?

[00:20:37] Either.

[00:20:38] Oh, I see.

[00:20:39] Obviously, you and I know that the lower doses of lithium are much different in terms of safety profile than the high doses that you would maybe use in somebody with manic depressive illness,

[00:20:53] experiencing both poles of manic depression.

[00:20:55] Outside of that, though, can you quickly review with us all of those ancillary benefits aside from prevention of mood recurrences of lithium

[00:21:06] that you presented at the American Psychiatric Association Conference this year?

[00:21:12] Well, I think there are two most important benefits outside of this preventative reconnaissance.

[00:21:19] First is anti-suicidal effect of lithium.

[00:21:23] And there were some doubts about it, but still most of the meta-analyses show that lithium exerts very strong anti-suicidal effects in mood disorder,

[00:21:38] both in bipolar and unipolar depression.

[00:21:40] And what's interesting, it is not tightly connected with its effect on preventing recurrences.

[00:21:49] It's kind of a specific effect of lithium not connected with this prephylaxis action.

[00:21:55] So it is probably the most important, in my opinion, every patient having suicidal thoughts or suicidal tendencies with mood disorder should have lithium as a one or even addition of lithium to ongoing treatment.

[00:22:13] So it is first and probably the most important.

[00:22:17] And the second is neuroprotective effect of lithium, which is reflecting its anti-dementia action.

[00:22:26] Generally, bipolar disorders increase the risk of dementia.

[00:22:31] And lithium using decreased risk.

[00:22:36] Some people think that it's definitely decreased risk, even to the point like it is a normal and general population.

[00:22:45] And recently, there were very, very interesting studies showing that bipolar disorder increased risk of osteoporosis and lithium decreased risk.

[00:23:01] And there are effects of lithium on incidence of various illness or definitely comparing with other mood stabilizers.

[00:23:12] So lithium did increase risk for several illness and mostly decreased risk.

[00:23:19] For example, there was some study on the group of lithium patients and it showed that, for example,

[00:23:28] the asthma was a kind of lower prevalence in lithium-treated patient.

[00:23:34] Lithium can be very favorable as far as another incidence of other illness are concerned, like stroke, for example, and some cardiovascular illnesses.

[00:23:50] And generally, some big studies, lithium decrease all-cause mortality, not only suicidal mortality, but mortality with other illnesses.

[00:24:00] So it was generally what I was trying to present in New York.

[00:24:06] Yeah.

[00:24:06] And so I've wondered how much the reduction in osteoporosis and the reduced fracture risk,

[00:24:13] because my basic understanding is that lithium interacts with calcium to promote more aggressive bone turnover.

[00:24:20] And so you're creating newer and healthier bone to replace older, less healthy bone a little bit more rapidly with even low doses of lithium.

[00:24:30] And I wonder how much that affects overall mortality, because as I'm sure that you know,

[00:24:37] the osteoporosis is a huge risk factor for bone fracture.

[00:24:41] And any sort of hip fracture after the age of 80 does not have a very good five-year mortality rate.

[00:24:49] So I wonder how much of that decreased mortality is associated with the benefits of lithium with osteoporosis.

[00:24:57] What do you think?

[00:24:59] Well, there are very, you know, recent findings.

[00:25:02] So I cannot now interpret it on the basis of my practice.

[00:25:11] But you probably notice that this osteoporosis, you know, data were very fresh, you know.

[00:25:17] On the topic of lithium as an anti-dementia medication, even at low doses,

[00:25:24] where do you think lithium stacks compared to other dementia medications such as donepazel or memantine?

[00:25:34] Well, I don't think it's competitive.

[00:25:38] Still, there are some good findings in MCI and Alzheimer's disease with very, very low doses of lithium.

[00:25:48] For this, you know, dementia, lithium is definitely used in low doses in the concentration 0.2, 0.3, you know.

[00:25:56] And it is favorable.

[00:25:58] But how, in this case, lithium can be competitive to such, you know, donepazel or memantine?

[00:26:05] I don't think it is a competitor now.

[00:26:10] Okay.

[00:26:10] One of the most difficult things that I've encountered when using lithium,

[00:26:16] besides managing patients' fears and stigmas about it, even around low doses,

[00:26:21] has been convincing them to give it time.

[00:26:25] I've had a proportion of patients that I think are considered super responders

[00:26:29] that feel the uplifted mood and feel more emotionally regulated within a few days to a couple of weeks.

[00:26:37] But for most people, they either don't experience any change in that first week or two,

[00:26:44] or they experience some nuisance side effect before I think lithium really has a chance to work.

[00:26:51] You've really illuminated to me the fact that so many of lithium's benefits increase over time,

[00:26:58] up to two years of increasing benefit for a lot of these kind of secondary and even anti-suicide benefits.

[00:27:06] Versus a lot of our other drugs have kind of the opposite effect,

[00:27:12] with worsening side effects with long-term treatment.

[00:27:15] How do you counsel patients in terms of how long it will take for them to feel the benefits of lithium?

[00:27:23] And how do you get them to stick with it when it really seems to be best at preventing debilitating symptoms

[00:27:32] from coming back, but the patient doesn't necessarily have this aha moment

[00:27:38] where they feel it working like you can with some other drugs?

[00:27:42] Well, generally the patients are those who wear some recurrences, manic or bipolar recurrences.

[00:27:48] So my main aim to give them lithium is to prevent them from having these recurrences,

[00:27:56] and that will take some time to observe this.

[00:28:02] And I think that this early side effect, there are two kinds.

[00:28:06] One is hand tremor.

[00:28:07] It's definitely one third of patients.

[00:28:10] It's, it's, it's, it's, it's, so for hand tremor, I think there are two things.

[00:28:16] One, it's decreasing the dose.

[00:28:18] The second is using this beta blocker, such as propranolol, which is very, I think, effective.

[00:28:27] And the second is, in a lower percent of our patients, is some kind of polyuria.

[00:28:32] This also can be reduced by decreasing the dose of this.

[00:28:36] Some people found that we can try the amylo-right for this,

[00:28:42] but I don't think there is such a need when you just decrease the dose.

[00:28:48] Of course, there are extreme cases that there is some, some kind of diabetes or that diabetes insipidus.

[00:28:55] So in such case, but it is extremely rare.

[00:28:59] This should be discontinued, of course.

[00:29:01] On that topic, Dr. O'Malek have had back and forth conversations about the effective lithium on the kidney.

[00:29:10] And we know that chronic repeated episodes of dehydration can cause acute kidney injury

[00:29:18] and repeatedly over a lifetime can lead to chronic kidney disease.

[00:29:23] How much of lithium's kidney side effects do you think are related to dehydration from polyuria

[00:29:33] and patients not replacing that water versus other direct effects of lithium on the kidney?

[00:29:40] Well, there is some hypothesis linking polyuria and then some kidney injury.

[00:29:48] Generally, high level of lithium and lithium intoxication is definitely risk factor for the kidney.

[00:29:56] But the relationship between lithium polyuria and then nephropathy after several septic reels,

[00:30:06] I don't think there is a good connection with this.

[00:30:08] Okay. And Dr. Gami in that article actually estimated the lifetime incidence on lithium of chronic kidney disease

[00:30:19] at a much lower percent than most of the other literature shows.

[00:30:23] He put it at one to five percent.

[00:30:26] You mean Nasir?

[00:30:28] Nasir?

[00:30:28] Yes.

[00:30:29] Yeah.

[00:30:29] I know him also very well.

[00:30:32] Still, with the new cohorts, risk for lithium for kidney impairment, for kidney injury,

[00:30:41] is not much more than with some other good stabilizers, such as, for example, vulparate or so.

[00:30:48] But definitely in our study among Ixley, there is a slight decline of glomerular filtration late

[00:30:57] with lithium, which is a little bit more than due to aging alone.

[00:31:05] Right. And I wonder if that same effect is consistent, even if you use very low supplemental

[00:31:13] or those very low doses of lithium carbonate over a lifetime, if it carries the same risk.

[00:31:20] I kind of see lithium in a way.

[00:31:23] Describe it in terms of sodium and potassium as well.

[00:31:27] Which, as we know, with sodium and potassium, these are two other electrolytes that we have

[00:31:34] to keep regulated in a certain range in our bloodstream or else they can have disastrous,

[00:31:39] potentially fatal consequences.

[00:31:42] And so I feel like lithium is similar in really high doses.

[00:31:47] It can absolutely be toxic to the brain, to the kidneys.

[00:31:52] But I just don't see that same effect, especially in the ultra low doses.

[00:31:58] And maybe not even in, you know, doses below 450 milligrams of lithium carbonate.

[00:32:04] But I am not a lifetime expert on this.

[00:32:08] What do you think of that?

[00:32:09] Well, I think that definitely the incidence of kidney injury in our patients who had the mean

[00:32:17] lithium prophylactic level 0.6 was really low.

[00:32:21] So I think that keeping this concentration on 6 and in some patients even a little lower,

[00:32:28] it's for 0.5.

[00:32:30] But I don't have an experience with, you know, very low dose of this.

[00:32:34] Another also controversy.

[00:32:36] Controversive, because some people think that giving lithium in one daily dose is better than in two doses.

[00:32:44] I don't think that it is true.

[00:32:47] Most of my patients are taking lithium and dividing two doses.

[00:32:53] Yes, I was taught that by doing one daily dose that you can create a significant reduction in the

[00:33:03] potential for chronic kidney disease.

[00:33:05] But you don't feel like that's the case?

[00:33:07] No, no, no.

[00:33:07] I don't think that is, that there is no proof of this, no.

[00:33:11] Okay.

[00:33:12] When you talk to patients about starting lithium,

[00:33:15] how long do you counsel them that it will take to see the benefits of it?

[00:33:20] Well, it's just preliminary talk, I think.

[00:33:23] If I argue them about the benefits of lithium, they consent, they agree.

[00:33:32] Just one talk.

[00:33:35] What do you make of this idea of super responders

[00:33:38] and how long it takes for them to have a benefit from lithium

[00:33:42] versus the general benefit of somebody who would not be described as a super responder?

[00:33:48] Yes.

[00:33:49] So what was called by Paul Groff, excellent lithium responders, right?

[00:33:54] Or restitio in integrum, right?

[00:33:58] That's my new Latin phrase is restitio in integrum.

[00:34:02] You know, incidentally, this concept of excellent lithium responders

[00:34:06] was given on the conference in Kentucky, in Lexington, Kentucky,

[00:34:12] who was taking place in 1999.

[00:34:15] I didn't know that.

[00:34:16] Yeah, yeah.

[00:34:17] By Paul Groff, he put the term excellent lithium responders

[00:34:22] for patients who, during the mostly monotherapy with lithium,

[00:34:27] don't have any recurrences.

[00:34:30] And just after this, we did some study for 10 years with patients

[00:34:35] studying lithium in the 70s and in 80s.

[00:34:39] Then we found that both group of patients had the percentage of lithium responded on one third.

[00:34:47] So in one third of bipolar patients, monotherapy with lithium can just make them completely,

[00:34:55] you know, healthy, provided the lithium will be given them.

[00:35:00] Right. And restitio in integrum, just for my listeners, in Latin, it means restoration to the original condition,

[00:35:08] or this idea that somebody who has an underlying biologic severe mental illness with the introduction of lithium

[00:35:18] can be restored to their original condition and not deal with the ups and downs throughout life that they would have otherwise without lithium.

[00:35:27] You know, it applies to 20 to 30% of bipolar patients.

[00:35:33] And what we also found that in our father's study that these X-mened lithium responders have cognitive functions

[00:35:43] on the level of a normal person in some areas even exceeded them.

[00:35:48] And then also the concentration of BDNF in the cerebral, in plasma, which is something some people make hypothesis

[00:35:58] that the low level of BDNF, it's a marker of late stage of bipolar disorder.

[00:36:06] And our patient, an excellent lithium responder, even if they had history of illness 20 or 30 years

[00:36:13] and being on lithium, the BDNF was the same as in a health person.

[00:36:19] I've seen research, I believe in animal research in rats, where lithium actually, to speak to your,

[00:36:27] what you said about the pro-cognitive benefit that you have seen in some lithium super responders,

[00:36:34] is these animal studies that show that lithium is actually able to stimulate neurogenesis in the hippocampus

[00:36:42] or the long-term memory centers of the brain.

[00:36:45] So if you extrapolate that to humans, then that would explain at least some of the kind of pro-cognition effect

[00:36:54] that you might see in somebody who's a super responder.

[00:36:58] Well, there is some discrepancy between experimental and clinical observations.

[00:37:04] So in all experimental observations, lithium has pro-cognitive action.

[00:37:12] And as far as a clinical situation is concerned, some clinicians told that patients just have some cognitive complaints.

[00:37:21] As I told you, these excellent insulin responders are absolutely fine with this.

[00:37:26] So definitely, these cognitive complaints on lithium can be connected with the level.

[00:37:34] Probably the decreased level of lithium just can be beneficial for their cognition.

[00:37:42] Have you read the book of Kaidyanis' Unquiet Mind?

[00:37:46] Yeah.

[00:37:46] And in some place, she says about decreasing level of lithium and better functioning as far as cognition is concerned.

[00:37:57] And you know, Kay Jamieson was Dr. Elmalik's mentor when he was in training.

[00:38:04] Yeah.

[00:38:05] I see.

[00:38:05] Initially, it was Kay Jamieson's husband, maybe Dr. White.

[00:38:11] Richard Dwyer.

[00:38:12] Wyatt.

[00:38:12] Yeah, Wyatt.

[00:38:12] And Dr. Wyatt said, I think you need to work with my wife.

[00:38:17] And so Dr. Elmalik has so much gratitude for Kay Jamieson and everything that she taught him about manic depression and lithium, et cetera, et cetera.

[00:38:28] One of the reasons why I just love talking to people about their experiences is you see these inner weavings of different people in the profession that, you know, like you know of Dr. Elmalik, but you probably didn't know that he worked directly with Kay Jamieson many years ago.

[00:38:45] So one of the effects that I've had, I take about nine milligrams of elemental lithium a day.

[00:38:53] And one of the effects that I noticed that was very objective was about three to six months later, I stopped having cold sore outbreaks.

[00:39:05] I stopped having HSV related outbreaks.

[00:39:08] And you did some of the original work on lithium's ability to directly inhibit that DNA virus, which lives within us and remains dormant in our system, pops up from time to time when we're having a lot of stress.

[00:39:25] My question, do you think that most people can benefit from supplemental long-term low doses of lithium?

[00:39:35] The lithium effect against herpes infection and cold sores and all this, we did it with Jay Amsterdam from the University of Pennsylvania.

[00:39:44] Then we found that in half of lithium treated patients which have labial herpes infection and vanished completely or the recurrence and significant decrease.

[00:39:54] But they were just having the normal or regular concentration of lithium for this prophylaxis, prophylectic action.

[00:40:05] And as far as the lithium effect of coronavirus is concerned, big study, Belgium, France, UK, the patient with therapeutic lithium level have significantly lower chance of COVID infection than with lower lithium level.

[00:40:23] As far as the anti-herpes effect in Polish group, we also estimated lithium level and red blood cells.

[00:40:33] And we definitely find that the effect was better with higher lithium concentration and higher concentration in red blood cells.

[00:40:39] So as far as the anti-herpes, that definitely is a concentration.

[00:40:45] I cannot, you know, discuss about very, very low lithium level.

[00:40:48] And I was somewhat surprised because I had reviewed all of the evidence on that effect of inhibiting the herpes virus ability to replicate.

[00:41:00] And all of the studies are using doses of, I would say at a minimum, 600 milligrams a day, which is roughly equivalent to elemental lithium of, it might be more than 50 milligrams, but somewhere north of 50.

[00:41:16] 600, 600, it's, it's, it's, it's, it's, it's, you know, whatever, you know.

[00:41:20] Right, right.

[00:41:21] But it was somewhat surprising for me.

[00:41:24] And it changed the way that I thought about that impact.

[00:41:27] When you experience an effect for yourself.

[00:41:31] And I had, when I started medical school, I had one or two outbreaks a year, usually around times of stress or when I would get physically like a viral illness.

[00:41:42] And I have not had one in three years now.

[00:41:46] That is the, the, the best piece of evidence that I can imagine in terms of convincing me that even the low supplemental doses may have this ability to inhibit that viral replication.

[00:41:59] So it makes me wonder about using these really low doses over time for some of the other benefits.

[00:42:08] And again, like I've mentioned before, if it's given enough time, can those benefits build over time?

[00:42:16] And go ahead.

[00:42:19] Yeah, yeah.

[00:42:20] Because it's, it's, it's very interesting observation, but I don't have this because I have only observation with this, you know, regular level of, of listening.

[00:42:27] Right. And it's interesting to me because the lower the dose, the less likely you are to have the side effect.

[00:42:35] The side effects are very dose dependent and blood level dependent.

[00:42:38] And if I can get clinical efficacy, even at doses lower than what will reveal a 0.5 or a 0.6 blood level, that to me means that I have an even greater benefit to risk ratio of this drug.

[00:42:55] Did you see doctors?

[00:42:57] I think his name is Carlos Spuch, a Spanish researcher.

[00:43:01] He worked with Dr.

[00:43:03] Sadeer Gad, who is in New York city and works in addiction.

[00:43:09] They did a study of 28 bipolar patients that were all admitted to the hospital with COVID.

[00:43:16] 14 of them were on lithium.

[00:43:19] 14 were on other mood stabilizers.

[00:43:21] But the interesting thing that they did is they measured 18 different inflammatory markers throughout their hospitalization.

[00:43:30] A lot of different interleukins primarily.

[00:43:33] And what they found was outcomes wise, nobody on lithium ended up in the ICU.

[00:43:39] So they already had COVID.

[00:43:42] It didn't prevent the infection.

[00:43:43] But what it did seem to prevent was the over aggressive immune reaction after COVID.

[00:43:51] Typically what leads to somebody's lungs getting overwhelmed with immune cell debris and impairing oxygen carbon dioxide exchange.

[00:44:00] So that study was another really interesting one in terms of illuminating how lithium may have that effectiveness against COVID.

[00:44:11] Do you have anything to add about COVID?

[00:44:13] I know.

[00:44:14] I know that it's on the paper about lithium and COVID in clinical settings.

[00:44:23] If you were to rank every psychiatric drug or chemical for all conditions in terms of a benefit to risk ratio, where would you rank it?

[00:44:33] And then why do you think it is so underutilized?

[00:44:35] I think there are two main reasons.

[00:44:38] One is, you know, introduction of many other drugs having a mood-stabular effect and heavy promotion of these drugs by pharmaceutical companies.

[00:44:49] Why lithium from this point of view is kind of orphan drug.

[00:44:53] And any pharmaceutical company stands after lithium.

[00:44:57] The second reason for lithium being underutilized, it is considered as an old drug and a toxic drug and having many side effects.

[00:45:11] And this approach is definitely very common among the general practitioner, but it can be also found in psychiatrists.

[00:45:23] So the second reason is that lithium is considered as an old drug and toxic drug and having side effect.

[00:45:30] The concentration should be estimated.

[00:45:33] And this approach is absolutely common against general practitioners, other specialties, but in some small percentage of psychiatrists, it is also present.

[00:45:46] Right.

[00:45:47] And when I learned about lithium, I learned all about its horrible side effects and how dangerous it was.

[00:45:55] And I didn't use it for a while.

[00:45:58] Luckily, I did work with Dr.

[00:46:01] Al-Malik, who helped me to be a more critically thinking psychiatrist.

[00:46:06] And again, when I started to use more lithium, I just started to see my patients doing better as a whole.

[00:46:14] Not that it is the right drug for everybody, but in terms of where I rank it, I just don't see any other medication that I use regularly that has the same benefit.

[00:46:27] And the risks are, they're so overblown compared to the actual risk that I see in my patients.

[00:46:35] And again, part of that is because I do tend to probably, you would probably consider me underdosing it, but I am seeing the effects build over time if I can give it enough time.

[00:46:47] In terms of using those low doses, one of the things that Nasir Gami talks about and believes in is mood temperaments, hyperthymia, cyclothymia.

[00:46:59] I'm curious as to what is your perspective on lithium's role in mood temperaments, both with and without comorbid, bipolar or manic depressive illness?

[00:47:10] I don't have any experience to begin with, but about this exaggerating side effect of lithium.

[00:47:19] I became now the guest editor of special issue of General Pharmaceutical devoted to the 75th anniversary of lithium introduction.

[00:47:28] And it's the first paper is already available, which is freely available to pharmaceuticals, authored by Bob Post and myself.

[00:47:38] It is entitled, what patient with bipolar disorder should know about lithium.

[00:47:44] So you can take it from PubMed, underline this exaggeration of lithium side effects.

[00:47:51] As is, you know, bipolar spectrum or even, you know, bipolar temperament and using lithium.

[00:47:57] I don't have any experience.

[00:47:59] What about does the safety profile of lower doses, does it change significantly in the elderly as long as you factor in that they have a more porous or open blood brain barrier in your dosing?

[00:48:14] I think that definitely in our patients, which were on lithium for 40 or 50 years or more, we definitely reduce the dose of lithium when they were 60 or more.

[00:48:30] It's recommended to reduce the dose.

[00:48:33] In your experience, has it still been a very safe drug to use even in older patients?

[00:48:40] Yes, yes.

[00:48:41] Provided we have adequate dose as low as possible, of course.

[00:48:46] Right.

[00:48:46] One thing that I've noticed in my lithium treated patients, probably the worst quote unquote side effect is actually with abrupt discontinuation of lithium.

[00:48:57] And the return of lithium and the return of lithium and the return of lithium and the return of debilitating symptoms like suicidality, recurrence of mania and depression, possible susceptibility to viral illnesses or HSV outbreaks.

[00:49:11] How serious is lithium withdrawal or abrupt discontinuation?

[00:49:17] And is there a risk of creating any sort of rapid cycling if a patient is going on and off of their lithium repeatedly?

[00:49:24] I think that the most data of the reverse effect of lithium discontinuation applies to patients with bipolar 1.

[00:49:33] Not bipolar 2.

[00:49:35] Lithium is not used so frequently.

[00:49:38] But definitely as far as bipolar 1 is concerned, discontinuation of lithium can have very detrimental effects such as recurrence and resistant occurs of this.

[00:49:50] However, there was later paper.

[00:49:53] First author was the Netherlands author, Ralph Kupka.

[00:49:58] And they did the meta-analysis of old lithium discontinuation and then resuming lithium.

[00:50:06] What they found that very bad effect was only 15% of patients and the rest after resuming lithium was doing very well.

[00:50:14] That's good to know.

[00:50:16] What are your most exciting areas of research in psychiatry moving forward?

[00:50:22] You mean not only lithium, but generally?

[00:50:24] If there's something exciting about lithium coming down the pipeline, then that would be fine.

[00:50:29] But yeah, in general, either one, either or.

[00:50:31] Well, I think that still some theoretician of psychopharmacology like Edward Shorter said that it's a form of psychopharmacology.

[00:50:42] And I think that psychopharmacology is alive and well.

[00:50:46] There are new drugs, not much antidepressant, but antipsychotic.

[00:50:50] They can make the patients in the way of the precision medicine to do better.

[00:50:57] And I think that the problem with lithium is to make some battles about the utilization of lithium in more patients.

[00:51:08] That the mold could be beneficiary of lithium.

[00:51:13] I don't have many experiments with the new psychedelic drugs.

[00:51:18] I have some experience with ketamine.

[00:51:20] But ketamine, now it's S-ketamine with nasal spray.

[00:51:26] But I have some experience also with intravenous ketamine, which was also good antidepressant and bipolar resistant depression on lithium or some other wood stabilizers.

[00:51:40] My son, in his center, will be doing some project of psilocybin in depression, which is kind of international project.

[00:51:53] And the main investigator, Guy Goodwin from Oxford, which is the previous chairman, I think it is.

[00:52:01] That will be exciting if we have a treatment in psilocybin moving forward that patients can utilize for a short amount of time and then have these long-lasting benefits, even without repeated administrations of the drug.

[00:52:17] I think we have a culture of drugs being something that need to be taken every single day.

[00:52:25] And that clearly benefits some entities that have a vested financial interest, but it may not be the best way to do things medically.

[00:52:36] If we can intermittently administer a drug that can have sustained and long-lasting benefits, then we'll almost assuredly have a less severe side effect profile.

[00:52:48] I worry that the psychedelics will have a hard time getting approved here in the United States because they will not be an everyday drug.

[00:53:01] There may not be enough money to be made off of them, similar to lithium in the fact that I prescribe a 90-day course of lithium to a patient and they pay $8 for it at the pharmacy without insurance.

[00:53:15] So I'm a little bit skeptical.

[00:53:46] So I'm a little bit skeptical.

[00:53:46] I don't know what the actual long-term effect profile of a drug is until it's been out for 15 or 20 years.

[00:53:52] So don't bite on the newest, hottest state-of-the-art drug that comes out until you have more information.

[00:53:59] You know, now for me, you know, the later part of my career, the aims are to keep pace with what's new in psychopharmacology and then the use what I know, my knowledge to help as much as many patients as possible.

[00:54:17] All right. I have one more question.

[00:54:19] And it's a big question.

[00:54:21] And it's something that I think a lot of people that go into the field of psychiatry are curious about.

[00:54:27] And there's a lot of different opinions on it.

[00:54:30] But what is consciousness?

[00:54:32] And how do you describe mental illness within the construct of whatever consciousness is?

[00:54:39] As a matter of fact, together with my son, we publish some paper about the new in Psychiatria Polska, in Polish.

[00:54:49] But it is in PubMed about the consciousness in the evolutionary and neurobiological background of this, taking mostly experiences of the American biggest scientists such as Joseph Ledoux, Antonio Damasio, Robert Leger, and then recently passed away very big scientists of consciousness.

[00:55:17] You mean how I perceive the mental illness in the context of consciousness, something like this?

[00:55:24] In relation to our unique human ability to be aware of ourselves and be aware of processes that are happening inside of our brain that are more subconscious or that we don't have total voluntary control over.

[00:55:42] Well, it's connected with the phenomenon of insight.

[00:55:47] Definitely, definitely in schizophrenia, there is a problem of lacking of insight.

[00:55:55] But as far as mood disorders are concerned, I don't think there is a great disturbance of consciousness.

[00:56:02] I think that it can be also relevant to so-called altered states of consciousness with all this psychedelic drug.

[00:56:13] But I don't see an issue of consciousness with mood disorder patients.

[00:56:19] They have kind of extreme feelings for ups and downs, but I think their consciousness should be intact.

[00:56:26] What about the floridly manic patient?

[00:56:30] The very severe mania where the person has an episode, but then they come out of it.

[00:56:36] And in my experience, sometimes they do not have any memory of what happened during the episode.

[00:56:44] Almost like they lost consciousness.

[00:56:47] I don't see it so much with episodes of depression, but I guess you could look at another kind of the severe end of that and looking at catatonia.

[00:56:57] And I haven't actually thought about that or ask patients who have been catatonic how much they remember about their that time where they were not eating, not drinking, not moving.

[00:57:09] But I certainly have seen it in very, very manic patients before they get any treatment.

[00:57:15] And then after a few days of lithium or an antipsychotic that brings them down a little bit faster, then they don't have this great memory of what happened during the manic period of the episode.

[00:57:30] Well, such patients, I think, may exist, but some manic patients have some remorse while being in depression, what they did when being manic.

[00:57:41] So they must have remembered, you know, this.

[00:57:44] And I think that this disturbance of consciousness, of course, in very severe mania, but probably in some kind of schizoaffective also psychosis with great intensive dog symptoms.

[00:58:00] So, OK, in some manic patients with extreme mania, they may be disturbed by the consciousness.

[00:58:05] OK, and then with schizophrenia, I just thought of this while you were talking about it.

[00:58:12] Suicide in schizophrenia is such a major consideration as a clinician, something that you it is difficult to predict.

[00:58:21] It's very impulsive.

[00:58:24] Do you use any sort of dose of lithium or do you recommend that for its anti-suicide effect in schizophrenia as an adjunct medication?

[00:58:35] Well, I think that definitely clozapine was found to have anti-suicidal action in schizophrenia.

[00:58:42] I don't think if this anti-suicidal action of lithium just extends to schizophrenia.

[00:58:47] Definitely it was proved to move disorder.

[00:58:51] But as far as clozapine, I think that it would be good for the patient with schizophrenia having suicidal tendencies.

[00:59:00] Well, that's all I got for you.

[00:59:01] I really appreciate your time.

[00:59:03] It was wonderful to talk to you and to learn a little bit more about, you know, your history in psychiatry, as well as it's just great to talk to somebody who has been using lithium for a long time.

[00:59:18] You have a lot of experience with it.

[00:59:20] And I really do appreciate coming on for my listeners, but also coming on and talking to me and corresponding with me, even though I'm like I said, I'm a small fish in a small pond.

[00:59:32] So I really do appreciate it.

[00:59:34] It was also my great pleasure just talking to you here.

[00:59:40] Absolutely.

[00:59:41] All right.

[00:59:41] Well, you have a good rest of your day and hopefully you have a good weekend and I will hopefully talk to you soon.

[00:59:47] I can do PDF of this article.

[00:59:49] Okay.

[00:59:49] Perfect.

[00:59:50] Perfect.

[00:59:50] Perfect.

[00:59:51] All right.

[00:59:51] You have a good day.

[00:59:53] Yeah.

[00:59:56] Thanks again for watching and or listening.

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