We acknowledge Aboriginal and Torres Strait Islander peoples as the first nations and the traditional owners and custodians of the lands and waters known as Australia and Māori as Tungata Fenua in Aotearoa. We honor and respect the elders past and present who weave their wisdom into all realms of life. Welcome to another Psych Matters podcast from the Royal Australian and New Zealand College of Psychiatrists. Psych Matters is a series of discussions on training and practice issues facing trainees and fellows of the college. Another important topic is mental health. Hello and welcome to the latest RANZ CP podcast and we're talking today following the introduction of Esh Ketameen to the pharmaceutical benefits scheme. I'm Professor Mell Hopwood from the University of Melbourne and I've got the pleasure today of being joined by Professor Colin Lou from the Black Dog Institute and University of New South Wales. Welcome, Colin. Oh, hi, Mell. It's a very exciting mouth on the 1st of May that Spavator is on the PBS which means that you can get 8 doses of Spavator the medication cost for the PBS price of about $31. But can you tell us more about what this means for Australian psychiatrists? You know, what is Esh Ketameen? What do we need to know about it? So for those who are not familiar, Esh Ketameen, the Rhesemic Isomer of Ketameen, is a competitive NDMA receptor antagonist. So works on glutamatorgic transmission in the brain. Esh Ketameen has been around for a long time, actually as an anesthetic drug which not many people will be familiar with. It works predominantly via glutamate, not being a target we've successfully landed before in mood disorder treatment. As you well know, we've tried a number of compounds but they've been difficult for human beings to tolerate or to get them to be effective. So by acting in this manner, Esh Ketameen activates glutamatorgic systems in the brain and we know the NMDA receptor is quite widespread, glutamators are widespread, excitatory transmitters system in the brain. And the NMDA receptor is richly found in some of the key limbic areas that we think are important in mood disorders like major depression. The trial work with Esh Ketameen in brief summary has been in treatment resistant depression and that's the indication it's got on the PBS4. Technically defined as failing to adequate trials of oral antidepressants. Of course there are limits to that definition aren't there about the role of social and psychological treatments and we'd expect them to be part of defining properly treatment resistant depression as well. Esh Ketameen is available as an intranasal spray. We'll talk a little bit more about the practicalities of that but the key thing is it's a treatment delivered at a treatment centre and we can talk more in a minute about what that looks like. From the first to May as Colin indicated, subsidised on the farm of surgical benefits scheme. And there's a set of other issues around it. That's a terrific thing because the cost of this drug is prohibitive. And the reality even though it's been licensed by the TGA for around 18 months now, it's really not been available to people outside trials because the cost has been prohibitive. And Melbourne you've emphasised the NMDA receptor. Are you saying that it's quite different to all the other antidepressants we have where we are typically talking about, you know, Nordrenaline, Certulein, Dopamine. And what difference would you say we see in the results for something like Esh Ketameen, you know, Dispervata, nasal spray, formulation compared to standard antidepressants? It definitely is the first in class in that sense of agents that work via the glutamateurgic system. Because of that widespread exotatory role, it's reasonable to think glutamateurgic transmission might be relevant to disorders like depression. It's interesting we tried a lot with the monoamines to subclassify depression, didn't we? What's a serotonergic depression look like? What's a noradrenergic depression look like? And I think for various reasons by large we weren't successful. So can I honestly say hand on heart, I can recognise a glutamateurgic depression? No. And the trials we've had up to this point with Esh Ketameen wouldn't define that either. That's a little bit about the limit of who gets into trials. So we always would like to know for example to those people with a profound melancholic depression with severe psychomotor retardation. Given the ACT letters you might expect they'd be more likely to respond. But we don't know because we struggle to get them into trials. So at this point we can't define but what we can see from the trials that are uniquely done in people with treatment resistant depression. We don't do that very often. That there's a group of people who didn't respond to the classical monoamines antidepressants who do respond to this. The trials suggest that in people who failed two or three antidepressants about 50% got better on the combination of Esh Ketameen and a new antidepressant versus placebo and a new antidepressant. So if you look at star D, the rate of response to the third conventional treatment was probably around 15%. That sounds pretty good. I think based on our experience and I'll be interested to hear about yours in a minute, of course that rate goes down a bit the more treatments you've had and I think intuitively that's not surprising. And it's important to acknowledge from the outset 50% is not 100% not everyone responds. I think in this day and age where we've not had new treatments for a while a novel mechanism generates high public expectation out there in the TikTok world. And I think we need to be quite careful because for patients who failed a few things, he's the new treatment. Sometimes if they're a non-respondent they can be a very disappointing experience. I think we need to be clear about those numbers. That's a really good point. I've been really excited about this whole field, Malcos. I think it's like a whole new field in psychiatry that we started working with generic. Receemic ketamine back in 2012. And I must say we saw very good results. And this is the whole ketamine field that even in people who have a very high level of what we call treatment resistant depression that hasn't responded to even multiple medications or some cases even, you know, not got better with these CT can respond to ketamine. And not only can they respond but it can happen very quickly. And I think a lot of that is put down to the fact that these work very differently on the glutamate system rather than the standard mechanisms. And of course, SKTamine is one formulation of ketamine. There's a number of formulations now coming out. But in Australia we now have two main formulations of ketamine available for clinical use. One is the, you know, this provider SKTamine spray. And the other one is the resume ketamine which is available as a generic drug and which has been used for decades now in Australia for anesthesia for sedation. But which a whole series of research studies including our own done here in Australia and overseas have shown have very powerful effects for treating depression. So it's very exciting that we have both of these drugs that are available now for treatment of treatment resistant depression. And I think where in our clinic before when we offered people a choice of spravato or generic ketamine, both of which have shown to be very effective and safe, the choice of income down to cost. But of course, now the cost of both drugs with the PBS subsidy is lovely equivalent. I'm interested in just in your clinic because I think there'll be many people thinking, well, is this going to be like describing a new drug? You know, when the latest drug comes out, we read the prescribing guidelines. I do an assessment, I write a script, I send you off. And then here we go. I mean, you mentioned it's an in clinic treatment, but it's, it's a simple matter of sitting you down in my consulting rooms. You have the few sprays or you have an injection, we measure your blood pressure a few times and then off you go. Not quite. So let's talk through a few of the practicalities. I think the first of them to say the data really on the showed in a proportion of patients with TRD, a very rapid and early response, unusually so within hours. Let's a lot of questions initially in the research didn't about, so is this a thing we use once? What's the benefit of that? Is that the pattern for every responder as well? The evidence we've accumulated now says, first of all, no, it's not everyone who responds who has the magic first few hours response and that's, that's important because patients have heard about that and expect it. And what we've also shown is actually continual use over a period of time does do as do other treatments for depression reduce the risk of relapse when the treatment's been effective. So a course of treatment with Ash Ketermean generally looks like twice a week treatment for four weeks and that will give you a guide to efficacy. During that time there will be dose adjustment depending on response and tolerability like most things and generally we do that every couple of weeks. Just consistent with it's not always the first dose that tells you if the treatments are effective we then dose weekly for four weeks then fortnightly out to a treatment period of around six months. This begs a whole lot of interesting questions about why six months but relevant to why is that this is a treatment you have to attend a specific treatment centre for. in that sense a little like.
CT. You can't just go into a room and have it. Treatment centers need to go through a certain amount of training to be certified and they need to have resources available like nursing staff to observe during the period of treatment and a close relationship with the pharmacy because this is after all a schedule eight drug that needs to be handled with appropriate caution. Patients go into the treatment center for treatment on a treatment day so initially twice a week. They'll be there for about an hour and a half. Whilst they literally administer the drug themselves, importantly there are no takeaways. That's not this treatment. With the treatment we observe post-dosing, particularly for two major impacts. One is dissociation, which is common. Transient and generally of a mild nature. I've observed, we've had a number of patients unsurprising with the trauma history as NETRD service does and I've been watching for difficult dissociation in that group. And I have to say it hasn't happened with any particular frequency which is of an interesting. We also observe blood pressure closely because there can be an increase in blood pressure with this treatment, not frequently requiring intervention but often a slightly more prolonged period of observation. We also monitor for other side effects during treatment, particularly as a strong interest in bladder side effects. Given the problems we've seen in some people who misuse ketamine in much larger doses of course. Patients are usually in the clinic for something like an hour and a half, maybe a couple of hours for the first treatment. Some patients will experience sedation later in the day so you can't drive yourself home from clinical, operate the proverbial heavy machinery for the rest of the day and that's an issue. And because of that inconvenience of travelling to a treatment site, I haven't talked about six months treatment to start with and most people are happy with that idea as their first go. The obvious clinical question in this highly relapsing disorder is what happens at the end of that time? Maybe we can come back to that question because I'll be interested to hear what you say. But for most people, six months of an incentive treatment which will still have some ongoing cost attached to it is a big commitment. Just briefly I'll touch on that cost. So great drug subsidised tremendous and it's brought this down into a scalable thing for many, many more people. There is still a cost for the nurse, it does the observation and the pharmacist. And in most centres and I can't quote every centre, that's going to be somewhere in the vicinity of $350 a treatment. It's not nothing. And across a course that will amount to a few thousand dollars. Clearly patients need that information up front to give appropriate informed consent. So that takes us into a sphere of costing treatments in psychiatry which can be a cause of some discomfort I think for us. But I think we need to be upfront about that. I hope that you're enjoying this podcast. If you have a topic suggestion or would like to participate in a future episode of Psych Matters, we'd love to hear from you. Please contact us by email at
[email protected] There are some of the practical issues from my point of view. I'm interested in what you think about that and what some of the issues in it might be. Yeah, and a really interesting mal and I mean you've raised a number of issues that I'm keen to revisit. You know, the first one starting with cost. Certainly in my clinic we see a lot of people with difficult to create a treatment resistant depression. And they often come to me asking, should I have ketamine or SKTMEN or ECT? And I must say now with a lot of people, I think ECT is an excellent treatment done well and safe and highly effective for depression and suicidality. But for a lot of these people I would actually be recommending that you have ketamine first. And if that doesn't work then go for ECT. But because of the treatment cost issue, often that's not an option. And not because of the drug cost but the treatment session cost. Whereas ECT is covered by Medicare and the health funds but the ketamine treatment cost is not. I think that's something that we do need to address as a college. And I must say, it might sound like why does it cost $350 if it's just a nurse observing and the pharmacy cost. But certainly in our centre we found that to do a clinic well, it's a bigger thing is setting up an ECT service. You know, we have detailed policies and procedures, we have training and credentialing of staff, we have a whole set of clinic forms, OPPOETISY Assets with Consent Form, we have a specialized customized treatment area. The whole environment is very important in terms of low stimulus but then increasingly and with a lot of the learnings from psychedelic assisted therapy, we're finding that the whole idea of mindset and the setting is actually very important for optimizing outcomes. It's quite different to say taking a tablet or pro-zac. Whereas if you take a tablet or pro-zac, whether you're listening to music, whether you're in the shower, it probably doesn't make a lot of difference. What is your mindset and what is the setting when you're taking that tablet? Whereas with ketamine, we are finding it does actually make a lot of difference to the actual experience and both safety but also the effectiveness of the treatment. So people are saying to us that when we optimize the setting setting, it's almost like a 20% increase in dose, which is really interesting because I would not have expected that. But I think that's also why a specialized setting, it's not just a kind of, "City of my office, you know, have a treatment, I would take a blood pressure a few times and off home." I don't think that is the optimal way to give ketamine. One other aspect you touched on with safety, which I think is really important, is there's a lot of awareness of safety monitoring during the one and a half to two hours, but there's a lot less awareness of the importance for monitoring for cumulative side effects. Because the serious effects like bladder, liver effects don't happen in the two hours after a treatment, there are things that happen with repeated treatments. And we've seen this in the clinical trials as well as in the recreational drug use literature. So that's why we actually developed the ketamine side effect tool as a structured framework to guide people through safety monitoring, not just at each session for two hours, but in between sessions. And that's why before we do every session, every treatment, we actually ask people particularly of things like, are you having any bladder symptoms? Because they might be having some urinary symptoms, they think it's unrelated, so they don't mention it, instead of which they're actually getting some inflammation of the bladder, which might be related to ketamine, but they don't tell you because you didn't are. So that's why I think a structured assessment that is done at every session is actually very important. And we know that when you do that structured assessment, both from the studies of esketamine and ketamine, that you will pick up some people where you score a positive on those symptoms, you then have to actively manage that. You might look into it, are they having a urine tract infection? Do we slow down the dose? Do we miss a dose? And with that kind of active management, then it's been safe. But I think my concern is that if people launch into clinics without that kind of active management that's happened in the research trials, just thinking always been safe, it's not a problem that we might end up doing some harm to some people. Yeah, I totally agree. There's a few things in there, isn't there? One of them is about the placement in the order of things. Whilst the trials have been conducted in a group who are a little more towards the failed two or three antidepressants, I think we all know that that's still a very heterogeneous group. In fact, our first two choices of antidepressants were not very good at knowing which ones to choose even. So, I don't think this is a treatment for everyone who might at least in theory tick that box. I think in practice, it probably won't be because of the level of commitment involved, and I think that's okay. It then does beg those complicated questions about where does it fit relative to treatments like complex augmentation regimes, prolonged therapy, DCT. I would say at this point in time, all of those treatments are substantially more evidence-based than psychedelic therapy at this point. You made also, I think, a very good point that at this point in our evolution of the use of compounds like ash ketamine, this does require knowledge and specific skill and the right environment. We've set up an environment that I think the literature reflects is appropriately calm and tranquil. There's some interesting experiential data about people wanting their own music track to listen to, for example, during treatment. Staff are familiar with the procedure. We do it in a quiet area of the hospital. All of those things are relevant, and this is not, I don't think, a treatment that's well set up to just an anti-chambering, what's otherwise a very busy practice. So, a fair bit of thought needs to go into that. There's a challenge there in the generalisability of the availability of the treatment. So, you know, if we only end up with a handful of centres in the middle of large cities, that's a challenge. I think we need to continue to work with regulators and funders about how to make this equitably accessible, but safely so. I concur there very strongly. We don't have the evidence at this stage to say, "Yeah, this ahead of ECT," or "Or augmentation with lithium," or whatever your favourite is. and a team.
But I agree with you if you go to patient preference, we've moved into an age where patients clearly express their preference more readily and often very strongly have one. I had an interesting experience during our trials with Ash Ketamine when we did a little bit of medium relation to the trials. And we've got a whole lot of referrals from general practitioners specifically for Ash Ketamine therapy. I'm 99% sure most of them were generated by the patient. And you know, if you go out to the blogger's fear, there's an awful lot of information out there. And I'd say if you haven't experienced that before, part of our reaction needs to be made as implying before, people really get informed consent. This is not magic, it's a treatment. It works for a good proportion, but it does not work for everybody. And here are the issues in that treatment. I always include in that a startup assessment that discusses it in with the other options. Very much leaving a person with a sense that we occasionally come across with they say, "Turkey, don't we? This is the last resort. And if this doesn't work, I'm doomed." Well, that's not a good thing for people to be feeling. And I think the same can occur with Ash Ketamine therapy, too, if we're not careful. Yes. And I think the other thing about picking up on something said that's really important, because we get a lot of referrals like that in calls and the public, et cetera, who see this as a miracle cure. It's almost like, I'm depressed. I've got multiple problems in life, financial, relationship, et cetera. I will just have four weeks of Ketamine or S-Ketamine. And then I'll be cured. And so part of the informed consent, I think-- I talk people through very carefully. And some of the things we've already discussed, it doesn't work for everyone. I think that kind of initial detailed assessment, which is a kind of a train to do, to look at, why are you feeling depressed or distressed in the first place? Is it depression? Is it other issues? There's some people who come to us for Ketamine treatment. And where we end up recommending something else. We think you're better off going and having therapy for this particular issue, addressing these issues in your life, maybe trialling other medications first, because we've actually explained in detail the commitment and the cost of coming to this in clinic care. And that it's not just coming for four weeks. That for most people, particularly if your depression has been difficult to create a treatment resistance, that itself predicts the need for longer ongoing treatment. We've had some people in our clinic who've been coming for two or three years. These are usually people whose depression has been very difficult to create, you know, been on over a dozen medications, had ECT, without much response, et cetera, have, pleasingly, had really good improvement with Ketamine or S-Ketamine, but needed to continue. But it's very important that people are made aware of that at the time of informed consent at the outset. And the other thing I also think is really important at the time of informed consent is people have also heard, you know, the miraculous people being catapulted from being depressed to well in a day. And I've seen that. I've seen that both in our research trials and in the clinic over the last decade. But you can also go the other way very quickly, both in terms of going back into depression and suicidality. So I think for people who are interested in using these treatments, you know, my advice is, it's very easy to start Ketamine or S-Ketamine. The issue is what do you do afterwards? And you need to put a framework in place for safe monitoring and safe management if a person should rapidly become suicidal in 24 hours. What is your safety management plan? And I think we do people that deserve this. If we launch into treatment, you know, with minimal assessment, a lot of enthusiasm, you know, very quick to start, but without having talked them through, you made them aware and also put into place a lot of these things. I mean, are there other things as well that you tell people at the time of consent? Yeah, I think part of that goes to seeing S-Ketamine treatment as part of an overall treatment program. So patients need appropriate clinical support because treatment may work, it may not work. People can relapse even on treatment. All sorts of things can happen as we know clinically. It's very important for me to be clear about my role if I'm the S-Ketamine clinic doctor, who are you going to if you're running to trouble? I would be concerned if people were relying on a procedural clinic if I can use that term for the entirety of their care. I also agree that setting expectations at the start is very important and one of the trickiest ones is how long to continue. Many of the patients we've treated with S-Ketamine have had multiple episodes of depression in their life, experienced multiple relapses, and are rightly nervous about the prospect of stopping something at say six months when they found something that's worked. They're often, "Oh, do I have to?" Well, we do have data that says in terms of safety, extending beyond that time doesn't seem to be additively a particularly strong problem. Now, there are limits on how far that data goes, and that's important to acknowledge. So, safety-wise, I'm less concerned, I think the bigger question is, how do you know with a maintenance treatment when it's still being effective? The highest risk of relapses after an episode is of course the first six months. So, if we get you through that period and we do the other things that might be relevant in your case, it may be that continuing S-Ketamine maybe on that point will not alter the risk of relapses. Now, if you've stopped it and you relapse soon afterwards, you're going to come to me and say, "I think I'd like to restart it and stay longer," and you're probably right. And it is a pleasing thing that after some debate, the PBS Rules Enable Retreatment and Extended Treatment, where appropriate. And I think that's a good thing, because treatment-resistant depression is a complex set of problems and not one disorder. And for many people, a chronic relapsing, remitting or just persistent disorder, that no one way of doing things is always going to work. I'm interested, how do you handle that? How long should I stay on it for question? I think your recommendation of saying to people that you should plan to be on it for at least six months is really sensible. And we're kind of getting away from that, this is going to be the miracle cure, four weeks of treatment and the rest of my life, I'll be fine. Now, after six months, 'cause this is a common question, how long will I need to continue for? We're very sensible question. We would say then, we will work with you for ongoing discussion. And at that point at six months, we might say, okay, we could try tapering off. That's what you want to do with very careful monitoring. And then if you're starting to relapse, we will know, maybe we need to go back on. So it's kind of very much individually determined. What I think is very risky, man, was happening maybe even about 10 years ago when ketamine first came on the scene, which is of course closely related to S-ketamine, is that people were very excited about the efficacy. Clinics were set up, people were treated. They were well in remission, everybody is happy, and then they were discharged, and there was no follow-up. And colleagues around, there were all contact me saying, these people are now then making suicide attempts and turning up to the emergency department. And I think there was a lack of realization of the importance of follow-up. So that's for that reason, we require that everybody in our clinic, like you, we only managed to catch me in S-ketamine treatment, but they have their own psychiatrist, or if it's in a rural setting, you know, like a GP, who's going to be closely involved in place of a psychiatrist, who's going to provide ongoing care and monitoring during the treatment and afterwards. Because I think we don't do people in service. If they come to us for a period of treatment, they will, then they're discharged, there's no follow-up. And it can be terribly disappointing, you know, to be well and then fall back into depression. But I think if we prepare people for this, and also have a plan for how to manage this, this is really important. There's one more thing, Mal, I just wanted to say, for people thinking about using these drugs. And, you know, in our centre, which is kind of almost quaternary referral, people with treatment, resist and difficult to treat depression, and often a lot of comorbidities, a lot of trauma. I think maybe even 50% of people at our centre have had significant trauma in childhood adulthood. And we have seen some people wear under the acute effects of the drug, and you know, there's some similarities to psychedelics in terms of that eager dissolution, the dropping of your defenses, that people tell me that they feel suddenly, intensely suicidal and can feel quite distressed. And I think this is again, it's very important that the clinic has measures to routinely deal with this as needed, because this can occur. And I just wanted to say that to people, because this idea that it's a very safe drug, you know, this is not a problem, we don't need to worry about any of that. I don't think it's correct. I think anyone wanting to give these treatments with esketamine or ectamine needs to be aware of that, and needs to be prepared to deal with that. We currently run a three-day training course for psychiatrists through the Black Dorg Institute in Sydney. It's also run on lines of people can attend, because it's a fascinating field, but there's a lot to know to really effectively and safely give this treatment. Agreed. And I think it goes to how you operationalise your role as the psychiatrist within that service. So even in a procedural service, availability of the psychiatrist who knows the issues with this therapy is very important. So I see myself as available to the clinic throughout dosing time. To problem solve as things arise, because asking someone who's not well trained in that area is unwise. I would agree entirely. So look.
Colin, I'll ask you, is there any last issues you'd like to raise? I think this is a great development. It's like a whole new really effective treatment in psychiatry, and in my reading of the literature, it is the only treatment to have been shown in head-to-head studies to have efficacy at the level of ECT. As you know, there's a number of studies where it will be randomized to ketamine, not so much S-ketamine, but ketamine or ECT, some show that ECTs, more effective, some show that ketamine is more effective, and I think it depends on the type of ECT. But really, it speaks to how highly effective this class of drugs are. But having said that, I don't think it's simple to use. I don't think it's as simple as prescribing, you know, the latest antidepressant pill that comes out, where you might just do a one-hour training session, and then you know, get out your script pad. I think there's a lot more to giving these drugs than that model. Look, I'd entirely agree, adding glutamatergic agents to what we've got in our kit bag to treat difficult to treat depression is, in my view, a real advance. It's not everything for everybody, but we shouldn't underestimate how important that space is. We're talking about people with severe and disabling conditions that make a major contribution to why this is one of the most disabling health conditions on the planet. And to have treatments that have that level of evidence is very important. We've had things come and go that have had varying levels of evidence. I think this mechanism is a real sticker and a real useful addition. I look forward to seeing how it rolls out now across Australia over the next little while, and no doubt looking forward to discussing it further in the future. Thank you, Colin. Thank you. We hope you enjoyed this episode of Psych Matters. Feel free to share it with others and keep an eye out for future episodes. Psych Matters is produced by the Royal Australian and New Zealand College of Psychiatrists.
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