Psychiatry & Psychotherapy Podcast - Ketamine Update with Brandon Kitay, M.D.

Episode Date: January 27, 2022

Esketamine is the first non-monoaminergic based medication which is FDA approved and indicated for treatment refractory depression. A longer duration of undertreated depression is associated with poor longitudinal functional outcomes. Instead of cycling patients through monoaminergic antidepressant trials and cognitive behavioral therapy approaches, according to Dr. Kitay, providers should consider treatments like esketamine much sooner in the treatment course. By listening to this episode, you can earn 1.25 Psychiatry CME Credits. Link to blog. Link to YouTube video.

Hello and welcome to the Psychiatry and Psychotherapy Podcast. I'm here to talk about getting rid of burnout, increasing job satisfaction, and feeling like an expert in what you do. One thing that created a lot of burnout and angst for me was trying to get continued medical education right at the last minute. So why not join the CME membership and do CMEE while listening to this podcast? Go to Psychiatrypodcast.com. Sign up, sign in, take the test, and the certification is email to you in seconds.

All right, welcome back to the podcast. I am here today with Dr. Brandon Kite. He is a MD PhD at Emory, who was previously at Yale, who did some of the initial ketamine, esketamine drug trials. And so it looked like Emory kind of recruited you to take over their interventional psychiatry department there or part of it. Can you tell me a little bit about that story on what's going on with you lately? Yeah, yeah, sure. So, so let me start also just with a few disclosures because our discussion today. Yeah, let's do that. Yeah. Talk about some novel therapies. So I have received some salary support historically from Jansen pharmaceuticals, who are the makers and proprietors of S-ketamine, Spravato.

I've also received some salary support and consulting fees from Sage Therapeutics. I've been on some scientific advisory board. and received honoraria for Jan's and pharmaceuticals around implementation and deployment of S-Kedamine and clinical practice in Southeast Asia. I've also received some consulting fees and actually salary support from Otsuka Pharmaceuticals for involvement in their Psycunational Forum. Also, as an Emory University faculty and Emory Healthcare employee, I also just have to say that not every opinion expressed here or none of the opinions expressed here represent that of my institution, and they are my own opinions. So with that out of the way, that's good. Well, can I ask you about the financial relationships? Are those currently ongoing? Like, did you bring

those from Yale to Emory with you? Yeah. So I was a study physician on multiple studies, including the suicide study with S-Kedamine, as well as the flexible dosing study, and the open label extension studies as a study physician, so I got some salary support through them. I've received one-off honoraria from Jansen Pharmaceuticals to do these scientific advisory boards, I think as recently as about a year ago. And I may be involved in some ongoing clinical trials, which I can't speak of about today, but that are involving acetamine with Jansen pharmaceuticals. Okay. And I have no conflicts of interest to report at this time. And if you're listening to this episode and you are a psychiatrist or mental health professional who needs continued medical education, we will be giving a free CME for this discussion. If it's an hour and a half, we'll be giving 1.5. So head over to my website, Psychiatrypodcast.com. There's a place where you can look up for the free CME there. And if you're part of my mailing list, you'll get an email with the link to that as well.

And thank you for that. I appreciate that. Yeah, yeah. Okay, so kind of let's slow down a little bit, go back to you did your residency at Yale, you stayed on as a, it looks like a chief, and then an interventional, you did like some interventional fellowship there. Is that? Yeah, so I was, gosh, where we start? So New York, I went a race, grew up mostly in Florida, did my MD PhD at the University of Miami, wanted to do neurosurgery, did my PhD, proceeded to neurology. and then decided ultimately that psychiatry is clearly the best field, superior to all others and clinical neurosciences.

I went to Yale where I was in the neuroscience research training program, and I call myself a recovering bench scientist. So I was doing very basic science research for my PhD looking and using Drosophila, so fruit flies as a model organism to do forward genetic screens to look at neural maintenance factors. and protective factors in the brain. And dabbled a little bit in trying to develop novel models of psychiatric illness and Drosophila. Actually, I was dosing fruit flies with ketamine.

That's an interesting story for another time. What? Yeah, yeah. But I really, I love clinical care. I really love working with patients. Obviously, that's what draws so many of us to psychiatry. And so I shifted focus. around my sophomore junior year of residency training and joined the Yale Depression Research Program,

where my primary mentor, research mentor was Dr. Gerard Sanakora, Jerry Sanochora, who is world-renowned expert in glumaturgic therapies for depression. I was a chief resident and did a fellow year in quote-unquote interventional psychiatry, which is sort of this emerging subfield of psychiatry, which encapsulates on all things that involve neuromodulation, so things like TMS, ECT, vaginal neurostimulation, DBS, as well as novel therapeutics, like things that just require more expertise in training to deploy or administer, like ketamine, S-Ketamine eventually, and potentially psychedelics in the future. Did some research with them.

I joined the faculty as an quote-unquote interventional psychiatrist. also kind of would be analogous to other academic institutions there, treatment-resistant depression programs, for example, more of a consultative kind of a service, and developed a really deep research interest in treatment-resistant and severe mood disorders. I was involved as really a resident, a fellow, and then as a junior faculty as a sub-investigator on multiple clinical trials in the treatment-resistant depression space. And one of the things that we start with, which I think a lot of academic institutions struggle with, is patient recruitment in getting real-world accurate patients to come into clinical trials. And through several

degrees of separation, I became involved in collaborative care, which is an integrated, not integrative, but integrated behavioral health model to bring mental health resources into primary care. And the idea was because Yale, believe it or not, or Yale New Haven Hospital does not have an adult outpatient program from which we could potentially draw TRD patients or subjects from was, well, let's work with primary care when the United States does, I would say, the lion's share of depression treatment, I think, in the country from a psychopharmacological perspective, and see if we can, one, develop a program to help them optimize the care that they're delivering, but also to develop a pipeline to have good real-world subjects that I

could know have very good, adequate medication trials, right? when I have a patient who comes to me off the street, for example, for a clinical trial, I'm often having to dig into pharmacy records, you know, contact with their outpatient psychiatrists to get as detailed of an assessment of their past med trials and the adequacy of those trials, which you know is not impot. It's brutal. It's brutal. Brutal.

I salute you for that. But I sense there's some, first of all, I sense there's some, like, almost like, it's almost a loss that at Yale you were having such a hard time recruiting these patients. or it feels like almost some sadness there. Yeah, you know, because I think, you know, historically when we think of recruiting patients for clinical trial or for research studies, especially in psychological or neuropsychiatric research,

oftentimes it's you hang up a sign, you offer some money, and patients kind of roll through your door and they call you, and they're not necessarily, quote-unquote, real-world patients. And I think, you know, in psychiatry, I think we often struggle with,

you know, the clinical application and the implications of the reductionist style of how we design these clinical trials. Are we treating rural patients for whom these therapies are likely to be efficacious when they deploy into the community? I think there was an adage that I heard somewhere is when there's a new drug on the market, you better hurry up and use it before it stops working. Adly to get out into more widespread use sometimes no longer bears the efficacy that it was once reported in these beautifully designed and well-controlled studies.

And with often charismatic leaders and support staff. I know because we run this like IOP partial program and we do research off of it. And I can tell you that the therapists are very invested in good outcomes because of that. And it does create this elevated effect size. I believe it. I believe it 100%. But I love it. it's the best thing. I think we should do things on that. Yeah. So, so you're absolutely right.

When we're looking at a clinical trial, we like to say that we're providing standard of care, quote unquote, is controlled, but we're not. Clinical trials are head and shoulders above standard of care. I mean, think of how many assessments you're asking so much time with a patient. And so, for example, with the S-ketamine trials, you're beating, having to beat not only placebo, but because of also, if you look at the indication, right, it's not for monotherapy. All patients in those clinical trials were started on a new antidepressant, a new SSRI. So S-Ketamine actually beat out placebo as well as a new SSRI or a new medication trial, right? So you're absolutely right. It's really challenging in that regard to recruit and also to have confidence that what you're doing is going to have real world of thinkability sometimes. Anyway, fast forward. So for personal reasons, I was looking to make a move to the South and actually partially due to the weather too. And so when I was exploring opportunities, you know, I reached out to Emory and, you know, they quickly invited me down for an interview. And I thought that they were going to be really excited and interested in all of this cutting edge interventional psychiatric work I had been doing in the education.

And ironically, what they were most interested in initially was all this integrated collaborative care stuff that I had been doing. Oh. Because the landscape of access to mental health care in the South is really challenged. But especially within the Henry Healthcare health system, it's a very large heterogeneous network. And the Department of Psychiatry and the adult outpatient program in particular is incredibly small by comparison. So fast forward, I'm now the director of behavioral health integration for Emory Health Care. So a fancy title. I'm still feeling out what it mean.

Fancy title for fancy man. Right. But really the goal, the goals as I see them, is to how can we improve the mental health ecosystem within this very large health network to improve patient access to evidence-based therapies and treatments and also help the flow of. patients through the health system from the point where they're potentially first identified as having a depressive disorder or some sort of psychiatric disorder through their initial medication or treatment trials and then also getting them to things like interventional

psychiatric treatments. So my work in the ECT world, right, when we represented minorities are very rarely referred for treatments like ECT or ketamine or S-Ketamine. And so part of my mission with integrated care and my personal vested interest is actually how can we use integrated care as a vehicle to get more people into these highly specialized therapies, which are often reserved for people who have higher SES, greater access to these therapies than patients who actually would really benefit from them as well in the community. And that also includes stigma-based barriers, you know, around these treatments. You know, geographic barriers are not trivial. You have to travel along distance in order to get a treatment where you can't drive home from the treatment, for example.

So how do we think about interventional psychiatry and things like ketamine and S-Ketamine from the system's perspective is really where that lands me. I am part of the neuromodulation and the treatment-resistant depression program here at Emory. I do not lead or direct it, but I do still get ketamine and S-Ketamine treatments. I do ECT several days out of the month. And I am part of the consultation service in terms of treating patients. amongst these different modalities. And my psych services research approach will eventually, again,

looking towards how can we improve targeted access for treatment-resistant depression, patients in primary care into these therapies, both clinically and through research protocols. So that's kind of where things are moving. I've only been at Emory for, gosh, a little over a year. And so a lot of my efforts have been directed on implementing collaborative care. and at that point, but we're starting now to really look at how can we truly integrate and drive patients towards the interventional treatments. Right, because the sooner you can get like a severely ill person to those effective treatments,

the better it's not good to leave someone ill for protracted periods of time. Yes, similar to psychosis. Duration of untreated psychosis, we know is bad, duration of, I would say under-treated depression is also very bad for longitudinal functional outcomes. And, you know, if we think about it too, touching upon the psychopharmacology of how we think ketamine and S-Ketamine work, you know, really we have a first-in-class medication that's a non-monoaminergic-based medication for depression. FDA approved and indicated for depression.

And instead of cycling patients through multiple monoaminergic-based antidepressant trials in combination with cognitive behavioral therapy, we should be thinking about treatments like this much sooner in patients' treatment courses than I think we do traditionally. Yeah, so take us through maybe some of the research findings that you were part of and kind of where the field is, I guess, now. and yeah where would you like to start with that? Yeah, I guess I'll, let me maybe start chronologically. So, you know, when I was at Yale, really the ketamine research, and maybe we should also operationalize some definitions. When I say ketamine, I'm talking about the racemic mixture, which is used for intravenous ketamine as a general anesthetic,

which is not FDA approved. for use as an antidepressant. So we should be clear about that. So ketamine, which is off-label times since the 1960s, been around, is an off-label therapy at this point, whereas S-Ketamine is the proprietary product that is intranasally delivered, compounded again by Johnson Pharmaceuticals, and is the S-and-Shamer taken out from the leic mixture. Yeah, what do you, gosh, I can't.

have to interject here because like I hear a lot of these patients reaching out to me and they're like hey what do I think about ketamine pills like there's these like online kind of like get your ketamine for cheaper amount you'll meet with like this non-md provider often get shipped ketamine and you'll do it in the comfort of your home yeah so yeah they call them trokeys they're often compounded into these like sucking candies or there are some pills that are compounded. You know, the challenge is there is some research, not high quality evidence, supporting maybe that orally delivered ketamine can be helpful either as a maintenance strategy for some patients or even as a primary treatment strategy for certain patients.

But what we know about the psychodynamics is that ketamine is not very orally bioavailable. So the likelihood that patients are actually getting reasonable serum or, or brain levels of ketamine when ingests are taken orally at the doses that are available is not going to come nearly close to what we know currently as being therapeutic doses from dose-finding studies with intravenous ketamine and now intranasal as ketamine. There are a couple of things too, just to make the audience aware of, is that IV ketamine or ketamine can also be compounded as a racemic intranasal delivery. system. People have been doing that for actually quite some time. And it can also be delivered

intramusculately. I am. So there are a lot of clinics that are doing intramuscular ketamine for convenience. And, you know, there is a sub, you know, section of people that are also doing ketamine-assisted psychotherapy. And oftentimes that comes in the form of delivering ketamine, either IV or intramuscularly. I have to say from a safety perspective, I'm not an advocate for home ketamine use in administration. I mean, it is a general anesthetic. One of the primary effects or side effects is dissociation.

It is a dissociative anesthetic. Yeah. So doing that unsupervised is not necessarily the safest thing, especially for somebody with severe psychiatric illness. And there are some physiological consequences. So ketamine and S-ketamine can cause increases in blood pressure. On average, it's about 5 to 10 millimeters of mercury systolic, but patients who have hypertension at baseline,

and they can get them into hypertensive urgency. And so really these therapies, in my opinion, at this current stage of implementation and deployment, really should be done in a supervised setting. And I know I probably just said a bunch of things to unpack, especially maybe the ketamine assistant psychotherapy part no no well i think the main point is you know you you're working in um this ivory tower to produce this amazing elite level research and a couple years down the road it gets you know capitalism takes place right um and now you have like kind of like a

it's a cottage industry a cottage industry of you know just and and and And the thing is, is that you are, you know, digging into the medical records, trying to figure out what they've taken, making sure they've had adequate doses, you know, you're doing your due diligence. And, you know, my concern always is like, okay, how does this actually translate to, like, the everyday practice, you know, and are people just, you know, being now poorly screened, taking home ketamine because it's widely available where it's, like, underdosed and it's the potential side effects are, you know, not being monitored.

So I think this is my public health statement that goes along with this episode. I agree. There are a lot of cash-based practices. A lot of them are run by nurse anesthetists, anesthesiologists, without any psychiatric support. And I really need to be careful because you're right. I am coming from an ivory tower. And there are actually many excellent ketamine providers in the community. community that are not psychiatrists. And they do their due diligence in working very closely

with community psychiatrists to provide access to ketamine in combination with them. But you're right, there is a real potential for a lot of, you know, near malpractice when it comes to ketamine-S-ketamine delivery, mostly ketamine delivery, I should say, because it is an off-label treatment. S-ketamine, fortunately, the FDA approved it with the stipulation. that they had to establish a rents. So similar to clausapine, there is a rems around S-Kedding administration that involves, you know, sending data back to the RENs in terms of monitoring for long-term safety.

And patients must consent to do things like not drive on the day of treatment to remain in a monitored setting for a full two hours before they're allowed to go home. These are standards that must be upheld per agreeing to participate and receive treatments through the RENs at this point. in time. So S-Kedamine does have a lot more guardrails than intravenous ketamine at this point in time. But you're right, it does create an access problem. So, sorry, I'm like, most of the people who listen to this podcast probably are okay with jumping around a little bit. But talking about like the post-marketing safety concerns of S-Ketamine, there was a podcast I listened to

recently, which I think I sent to you. I don't know if you got a chance to listen to that. I did not the opportunity to listen, but maybe you can... I will bring up this study if you're... I'll probably post this to YouTube, so if you're a listener, you could go check on my YouTube and kind of follow along with what we're showing here. But basically this study was looking at the FDA adverse events reporting system, the Farrar's database from March 2019 to March 2020. And the reason why there's this database is to look for more rare side effects,

to look at side effects that occur in kind of protracted course of treatment rather than the shorter course of the randomized control trial, detect these kind of things that escape detection in the randomized control trials. So what they found was they found 2,274 eschatamine-related adverse events in 962 patients. So each patient had about 2.4 events. And some of them were a little bit concerning to me. Obviously, like, dissociation was pretty common. 212 people had that.

But the mean time to onset was 20 days, which when I read that, I was like, huh. So are people, it's like you start this treatment and then after, you know, you've progressed in this treatment for a while. Like, there's, is this dissociation more protracted? I don't know. I guess I'll pick your brain on that. Like, have you seen people with more of a chronic dissociative experience after taking this? I have not. It's usually, yeah, I'm curious about this 24 or 20 days.

I'm not sure how to interpret that based on the data. But so let me, I guess, provide some context. So dissociation is typically, you know, as a direct pharmacological side effect with the medication experienced, you know, while the patient and the patient has the medication in their system. Ketamine is very rapidly metabolized. And so most patients, for example, the peak time to onset of a dissociative symptom is usually, especially with X-Ketamine, the kinetics are a little different with IV, is within the first 10 or 20 minutes of administration of an instrument.

nasal dose. And most of my patients, the lion's share, are, are no longer experiencing any dissociative side effects by approximately 60 minutes or at the worst, the 90 minute mark. Most of my patients are very upset that they have to stay with us for a full two hours, because most of them are ready to go around the hour and 20 minute mark. Okay. What I will also say about this, though, is, again, we're deploying this to the community. And I do wonder if S-Ketamine is being deployed with a lot of patients that may have much more complex psychiatric comorbidities like a comorbid personality disorder, patients with PTSD-related symptoms. There is also some evidence to support that IVKedmi may be an effective treatment strategy for patients, for example, with PTSD.

Again, smaller studies need much more rigorous lines of research. And so I'm wondering if perhaps that is what's being reflected here. Again, maybe more of an association based on the fact that we have this very severe patient population that might have a greater propensity towards experiencing dissociation independent of the medication. But I'm not sure how this was controlled. So I can't speak to that. So that is a curious number to me.

Yeah. Let's see. And the other ones that were a little bit concerning to me, nausea, vomiting, those weren't as concerning. But that is a known side effect. You know, I often talk to my patients around, you know, if you tend to have nausea associated with a general anesthesia, if you've ever had general anesthesia before a patient may be more likely to.

And in fact, it's not uncommon for me to premedicate a lot of my patients with undansetron or some other antimimetic before we get. started with treatment. And that's, that is a common known side effect. It's been rare that I've had patients with like protracted vomiting. It does happen. But it can be very uncomfortable. And I've had some patients tell me that when they go home, they do continue to experience nausea, especially when we're in an acute course of ketamine or es ketamine, which is a, you know, twice per week treatment for about three to four weeks, depending on which modality. So, So that is something that I have seen that I'm not surprised about.

Okay, this was surprising to me. Suicidal ideation. The number was 64 people. Meantime to onset, 8.3 days. What surprised you about that number? Surprising is that, well, first of all, I'm trying to understand, okay, so this is reported either by physicians or patients. Did they have suicidal ideation before?

or did they not, you know, is this worsening of the, is it's like the suicidalization came back, you know, 6.4, 8.3 days. Sometimes what I've seen is that ketamine works really well for the first day or two, but then like the kind of like, there's like a sort of coming back of the suicidal ideation. I don't know if you can speak to any of that. Yeah. So I think it's important to, and this is actually a really important point to highlight. And it's actually very explicit on the label, which I think is also important. So let's talk about S-Kedamine really quickly. So the S-Ketamine actually has two indications. The first indication is for the symptoms of depression in patients with treatment refractory depression. There's no definition on what that means there are how many medication trials as an

augmentation to an oral antidepressant. So TRD, right? But Jansen also got a secondary indication based on their suicide studies. And the secondary indication is for the management of major depressive disorder in patients that are also experienced in suicidal ideation to treat the depressive symptoms. So it's really important that I think the audience understands that what those clinical trials were able to demonstrate was that we were able to improve the depressive symptoms in patients that were experiencing depression with suicidal ideation. But actually, it did not demonstrate that it necessarily had a significant statistically significant impact, which I'll maybe mention in a second, on suicidal ideation in the world itself.

Huh. Important to understand that while we like to think, or maybe conflate the notion that ketamine and S-Ketamine have anti-suicidal properties, what we can understand. what we can say, I think, much more confidently is that it can treat the major risk factor, modifiable risk factor associated with suicidal ideation, which is the severity of depressive symptoms in patients that have in DSI, maybe a question with suicidal ideation. So I'm actually not personally so surprised by those numbers because think of the target population for whom are receiving ketamine risk.

These are high risk, severely depressed patients that may have been referred because they have the indication of major depressive disorder of suicidal ideation. So not unreasonable that patients would report they would either continue to experience or have a recurrence of their symptoms, including suicidal ideation, because it is part and parcel of their, the expression of their depression. And you're right. So one of the major drawbacks to ketamine and S-Ketamine therapy is that the benefits are transient and potentially ethereal in nature. One of the major challenges with ketamine and S-Ketamine therapy is when do we stop? You know, by and large, the symptoms can return pretty quickly in these patients. Now, is that

inherent to the demographic? Is that inherent to the neurobiology or the therapy? That's a little bit unclear at this point in time, which is why there is no real end date. So for example, you could do S-Kedamine or IV-Katamine as maintenance therapy at infinitum at this point. Is it something about that frustrating for you? It's like you wish it was different or I don't know. Well, we do because, you know, I don't feel good about giving somebody IV ketamine every week or every two weeks for five years. Because there are some patients, severe patients that do come in that frequently. And maybe that's my own bias that I need to maybe look into or try to understand, because perhaps

that's no different than coming for psychotherapy, right, every week or biweekly. But we are introducing an exposure to something that, which this study may comment on, is we do not know the long-term consequences of chronic, multi-definate exposure to the Phaetamines, right? There are serious concerns for might this impact cognition? might this make people more vulnerable to psychosis? I think the evidence to date is best we can, suggests that it does not impact or have those side effects. The best data actually we have is from ketamine abuse studies,

many of which come out from Southeast Asia, where ketamine abuse is much more common. Patients are at a higher risk for developing psychosis. They're actually at a much higher risk also for developing bladder symptoms, interstitial cystitis. This is with chronic nearly daily higher dose misuse and abuse than what we're exposing patients to through these different treatment protocols for depression. What do the people look like who use ketamine that heavy, like down the road, like after a couple

years? I kind of have an idea of what like someone who uses methamphetamines at a high dose daily after a couple years. They come in. They're angry. They're detox. They are sleeping all the time. They're very angry. Like what is someone who comes in who's been using that much ketamine look like?

I'm curious. That's a great question. And to be perfectly honest, I do not have any clinical experience with somebody who has abused or misused ket chronic ketamine. It is not common. Yeah, it's not common here. And so. I don't know if I have some good clinical pearls. So if one of my listeners works in Southeast Asia and deals with us on a regular basis,

shoot me an email. I want to hear from you. Very good question. Okay. So we're like talking about some of the side effects. We're talking about some of like, you know, to treat or not to treat how long to treat. You know, with psychotherapy, I think my pushback would be like, I think a lot of the psychotherapy studies show that even when they stop psychotherapy, they continue to,

be on lower doses of medications, you know, not need, you know, be more resistant to depression, more resistant to, like, relapse. But of course, like, the population that's the treatment resistant, it's kind of like a different population in my mind that's like, like the patients that I've sent to ketamine are in psychotherapy. They're not doing good. You know, they're on medications, you know. And I'm like, what else will work for this person? Help me. me. I'm really glad you brought this up because I want to get back to this ketamine-assisted psychotherapy notion and think a little bit about the mechanism of action. So what we think, and this comes from a lot of preclinical studies that was done by Phil Scholnik and Rob Berman,

Juan Berman at Yale and work we've done and Dr. Santa Cora has done looking at neuroimaging, functionary neuroimaging studies with patients with ketamine. You know, the, the punchline line, it's not about glutamate necessarily, but it's about what is glutametric neurotransmission doing and where. So, you know, the greatest density of glutametric neurotransmission is occurring mostly in the cortex, right, which is a much higher order, right, brain area, which is not well targeted, pharmacologically speaking directly. And what Ron Duman's work really showed was that ketamine can very rapidly induce synaptic plasticity. So he's did some really cool studies where you can trace, you can label dendrites in the prefrontal cortex,

and mice or rats that are experiencing chronic unpredictable stress, which is sort of our face-valid model for depression. And those dendrites look sick. You know, they have very few synaptic spines. They're kind of narrow and skinny. You give them a dose of ketamine, and they're giving it intraperitoneal. And you look 24, 48 hours later. You've got these beautiful tufty dendrites. They look great. And what the suggests is that what ketamine is doing is it's enhancing synaptic plasticity, so the propensity to form new connections, change connection features in the brain,

on a very short time scale. And in areas of the brain, that might be really important for the corticolimbic model of depression, right? Things like we're cognitive control, you know, negative affect, evaluation, things like that might occur. Now, there's a thing about synaptic plasticity, though, right? It's not enough to induce a change morphologically speaking, right? You got to use it or you're going to lose it. And so maybe where we're failing patients with ketamine therapy or things that capitalize on inducing synaptic plasticity

is that we're losing or we have an absence of the context, the behavioral, the cognitive, the psychological context, that we can capitalize and really make the synaptic toxicity stick around and induce long-term changes. And so when I hear ketamine-assisted psychotherapy, and what I think a lot of people think about is, let's process your journey while you're intoxicated or you're dissociating on ketamine. When I think about ketamine-assisted psychotherapy, what I'm thinking of is we have a plasticity window after giving somebody a dose. how can I optimize and maximize the likelihood that your learning models of psychotherapy are going to be maximally engaged? So, for example, why don't we couple ketamine-assisted psychotherapy?

By the way, this is not my novel idea. There are many clinical trials going on that are being proposed to do this, but couple ketamine-assisted psychotherapy with cognitive behavioral therapy, CBT. And not while the patient is experiencing dissociation, but develop a novel protocol that, that actually, you know, capitalizes upon what we know from functional imaging studies and the window of opportunity, you know, from morphological studies. You know, and this also carry... Is the window for like two days? Is that what you're thinking? When you're getting a single acute dose, for example, of ketamine, that seems to be the window. Now, ketamine, when we were using it clinically, as I mentioned, during an acute series, it's a, you know, twice a week treatment for...

for three to four weeks. It's really interesting. If you read the early, like Ron Berman studies, Rob Berman studies, I'm sorry, from Yale in 2000, that was really cited as kind of a seminal paper that really kicked off this whole IV ketamine for depression journey. And you look at the dose response timescale, right? You're looking at deciments in, with the Hamd in that study, like on the scale of hours to days, right? When you extrapolate that and start giving it to larger patient population. Some patients do get a benefit, but what I would say what's more common is that you see

incremental improvement with serial dosing in terms of looking at a madress, a hand-bee, with whatever your favorite measurement-informed scale is. And so while it's still rapid in the context of comparing it to an oral antidepressant, I would say most patients do not begin to see at least a response, 50% reduction on some validated scale,

until within one to two-week mark. We shoot for remission with serial dosing, but to your point, when should we dose it, I think you can imagine canter-leaving a good course of CBT with ketamine therapy over the course of several weeks. That might be a really great strategy, one, to enhance the durability of response to ketamine, and also to induce those long-lasting changes

that we know is unique to psychotherapy and often absent from our pharmacotherapy, therapies or other somatic therapies for depression, right? Therapy really is the best, long, standing, the most durable therapy. I think we have in psychiatry. What is? Psychotherapy. Oh, and who was the guy who you said, the synaptic plasticity academy, what was his name,

the guy that did that study? Oh, Ron Duman, D-U-M-A-N. So he did a lot of the, his lab at Yale was doing a lot of the pre-clinical work. So in mice and rats, where you can see some really great, great, micrograss, right, some cool imaging. And there's been many review articles that really kind of also encapsulate the mechanism of action or the theoretical mechanism of action of ketamine, looking at it from multiple levels of nervous system organization. You know, when I often lecture to residents and medical students, I really, in this modern age of psychiatry, challenge us

to think beyond the synapse, right? Because the brain is so complicated. You have to think of multiple levels of organization. Yeah. Challenging, right? But, but ketamine is a solo drug does a lot of different things. Okay, so which of these studies do you think is the one that would be the... Well, I think that second paper, like, yeah, would be, that's a review article. I'm thinking, right, that one has some really nice images.

Yeah, I want to see the images. I want to see, like, what are we actually... Back up. There you go. Talking about chronic stress. Wow, stress and ketamine. Okay. I can walk you through that image if you want. Yeah, let me see if I can get a blow up of that image.

And if you're on YouTube, you can benefit from this. Otherwise, we'll just describe it. This is also a great summary figure, just looking at mechanism of action. Yeah, so, okay, walk me through this image here. So we're looking at a black and white image of a single dendrite in the cortex of a Alice on and panel A. And what you're looking at are, and so that they've used a fluorescent biomarker.

That's how we're lighting up this axon so that when you look at it live in vivo, you can track, trace this neuron back. So this is the same dendrite and the same animal that we're looking at, by the way. So it's not like it's two different animals. We're comparing, you know, a cohort, like a traditional pathology section. So this is really looking, looking in the same. axon, or I'm sorry, same dendrite in the same animal. And so what you're showing here is, what does that dendrite look like in a mouse or a rat that has experienced chronic stress

for 21 days? And this can come in multiple different flavors. Usually it's some chronic, unpredictable stress model. I'll spare the audience. No, don't spare the audience. What are they doing to these poor mice? I don't know specifically, but sometimes what they'll do is they'll randomly come in during the course of the day, they'll restrict the animal in a tight confines. Like metal wires restrict the animal. Sometimes it's more like restrict movement for lack of a better image like kind of a straight jacket kind of a thing. Sometimes it's removing or increasing scarcity of food. There's different kinds of chronic unpredictable stress models. There's even like bully models where you can put mice or rats in a home cage with an animal that's dominant over

it. And so that's a model of, you know, bullying stress, essentially. So there's different kinds of stressors. But unlike, no, not unlike the real world, when we're exposed to chronic stress, right, it can be cumulative and it does have biological consequences. And this is what the dendroid looks like. You can see that it looks kind of skinny or narrow. It's not very robust kind of in its dendritic shaft. There are fewer what the arrows in the right hand side are pointing out are dendritic, spines. So these are contact points that would be with pre-synaptic neurons, which indirectly suggests that there's less connectivity overall in that area of the brain. And here on the right-hand side, in that same stressed animal, what we've done is we've given a single dose one day after

an intraperineal bolus of ketamine. And, I mean, without having a science background, right, or, you know, you can look and see that there's pretty considerable differences, right? There are more dendrites, more opportunities for connections pointed out by those arrows. And even just the morphology of the dendrite itself, it's more robust, it's kind of toughier. It just looks healthier. It's impressive. And I think... And actually, just to take you down, if you look at the image below...

Okay. So this is comparing a human model of connect- right? And so here what we're looking at is a functional connectivity study. So looking at areas of the brain that are wired together in patients with depression. And usually when we look at functional imaging studies, we think increased activity in the cold signal. But actually with this image is showing in the dorsalateral horizontal cortex in blue is actually hypokinectivity or less connectivity in that area of the brain in a patient with depression. 24 hours after giving a dose of ketamine, what you can see in the DLPfc in that area of the brain is that that hypokinactivity

has gone away, meaning that there is enhanced activity in that area of the brain, which suggests that potentially this is kind of a similar mechanism to what we're seeing in the animal models. That's really cool. I think people will be impressed by that sort of that image. If you see that, I'll put that in my show notes up or, you know, the article that goes with this and we'll put it on the website we'll put it in the YouTube if you guys want to check that out with us it you know my thought is that there's a lot of ways to increase sprouting of dintrhic spines like exercise increase bdnf you know so if you're um SSRIs increase bdn f i don't know why we all i think we all love bdn f as an earth traffic factor because it has brain in it brain drive it's because it's uh the miracle growth

for the brain right it's like sprouting that little chia pet you know there are other nurember neurotrophic factors that is out there. I also have a cell signaling background too. I would like to be educated on what you can teach us here. But yes, no, no, you're right. So trophic support, I think, is growth-enhancing support of the nervous system. Again, from a cytos architectural perspective, I think is important. But also from a genetic and transcriptional perspective, right? But go ahead, I'm sorry. ECT as well. I've heard increases BDNF, right? So ECT you can think of as enhancing synaptic plasticity by, in a very robust, non-specific and coordinated

fashion, enhancing, you know, electrical activity, right? You're causing the patient to have a generalized tonic chronic seizure. You're causing not only electrical stimulation, which leads towards wholesale release of all of the endogenous neurotransmitters, right, in a very coordinated fashion. over multiple treatments. And so, yeah, ECT is just another way of very robustly and in diffusely, let's say, in probably multiple areas of the brain-inducing synaptic plasticity, which is why I think it's so effective. I think in psychiatry or historically, you know, in medicine in general, we're always looking for precision medicine. But because of the complexity of brain and human behavior and things like that, I actually think precision is probably not.

going to be effective. We actually need multimodal. Right. Well, you know, we like to, we like to, we think in a category of three usually, our working memory can only think so many, like maybe seven things at once, right? So we usually like three things. We have to remember we have a hundred billion neurons, some with 40,000 connections. And so like, it's so infinitely complex, you know? And it's also not a matter it's like you tune one thing up a little bit and then 50 other things change in multiple directions and other areas of the brain. And it's also not consistent amongst individuals, right? I think there are many roads to depression, right? And there are also many roads to these behavioral and psychiatric phenotypes. And so probably we're precision medicine in psychiatry. I know

this is a little bit of tangent that's going to come in is, you know, looking at a patient pre-posts as they perform in different domains when they're in a functional neuroimidro, right? And looking at individual changes for that person depending on how their brain is wired and connected, of which things like neuromodulation, TMS, right, is a great therapy because you can sort of put it around the brain in different areas and target different neuro anatomical structures. Or we can get at psychopharmacologically if we have good drugs that can target different areas of the brain based on neurotransmigative specific. Yeah, one of the patients that I see that are struggling with depression that have often not responded

to treatment, there's something in their life that's going on that's like on this chronic stress, right? So they may not be held down by human like a mouse's or sometimes they are held down by humans, unfortunately. But there's this chronic, chaotic stress, often, you know, drug use in the home that they can't control, often, you know, relationship conflicts. The classic one I'm thinking about that I see, I've seen a lot and a lot of patients that have revital is just this chronic unhappy marriage, right? You know, it's not even that there's so

much conflict, but it's just feeling unfulfilled or dissatisfied with your relationships that is critical. A lack of connection, you know, the opposite of connection, more abrasiveness. I can't tell you how many people came back from Thanksgiving and told me about how like it's the opposite of like warm, hospitable, happy Thanksgiving, you know? It's like I was choking my parent and we were telling each other that we were never going to talk ever again or, you know, my spouse stormed out of the house and would not come back, you know, I mean, all this just deep, deep unhappiness that's out of their control. So I'm thinking, is, where does ketamine fall in line?

Like, you know, like, okay, are we talking about, like, a lot of the patients that are chronically depressed have personality disorders? Like, are we excluding those from the studies? So would you exclude those from people you would want to treat? Like, where in sort of the trajectory do you see? this intervention fitting in? I mean, this is

a phenomenal question. I think everybody deserves an opportunity to try an interventional treatment potentially. And the reason why is because by and large, the risks are not that great, in my opinion. These therapies

are relatively safe. And I am no better at predicting who will respond to any of these therapies than chance. You know, the other piece to this, though, is I cannot tell you how many patients that I've seen in consultation, gone to course of ketamine. There's either residual symptoms or they did not get better. And as I got to know then, being a good psychiatrist, not just a consultant who is just here to sling ketamine,

really, you know, dug up the core conflicts, right, or the stressors that are really driving what I believe is more important. And so there are many patients for whom I've said, no more ketamine, go to psychotherapy. Or what has ketamine afforded you? Perhaps it's more resilience or at least resiliency in the face of these stressors. But an acknowledgement that it is not going to be a longer term solution for these problems where things like psychotherapy or some sort of social intervention might be more important. So it's funny. You said that the brain thinks in these rules of three.

freeze, when I counsel patients around, and I do a consultation, I often say ketamine is actually probably, people think it's like the most important thing. It's at most a third of their overall treatment plan. The other two are a good rational oral antidepressant regimen, right? Because I know that if you're going to get better from ketamine, I'm going to need good mechanisms or ways to keep you well because of the potential for durability of response. But the third part is that psychotherapy component. It's not the best analogy, but I like to use it a lot, is I can update your hardware, right, with these meds or the therapy.

And psychotherapy kind of is like updating the software, right? But it's up to you to also write that great American novel and practice what's going on in the psychotherapy session in the community and the world. And those are the things that are much more important than the drug or the treatment itself. And that's actually really how I think about this. I do think about ketamine and ECT very much in a biopsychosocial, you know, formulation. And I'm not afraid to tell patients that I don't think ketamine is the right treatment for you. Go to couples counseling.

Resolved the dynamic conflict, right? I remember when I was on my interview trail for psychiatry, I remember talking to a chair of a department, I won't tell you where. But I was interested in psychotherapy, and he was interested only in psychopharmacology. And so I think like We still have that tension in our fields I just I just don't know But like I have this I have this impression that Okay I think I think that there are a class of people

That whatever they're doing They think is like the best thing to do Right and so then they create all these like psychological defenses Against anything other than what they're doing And then also they create if they're more cluster B

I would say then they go all bad also on the other types of things right so I think it's a balance for me of like being open to treatments I'm not doing and while maintaining like

belief in the treatments oh you know it's like ketamine for me ECT they're part of the regimen they're part of the sort of the algorithm that's in my brain. And so like when I hear from you, psychotherapy assisted ketamine, I'm thinking about this one patient that didn't respond to ketamine, but I was like, what if I was like really on him like,

okay, we're going to meet twice a week during that ketamine period to do some of that psychotherapy. Would that be, would that make a difference, you know? I think it's an interesting question, and I think it's an important research question, right? can we enhance the response rates by doing it in that matter? We might find that. The other thing that sort of came to my mind when you were saying this too is I have divorced myself a long time ago of thinking that psychotherapy is not a biological treatment.

Oh, it's totally a biological treatment. It's totally a biological treatment, right? So I never appreciate that. that distinction anymore or I very much try to, I avoid that distinction because the brain is meant to not operate in a vacuum. It's about context and psychotherapy and actually what I think, what I'm thinking more about is the problem with psychotherapy is that we can only model or do so much, right, within an office context, which is still a very artificial construct, right? A very artificial frame. And, you know, I've heard in your previous podcasts talking about the importance

of nutritional psychiatry and exercise. And I think actually in one of your recent podcast you've mentioned, you've not necessarily been so successful in getting patients to do more exercise, right, as part of their treatment regimen. You know, I'll say, though, for the record right now, I've had more success as I've progressed and as I've progressed with certain clients. So I just had a patient today tell me she just started working out three times a week and doing like good you know working out in a group for around 45 minutes to an hour like pretty high intensity like on a rowing machine and I was totally enthusiastic about that you know there's only so much that like one modality will give you so I always thinking like okay if I'm doing the therapy if we're doing this

the medications, like what else? And we've gotten them so far. How do we get them to that next level, right? I am really interested in how can we influence behavior outside of the clinic, right? Outside of the academy of our office visit, outside of our Zoom sessions. And that's actually something I'm really interested in in terms of how can we use technology in order to drive that and also use things like behavioral economics, right, as a motivating factor for people. But also, how can we provide that feedback for people in those times when we're not with them? Right. So, so for example, through apps, passive monitoring, a big part of my job in the, right now for behavioral health integration is, you know, how do we capture screening data and how do we use measurement and

important care approaches? But what I really want to do is, how can I digitally prescribe somebody something and passively monitor how they're doing at home and provide encouragement when they're doing well, but also provide motivation when they're not, as a way to optimize care in a very step care approach. Because you can imagine that would be a really great way to increase the efficiency of our treatments and therapies if we can motivate people to do things in much more real time, psychotherapy or whatever. Give people points and gift cards for doing CBT, you know, contingency management kinds of things, right, for taking their medications on time and adhering to their psychotropic regimen.

I mean, these are great ways, I think, that we can start thinking about optimizing care when they're not with us. And they're really important in collaboration with ketamine and oral antidepressants and everything else. We're trying. There's a study where they force rats to exercise, and it didn't help them at all. You know? So it's like, we can't.

It's like one of these things, like you have to choose out of your own free will, right, or your belief in free will, that you can make a change that will impact your life and it will impact your life. I think the podcast is one of those ways for me. That's how I get out of this sort of like hopeless place. Because I have people who reach out to me who after like a year of working out reach out. And they're like, hey, Dr. Peter, I just want to let you know. Like I listened to your episode a year ago on strength training, started working out.

it has really helped me. And, you know, I'm feeling so much better, blah, blah. So I think that for me, it's like we need more Dave Ramsey's of the exercise diet, like healthy lifestyle world, you know, where it's like, you know, Dave Ramsey is really good at encouraging people to get out of debt, right? And so it's like we need people out there who are encouraging that. I think there's also something to the exploration. components where, gosh, maybe folks in the psychotherapy community are not going to like hearing

this, but sometimes I tell patients, I don't care what psychotherapy modality you choose, whether it's psychoanalysis, whether it's CBT, DBT, mindfulness, EMDR, if it appeals to you and there's something in it that you feel you can be invested in, that, I think, is actually much more important than the modality in and of itself. And there may be some, you know, some truth to the fact that certain modalities are obviously better than for certain conditions, but really it comes down to whatever anybody is willing to engage in, engage in deeply and get a sense of mastery over, right? I think is actually probably where some of that is driving.

It's not about the act of getting on the treadmill or the hamster wheel or whatever, so to speak. Right. Right. It's the drive to do so. And also maybe what the, even the physiological drive, right? Maybe those rats didn't do better because there wasn't a physiological context that was important to them to get on that. So, okay, two things in regards to that. First thing, my schema-focused therapy episode had an email like from someone who was a DBT therapist, Dialectical Behavioral Therapist, and they were like, I can't believe you're not, you're talking about borderline precise order without talking about DBT. And they pointed out, I mean, I started the episode with like a very brief, no nuance.

like here's some studies that compare schema focus therapy, other things, and it actually does help people with borderline personality disorder. I'm going to do another episode where I go through all of the nuance, and I have all these like side-to-side studies comparing active therapies in people with borderline personality disorder.

And there are multiple different types of therapies that work and work well and have good effect sizes. So what I said to this person was like, hey, I am so glad that you're passionate about DBT, please don't take my episode on schema therapy as like a hit on DBT. Like I think it's great that you're passionate about that. People need that. Keep doing what you're doing.

But I would also add like there seems to be this thing called therapist effect where there's some therapists that are more effective than other therapists. And I think what we should do is work on developing the skills that are between therapy as well. And this is what I largely teach to the residents in the, in the program that I teach at Melinda is like, what are these kind of commonalities? And it's like the Therapeutic Alliance series,

if you haven't gone through that series, go back, listen to that, you'll hear some of these things. So yeah, I would agree with you on that. Like, it's absolutely, like, what is your connection with that therapist like? Are you able to be honest with them? Do they reduce your shame when you're talking about things?

Are you able to process in difficult interpersonal situations that you feel with them as well? would say that's key. Like if you're upset at them and you say that, can they take that? Do they know how to process that with you in a meaningful way? Anyways, that's my thought on that. Well, yeah, for me, that's encouraging, actually, you know, in the sense that maybe the packaging is not as important as we want to think it is, right? And the specificity and the focus. Because I think that what that suggests is that there are some very core reductionist principles that do enhance the efficacy. Again, I think it speaks to the fact that we can probably do maybe either less

manualized or less structured kinds of psychotherapy and have just as much effect or benefit for our patients, which are purely based on, again, sort of things that you teach for, which is... I think it's based on, like, their experience of empathy, their experience of you together with them. Is there like a wee-ness, you know, is there a... we are together in this, going through this, is there a reduction of shame? Can they speak about difficult interpersonal situations between you and the person?

Oh, I remember the second thing I was going to say and it was about exercise. Now, I definitely believe that people should consider strength training and squatting and deadlifting. There's something very, very elegant about the progressive nature of like stress, creating a stress that you can modulate and incrementally increase over time.

That being said, there are things that people enjoy doing that I think I've come to this place of like what exercise gives you pleasure because you're going to do that more often for me lately it's rowing I got this nice German single I follow you on Instagram I've seen you rowing and I saw I think recently you were tempted to convince someone else to try it I had um my actual my strength coach came out and I've coached him um as well and so he uh he came out and he got in it and he got so scared that he had to get out of the boat. Like he did not want me to let go of the boat because it was so wobbly.

But yeah, if you're, when you are in Orlando, come down and I will teach you how to row and we'll have some fun with that. Okay, back to ketamine. I feel like we should probably get back to ketamine. And I haven't, I don't feel like I've fully fleshed out this like question of, when should we consider ketamine as ketamine in the trajectory. of sort of patient care, when should we not consider it?

When should we consider other things? And it seems to me like what I'm hearing from you is that it should be an option that is like, this is an option for all patients who are suffering with depression, suicidal thoughts, and we should also consider it as like part of the overall, like, thing. So if someone's running like a ketamine clinic and ketamine is the answer for every solution,

that comes into the door, that's probably not ideal. Not ideal. And I'll just also add another comment that just came to mind too is there's something also very different about a fee-for-service cash ketamine practice, right, and the selection bias of patients that are coming in there, but also the fact that if you have to shell out $600 for every ketamine, you know, and you buy three ketamine treatments, get the whole with 1-3, there's going to be such an inherent bias for a patient to potentially get better from that therapy.

Oh, the increased placebo response. Because that the expectation, yeah, sure, no, it's the same reason why like. Critically important. But getting back to your question, yeah. So I think maybe what you're asking is a little bit about how do we think about this practically like in an algorithmic kind of approach? Sure, yeah. Are you thinking about who is a good candidate and who is not a good candidate?

Yeah. Yeah, what does the evidence say at this point? Yeah. I mean, so all of the evidence, you know, the majority of the evidence for depression, you know, is we're really looking at, you know, as true blue as we can, treatment resistant depression, at least two optimal failed medication trials. I like to see patients at least have a good course of psychotherapy, usually a manualized psychotherapy, CBT,

but it's not a deal breaker, but it's also hard to come by, right? It's sometimes it's both to get patients to do that. Clearly, I'm thinking about when I'm doing a risk, you know, stratification is the degree of functional impairment, right? Are we talking about somebody who's in bed all day long, not leaving the house on the verge of being hospitalized due to functional impairment or suicidality, right?

Clear kind of slam dunk. But if you have somebody who's relatively functional, going to work and, you know, taking care of child care responsibilities, relatively speaking, then what do you do, right? I have a lot of patients like that, you know, that are professionals, working professionals that are still, as you know, suffer. And this is really where the practical considerations come in. And actually, that's what I think most of.

So being an interventional psychiatrist, right, I am in the very unique position of having access to everything. So a patient comes through my door, they're not coming to me for ketamine necessarily. They're saying, what treatment at, you know, is the best treatment for me? TMS, MAOIs or some other, you know, more higher degree down the algorithm oral antidepressant trial, ECT, ketamine, S-Ketamine, clinical trial, right? I have the corneocopia. And so when I'm thinking about this, I really do take into the core symptoms, what the patient is experiencing, how quickly I need to get them better, usually going to push me

towards something like ketamine or ECT, and practically speaking, what can we do with the patient? You know, the patient can't drive on the day of treatment for ketamine, S-Ketamine, and ECT. There are potential reimbursement or insurance-based issues, right? ECT generally is covered by everything. Ketamine S-Ketamine growing and increasingly in terms of commercial insurance coverage, but that can be a barrier sometimes. Can I get the patient to and from treatment? Do I have a patient who I am concerned about from a medical, cognitive perspective that may not be a good initial candidate for ECT that maybe we try ketamine first, sort of as a lead-in, see if they get better from that?

Right? Because it doesn't involve general anesthesia. While there are some, you know, autonomic nervous system considerations, it's, you know, not nearly as taxing on the body as ECT might be. And so these are actually the things that I take into account. And what is the patient most invested in? I have some patients that want to be very conservative and they want to try TMS. I have some patients that want the gold standard, right, which is still considered ECT at this current point in time. There are actually studies going on and I was involved in. I was a Pecori study that's comparing IV ketamine to ECT head to head in an open label trial to see what is a better patient.

patient-centered outcome for these two modalities head-to-head. Never been compared head-to-head. So I really do take patient preference. Is that out yet or that's coming out? I believe they're still recruiting. So that study is either ongoing or it's about to complete its recruitment and then it'll probably be a couple of a year or two. That's going to be a fascinating study.

It's not quite comparing apples to apples because there are some temporal elements to it. So, you know, ECT we say about six treatments. and so, but sometimes these patients can need more ECT compared to the, you know, six treatments of ketamine that they're getting. But anyway, without getting into the details of that study, it will be very interesting to see what the results are for that particular trial. But again, I don't, TMS and ketamine had never been compared head to head. You know, and just daltly speaking, you know, just from my experience, I've had patients that I've done ketamine, didn't respond, we did ECT, did great. I had patients that we did ECT, did terrible,

we converted to ketamine and didn't get better. And then I've had patients who we did and they didn't get better. And then we did a critical reevaluation and more psychotherapy. Yeah. You know, I would like to see, and this is what I talked in my, in the episode on psilocybin assisted psychotherapy, one of my critiques of those studies that are coming out is it's like they're on the wait list to get it or they're getting it. Yeah.

And then they swap. And so everyone eventually gets it, right? Which is, okay. Why did they do it that way? because everyone who signs up for those studies wants that type of treatment, right? Or the wait list is often like some sort of placebo with the therapy.

It's like, you know, trying to hide that from the patient that they're getting the psilocybin, which is really hard to do. In the self-selection bias is, you know, very challenging. But my critique on this type of thing is like, for me, it's partial program.

Like, that's where I really see a lot of the, people getting better or something else, right? It's not wait list or, you know, placebo. It's like, so I would like to see some of these things head-to-head with like a good, you know, 30-session partial program, like DBT partial program. That's where I think. But, you know, that being said, like we have like in the system, like at the university that I've been associated with for a while, we have people who have been. through the partial program who don't get better, who go to ECT. We have people who come in, who have had ECT, go through the partial program.

One girl in particular that comes to my mind had been through ECT like a year before. I'd still chronic suicidality. She went through DPP track for about six months. And then she went through the track that I run, which is kind of a unique approach for another, you know, six months. And, you know, through a series of, things she got better through, you know, basically really intensive psychotherapy. That being said, you know, how was she able to get a year of partial because she was in and out of a psychiatric hospital every time you go to a psychiatric hospital, the partial days reboot.

So not all patients are severe enough to get that prolonged course. And if you look at these like DBT mentalization, transfer focused therapy, a lot of these therapies, the initial studies that are so promising are really extensive. Like the mentalization one that I love so much, it's like 18 months of partial. You know, it's like. And they're not practical for most patients, right? Well, I think this is where we need like a full-fledged lobbying, you know, like effort. It's funny.

So I just gave a, like, just came this morning. from giving a talk to the, we have a prevention medicine fellowship program as part of the internal medicine residency here at Emory. And they wanted me to talk about prevention strategies and mental health and psychiatric treatment. And I really took pause. And I struggled because what prevention strategies do we have in psychiatry? Well, we can't even agree on what we're treating.

But I think you're right. You know, we focus so much on the treatment aspect. and the rigorousness of the treatment once people present. But what if we had something that was moderately intensive for patients that were subclinical or looked like they were at high risk, right? That might decrease the potential resource allocation we need for something like that, still steeped and very much involved in those principles. And also maybe think about coupling, like you said, instead of ketamine with psychotherapy,

it's really psychotherapy and we're going to augment with ketamine, right? It's the other way around. Really thinking that the intensive PHP and programs are actually the primary intervention and the ketamine and those kinds of things are sort of in the background to help promote the rapidity of response and perhaps the durability response. So I'm 100% agree with you. It's just funding these kinds of studies to get the evidence base that I think we want and need is really difficult.

You know, and, okay, there are good studies. We did one in my, the program that I'm a part of, medical director of that, you know, we looked at like the financial saving of someone going through the program. Something like $15,000 was saved. Maybe in hospitalizations, I presume. And like, so they looked at like the two years before and the two years after treatment and the amount of money reduction. Well, yeah. There's tons of these studies that exist. So it's like, in my mind, it's like, yes, treatment will reduce costs, but you have to have like a, yeah, anyways, it's like such a big issue.

If you compare it to the amount of money we spend in, you know, pharmacology and drug development, right? And how many of those actually make it to market, right? you know, billions of dollars for medications that never make it to market, you know, and if we shunted some of that resource allocation, the things that we do know work, right, and work really well and maybe, you know, combine these things. And what I will say is I think the pharma industry is beginning to get wise to this, because these are the kinds of things that I'm being asked about sometimes as a consultant or what I think is the most important.

and it's really looking at your treatment, your drug treatment, and how it works in context, right? And so combining it with an app or combining it with a psychotherapy, you know, I think when NDMA potentially gets FDA-free, right, I think the evidence right now supports that NDMA monotherapy without the psychotherapy component is not effective. It doesn't separate from placebo. It really is for PTSD, that. So, you know, I think that we're going to have to start thinking about, we think about, especially for mental health treatments, repackaging our therapies and including the treatment setting in the context in the label.

And I think that's probably what's going to happen with psilocybin, you know, because if you look at these treatment protocols, you know, it's not a, it's not like a traditional drug study where you're a single dosing, right? The patients get all of these, you know, preparatory sessions that are very extensive, right? And these post-processing sessions, right? And monitoring a quote-quote set and setting. and all of these other things that, you know, I would argue that if the FDA went to approve this, and they're going to say, well, this is great. When you market it to the general public,

you're going to need to have all of those elements because that's what you showed in the study, right? It's not going to be just giving somebody a dose of civil side in an office setting and going on their way. It's going to be, how are you going to develop a treatment package around this? And that's where development is moving. And I hope that there's a fidelity in that, you know, and that's where I'm like, I kind of push back on some of the ketamine stuff. It's like at home ketamine, take your own ketamine. It seems to me like this is, well, if I was starting that company, I'd be very worried about getting sued because you're veering from normal protocol. And it seems like there's some risks that you're not able to monitor as well. Well, again, remember S-Ketamine has that guardrail. It must be administered in a monitored setting. It is part of a REMS, right?

It does have those FDA requirements, and the individual physician is deviating from that protocol, and there's certainly medical liability there. But recall that, you know, IV ketamine is off-label, right? So whatever you're doing there, it's sort of your license and you're on the line. Yep. And again, that's not to scare people, because in medicine we do most things, in fact, are off-label.

If you actually look at the label and the indications for most antidepressants, right, we prescribe them to patients without actually the indication, right? A lot of the SSRIs, for example, don't have, you know, approval for other psychiatric conditions for which, you know, we think they probably work well, right? But, yeah, I agree with you. There is a real concern there that the FDA and, you know, a regulatory bodies need to be very thoughtful and how they are going to regulate these therapies so that there isn't that potential for misuse

and let's just say inappropriate implementation. Yeah. Very good. Well, hey, I think I might have to bring you back on and do like a part two. I think we kind of talked about that, like ECT or something, TMS. I haven't done one on TMS. But anything else you'd like to say before we kind of wrap up our time here?

No, of course, I just want to say, you for inviting me. I've been a long-time listener for some call or so. Thank you. Thank you for, inviting me. I enjoy listening to the podcast. I also want to give a shout out to Dr. Trankel. Yep. At Loma Linda. Oh, yeah. So I met back to meet her a couple years ago. She came to, we did an interventional psychiatry, a CME course, and she came out with some of her residents. She's great, great to work with. I invited her on, but she got, she got, she's, she's, She had work. I texted her this morning. She's like, I have work. I'm busy. But maybe she'll hear this and have a- Oh, she'll be-

I have FOMO and she'll want to come back to it. She'll be very thankful that you gave her a shot out. Yeah, what else? When did you start listening to the podcast or how did you find it? That's a good question. I think I want to say I found it through either Apple Podcasts, or I really think it may have come up on my Instagram, actually, the algorithm. Oh. The algorithm in the background is where I found it. And then I think I reached out to you, just commenting about how much I appreciated the other content. And I'd say, hey, I'd love to come on at some point to talk about this really exciting, you know, emerging field.

I think I reached out to you. I was still at Yale. This is really around the time when S-Kedini just got FDA approval. So it actually might be like two or three years ago. Yeah. Yeah, I think I wanted you to get like a mic and you were going to go to the library. And like I was like a little bit too obsessive at the time about like the sound quality. But I think with Zoom and with COVID, I've just had to kind of accept that it is what it is.

They've been great. I think they've sounded incredibly professional. I really appreciate the content. It's giving me a lot of food to have bought. I love for passive reception of information. and also the online resources are great. Sorry to plug and give you an advertisement, but having all of that data,

the sleep episode was very actually helpful for me because sleep is such a transdiagnostic complaint. And in my primary care work, you know, it's always a challenge about counseling primary care docs around how rational prescribing versus insomnia. So that was a great. Yep, 100%.

Okay. Well, thank you so much for coming on. Once again, Get free see me for this episode. I'll put a link in the show notes for that. And we will have some sort of write up with some of the citations from this episode if you want to dig deeper into things. And yeah, please let me know what your thoughts are. You can contact.

Are you publicly on Instagram? Do you have a public Instagram or it's private? I think it's private. But if people do want to reach out to me, I'm happy to share my email address. Okay. Is that okay? Uh, you will put in the show notes. Okay.

Awesome. All right. Thanks again.