Dr. Charles Nemeroff is Chair of the Department of Psychiatry and Behavioral Sciences at the University of Texas-Austin's Dell Medical School. He is also co-director of the Center for Psychedelic Research and Therapy, and director of the Institute for Early Life Adversity Research. His research is focused on the pathophysiology of mood and anxiety disorders with a focus on the role of child abuse and neglect as a major risk factor.
00:00 Introduction
00:52 Dr. Nemeroff's Research Journey
01:55 Childhood Maltreatment as Risk Factor
04:53 Advances and Challenges in Precision Psychiatry
07:33 Psychedelic Medicine (incl. blinding issues and potential adverse events)
20:50 How Psychedelics Disrupt the "Circle of Hell"
30:00 Psilocybin as Potential Treatment for Anorexia Nervosa
38:32 Screening for Childhood Maltreatment
41:30 Transcranial Magnetic Stimulation (TMS)
44:14 Focused Ultrasound
46:32 Prescribing MAOIs
49:34 Conclusion
Visit our website for more insights on psychiatry.
Podcast producer: Jon Earle
Dr. Charles Nemeroff is Chair of the Department of Psychiatry and Behavioral Sciences at the University of Texas-Austin's Dell Medical School. He is also co-director of the Center for Psychedelic Research and Therapy, and director of the Institute for Early Life Adversity Research. His research is focused on the pathophysiology of mood and anxiety disorders with a focus on the role of child abuse and neglect as a major risk factor.
00:00 Introduction
00:52 Dr. Nemeroff's Research Journey
01:55 Childhood Maltreatment as Risk Factor
04:53 Advances and Challenges in Precision Psychiatry
07:33 Psychedelic Medicine (incl. blinding issues and potential adverse events)
20:50 How Psychedelics Disrupt the "Circle of Hell"
30:00 Psilocybin as Potential Treatment for Anorexia Nervosa
38:32 Screening for Childhood Maltreatment
41:30 Transcranial Magnetic Stimulation (TMS)
44:14 Focused Ultrasound
46:32 Prescribing MAOIs
49:34 Conclusion
Visit our website for more insights on psychiatry.
Podcast producer: Jon Earle
NOTE: Transcripts of our episodes are made available as soon as possible and may contain errors. Please check the corresponding audio before quoting in print.
DR. THEA GALLAGHER:
Welcome to NYU Langone Insights on Psychiatry, a clinician's guide to the latest psychiatric research. I'm Dr. Thea Gallagher. Each episode I interview a leading psychiatric researcher about how their work is shaping clinical practice. Today, I'm pleased to welcome Dr. Charles Nemeroff, chair of the Department of Psychiatry and Behavioral Sciences at UT Austin's Dell Medical School. Dr. Nemeroff is also director of the Institute for Early Life Adversity Research and Co-Director of the Center for Psychedelic Research and Therapy. In our conversation, Dr. Nemeroff delves into the complexities of mood disorders, emphasizing the need for precision treatment and early intervention. He also explores psychedelic medicine, genetically tailored treatments, and the lasting impact of childhood trauma.
Dr. Nemeroff, thank you so much for being with us today on the podcast.
DR. CHARLES NEMEROFF:
It's my absolute pleasure.
DR. THEA GALLAGHER:
Wonderful. Well, we're going to just jump right in. And can you give us an overview of your research journey and what drew you to focus on the neurobiology of mood disorders?
DR. CHARLES NEMEROFF:
I started my career in basic neuroscience, and was interested in very basic brain mechanisms related to stress. And following my PhD degree in neurobiology, I enrolled in medical school after a postdoctoral fellowship in research. I wanted to blend my strengths in neuroscience with my budding strengths in psychiatry. And as I went through residency training in psychiatry, I focused largely on patients with mood and anxiety disorders and then focused even more specifically on a group of patients that were relatively resistant to treatment. And it turned out that many of those had a history of childhood maltreatment.
DR. THEA GALLAGHER:
Very interesting. And from that kind of insight, what findings came out of that?
DR. CHARLES NEMEROFF:
After 25 years of doing this research, it's been quite a sojourn. And so in the beginning I did laboratory work that suggested that early life stress in laboratory animals, either maternal separation as a model of early life stress resulted in changes in the brain and in the body that persisted for the lifetime of the adult. And then we moved those preclinical studies to clinical studies and started studying patients with depression or PTSD with or without early life trauma experience and were able to determine a number of factors that conspired to increase vulnerability to depression, bipolar disorder, and PTSD. And one of the biggest factors turned out to be child abuse and neglect. In the course of doing these studies, we realized that this was the ultimate gene-by-environment interaction model. There are lots and lots of data in all kinds of medical subspecialties that would suggest that if you're genetically vulnerable for something and then you have an environmental perturbation that promotes that disease vulnerability, you're more likely to get the disease.
The prototype would be lung cancer. You may have a propensity for lung cancer, but if you never smoke, you might never get it. But if you have genetic vulnerability and smoke four packs a day, then it's pretty likely that you'll end up getting lung cancer. Well, we discovered that for folks that were genetically vulnerable to depression or PTSD by virtue of changes in their genome, just mutations that spontaneously occur, those people who experience early life trauma and remember that the human brain doesn't develop until age 24 fully, so that the developing brain is very vulnerable to insult. If you have genetic vulnerability for a major psychiatric disorder and then on top of that you're exposed to untoward early life events, sexual abuse, physical abuse, emotional abuse or neglect, that markedly increases your risk to develop these disorders.
DR. THEA GALLAGHER:
Mm-hmm. Yeah. And a lot of the episodes of this podcast have focused on precision medicine and understanding why certain individuals are more treatment refractory or why even they might have more risk factors to developing certain types of mental illness. And it sounds like that's what this work has done. And are these things that you hope in practice more psychiatrists and medical professionals will be able to look for, measure and make clinical assessment and judgments as a result?
DR. CHARLES NEMEROFF:
There's good news and bad news. Let me start with the bad news. We just finished a very comprehensive review of the entire pharmacogenomics platforms that are available to clinicians that claim to predict which medications a particular patient will respond to as regards to an antidepressant in patients with major depression. And this summary is in press in the American Journal of Psychiatry. And our conclusion unfortunately is that none of the currently commercially available laboratory tests that claim they can predict antidepressant response to one or another antidepressant has any validity at all. It's wasting patient's time and money, as well as third-party payers. Having said that, I think the future of personalized medicine in psychiatry is really bright, and I think that we're getting better and better at what's known as polygenic risk scores so that we can identify patients who are at very high risk for schizophrenia, for PTSD, for major depression, I think that will become clinically useful. But in terms of predicting treatment response, I think it is the future, but it's not ready now.
DR. THEA GALLAGHER:
Okay. But it sounds like better findings that are going to lead toward maybe diagnostic criteria for severe and persistent mental illness, but not necessarily for the treatment portion. That's where the research needs to continue to grow.
DR. CHARLES NEMEROFF:
Yeah. I think all of us would agree that western medicine in general and psychiatry in particular currently by and large treats people when they are symptomatic. And what we'd like to do, partly because we have workforce shortages, is we'd like to identify an at-risk population and perhaps intercede early before they have that first manic episode, psychotic episode or depressive episode. And I think we are moving in that direction.
DR. THEA GALLAGHER:
Yeah. Well that is promising and exciting to see that this hopefully can ultimately translate to the appropriate and the most effective treatments for patients as well. And speaking of novel treatments, you're one of the growing number of researchers who are studying psychedelic medicine right now. Which piece of the puzzle are you currently working on and why are you focusing your efforts there?
DR. CHARLES NEMEROFF:
In terms of my own research in our department here at Dell Medical School, we want to apply scientific rigor to a field that is just rapidly escalating. You know that you can't look at any social media site or any lay public scientific journal without hearing about psychedelics. And this is a huge topic in America today. And fundamentally, people view psychedelics as a panacea and others view it as a peril. And we would like to focus on what's the data, right? Who are they good for, who are they not good for? And I would limit my comments to the use of these substances to treat psychiatric illness. A whole separate subject is where the people without a psychiatric illness could benefit in some kind of spiritual way from the use of psychedelics, but that's not what we're talking about. We're talking about is there a role for psychedelics in the treatment of refractory depression, refractory PTSD, refractory alcohol use disorder, nicotine dependence, perhaps opiate dependence, anorexia, those kinds of disorders.
And so if you look at the current data, I would start off and say that the MDMA clinical trials for the treatment of PTSD shows the most robust clinical advantage of that agent compared to placebo. These are largely patients with severe PTSD that have failed FDA approved treatments. And the company that sponsors, which is called MAPS, they just changed their name, I have no idea what the new name is, has three fundamental randomized controlled trials that show a real effect of MDMA in these patients really suffering with PTSD. But remember that like all of the psychedelic trials, and unlike any other trial in medicine, they're not blinded, right? Because the patients know when they take a psychedelic and the observers rating them could tell they've taken a psychedelic. They're randomized controlled, but not really double blinded studies. And that's a confound in these studies.
But in spite of that, the MDMA data for PTSD is inordinately positive. It's a big clinical effect. Now, how that's going to roll out as a commercial product is something we could talk about later. But from a scientific point of view, it's interesting. There's a recent study in Nature Medicine by Nolan Williams at Stanford who took the psychedelic ibogaine and treated patients in an open study with traumatic brain injury and PTSD and obtained phenomenal results. It was an open study, but nevertheless, the magnitude of the effect was remarkable. And then there are the psilocybin studies. There have been multiple psilocybin studies with usually either one, two or three dosings separated by a certain period, and there's very clear clinically and statistically significant effects in ameliorating depression, largely in a treatment resistant population. The magnitude of the effect is clear, but not as great as was seen in the MDMA PTSD studies.
And again, there is the issue of blinding. And in both the MDMA and the psilocybin studies, it's coupled with a form of psychotherapy. It's generally viewed as a combination of psychedelics and some form of psychotherapy. There are some outstanding questions here. The first is, do you have to have a psychedelic experience in order to have a benefit? To put another way, can you take a low dose known as a microdose of psilocybin every day and can you end up with a therapeutic benefit? If that's the case, that would be a game changer because currently when you administer a psychedelic, the patient's going to be with you for six to eight hours while they have this very intense experience, they have to be driven home by a family member, then they come back for so-called integration sessions. No one knows whether micro dosing is going to work. If you go on the internet, there are a ton of anecdotal reports from various people saying, I've been microdosing with psilocybin or LSD for two months, three months, and it's dramatically changed my life. Michael Pollan wrote a book about how LSD micro dosing changed his life, became a bestseller, but we don't have any really good control data in this regard.
DR. THEA GALLAGHER:
And is the hope if we do have the data, that people would be able to microdose on their own without the six to eight hour experience and the subsequent integration session so that it might have greater accessibility?
DR. CHARLES NEMEROFF:
Well, all of what you just asked is completely unknown. First, we have to know whether micro dosing is going to be effective. Secondly, the issue of widespread exposure of these drugs is a naughty problem. As you I'm sure know that in the 1970s, the Nixon administration fundamentally outlawed all psychedelic research, and the field was completely nascent for many years until a group in the United Kingdom started doing psilocybin studies looking at patients with depression. And that turned out to be a game changer because there was clear evidence of efficacy in patients that had previously failed all other treatments. There's now a resurgence for a number of startup companies that have psychedelic products and they're in one or another stage of clinical trials. There are a couple of other forces that are going on that are good, and then there's some that are concerning.
What's good is that the National Institutes of Health have now agreed to begin to support psychedelic research. And so that will absolutely result in a number of well-designed studies, peer-reviewed studies, which will help us answer a lot of questions. On the other hand, as you I'm sure know, that certain states have legalized psilocybin and other psychedelics, Oregon being the first state. And this has been done in a demedicalized model so that fundamentally in Oregon you can go to the mushroom store where the mushroom dispenser will recommend that you take a dose of three grams of mushrooms. The problem with that is mushrooms vary in their concentration of psychedelics. Three grams of one mushroom might be giving you more or less of a psychedelic psilocybin than three grams of another mushroom. You then take the mushrooms that you've purchased to a practitioner who has been trained via the internet for a certain number of hours, but there will be no medical screening of you, and there will be no medical guidance or monitoring during the course of your psychedelic experience.
Now we know that psychedelics increased blood pressure. We know that patients with cardiac disease could be at risk for having a more serious adverse event from a psychedelic. And I published a report in the last year, last December's American Journal of Psychiatry of a patient of mine who had a terrible psychotic episode after taking mushrooms on two consecutive days, and that patient did not recover for about nine months and required inpatient hospitalization followed by very severe depression. Thankfully, she's doing well now. If you step back for a minute and think about it, a couple of really important questions arise. One is, if you have a family history of bipolar disorder, schizophrenia or severe depression, is it a good idea for you to take psychedelics? Because will it flip you into a psychotic episode or a manic episode? And there are case reports that that's happened, and none of the procedures, at least in Oregon, are going to screen for any family history of psychiatric disorder.
That's one concern. The second is who is going to provide oversight to the widespread availability of psychedelics, right? It's obviously not going to be the state medical board. Who is going to determine the medical oversight of delivering these very powerful medications? And my concern is that in the spirit of trying to understand who a psychedelic is good for, who are they not good for, we have to do this research and I don't want there to be a series of adverse events that throws us back into the Nixonian era. These are really powerful medications.
DR. THEA GALLAGHER:
Yeah. And it sounds like this is where your scientific rigor comes into play, and the other psilocybin researchers we were talking to also kind of emphasize understanding. Yeah. Is it understanding the dosage, understanding the environment, understanding how much integration or supervision of the process is needed. And speaking of the scientific rigor, this issue of the blinding, is that just an unavoidable problem because psilocybin is essentially like a PRN kind of medication, if you will?
DR. CHARLES NEMEROFF:
It's a real conundrum, the blinding. And we've talked about this for hours among our research group to try to come up with an idea. One idea is what the current tact has been to use low doses of psilocybin as the control. In the compass studies, they used one milligram, 10 milligrams and 25 milligrams. And the idea was that one milligram was fundamentally placebo. 10 milligrams might tickle you a little bit, but it's not terribly active and 25 milligrams is the full dose. And that is an interesting approach, but it still doesn't help with the blinding. The second approach, which no one's ever done before, is to use virtual reality to create a kind of psychedelic experience that would not be drug related, right? I could slap a virtual reality headset on you, and I could play yellow submarine and have all sorts of cool animation and maybe has the walls breathe in what would be likened to be a psychedelic experience.
That's a possibility as a control. Another idea would be to use psychoactive substances that are not psychedelic like an amphetamine analog. Amphetamine has definite effects, but it's not a psychedelic, but it definitely does change the way you're thinking and feeling at the time. We're proposing to do that in a study to compare MDMA with D-amphetamine as an appropriate control, but I don't know of any other way to get around this problem.
DR. THEA GALLAGHER:
Yeah. Very interesting challenge that it sounds like you're putting a lot of effort and thought into seeing if there's a workaround or a work through. And given some of the promising results of psychedelics in treating treatment-resistant depression or alcohol use disorder, are there certain conditions that you feel more hopeful about with psilocybin? In the future, I know you said also maybe watching out if you have a history of psychotic disorders in your family, maybe that's kind of a warning sign, but are there conditions that you feel more hopeful with and are excited to see where the research goes?
DR. CHARLES NEMEROFF:
Yeah. The way I look at this is I think what psychedelics do is they disrupt what I call the circle of hell that patients go through. Treatment-resistant depressed patients fundamentally sitting around and they have this redundant tape that goes through their mind that fundamentally says, I'm a bad person, I'm a burden on my family, I'm a failure, I've made a huge amount of mistakes in the past, life isn't worth living, I can't enjoy anything. I'd be better off not being here. And this is a tape that plays over and over. For patients with anorexia nervosa, they spend 80% of their time thinking about food, right? They're thinking about how every molecule of food is going to add body weight to me, and they're thinking about, how am I going to get through today where I'm supposed to eat with my mom and she's going to be watching me and I'm going to move my food around on the plate, and as soon as I eat, I'm going to go to the restroom and purge.
Again, it's a tape that runs through their mind. With addiction, it's pretty clear. And I'm sure you're aware of it, and the listeners are that with addiction, your whole life revolves around whatever you're addicted to. And when am I going to get the next dose? How am I going to keep it from everybody? Then after using it, I feel guilty about it over and over and over. And then OCD similarly is obviously a disorder of intrusive thoughts that won't go away that make people miserable. PTSD, those recurring nightmares, the hypervigilance, the avoidance. All of these diseases have one thing in common, which is the default network where your mind goes when you're not engaged in another activity is this tape that constantly runs through your mind that's self-deprecating and miserable. And I think what psychedelics do is they blow that up and they allow you to be able to get out of that rut.
One of the best examples is the studies that have been done in patients with metastatic cancer. If you have metastatic cancer, it is very hard not to think about end of life issues because they're real and they're miserable and they're anxiety provoking and they're frightening. And yet the psychedelic studies that have been done have shown that after a dose of psilocybin, these patients actually have less depression, less anxiety, less concerns about end of life. That's why I believe that whatever the neurobiological mechanism is, I think what they do is allow you to get out of that circle of hell.
DR. THEA GALLAGHER:
It's interesting, this theme that you're tying between all of these conditions, even one that we might say is more of a physical condition, is this feedback loop in the brain. And that's kind of breaking up the loop, shifting perspective seems to be some of what you're seeing with the psilocybin intervention.
DR. CHARLES NEMEROFF:
The problem with the plural of anecdote is not data, but you do need to listen to your patients. And I've had a lot of patients say to me, I was in Afghanistan, I saw horrible things. I came home, I drank too much. I wasn't kind to my spouse, I wasn't as good a father as I should have been, and I was treated with SSRIs and therapy and they helped a little bit. And then I went to Costa Rica and I was administered a psychedelic and I lost my desire to drink. And I sort of looked myself in the mirror and realized I'm just not being the kind of person I want to be. When you hear that five times, 10 times, 20 times, you need to listen to your patients. And so I really believe that for some patients, this will be a boom, an absolute boom. On the one hand, I'm concerned about widespread availability through non-medical distribution routes. On the other hand, I'm worried about if these substances are approved by the FDA, are they going to be widely available because of the cost.
DR. THEA GALLAGHER:
As in they're very expensive?
DR. CHARLES NEMEROFF:
Well, pharmaceutical companies are there to make money. And if you look at the pricing of some of the recent medications that are coming to the market, they're expensive. And society seems to be able to accept a $30,000 cost for chemotherapy for forms of cancer, and that's paid for by third party payers. Much less likely to accept a charge like that for a psychiatric illness. And so I would be really disturbed if it turned out that MDMA was approved for PTSD, but imagine that the charge was $10,000 and that Blue Cross and Blue Shield won't pay it, and I'm not picking on them in particular. Well, then it would only be available for those who could afford it. And that's a problem.
DR. THEA GALLAGHER:
I think it sounds like from talking to other researchers though, the one thing that's particularly promising about psilocybin maybe versus other SRIs or other kind of frontline interventions for mood disorders, et cetera, is that it does seem in the studies like the Michael Bogenschutz study with alcohol use disorder, is that one dose seems to be so powerful. Yes, I mean, if it's marked up to this astronomical price that won't be affordable for anybody, but it seems like the uniqueness of a psilocybin intervention, if the research and the science continue to go in this direction, it seems like there could be a benefit of having it be kind of a one-time use intervention.
DR. CHARLES NEMEROFF:
Obviously, Bogenschutz’s study was a wonderful study. It showed a very dramatic effect in a very serious group of individuals who had severe alcohol use disorder. There's no question about the findings, and I'm very excited about those studies. And I think from what I've heard from my own patients who've had the experience with psychedelics, not just psilocybin, I think that it's extremely promising. There's no question about it. If you have a chance, the FDA put out a briefing document on psychedelics to guide companies who are developing psychedelics for clinical use. And one of the points they made in this guidance is that they're very much focused on the durability and persistence of the effect. The question is, if you're treating somebody with depression or alcohol use disorder and you treat them with psilocybin and they have a great response, how long will that response last? And then what is the safety and durability about subsequent treatments? One of the things we've learned about ketamine is that it can be effective in some patients transiently, but it's relatively transient and not terribly persistent.
And then patients need to get dosed with ketamine over and over and over again, and that's a problem.
DR. THEA GALLAGHER:
Yeah. I think it sounds like these questions have more questions to them and something that hopefully continued research will expose or help to understand, again, the durability of some of these interventions. You're the first researcher we've talked to who has talked about eating disorders and psilocybin, and I think it's really interesting 'cause you're kind of talking about this similar feedback loop and any kind of intrusive-ish thoughts around shape and weight, that sounds like a population you're hopeful that could benefit from psilocybin or psychedelic intervention?
DR. CHARLES NEMEROFF:
Yeah. This really fascinates me because number one, anorexia nervosa has the highest mortality of any psychiatric disorder. Number two, there are no FDA-approved treatments for anorexia nervosa. If you think about anorexia, and I've treated these patients, I'm not an expert in this area, but I've treated some of these patients, it's so akin to addiction, I can't even tell you. The typical patient would say to me, I've decided to abuse laxatives to help myself keep my weight down. And so I go to the pharmacy and they have the same kind of excitement about going to the pharmacy and furtively buying laxatives. And then they bring them home. And when they describe taking them out of the tinfoil wrapping, it's the same description that cocaine users describe about the excitement they have, and then they engage in this behavior and then they feel remorse and regret the way many substance abusers do.
And so it's a behavior that it's egodystonic. They don't like it, they wish they didn't have it. They often know that it's damaging to their health. The majority of these patients are women. They haven't had a menstrual period in years. They're damaging their heart, they're damaging their bones. They know it's bad for them, but they can't stop it. And the idea of them eating a McDonald's Big Mac is as aversive as anything you and I could conjure up that would be aversive to us. They are in this circle of hell. We're doing an anorexia nervosa study. We're just starting to enroll a psilocybin study in order to see whether this could be helpful.
DR. THEA GALLAGHER:
Yeah. It seems like your primary objective is escaping this circle of hell regardless of the content, and that would be really powerful if that is the case.
DR. CHARLES NEMEROFF:
The other study we're doing that I think you'll find of interest is we're taking people with extremely treatment refractory depression, we're going to dose them with psilocybin and then follow it with transcranial magnetic stimulation. The idea that psilocybin will soften up the beachhead, so to speak, so that the brain would be more responsive to TMS, which is an FDA approved treatment for depression.
DR. THEA GALLAGHER:
Yeah, that's very interesting. I think from a mechanism perspective, trying to intercede or build on the impact of the psilocybin with TMS. And where do you see that from a mechanistic perspective? Again, maybe shifting things around initially and then is it assimilation or what's your theory there?
DR. CHARLES NEMEROFF:
First, knocking them out of the circuit. And then, because we know from brain imaging studies that what psychedelics do to be sort of very succinct is that brain areas that normally communicate a great deal communicate less under psychedelics and brain areas that hardly ever talk to each other increase their communication. We think by doing that, getting people out of the rut that they're in neurobiologically, that they would be more responsive to TMS.
DR. THEA GALLAGHER:
You're pulling together a lot of theories maybe about the way that TMS works, the way that psychedelic medicine works. And if you were going to bring in this third prong of genetics and what we were talking about originally to kind of create a powerhouse of precision psychiatry, how are you hoping the genetics information will integrate with these interventions?
DR. CHARLES NEMEROFF:
Eventually, let's start with the fact that the genome that you and I have and everybody has is immutable, meaning it is what it is, it's not going to change, so that the whole genome sequencing will eventually be part of your electronic medical record. And it only has to be done once. And when this was started with the human Genome project, it was very expensive, now it's not expensive. All of us will eventually have a whole genome sequencing as part of our EMR, and from that, we'll be able to glean a number of things. First, we'll be able to glean some highly heritable diseases like sickle cell disease and Huntington's disease very easily, cystic fibrosis, et cetera. But it will also allow us to determine the high likelihood of risk for one or another disorder. And all of us are at risk for something.
Some of us are at risk for diabetes, some of us are at risk for bipolar disorder, and this largely involves the polygenic risk scores that I've shown you. What hasn't been done yet in a large population other than in the UK Biobank, which I've been very critical of, and I'll tell you why in a minute, is to take, let's pick a number, 500,000 people that all have whole genome sequencing and then develop polygenic risk scores and then determine how they do over time and what they respond to if they have one or another illness. This has been attempted with the UK Biobank, which is a great beginning, but the issue with that has to do with what's called deep phenotyping, which is how carefully do you characterize the psychiatric diagnosis? And the problem with the UK Biobank is that if the word depression appears in the EMR, they're counted as depressed.
They don't get a structured clinical interview in which you could know for sure not only whether the patient has major depression, but what kind of major depression do they have. If we could develop a Framingham-like study where you could actually obtain genetic material and then follow patients over a 10- to 20-year period and be able to see their development in terms of mood and anxiety disorders, bipolar disorder, that you'd also collect data on environmental events like childhood maltreatment, etc. Then you could construct an amazing catalog that would lead to personalized medicine.
DR. THEA GALLAGHER:
A catalog for each person you're kind of talking about.
DR. CHARLES NEMEROFF:
Fundamentally, there are two parts to personalized medicine. One is what are you at risk for? And the second is what do you respond to? And most people in the field are focusing on the “what do you respond to” question. And it's important. If you have bipolar disorder, are you a lithium-responder or aren't you a lithium-responder? That's a really important question, and we still can't answer it, right? But an equally important question is what are you at risk for?
DR. THEA GALLAGHER:
Yeah. And it sounds like this is where precision medicine could really grow, and again, bring all of this information together, like you said, for this individualized catalog. It sounds like from your original research or what we were talking about earlier, you also see a history of childhood trauma as a factor that it seems to impact a large majority of people psychiatrically in their future. How do you integrate that understanding? Is that something that you would like people to be screened for as early as possible and treated for, or again, kind of given evidence-based treatment or just put into their catalog as a major risk factor?
DR. CHARLES NEMEROFF:
Thank you for asking that question. Childhood maltreatment in the form of child abuse and neglect is a more powerful predictor of health, not just mental health, of health than any other single risk factor. More than tobacco exposure, for example. And individuals with a history of childhood maltreatment have higher rates of obesity, diabetes, asthma, heart disease, stroke, and certain forms of cancer, as well as all of these psychiatric disorders we've talked about. There is a screening tool that we use called the Childhood Trauma Questionnaire. It's available on the internet. It's very simple. Patients fill this out themselves, and I have every patient fill it out, and oftentimes patients find talking about early life trauma difficult, and it's easier for them to put it down on paper. And I like this better than the more standard ACEs questionnaire, which has been much more widely used, but I think is a little more problematic.
But if you should use something to screen for child abuse and neglect, and what you'll find in the mental health field is if you're treating people with depression, particularly chronic depression, and they haven't responded to cognitive behavior therapy, they haven't responded to an SSRI, you'll find a preponderance of patients in that group with a history of childhood maltreatment. And how those patients should be treated best is unknown. And one of the things I'm interested in, well, maybe psychedelics would be helpful in this population
DR. THEA GALLAGHER:
In saying you're hoping that for the treatment resistant, 'cause there are some evidence-based treatments, like you said, with CBT or an SRI, that could be helpful for people. But if they're in the group of people that does not benefit from those interventions, what else do we have for them? And I think that's really the question inspiring a lot of this precision psychiatry.
DR. CHARLES NEMEROFF:
Absolutely. I do want to make sure that I say about the accelerated theta burst transcranial magnetic stimulation because you were asking me about treatments, and we've spent a lot of time talking about psychedelics, but I think that this is one of the most exciting advances in all of psychiatry. And this comes out of the Stanford group. And so what they did, which was just incredibly appreciant, was as you probably know, standard FDA-approved TMS is one treatment a day, five days a week for six weeks. And so it's very disruptive for families and patients because having to come in every day for a 45-minute treatment for six weeks is difficult for many people. And what the Stanford group did was they did two things that were very special. The first thing they did was to say, we're going to use magnetic resonance imaging to target in each individual patient the dorsolateral prefrontal cortex, so you know exactly what the target is in a given patient to apply the TMS.
And then the second thing we're going to do is we're going to give them a treatment for 10 minutes every hour for 10 hours in a row for five days in a row. The patients would come in and they would get treated every hour for 10 minutes with this accelerated theta burst TMS. And after five days, the response was hard to believe that these were people that had failed every treatment known to mankind, including ECT, ketamine, and everything else, and they had a 70 percent remission rate. This is an absolute game changer for psychiatry, and hopefully it'll eventually be paid for by third party payers. But the fact of the matter is, it can shorten inpatient hospitalizations, people that were this sick and suicidal, and the data which has now been published is we haven't seen data like this in a very long time or really never.
DR. THEA GALLAGHER:
And will there be subsequent studies to show how robust this data is and then hopefully have it integrated into academic medical centers and beyond?
DR. CHARLES NEMEROFF:
Absolutely. I mean, one of the questions that the Stanford group is examining is, well, how long does it last? Do the patients need retreatment, and if so, when? How effective is the re-treatment? We did a bipolar depression study—haven't broken the blind yet to see how well they did—but the impression of our faculty was that they did well, and bipolar depression is pretty hard to treat. I think it's a major advance for the field. And on the back of that, there is a new experimental treatment, neuromodulation treatment called focused ultrasound. And what's interesting about focused ultrasound is unlike TMS, which is pretty limited to the cortex, the outer part of the brain, focused ultrasound can go to deeper parts of the brain. And we just finished a pilot study focusing on the amygdala.
And as many of the listeners will know, the amygdala is an area of hyperactivity in patients with stress-related disorders, particularly depression and PTSD. And we were able to reduce the activity of the amygdala with focused ultrasound in this small study. And the patients that were a mixed group of depression and anxiety showed a very robust clinical response. Really exciting.
DR. THEA GALLAGHER:
Yeah. We've highlighted a lot of great research, some that we can hope to see or is already in practice, some that we can hope to see in more widespread practice and accessibility in the future. And it also sounds like you're a clinician who has been motivated by your treatment of patients. And for our final few minutes, any words of advice, wisdom, direction for those psychiatrists who are in practice and maybe less directly connected to the research? I think that trauma screen you were discussing can be a great tool to use, but any advice for those psychiatrists in practice, what can they do with this information at this point?
DR. CHARLES NEMEROFF:
The great thing about treating depression is there are a lot of opportunities out there, and because we can't really predict what a patient will respond to, each of you have to develop an algorithm for your own practice. I think in general, I start people with an SSRI. If they don't respond, I switch to an SNRI. There are some patients that need inordinately high doses. It's not unusual for me to prescribe 450 milligrams of venlafaxine, for example, for patients with treatment resistant depression. The combination of antidepressants like venlafaxine and mirtazapine, for example, the use of MAOI inhibitors. The new generation of psychiatrists, meaning the last 30 years, do not know how to prescribe MAOIs, and they're afraid of them because of the so-called cheese reaction. They're great drugs that work really well in people with treatment-resistant depression. I've got psychiatry residents who've never prescribed a tricyclic antidepressant because they're only prescribing SSRIs. All of these are options for patients with depression. And I think as psychiatrists, we should be compelled to offer patients what's available in the current pharmacopeia.
DR. THEA GALLAGHER:
And it sounds like being maybe less apprehensive and really following the data, following the science and not overinterpreting maybe certain negative findings?
DR. CHARLES NEMEROFF:
Yeah. I think follow the science is the right answer. I think one has to be sanguine about all the hype about certain treatments, and one has to be sanguine about the concern about adverse events. I think the best example I could give you, I'm a geriatric psychiatrist by training, and there's a warning about an increased risk of stroke if you use atypical antipsychotics in the elderly with dementia. There is a statistically significant increase, but the absolute rate is very low. And if you have an elderly patient with dementia and prescribing an atypical will allow them to stay at home compared to going to a nursing home, it's worth the risk because it's a pretty low risk of them having a stroke. I think people often do defensive prescribing 'cause they're worrying about medical legal consequences, but if you ask yourself what's best for the patient, you'll be guided in the right direction.
DR. THEA GALLAGHER:
Well, those are wonderful, I think, words to be inspired by in practice. And thank you so much for bringing all this promising research to the forefront, and we'll be excited to continue to watch where it all goes.
DR. CHARLES NEMEROFF:
Thank you so much for inviting me.
DR. THEA GALLAGHER:
Thanks so much for that conversation, Dr. Nemeroff. If you enjoyed this episode, be sure to rate and subscribe to NYU Langone Insights on Psychiatry on your podcast app. For the Department of Psychiatry at NYU Langone, I'm Dr. Thea Gallagher. See you next time.