Dr. Alan Schatzberg is a Professor of Psychiatry and Behavioral Sciences at Stanford Medicine, and Director of the Stanford Mood Disorders Center. His research examines the biology and psychopharmacology of depressive disorders. An NYU School of Medicine alumnus, Dr. Schatzberg was President of the American Psychiatric Association from 2009-2010.
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For more information:
https://med.stanford.edu/profiles/alan-schatzberg
Visit our website for more insights on psychiatry.
Podcast producer: Jon Earle
Dr. Alan Schatzberg is a Professor of Psychiatry and Behavioral Sciences at Stanford Medicine, and Director of the Stanford Mood Disorders Center. His research examines the biology and psychopharmacology of depressive disorders. An NYU School of Medicine alumnus, Dr. Schatzberg was President of the American Psychiatric Association from 2009-2010.
Topics:
For more information:
https://med.stanford.edu/profiles/alan-schatzberg
Visit our website for more insights on psychiatry.
Podcast producer: Jon Earle
NOTE: Transcripts of our episodes are made available as soon as possible. They may contain errors.
[00:00:00] DR. THEA GALLAGHER: Welcome to NYU Langone Insights on Psychiatry, 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 translates into clinical practice. Today I'm speaking with Dr. Alan Schatzberg. Dr. Schatzberg is a professor of psychiatry and behavioral sciences at the Stanford University School of Medicine and director of the Stanford Mood Disorder Center. A graduate of the NYU School of Medicine, Dr. Schatzberg is a longtime leader in the field of psychiatry authoring more than 700 publications and abstracts and serving as the president of the American Psychiatric Association. In our conversation we explore new and novel treatments for depression, including a form of magnetic therapy that Dr. Schatzberg has helped pioneer.
Well, thank you so much for being on the podcast today, Dr. Schatzberg, we're so excited to have you, an NYU alum, here to, to share some of your thoughts about the work you've been doing.
[00:00:58] DR. ALAN SCHATZBERG: Glad to be here.
[00:00:59] DR. THEA GALLAGHER: You've been studying the biology and treatment of depression for many years. So for listeners who may not be as familiar with your work, can you give us some of the overview of your research interests?
[00:01:11] DR. ALAN SCHATZBERG: Well, I've been in- involved with the... Studying the biology and treatment of depressions since the 1970s.
[00:01:19] DR. THEA GALLAGHER: Mm-hmm.
[00:01:20] DR. ALAN SCHATZBERG: It's a bit embarrassing, I guess.
[00:01:22] DR. THEA GALLAGHER: Impressive, I would say. [laughs]
[00:01:23] DR. ALAN SCHATZBERG: Uh, well, [laughs] anyway. So we've studied the biology from, from multiple kinds of vantage points over the years. We started out, uh, doing research focused on the catecholamine hypothesis, these are... Uh, this was the hypothesis that norepinephrine metabolism was involved in the biology of depression, uh, based on a lot of the early psychopharmacology. Most of the early drugs were heavily noradrenergic in their... In terms of their focus, in terms of their activity. And I started out working at Harvard with Joe Schildkraut, who was a professor of psychiatry and who came up with what is one of the most cited papers in psychiatry, called The Catecholamine Hypothesis Of Affective Disorders. We, uh, then kind of segued to looking at the interaction of cortisol, a glucocorticoid, which is a stress hormone, on a monoamine called dopamine, which is involved in psychosis to try and understand the biology of and treatment of psychotic or delusional depression. So these patients are the most severely depressed patients, they represent approximately .4 to .8% of the subject of the population. They represent about 18... 15-18% of all depressed patients.
They are commonly m- misdiagnosed or undiagnosed because they have the psychotic features that they have, are often hidden. They do not kind of, uh, voice these, uh, symptoms, they're often quite nihilistic or paranoid. They have thoughts that they've lost everything, they're impoverished, that they-
[00:03:12] DR. THEA GALLAGHER: Mm-hmm.
[00:03:12] DR. ALAN SCHATZBERG: Have, uh, delusions of guilt. And they tend not to respond to the antidepressant agents. They inters- uh, in- instead respond to either ECT, electroconvulsive therapy, or the, uh, uh, combination of an antidepressant and an antipsychotic. So we did a lot of research on this excessive activity of the cortisol access, the hypothalamic pituitary adrenal access. And eventually developed a possible treatment for it, namely a glucocorticoid antagonist, which is mifepristone. So mifepristone has got a lot of, uh, a lot of play in the press in the last, uh, uh, weeks because it's the French abortifacient agent, ab- French abortion tr- uh, pill. And it's an abortion pill because it blocks progesterone, but at high doses it also blocks cortisol. And in fact, now is approved as a treatment for Cushing's disease, which is a disease of a pituitary tumor that produces too much ACTH and eventually too much cortisol.
But mifepristone, in blocking cortisol, could be used to treat delusional depression. And so we, uh, did a lot of work on that. We s- uh, at one point s- founded a company, uh, on, on that, that I still have some involvement in it. And it didn't pass phase III because as you pushed the dose up, the blood level flattened out, uh, in terms of the pharmacokinetics, so we couldn't get the blood level high enough to, to block the massive amounts... Increases of cortisol that we were s- seeing. And when you give the mifepristone, since it blocks the system, the system in fact becomes more active, it tries to produce more cortisol, 'cause cortisol is absolutely necessary for glucose regulation, stress regulation, immune response, etc., etc.
Anyway, we're still very interested in psychotic depression. We've then, uh, done a lot of work around the psychotic depression, which led to a number of very in- innovative fMRI, uh, studies showing different paradigms that you could study, different activities in the brain, default mode, a resting state, salience network, etc. that came out of, uh, our work on actually psychotic depression. We've had other areas of interest, in terms of drug development. One of the areas that probably has been the... Occupying a fair amount of our time in the last five or six years is the question of ketamine, esketamine and the psychedelics. And ketamine has been purported to work because it is an antagonist for a receptor for glutamate, called the NMDA receptor. And as an NMDA receptor it somehow produces a relief of depression. Now, glutamate is an excitatory neurotransmitter, it's the oxygen of the brain. So if you block it, why would you get an antidepressant effect?
Didn't make... Doesn't make much sense, but one theory is, that glutamate is so well conserved, it has other receptors, that if you block the NMDA A- receptor on the postsynaptic neuron, that the presynaptic neuron would ca- would release more glutamate and that would interact with other receptors, an AMPA receptor for one. And that may be, uh, may be, uh, the mechanism. That didn't really work for us and hasn't. Ketamine, esketamine do in fact block the NMDA receptor, but there are a lot of NMDA receptors that have been studied as antidepressants and they fail to meet the mark. They fail to show efficacy. Memantine, memantine, which is a drug used for dementia, i- is one such drug. So we started to think maybe there are other mechanisms that are involved and we can talk about that.
So those are some of the things we've been involved in, we've gotten involved in norketamine and psychedelics a little bit. We've, uh, done over the years also work in pharmacogenetics, can you develop a blood test that in fact will predict response or, uh, uh, to a particular drug? Some controversy about some of that work in the field. We were some of the earliest prospective RCT, randomized control trials, in that area. And so we've gone and done lots of the different things in, in, in psychopharmacology. So I'll pause there and we can-
[00:07:56] DR. THEA GALLAGHER: Okay. Great.
[00:07:57] DR. ALAN SCHATZBERG: Pick up from there, but any questions?
[00:07:58] DR. THEA GALLAGHER: Yeah. Well, it sounds like you've been busy since 1970 doing a lot of [laughs], uh, great work in this field. And is your work... Uh, does it continue to be focused specifically on people with severe depression and that, that smaller subset that you're talking about?
[00:08:12] DR. ALAN SCHATZBERG: We're not studying psychotic depression actively right now, we've been studying non-psychotic severely depressed patients, looking at immune response, uh, and, and immune activity in those patients. We've been doing suicide studies in non-psychotic patients, we can talk about that. But right now we're not actively studying psychotic depression.
[00:08:36] DR. THEA GALLAGHER: Mm-hmm. And, and one of the interesting themes that we keep seeing with this podcast is that so many of you in the field who are doing this groundbreaking work, it, it's really about this personalized medicine approach, figuring out what works for which person, especially these people, uh, that don't necessarily benefit from maybe a typical protocol of an SRI and treatment. You're looking at people who might need something else. And finding that it might be a number of different things for different people.
[00:09:10] DR. ALAN SCHATZBERG: Well, there's a great deal of hope that we can develop in psychiatry, a personalized medicine approach akin to what we do with other disorders, particularly cancer, right? So patient has a cancer, they may do a biopsy or they may do an excision of the tumor. They will type the, the t- cancer from a genetic and a, uh, a second messenger perspective. That allows them to potentially match a particular kind of oncology drug to a particular kind of cancer. And for some cancers that works pretty well. I think we have to be a bit hesitant to declare cancer, uh, as now cured, right? We all know a lot of people who unfortunately still succumb to the disease. But there is some... In certain cancers, there's considerable improvement. And some of it is not necessarily on genetic typing, but some of it is on allowing the immune system to in fact, uh, attack the tumor, by in a way opening the gates, if you will because the tumors produce, uh, a shield. And so for melanoma, certain lung cancers, there's been considerable progress with these, what some people have called gate- gateway or gating drugs or im- immunotherapy. But there... These drugs can in fact facilitate our own immune response to, uh, knocking off the cancers.
So we haven't gotten there yet, uh, in a lotta cancers, but we're just starting to get there in psychiatry. And there have been different approaches. We started out in the '70s and early '80s by looking at a metabolite of brain norepinephrine. So norepinephrine, if you remember, catecholamine is found in the brain. It's found in the periphery, it's noradrenaline. And it controls in part your heart rate, your, your autonomic system, your sympathetic nervous system. Your, uh, your, your, uh, GI motility, etc. And so we were measuring, with Joe Schildkraut, a metabolite that was preferentially coming from the brain. 'Cause most of the metabolites that you measure in the urine or in the blood, uh, are derived, uh, from the periphery. But one metabolite, methyl hydroxyphenylglycol, seemed to be coming actually more from the brain. And so we reported early on that people who had very low levels of this norepinephrine metabolite from the brain seemed to respond preferentially to drugs that were particularly noradrenergic in their effect on blocking reuptake of that monoamine. Those patients did very well.
The... Oh, and, and so we, we reported this. A number of other groups, Leo Hollister at Stanford reported that. Jim Maas, uh, uh, from the collabor- the study in depression. A number, there were a number of reports on it. But it did... It wasn't easily adapted, for a coupl- adopted, uh, or... For a couple of reasons. One is you had to have... You had to collect urine for three days. Well, that's a lotta urine.
[00:12:44] DR. THEA GALLAGHER: [laughs]
[00:12:44] DR. ALAN SCHATZBERG: And you had to have the patient drug free.
[00:12:47] DR. THEA GALLAGHER: Mm-hmm.
[00:12:47] DR. ALAN SCHATZBERG: Which was difficult 'cause patients were taking all sorts of meds that could affect the test, etc. The other issue was, we were good on the low MHPG side, but there were patient... Not every patient had low MHPG, this was a heterogeneous disorder, which is still a problem for depression. Multiple forms, genetically and biologically. And we had a very high MHPG group that seem to had a different dysfunction in norepinephrine turnover, there it seemed to be that the body was producing a lotta norepinephrine even in response to stress or in response to overcoming what was a defect in the postsynaptic receptor. And we didn't have a great handle on what those patients needed. And that, I think, hurt that development.
Since then there have been all sorts of, uh, other attempts to develop personalized medicine. Most of them have not been there, in terms of success, to some consternation on the parts of practitioners as well as researchers. It still is, uh, an issue. But it's a, it's a, it's an important goal. It's an admirable goal. And we all strive to get there.
[00:14:03] DR. THEA GALLAGHER: Yeah. And once we can have those personalized medicine approaches you... It'll be better to, like you said, be able to have treatment protocols that we know work for, for a different individual struggling with different things. But for those out there who are clinicians right now and they're working with patients with severe depression, what do you think is the best option? You know, you said you've done some research with ketamine and psilocybin, there's becoming more access to those kinds of treatments. What do you see right now as the most powerful treatment for severe depression?
[00:14:39] DR. ALAN SCHATZBERG: I would think that the most powerful treatment probably remains electroconvulsive therapy, but it also is potentially the most problematic because of its cognitive effects. It's effects on memory, particularly with bilateral administration. But, uh, what are other things that seem to work and where do they fit or whatever? And a few comments, if you will. I think there's been a hope that certain drugs that produce a psychotic-like reaction, a psychedelic-like reaction or a dissociative-like reaction, are going to be panaceas. That they're gonna kinda cure all forms of severe depression. But when you look at their response rates, while some people have a dramatic effect or a response to ketamine, the response rates are still under 50%, if you look at some of the data that the Yale folks have put out in terms of their very extensive experience [inaudible 00:15:45] refractory depression, but still in the 40s.
If you look at the study that Compass, which is a company I've consulted to, out of the UK reported in, in the New England Journal on their phase II study. 25mg are separated from 1mg, which is a punitive placebo, at three weeks after single dose administration. But the response rate or the remission rate was still in the 30s, 37%. So even in these very potent psychotic-like, psychotomimetic kinds of treatments, you're not seeing 100% responses. People need to be mindful of that. Somehow patients have had this notion that these, uh, drugs are gonna blast them out into outer space and cure their depression. It don't work that way. The response rates are much, much lower than the press in fact, uh, reports. But I think they have a role. I think the problem that we have with ketamine, with esketamine, with psilocybin, is durability. And we don't really have really good long-term data with ketamine or esketamine. We have some with esketamine, I think, uh, uh, but, you know, are there in fact drawbacks from administering ketamine and esketamine repetitively over long periods of time?
With psilocybin we don't have the protocol, we don't know. We've only done single dose. We don't... There are s- There is one blinded study that, uh, of two doses. But mo- mostly, uh, we have limited data on terms of durability. So that is an issue and we don't know what the liability is on, on repeated administration, particularly, particularly in terms of drugs that might be abused.
Now, having said that, mindful of your question about the practitioner, I have a great deal of concern... And there was an article in the New York Times maybe a month ago, about practitioners who write scripts for oral ketamine that i- is made up by a compound pha- pharmacy in the community where it's relatively inexpensive. And then they kind of hand this out with people taking it as often as daily. Now, this to me is a major risk for psychiatry and for patients. Ketamine can be addictive. You can develop tolerance. You can develop dependence, etc.
In Asia where there was a more ad libitum use or access, just as PCP in China, there were hundreds of thousands of ketamine, uh, addicts. At one point China petitioned the World Health Organization to make ketamine a Schedule I drug. So this is a real problem, this ad libitum free access. Uh, it is potentially dangerous. Now, there are a couple of... There are two or three companies that are trying to develop proprietary, uh, eventually hopefully FDA approved oral ketamine, but to be given on something like a twice-weekly basis with a long, uh, a slow release kinda formulation. That may turn out to be... One, it'll be... turn out to be safer and it'll also be studied so we'll know what the long-term risk is, uh, about those. And one of them is a company called Douglas Pharmaceuticals, a company I've done some consulting with. They've done a phase II study that they have done a press release on.
So the psychedelics, very exciting, very interesting, but we need to know a lot more. And we can come in more, in terms of some of our interests, in terms of the mechanism of action of ketamine and esketamine.
[00:20:01] DR. THEA GALLAGHER: Mm-hmm. Yeah. Can you, um, talk a little bit about the mechanism of action there? And it sounds like what you're saying... And I'll just pause for a second here. But it sounds like what you're saying is you, you don't necessarily think this idea of oral ketamine is, is necessarily the answer.
[00:20:17] DR. ALAN SCHATZBERG: Could be the answer-
[00:20:18] DR. THEA GALLAGHER: Or it concerns you a little bit?
[00:20:20] DR. ALAN SCHATZBERG: People making up... Uh, doing a compound pharmacy approach, in the absence of any data. And it's data on efficacy, data on safety, but also on bioavailability. Uh, this is not a drug that was developed as an oral. This drug was developed as intravenous for anesthesia and for... Eventually for pain. So ketamine is not a drug that is an oral tablet. I mean, so, uh, there's very little data on... Or very little, uh, data on what blood levels are attained. What blood levels are needed. What blood le- blood levels may be too high. We don't have any of those data. And, uh, you, you don't... You're not dealing with a proprietary formulation where all of this is worked out. Worked out for the field. Worked out for the company. Worked out for the patient. Worked out for the practitioner. So I don't think this is a good thing.
[00:21:27] DR. THEA GALLAGHER: Yeah. And I get what you're saying is that even if... So, the research is looking promising, but don't get too ahead of it with something that actually maybe hasn't been studied to a large extent. Like and you're saying oral ketamine is one of those drugs?
[00:21:45] DR. ALAN SCHATZBERG: Yeah. This article in The New York Times had several cases where people in fact started to have all sorts of secondary issues. They started either developing, uh, dependence on it. They had side effects. I mean, there are, there are all sorts of issues that need to be worked out before you use, uh, an oral ketamine, particularly long-term.
[00:22:07] DR. THEA GALLAGHER: Mm-hmm. Yeah. And, and to go back to that question about mechanisms-
[00:22:11] DR. ALAN SCHATZBERG: Okay.
[00:22:11] DR. THEA GALLAGHER: Can you talk a little bit about mechanisms and interestingly we were just talking with, uh, Dr. Michael Bogenschutz about his psilocybin and alcohol use disorder study. And he was saying how it, it's, it's interesting that they don't exactly know exactly [laughs] what's happening on the mechanisms side. So what do we know with regard to ketamine and, and mechanism?
[00:22:33] DR. ALAN SCHATZBERG: Well, there's been a lot of interest in, uh, that ketamine is an NMDA antagonist. And this question of whether in fact you, you're getting a secondary release of glutamate and stimulation of postsynaptic receptor called AMPA. So that, that is one theory. Now, a number of years ago Carolyn Rodriguez, who, who runs our OCD program at Stanford, OCD research program, had reported while she was at Columbia that intravenous ketamine in refractory OCD patients produce a dramatic ant- anti-OCD effect. And it lasted for about at least a week. So she was seeing longer term kinds of effect from, from an intravenous... One intravenous administration of ketamine.
Well, that study reminded me of a study that Larry Koran, who was her predecessor, is now Emeritus at Stanford, had done looking at oral morphine, which is a mu-agonist opioid analgesic, in refractory OCD. He took refractory OCD patients about 10 years before Carolyn and he... And did a double-blind, double-crossover study involving lorazepam, morphine, and placebo. And he showed that oral ka- oral morphine 20-30mg I think was the dose, had a dramatic effect the next day in refractory OCD patients and they lasted five days. Now, he pointed out that there's some NMDA antagonist effects there and perhaps that's what... Why it was working. This is before ketamine had been shown by Carolyn to be effective in OCD.
Now, around the time that Carolyn came out with her OCD in... Ketamine OCD study, a group in Brazil, first author Pacheco, reported in an animal model of pain using... You take rats and you, you, you see how long they can keep their fore paw on a hot plate. And if you give them an analgesic they can keep their paw on the hot plate longer. This is a very low level pontine kind of response. And the animals were able to tolerate the pain, uh, if they gave, uh, them ketamine for, for a certain amount of time. But when they gave them the naloxone at the same time, which is the antagonist for the opioid recep- the opioid receptor used to reverse overdoses, Narcan, uh, they showed that, uh, Narcan basically reversed the ketamine's analgesic effect in the animal. And so what they showed was that ketamine was acting through a mu-opioid, uh, effect.
Okay. So we started to argue, "Maybe there's a less here about ketamine being an NMDA antagonist, but maybe ketamine is really acting as a opioid." So we did an experiment, published this in the American Journal of Psychiatry in... Uh, Nolan Williams the first auth- author. Borris Heifets is the second author. Came out of our lab. And what we showed was that if you took depressed patients who had these, "Ah-ha, ketamine is wonderful." It, you know, response of, "I feel terrific." If you repeated the ketamine, but one time gave them Naltrexone, or you gave them placebo, those people when they got Naltrexone, which is like Naloxone, did not have an anti-depressant effect. And we did it in random order, uh, etc., etc.
And so we showed that ketamine's powerful antidepressant effect is blocked by the pre-administration of an opioid antagonist. That s- finding has now been replicated five or six times in lower animals, in rats. The behavioral effect of ketamine or esketamine in the animals is blocked by pre-administration of Naltrexone or Naloxone in mice and rats. So I think it's clear that it has an opioid effect. It doesn't mean that there isn't an NMDA antagonist effect. And I would suggest that the NMDA antagonist effect is not the antidepressant effect, it... NMDA antagonism gives you plasticity, it's very involved in memory and other things. It gives you durability and it may be that the NMDA antagonism is giving you the durability to the opioid effect. And so in, in ketamine or esketamine.
There are now papers, two papers, from the [inaudible 00:27:43] group, [inaudible 00:27:45] these very elegantly demonstrated that esketamine, the animals will self-administer esketamine. That the binding of esketamine, which is the more potent and anti-mirror ketamine, is about the same to NMDA, which is supposed to be the mechanism of action, as it is to mu-opioid, uh, receptors. So ketamine, esketamine is about as potent, slightly less, uh, an opioid agonist as it is an NMDA antagonist. So those opioid properties could be good, but they also could present problems over time with patients maybe developing some tolerance, etc.
There is one paper from... In Nature in the last year that suggests that the dopamine response that you see when you bind to opioid receptors is less with esketamine than with opioid... Typical opioids, that may be something that in fact is protecting, uh, so that you're not getting a kind of the same degree of euphoria with it. We need to study more.
But there's no question, I believe, that ketamine, esketamine are binding to the mu-opioid receptor, which is your pain receptor and has an effect on mood. And that effect can be blocked by the antagonist and that effect underlies the behavioral responses typ- uh, suggestive of an antidepressant effect in lower animals and it blocks the antidepressant effect in depressed patients.
[00:29:27] DR. THEA GALLAGHER: And does there need to be continued dosing of the esketamine in order to see these results? Or, or can it... Like I know that some people do it for a certain period of time and then they see maintenance of gains. Or is it the idea that they have to stay on it?
[00:29:41] DR. ALAN SCHATZBERG: If you look at the esketamine, which is Spravato study done by the company Janssen, uh, and filed for the FDA. What they did was... So all the, uh, Spravato studies in the package submitted to the FDA, involve Spravato or esketamine, plus an antidepressant or placebo plus an antidepressant. So what they did was a long-term maintenance study. They treated people with Spravato and they took the responders... Plus Spravato plus antidepressants. And after a few months they said, "Okay. We're now going to continue the antidepressant, but if you're taking Spravato, we're gonna give you saline. And if you're on saline you'll continue on saline."
And what did they find? The patients had a much... Continuing on an antidepressant, the patients had a much higher relapse rate than is seen when people just come off antidepressants. And these people stayed on their antidepressant. So obviously much more rapid relapse and a much higher rate of relapse. Still about half the people were able to get off, but there are people who are not gonna get off and you see that clinically. And then the question is, is this a dependence in some way? Physical, psychological? Is that mediated through the mu-opioid receptor? Uh, we need to know more.
Now, it may very well be that that is what these patients need, it's possible that some forms of depression need to be treated through some mu-opioid agonist effect.
[00:31:28] DR. THEA GALLAGHER: Mm-hmm.
[00:31:28] DR. ALAN SCHATZBERG: It is. Can we develop-
[00:31:28] DR. THEA GALLAGHER: For the long-term you mean? Yeah.
[00:31:33] DR. ALAN SCHATZBERG: Yeah. Can we develop safer mu-opioid agonists maybe that can give you antidepressant effects, but not necessarily dependence effects? We need to be able to study that and see if we can do that. That is going to be, I think, uh, an area that needs to be developed. It is happening already. S-methadone. So methadone is an NMDA antagonist, like ketamine, but it's an opioid, right? And has mixed opioid, uh, uh, agonist and antagonist effects is used to the treatment of opioid dependence. And it has two enantiomers, there's an S- and there's an S- or D-, an L-. And the S is thought to be supposedly weaker at mu and it has been argued to not have any mu. Well, there's a paper that just been posted from the [inaudible 00:32:35] group showing that S-methadone is about, uh, powerful as a mu as the... Uh, it's enantiomer.
It is not an... It is about the same for MNDA as it is for, uh, mu. And that may be different than the other enantiomer. But at the same time, the drug at the dose being studied, which is a very low dose, is not achieving efficacy in the phase III trials that have been reported. So again, it's, it's an opioid, you know, and the question then is, "How much?" Uh, maybe if your dose is too low you're not gonna get the... Enough opioid effect to get the positive effect. Research is going on, at times with drugs that people would like to say are not opioids, but they are opioids. And we need to embrace that this is an interesting area that could yield some information.
But, uh, I think we're likely to not have some risk when we get to the doses that are needed that are high enough to give you some antidepressant effect.
[00:33:47] DR. THEA GALLAGHER: Mm-hmm. And, isn't this some of the hope with psychedelics that it might be able to be administered once or twice and have long-lasting effects? And is that some of the hope of the research there in that it might not be something that has to be continued for maintenance of gains?
[00:34:06] DR. ALAN SCHATZBERG: Well, in the COMPASS study in the New England Journal, Guy Goodwin, is the first author. Guy is a distinguished psychiatrist who is the chair at Oxford. They didn't see durability, you know, they, uh, if you look at three weeks, they got about 37% I think remission. But they didn't get more remission going out and they started to kind of lose some effect. So you're gonna have to probably... You're gonna have to give it more than once, so we don't know how often, I think. So that's one issue.
The question about psychedelics is an interesting one and if we have two minutes, let me give you a, a, a little bit for the listener about where we are with these drugs. Because the story is a little bit, uh, a little bit more complicated than just psychopharmacology. So for all of these drugs, ketamine, esketamine, psilocybin, DMT, there's MDMA, there is, uh, some opportunity for combining with psychotherapy. Okay? Ketamine, esketamine have been developed in the absence of a psychotherapy adjunct. They were tested in the context of a pharmacological adjunct, where the treatment is usual antidepressant. There are practitioners, in California particularly, who will use ketamine in the service of some sort of psychoanalytic, psychodynamically-oriented therapy to enhance insight to decrease resistance, to open up the, uh, individual to understanding their own dynamics, etc. That is not part of the FDA approved package for ke- for esketamine or for the typical use of ketamine.
For psilocybin, from years ago, psilocybin was used in conjunction with some forms of therapy. And so the FDA development was tied to using some guidance, uh, psychotherapy with meetings pre- the psilocybin experience and post. And accompanying the p- patient during the kind of trip, if you will, but without the therapist saying something to it. So it's a kind of a psychotherapy-assisted psychopharmacology, right? The therapy is assisting it, but it's not that the psychedelic is really designed to open up the insight.
For MDMA, which is used for PTSD, the the- the, the, the drug really does probably enhance the cognitive kinda behavioral therapy that it is combined with. So there it's the psychedelic is enhancing the psychotherapy.
So all of these are kind of nuanced differently as to where the therapy is and where the medication is. But that gets into the whole question of, how is the drug acting? So some would say that psilocybin is a s- serotonin 2A agonist. Okay? So serotonin, very important in depression, we wanna increase the amount of serotonin, simplistically if you will, at the postsynaptic receptor to increase the antidepressant effect, the calming effect. And what psilocybin does is act powerfully as a direct agonist at the serotonin 2A receptor. Independent of what may happen psychologically. So some would say it's a potent serotonin enhancer or agonist.
On the other hand, that agonistic effect is associated with a s- psychedelic effect, a psychosis effect. And others would say embrace that that psychosis effect, ala when I was, you know, starting out in the '70s, uh, in psychiatry and the Beatles and the whole thing and LSD and Lucy in the Sky with Diamonds and all that, you know, that there is insight to be had by the psychedelic experience. And that psychotic experience is transformative. We don't really know. We don't really know how important that psychotic experience is. We now know with ketamine that we can block a lot of the antidepressant effect by giving an opioid antagonist. I think that's the neat aspect of our research.
Can we do that with giving an antipsychotic? There are some suggestions that it could happen, but it's not really been studied in, in a way. The last thing I think I wanna say about the psychedelics, which is extremely important, they're incredibly powerful from a mind-altering perspective. The ketamine is mostly dissociative, people feel out of sync with their surroundings, etc. They may not... They often don't hallucinate with the psychedelics, they tend to m- more so hallucinate.
So they're very, very powerful, but being powerful, we have difficulty in having a blind. We test drugs by doing randomized control trials where we randomize the patient or subject to one drug or a placebo. And then we look at the comparisons with a hope that the patient does not really know what they're on. But in the study that you mentioned before on psilocybin and alcohol abuse, which was dramatic, uh, had a dramatic effect, those patients 100% almost knew that they were given the psychedelic psilocybin and not placebo.
[00:40:22] DR. THEA GALLAGHER: Mm-hmm.
[00:40:23] DR. ALAN SCHATZBERG: So they [inaudible 00:40:25]-
[00:40:24] DR. THEA GALLAGHER: It adds another layer. Yeah.
[00:40:25] DR. ALAN SCHATZBERG: Who's not blind. And it all-
[00:40:27] DR. THEA GALLAGHER: Yeah.
[00:40:27] DR. ALAN SCHATZBERG: And in, in the commercially sponsored studies of esketamine and psilocybin, the blinds are not inquired about. They don't ask the patient, "What did you get?" When they get inquired about, the patient is about... It's 100% that the patient knows. Well, that has a huge effect on the outcome. And it has a huge effect on whether we can be certain that we're really getting an effect that isn't all suggested by hope, by anticipation of the experience-
[00:41:04] DR. THEA GALLAGHER: Yeah.
[00:41:04] DR. ALAN SCHATZBERG: The trip, etc.
[00:41:06] DR. THEA GALLAGHER: Mm-hmm. Yeah. That's a really fascinating thing to consider when you're thinking about that research. Like you said, there's no, there's no real way to not know. So that, that, that does definitely add a layer there. And I wanna ask you kind of one more question, uh, specifically about your research, before we kind of wrap it up. But you have done so- You, you co-authored an important paper in 2021 about magnetic brain stimulation and we haven't really talked about that yet. Can you just give some insights about that study and, and what clinicians should know about that?
[00:41:39] DR. ALAN SCHATZBERG: Well, trans-magnetic stimulation involves applying basically a portable magnet to the scalp, often the prefrontal cortex, to stimulate a brain circuit that's probably involved in depression. And in work that, uh, pioneered by Mark George at the America University of South Carolina, when he was at that time with the National Institute of Mental Health. And the, the device was approved for treatment in refractory depression by a company called Neuronetics. It's a company I consulted to in the past. That device is approved and then there are, if you will, copycat devices. They get approved because they piggyback on what is kind of on a punitive d- device as a, as a similar kind of agent.
One of our folks, Nolan Williams led the ketamine study, uh, with Naltrexone, uh, who's a psychiatrist and neurologist out here and runs our brain stimulation lab, uh, has, uh, developed an accelerated theta burst. So regular TMS is given somewhere between 20 and 37 minutes once a day, five days a week for four to six weeks. So he figured out that you could in fact focus the stimulation on a, uh, on a, a theta wave in the brain and you could give 10 minutes an hour, for 10 hours. And you can do that in five days. When you do that, even in very refractory patients, within about less than three days those patients are feeling better. So unlike going four to six weeks you can really do this very, very quickly. He combines that with using brain imaging, if you remember before I talked about resting state. Well, resting state can to- show you the connectivity between key brain regions and you can then optimize where you place the magnet. So instead of placing it here, you might place it here or down here.
And that increases the efficacy as well. And this is now called SAINT, Stanford Accelerated Neurotransmission, or something, Neuromodulation. And there is a company, Magnus, that I've done consulting with, that is now approved by the FDA for this device, which involves a fMRI study followed by the a- administration of this intensively, 10 treatments a day, 10 minutes an hour. Uh, uh, to get more effect and more rapid effect. So we will see how this does in clinical practice, but it's a very exciting in- initiative by Nolan and his collaborators.
[00:44:35] DR. THEA GALLAGHER: Yeah. I mean, it sounds like there are a lot of unique, uh, approaches for treating these severely depressed patients. And, and there's a lot of hope, a lot... Which... You know, and a lotta questions, but a lot of hope in the future of this research. Um, but in closing, what advice would you give for like... Would you give to clinicians who are eager to keep up with research on major depression and to integrate the latest findings into their work?
[00:45:04] DR. ALAN SCHATZBERG: Well, I think listening to the NYU-
[00:45:07] DR. THEA GALLAGHER: [laughs]
[00:45:07] DR. ALAN SCHATZBERG: Podcast is probably a good place to start. Uh, certainly we have, uh, books, Chuck DeBattista and I, do a Manual of Clinical Psychopharmacology published by the American Psychiatric association. Charlie Nemeroff and I do a textbook of psychopharmacology. But the best ways I think are probably continuing medical education, going to the meetings, the APA, other meetings. Uh, reading up on, uh, the reading journals. I think we have lots of things that are coming out every month in the major periodicals. And the clinician would be, I think, uh, wise to kind of read s- some of those journals as well as attend continuing medical education conferences.
[00:45:51] DR. THEA GALLAGHER: Mm-hmm. Mm-hmm. And, and it sounds like and on top of that realizing that some of this does take time and we have to do more studies to kinda see, like you said, durability and some of the longevity of some of these interventions as well, correct?
[00:46:06] DR. ALAN SCHATZBERG: I think doing research is critical and encouraging patients to participate-
[00:46:11] DR. THEA GALLAGHER: Mm-hmm.
[00:46:12] DR. ALAN SCHATZBERG: In research is, is also critical for the field.
[00:46:15] DR. THEA GALLAGHER: Absolutely. Well, thank you so much Dr. Schatzberg for being on our podcast. Uh, we really appreciate your time.
[00:46:22] DR. ALAN SCHATZBERG: Thanks for having me.
[00:46:24] DR. THEA GALLAGHER: Thanks so much again for that conversation, Dr. Schatzberg. If you enjoyed this episode, be sure to rate and subscribe to NYU Langone's Insights in Psychiatry on your podcast app. For the department of psychiatry at NYU Langone, I'm Dr. Thea Gallagher. See you next time.