Lithium, the GOAT: Guest Intro, Rifaat El-Mallakh, MD

Ethan: For this series, we have joining us a world-renowned expert in bipolar disorder, Dr. Rifaat El Mallakh, Dr. El Mallakh is a faculty member at the University of Louisville, working in the psychiatric emergency room, running a weekly outpatient bipolar clinic, and contributing to the inpatient and consult psychiatry services, among so many other roles. He was and still is one of my most trusted, available and genuine mentors throughout my training. He has authored more than 300 scholarly papers with well over 5,000 citations (H-index 54). On a more personal note, I appreciate Dr. El Mallakh as a [00:01:00] teacher because he is always available and willing to field questions and engage in nuanced discussions, even with much lesser-trained and less knowledgeable students and residents. He is straightforward and will tell you when you are flat-out wrong, but then also listen intently and genuinely contemplate your side of an argument. He pushes trainees to use critical thinking skills, and consider the pathophysiology of our diseases, and the mechanisms of action of our medications. He engages with and educates his patients on their conditions, and dedicates his time, energy and efforts towards improving their lives and outcomes. He works with and listens to his patients, and most importantly, spends time getting to know them as human beings, not just as diagnostic profiles. And time is not something he has a lot of. He's constantly on the go, attending local, [00:02:00] regional, national, and international conferences, going to (drug) dinners, going to Grand Rounds (presentations), and independently evaluates the outcomes of treatments, regardless of who funded the research or any associations or affiliations he may have. He stands as a pillar of the bipolar community, but also takes care of the little guys, taking so many students and residents under his wing, helping them get into medical school, get through residency or facilitate entry into the job market. Dr. El Mallakh, tell me a little bit about your professional journey.

Rif: It starts with college, where we establish our interests as we get to know the world. I majored in biology and was very interested in mechanisms. I was interested in WHY. And biology, of course, is a wonderful field because you can see a lot about humans in biology, particularly in evolution and [00:03:00] medicine. Of course, the concept of evolution, of some selective process is actually ultimately very informative in understanding how we got to be where we are as organisms. Because I was interested in the WHY, that immediately led me to research because ultimately research is about the WHY. Initially, I got very interested in insects, actually, entomology, and I did my master's degree and I started out in entomology, had trouble with my advisor and switched, so I ended up doing my degree in genetics. My second advisor actually recommended neuroscience. At the same time. my mom said, ‘Go to medical school, young man.’ I'm a good boy, so I [00:04:00] did what my mom told me to do, I applied to medical school, not because I was really interested in medicine, but I was interested in biology and medicine is just a form of biology. But I applied to medical school specifically because my mom told me to. When I was in medical school, the advice of my masters’ advisor came back, and actually, because of his interest in neuroscience, the last course I took as a master’s student was anatomy, comparative anatomy and neuroanatomy. It was actually a pretty cool course cause we started out dissecting a shark. In the shark, the brain is actually in a straight line. So the cerebellum is at the bottom and then you go up a little bit and you get to the midbrain and you go up a little bit more and you get up [00:05:00] to the thalamus and everything is its own place and it's literally spread out on a straight line. It's really very easy to dissect a shark brain. So we started out with sharks and we had a cow, and actually this was a master's course, but we had a human brain, which was amazing. Each student had their own human brain, so people had donated their brains and, I'm forever appreciative to whoever donated their brain for us.

So I had already studied neuroanatomy before medical school. The other thing that happened was for the last year before I got into medical school, I actually worked as Cat Scan Technician. So I was in a hospital, Rush Hospital up in Chicago. In the 1970s, CaT scans were new enough that actually X-ray [00:06:00] technicians did not learn about CaT scans in X-ray technology school. It was just all brand new. As a matter of fact, the machine I worked on was an EMI machine, Electronic Musical Instruments. EMI was the company that came up with the first human CaT scan. The serial number of the machine that I ran, it was a clinical machine dedicated only to heads, was TWO.

Ethan: Did you realize that then, that you were operating the second machine that EMI made .

Rif: The second machine of that series, but yes. Nowadays, of course, you can have an entire CaT scan done in 2 minutes. In those days, to do one full Cat scan of the brain, one series took half an hour. A patient had to hold still for a minute and a half for each slice, and then you did [00:07:00] 12 to 15 slices depending on where you started. It was really cool. It was a nice job. I really liked it. I would always talk to the neuroradiologist and if there was an emergency, they would actually come into the room and they would explain things to me. And this was before medical school, but I had already taken this comparative neuroanatomy class in college for my masters, so this was just a continuation. From there, it was really an easy decision to do neurology. I knew a lot about anatomy, I was interested in mechanisms, and so I went to medical school at University of Illinois, but then for residency, I went to University of Connecticut and I started out in the neurology program. It was a bit frustrating to do clinical neurology [00:08:00] because like I said, I was interested in why. And in clinical neurology, all you learn is where. Clinical neurology is all about finding the lesion. It's all about anatomic destruction. There's several neurologic diseases that aren't about anatomical destruction, although they involve anatomical destruction, things like Huntington's and Alzheimer's, and Parkinson's. Why do these diseases happen? In those days. CT and MRI were brand new, and neurology got stuck in this whole thing of describing old diseases with a new technology. So all my educators, all my mentors, that's all they were doing, ‘Oh, this is what a stroke looks like. This is what a bleed looks like. This is [00:09:00] what loss of tissue looks like,’ and it was just… Boring. It's not too boring, but there was no why. It was all where. The interesting research in those days was all being done in psychiatry. In psychiatry, we have no anatomy, everything looks normal with our technologies. Physical exam looks normal. And so we had to actually be smarter, do studies that told you how cells and chemicals worked inside the skull that you couldn't get through without hurting your research subject. The research was very interesting and obviously very challenging. It still is. It was just fascinating.

So, after 2 years of neurology, switched to psychiatry. I stayed at the University of Connecticut. I went from being a [00:10:00] second-year resident to being a second-year resident again, but that was fine. It was a lot of fun. At the end of residency, I was looking for an academic job, so I can do some kind of research. My chairman and residency training director at University of Connecticut, both recommended I go to the National Institutes of Health (NIH), and do a research fellowship. I looked into it and my wife was kind enough to continue to sort of follow me. She had followed me from Illinois to Connecticut and now down to Washington DC, and I did a 3-year Research Fellowship with Dr. Richard Wyatt. I'm so thankful to that man. He was an amazingly patient human being, and really excellent researcher. Nowadays, we take the observation that psychosis [00:11:00] can actually damage brain tissue for granted, as a given. It was Dr. Wyatt who actually thought of that as a possibility, and he was doing a lot of the early research too. Understand that he was already then researching something called trace amines. So now, 50 years later, trace amines are finally making it clinically. So there's now a drug that works at a trace amine receptor. It's an intracellular receptor that may end up being an anti-psychotic. It was Dr. Wyatt who started studying trace amines and schizophrenia 50 years ago. It's unfortunate most people don't realize that. Modern medicine removes personality out of the picture. So [00:12:00] you can have people that were pioneers and nobody ever knows who they were.

Ethan: One person ends up getting the credit, but inevitably it's going to be hundreds, if not thousands, if not millions, of people that came before them to build the blocks to get you there.

Rif: Absolutely. But it is important to at least recognize the people that sort of maybe had the vision to begin looking into something. Dr. Wyatt also gave me a tremendous amount of freedom. He was actually married to Kay Jamison. Of course, people know her in two separate ways. So she is the co-author of the major textbook about bipolar illness, and wrote it with Dr. Goodwin. She also wrote some other biographical works about her own bipolar illness. [00:13:00] She was very interested in the overlap of the arts with bipolar illness. She went to England, and found that mood disorders existed in 60% of these poets, award-winning poets. A lot of people write poetry, but these are folks that actually got awards. The majority of them had a mood disorder. 40% had bipolar illness, which only is found in 1% of the population, was found in 40% of award-winning poets.

Ethan: Wow.

Rif: Since she happened to be my advisor's wife, what more can you ask for, my God! He was studying mainly schizophrenia. I was interested in bipolar illness. He gave me full freedom to do that. During those three years that I spent doing that fellowship we developed the original sodium pump hypothesis, which is still now, almost 40 years [00:14:00] later, the focus of my research.

Ethan: A mix between things that interest you and proximity and kind of randomness to switching mentors and your second mentor's wife being somebody who suffers with bipolar illness and also studies it for a living.

Rif: Right. So much of life is accident, right, sort of just random events. But all of them leading me down a very pleasant and maybe unique path.

Ethan: I have a tremendous amount of respect for him, and I'm delighted and excited to have him on to talk about one of the most important drugs in the history of psychiatry, Lithium.