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Lucy: [00:00:01] Okay. All right. Okay. Welcome back to PsychEd, the Educational Psychiatry Podcast for Learners by Learners. I'm Lucy Chen, now a PGY4 psychiatry resident at the University of Toronto. I'm excited to introduce to you the fourth episode in our four-part miniseries on schizophrenia, which will be an advanced look at the clinical management of schizophrenia, a discussion on treatment resistant schizophrenia and clozapine. So just a warning, the content in this episode is going to be a little bit more advanced than usual, but it's also ultra interesting. Alex, Henry and I had the pleasure of interviewing Dr. Gary Remington for this episode. He's a researcher and chief of the Schizophrenia Division at CAMH and an author of the 2017 Schizophrenia Treatment Guidelines. His knowledge base on the topic of schizophrenia is impressive and later into this episode, he reveals some fascinating context on the history of clozapine and the idea of ultra resistant schizophrenia and the future of treatment in schizophrenia. But to bring it back to basics, the primary learning objectives for this episode are as follows. One: to know how to treat a first episode of psychosis of schizophrenia. Two: to understand the important components of maintenance treatment in schizophrenia. Three: to know what treatment resistant schizophrenia is. Four: to know about the application of clozapine in treatment resistant schizophrenia and five: know some of the psychosocial interventions involved in treatment. This episode is based on the 2017 Guidelines for the Pharmacotherapy of Schizophrenia in Adults, which we'll include a link for in the show notes. And I thought I would just highlight a quick summary of some of the recommendations in the guidelines that we discuss.
Lucy: [00:01:46] Firstly, that antipsychotics should be recommended in first episode of psychosis, and we should use the lowest effective dose. We should consider changing an antipsychotic after four weeks with no response to treatment and after eight weeks with partial response to treatment. Maintenance on an antipsychotic should be at least two years or longer. Treatment resistant schizophrenia is failure of two adequate trials of two different antipsychotics and clozapine should be offered to patients who have treatment resistant schizophrenia. Family intervention should be offered in all cases where patients are in close contact with family. CBT should be offered. Social skills training, life skills training and employment programming are also really important to consider in management. So I'll also preface that we used a case from our earlier episodes, episodes ranging from 9 to 11. I'm not going to repeat the case to you, but briefly, it was about a young man named Muhammed who presented with psychotic symptoms that likely reflected a first episode of schizophrenia. He was brought in by his father after he presented with paranoid ideations and was a risk of harm to his father in the context of his psychotic delusions. He was admitted to hospital for stability, safety and treatment. So we can jump right into the episode. And I basically started to ask Dr. Remington about the treatment guidelines and how it's relevant to the case. So let's get rolling.
Lucy: [00:03:13] I guess firstly, because we're talking about the schizophrenia treatment guidelines, Dr. Remington maybe you can tell us a little bit about the guidelines first.
Dr. Remington: [00:03:21] Sure. The guidelines have been available, and certainly they're available through a number of sources now, different guidelines. But here in Canada, they've been available now for at least several decades and they were just updated in the last 12 months. The purpose of the guidelines is really to offer clinicians in the community the most up-to-date evidence-based approach to treating people with psychosis, whether it be schizophrenia or one of the other related diagnostic categories. And they walk us through the various aspects of treatment from the very onset of the illness to individuals who move into more chronic stages. They reflect in part, and when we establish the most recent guidelines, they weren't done absolutely independently. I think as most guidelines are now put together, there's an attempt to look at what's happening across other parts of the world and to ensure that the guidelines are similar in terms of not only intent but practice as much as possible one guideline to the next. So, for example, we looked at the the NICE guidelines as, as a comparator, one of the comparators when we put these together.
Lucy: [00:04:49] And I guess based on in the context of like understanding what the guidelines are in this specific case, we have, you know, a presentation of a first episode psychosis and is there, so I guess in this context, what would be the approach of treating, of treating this sort of presentation?
Dr. Remington: [00:05:10] Sure. Well, initially and you touched upon it when you detailed the case, obviously what you want is as much collaborative history as possible. So you have the family involved at this point, and it's critical in terms of trying to establish the background in terms of issues that that may have been identified while the individual was growing up. More recent incidents that may have precipitated this particular set of circumstances, shifts in behaviour that have been identified more recently prior to this particular encounter, other issues that that may be playing a role: trauma, difficulties at school, substance abuse, those sorts of things.
Lucy: [00:06:08] And I guess like, how would you approach treatment in this context and how would you kind of explain that to a patient and his family?
Dr. Remington: [00:06:15] Well, always, and I think that's the case in psychiatry in general, what you're trying to do is rule out any sort of medical conditions that might account for this particular behaviour. And so certainly at the outset, I think as we do with many psychiatric conditions, the intent is to try to rule out possible medical diagnoses. Although in fairness, in individuals like this, young people who come into the system, it's been established that very rarely will you find an organic cause for the underlying psychosis. But having said that, you usually go through the various routine investigations to ensure that there aren't other medical conditions that may be accounting for it. Particularly more recently, there is, of course, the need to look at other issues like substance abuse, which has now become much more prevalent in terms of pre-empting the diagnosis of psychosis as well. And it's particularly difficult during this period, which is captured in some of our strategies around diagnosis, because oftentimes in somebody who has a comorbid substance abuse disorder, that it may not be clear for a period of time whether or not it was related to the substances or whether it is a primary psychosis. And in fact, it may never be entirely clear on some occasions.
Alex: [00:07:53] So it sounds like a urine tox would definitely be part of that initial workup. Can we get into more specifics there? What else would be part of that?
Dr. Remington: [00:08:01] Well, you do the standard procedures like blood work, liver function, haematology and so on in order to rule out such things as thyroid conditions and so on. But once again, and we actually published work in that area here at the university a number of years ago, for all the tests we do do, very rarely do you find anything that would truly account for the for the condition that we're seeing in front of us. We don't do imaging routinely here, and probably what we don't pay enough attention to and it's becoming more and more evident, is doing a broad-based assessment for other areas of the illness that actually, as a rule, declare themselves before the onset of the psychosis. So we now appreciate that the first episode of psychosis that we see in individuals who perhaps ultimately get the diagnosis of schizophrenia, it's a bit of a misnomer to use the term first. It is the first episode of psychosis, but in fact, it's the end of the illness. The illness is in its final stages at that point, in as much as as there is a lot happened by that time, that is only picked up often through a thorough history.
Dr. Remington: [00:09:32] So for example, we often see changes in behaviour in the preceding months and years that involve increasing withdrawal, evidence of academic deterioration, social issues, those sorts of things. And when you look at the domains of the illness now, we talk about multiple symptom clusters and the ones that seem to be embedded when the individual comes to us with the first episode of psychosis are cognitive symptoms and negative symptoms. And going back to my point that I made at the outset, there is, I think, a need to better capture the extent of these as quickly as possible because they become the major factors over the longer term in functional recovery. And to that point, I would add that it's critical when you think of an illness like schizophrenia to distinguish between clinical recovery and functional recovery. Routinely, we assume that clinical recovery, and generally speaking clinical recovery is taken in the context of improvement in psychotic symptoms, translates to functional recovery, and that's simply not the case.
Lucy: [00:10:55] I guess this makes me think of like now DSM-5. They've included this idea of a range in the presentation of like between like schizotypal personality and schizophrenia. And so I wonder where along that spectrum we begin treatment, where in the guidelines is it appropriate to start an antipsychotic?
Dr. Remington: [00:11:17] And it's an excellent point. It's a point that we struggle with and the major part of the struggle is the hesitancy to intervene with a drug like an antipsychotic in individuals where you can't even be sure that that's what the illness is going to be. And as you're probably aware that we now talk about this so-called prodrome or clinical high-risk period before the onset of the illness, when we can begin to identify features that would suggest that this person may convert to a full-blown psychosis, but even in the best programs, we still only see a conversion rate of 20 at the best, perhaps in the range of 30%. So with that kind of conversion rate, you have to be very cautious about embracing something like an antipsychotic to treat a condition, in particular because with these individuals, it's not as though they're presenting with a first episode psychosis. It's often much more vague than that. It's a loaded history, perhaps with some unusual changes in behaviour or what we call soft positive symptoms, symptoms like magical thinking, those sorts of things.
Henry: [00:12:44] How do you know? So you have someone who presents with acute psychosis, you treat them with an antipsychotic. How do you know when to stop?
Dr. Remington: [00:12:53] Well, you raised a very good question. And indeed, that's the first and probably the most important questions that the individuals and families are interested in. Oftentimes, they're even reluctant to take the medication from the outset, but with resolution of the symptoms, as is so often the case in medicine, there's this notion that the illness has been cured and medication is no longer required. As recently as last week, we were talking about that, and indeed, in the guidelines, you will see that a position was stated whereby individuals who have a clear first episode psychosis are it's recommended that they take the antipsychotic medication for at least a year and a half before there's consideration of possibly discontinuing the medication. Having said that, we in the field actually have concerns about that kind of guideline inasmuch as it's a guideline that's very much influenced by what your primary diagnosis is going to be. So your chance of doing well in the absence of medication, i.e. antipsychotic medications, the general figure that you'll hear reported in the literature now is probably in the range of about 20%. And that's the kind of figure where you would say, well, we need to reassess these individuals and ensure that they do need to be on the medication. Having said that, we believe that that if truly the diagnosis of is one of schizophrenia, that it's considerably lower than 20%. Unfortunately, many people diagnosed with a first episode psychosis, though, have a multitude of diagnoses, some of which have a much higher chance of resolution and I think they load that 20% figure that is now talked about in the literature. So there are conditions whereby you should be considering discontinuing the medication because they are powerful medications and they come with a multitude of side effects. If it truly is a diagnosis of schizophrenia, we would suggest that you're probably going to need to take that medication indefinitely.
Henry: [00:15:17] How do you know if it's schizophrenia or just psychosis?
Dr. Remington: [00:15:21] Well, unfortunately, and it's in many ways the the most important question. And unlike so many other fields, we have done poorly in the field of psychiatry in terms of identifying biomarkers or endophenotypes that would firmly establish the diagnosis. So to your question, how do we know? We know based on clinical experience. But as I mentioned at the outset, one of the sort of protective factors that we build into this is trying to ensure that we have a period of time to watch individuals before we say with more conviction that this truly is a diagnosis of schizophrenia. But particularly in the first episode, you can see shifts in diagnosis over the first several years in particular. So the person who came in and looked like a schizophrenic individual may end up looking like a bipolar two years later, or vice versa. So time becomes one of the most critical factors in helping to make that distinction.
Alex: [00:16:26] So this is a lot for even us to think about, but I so I'm trying to put myself in Muhammed's shoes here. How do we explain, assuming this is true schizophrenia or at least at this stage, we have to believe that it is and we want to initiate an antipsychotic, how do we then explain to him the potential need for this to be a lifelong treatment?
Dr. Remington: [00:16:50] And oftentimes you try not to put that on the table initially. There's so much to take in at that particular stage that I think we're very cautious about making those sorts of ultimatums early in the course of the illness. And of course, it's not just Muhammad that we have to engage, we have to engage the entire family in particular, if we're going to see a buy in to long term care. So I think it's probably not in best interest to say, well, you have schizophrenia, you're on these medications for the rest of your life. I think we start off much more hesitantly saying this looks like a psychotic condition. One of the differential diagnoses could be schizophrenia. We may not know that for a period of time, but we do know that that the cornerstone of treating psychosis is an antipsychotic medication. So at least for the time being, we would advocate for you taking this medication and then with the resolution of the symptoms, we can begin to look at other options as we move forward.
Lucy: [00:17:59] And I guess that transitions to a question about how do you treat acute presentation of psychosis and how do you transition that into maintenance or kind of treatment as well.
Dr. Remington: [00:18:10] And there has been a fair degree of change in that area more recently. When I trained as a resident, for example, we were in a period where we were using incredibly high doses of medication with the assumption that more essentially was better. So at that time, the strategy was one of loading people with an antipsychotic medication with doses that were now, as we look back historically, much, much too high. Now we've taken an almost opposite approach and it's very much a start low and go slow strategy for treating acute psychosis. So, notwithstanding those individuals where they may be really acutely psychotic and aggressive, the strategy now may not even be confined to bringing people into hospital. Oftentimes now it's started on an outpatient basis, but the general agreement is that you can use low doses of antipsychotic and increase them. And why I'm saying that is, and we wrote about this a few years ago, what it's meant from the standpoint of maintenance is that at odds with what we used to do historically, which was to load people with high doses and then several months later begin to titrate downwards. In contrast, what we do is titrate up now more slowly. And it's very likely that the kind of dose that you used in people say, who weren't acutely psychotic and requiring high doses to control their behaviour, is that the kind of dose that you attain to establish antipsychotic control in that strategy probably reflects more of the maintenance kind of dose that you're going to need over the longer term. And as a practical example, let's use a drug like risperidone. When we used risperidone, we might have, and indeed when we did the original risperidone trial here in Canada, the highest dose was 16mg. But now what you would see if a drug like that was initiated, you see somebody started at two milligrams, three milligrams, four milligrams wait as long as possible between the different stages of titration and then once the symptoms were resolved, hold that dose. So it would be more common now to see somebody start at two and end up on four milligrams of risperidone than the old strategy of, well, let's give them 16mg of risperidone and work our way down as the psychosis resolves.
Lucy: [00:20:52] And did this transition happen as a result of adverse sort of events or...
Dr. Remington: [00:20:56] Well, we certainly had our share of adverse events. There's no question about that. We had a lot of trouble with with acute dystonic reactions and motor movements and so on. But it actually was driven in large part by work, again, done in part here at the centre, which was in the late 1980s and late early 1990s. We finally had the opportunity to begin to evaluate dosing centrally through imaging. Historically, it always had been done based on peripheral kinetics, but with the opportunity to look centrally at the relationship between these drugs, their dose and D2 occupancy, both here at CMH and at the Karolinska in particular, we were begin to we were able to begin to establish what amounted to very concrete thresholds for D2 occupancy and then link those to specific antipsychotic doses. And it was that kind of information that afforded us the opportunity to appreciate that the kinds of doses we've been using historically were just absolutely out of line. So, so when I trained as a resident I'll give you an example, we our starting dose of Haloperidol was ten milligrams. When we did our occupancy work in the early 1990s, we established that two milligrams of haloperidol crosses the threshold for optimal chance for clinical response, which is around 65% D2 occupancy.
Dr. Remington: [00:22:35] So we had for the very first time again these data that would allow you to take most drugs, not all drugs, but most drugs, and be able to say if you want to reach that kind of occupancy level, here's exactly the kind of dose that you need. And that in turn translated to a dramatic reduction in the doses that were being used on a daily basis for the treatment of individuals. We can't do that with certain drugs. And so, for example, people will say to me, well, what's the correct, we talked about clozapine at the outset, what's the correct dose of clozapine? I can't tell you the correct dose of clozapine. I can't tell you the correct dose of aripiprazole and I can't tell you the correct dose of quetiapine for different reasons. Clozapine and quetiapine because of their kinetics in terms of K off and aripiprazole because of its partial D2 agonism. But notwithstanding those three drugs, we could literally scan somebody and we have done that with most of the drugs and tell you what the proper dose of an antipsychotic is to optimise clinical improvement.
Henry: [00:23:51] So let's say we started Muhammad on a smaller dose of some sort of antipsychotic. When do we decide that that antipsychotic is not working for him?
Dr. Remington: [00:24:00] Good question. And we have to acknowledge that that decision making is being influenced now by the pressures of moving people through. So in 1994, I had a discussion with Pat McGorry, who started the first first-episode program in the world in in Melbourne, and his comment to me when we were talking about our PET data was I'm going to start somebody on two milligrams of risperidone and keep them on it for 30 days. And of course in the best of all worlds, that's probably not a bad strategy if there's no reason to increase the dose. But but in fact, that's not possible in acute care settings as a rule any longer and you don't need 30 days in order to establish whether or not a drug is working or not as a rule. In fact, some of the work, again done out of this particular centre has identified that in the case of antipsychotics, about 50% of the improvement that you see in antipsychotics occurs within the first 7 to 14 days of treatment. So the current recommendation and I think it was based embraced in the guidelines was that you look to whether or not you're getting a response in the first four weeks at a reasonable dose. And if that isn't evident and there's a partial response, you may choose to continue it for another four weeks at least, in order to establish whether that drug is going to work or not. Whereas if you're not seeing any response at four weeks, you're probably very likely not going to see a response with that medication and you might as well move on. Indeed, arguably, you should be moving on and we've not done that very well in past years. And the reason why it's so important to move as efficiently and systematically as possible is the data that suggests that duration of untreated psychosis is associated with poor outcomes. So clearly, you want to get from point A to B in a timely fashion.
Henry: [00:26:20] So say the medication didn't work at all four weeks in, do we, so we switch to another antipsychotic in the same class? Different class?
Dr. Remington: [00:26:31] Well, you raise a good point. The classes are not near as clear as when I was working as a as a resident. But you certainly switch to another medication, and most of them are of different classes, depending upon which way you want to define class. But when we published our data, looking at the first two trials before clozapine, we arbitrarily looked at two medications in particular, risperidone and olanzapine. And what you choose should be done in discussion with the individual who you're treating and discussion of the side effects that may occur with a particular drug and what they would hope to avoid and what they're willing to tolerate and so on. So, for example, an olanzapine-like drug, of course, carries a very high load in terms of metabolic side effects, whereas risperidone may be better in that regard, but carries a greater propensity for movement disorders.
Alex: [00:27:40] So taking this to, I think maybe its natural conclusion, if now we try Muhammed on a second antipsychotic and that doesn't work for him, what do we do now? I mean, I think we learned after two adequate trials, we try clozapine now because that's treatment resistant schizophrenia. But can we be very specific about what exactly is treatment resistant schizophrenia, because we don't, what does that mean in terms of the dose of antipsychotic and how long and...
Dr. Remington: [00:28:07] Sure. And treatment resistant schizophrenia really evolved through the 1980s, and it arose out of the recognition that these drugs, which were supposed to be a panacea, in fact, weren't. And so by the 1980s, it became clearly evident that there was a significant proportion of individuals with schizophrenia, in the range of about 30%, who weren't responding to the antipsychotics that we had in hand. Now, by the late 1980s, the seminal work with clozapine was done, and it identified that for those individuals, individuals who had failed two adequate trials of antipsychotics, of the other antipsychotics that is, in and adequate in terms of both duration and dose, then they would be deemed treatment resistant and candidates for clozapine. And we actually had data that came out of some of the work done here that allowed us to sit down and talk figures with individuals. So we knew that when somebody had their first break and they were treated with an antipsychotic, that roughly 60 to 75% of those individuals would respond to drug A. Now, if they didn't respond to drug A, regardless of what drug you chose for trial two, your chances of getting a response dropped from that 60 to 75% down to 15 to 20%.
Dr. Remington: [00:29:44] So we saw this precipitous decline in treatment response. But still, the guidelines are that you don't use clozapine until there's been two adequate trials if they can be tolerated. So we do advocate and I would argue that families, if they were told, well, here's clozapine as your second line treatment or here's another drug, and we can tell you in another 4 to 8 weeks whether or not that drug is going to work, they would probably choose to have the second drug trial before they moved to clozapine. But that said, if in fact you don't respond to that second antipsychotic and of course the odds are relatively low, because you only have about a 15 or 20% chance of responding to drug two, then certainly your odds for response to clozapine, now having met the criteria for treatment resistance escalate considerably. So your chance of responding to clozapine for that third trial would be in the range of about 40 to 50%. In contrast, where if you reached for a third non clozapine drug, the data would suggest that your chance of response with that third agent non-clozapine drug is probably less than 10%.
Lucy: [00:31:09] Can you tell us a little bit about what like how why clozapine is so special or maybe a little bit about the story of clozapine?
Dr. Remington: [00:31:18] Clozapine is a very interesting drug. I like history. So I'm going to bore you with just a bit of history.
Lucy: [00:31:23] Oh, we love it, too.
Dr. Remington: [00:31:24] Oh, good. Because. Because, in fact, having done a PhD in pharmacology and been in this field for a long period of time, I was trained that it was the hypothetical deductive strategy that would move us along in the field. But in fact, that hasn't worked in the field of psychiatry and clozapine is a perfect example of that. So indeed, the whole history of antipsychotics is a perfect example of that. So chlorpromazine, which was the first antipsychotic available to us, was never synthesised to be an antipsychotic, it was to be a pre-surgical anaesthetic synthesised in 1948 and 1949 serendipitously found to have antipsychotic properties and in 1952/1953 part of the work being done here in in Montreal was what took it to be established as an antipsychotic. Now clozapine has a similar story. Clozapine was synthesised in 1959, was supposed to be a tricyclic antidepressant and through various sorts of circumstances ended up being identified as an antipsychotic by the 1960s and was unique not because they had identified that it was a drug that worked with TRS, it was unique because it didn't invoke EPS at therapeutic doses. It was fast tracked and released in a small group of Scandinavian countries in the early 1980s and a cluster of people died within the first year following its release, later to be established secondary to Agranulocytosis. And it was for that reason that that almost all countries in the world chose to withdraw clozapine at that point.
Dr. Remington: [00:33:20] But seminal work done in the 1980s, looking at clozapine in those who failed other antipsychotics, allowed it to be resurrected in a lot of countries like Canada and the United States again, with strict guidelines in place that this would be the only population that it would be used in: people who had failed, as the criteria were established, two antipsychotic trials of adequate duration and dose or intolerable side effects that pre-empted adequate trials. So it was reintroduced here in North America in the early 1990s and revolutionised the field because for the very first time we had a drug that was different from all other drugs. But having said that, and I get this question asked of me all the time is, is to your point is clozapine a unique drug in schizophrenia? No, it's not a unique drug in terms of, I don't believe and I don't think the evidence supports that that clozapine will work better in first episode schizophrenia, where it works better is in treatment resistant schizophrenia. Now why would it work better in treatment in first episode schizophrenia is we now have data indicate that roughly 85% of treatment resistant schizophrenia walks through the door with a first episode psychosis. So so people don't evolve into treatment resistance the way we often conjure up that that term, a small percentage of them do but in fact, most people have treatment resistant schizophrenia when they walk through the door with a first episode psychosis. We don't have any biomarkers or endophenotypes to identify them. So as a result, we give them our two trials and then finally say you must have treatment resistant schizophrenia and we should put you on clozapine. And so for those individuals, I would like to see them at first episode get schizophrenia, but we struggle on two levels. One is, as of yet, we can't find biomarkers or endophenotypes that would clearly say you should be on clozapine from the outset because you have a treatment resistant form of the illness. And secondly, we clozapine is of the old sort of phenothiazine type of medication. It's a very heterogeneous receptor binding compound and to try to dissect what accounts for it's unique profile in the treatment resistant population has proven incredibly difficult. And to this day, we still have no idea why clozapine is effective in people with treatment resistance. Now, I should tell you, do I get to still talk for a minute? Okay. So we now recognise that only about 50% of those people who we identified as treatment resistant are going to respond to clozapine. So in the early 2000s somebody, in Montreal interestingly, coined the term ultra resistant schizophrenia and set up some criteria which we have since modified in a paper subsequently but we now recognise that in those who meet criteria for TRS, only about 50% of them will respond to clozapine, a figure that's made worse by the fact that many people will choose not to take clozapine. And if you have TRS and you choose not to take clozapine, again you're running with less than a 1 in 10 chance of responding to whatever antipsychotic they give you. But in terms of the clozapine resistant population or, what Mouaffak chose to call ultra resistant schizophrenia, it's those who now I focus on with most of my time in research because they are the group for which we have no treatment whatsoever. So for all the work that we've done, looking at what should be implemented after clozapine, and you see it in our Canadian guidelines, we actually drew a line in the sand. I think we were the first guideline to do that and we indicated that we would not make any recommendations for what to do after somebody failed clozapine and it was based on the recognition that for all the drugs that have been tried, none, including ECT, which probably ranks up there as one of the better options, has got enough data to say with conviction that there's enough evidence-based research to support moving the treatment algorithm beyond clozapine at this point.
Alex: [00:38:27] So there's not enough evidence from a guideline perspective to make clear recommendations there. But as a clinician who probably encounters that, what do you do to the ultra treatment resistant patient? What do you do for them? Typically.
Dr. Remington: [00:38:44] There's endless numbers of strategies, what almost all people do, because it just seems so intuitively correct, is that they try to augment with another antipsychotic. This idea that, well, clozapine doesn't have a lot of high affinity D2, so let's give them a D2, a potent D2 blocker like haloperidol or risperidone in combination or so on and so forth. But indeed, if you look at that, which is by far and away the most common strategy to try to treat clozapine partial responsiveness, there's no evidence whatsoever that adding another and it just it just keeps going on and on because we've tried so many different strategies: mood stabilisers, antidepressants, even glutamatergic compounds. Indeed, if you take a glutamatergic compound and you give it in addition to clozapine, there's often evidence of clinical worsening, interestingly. So we still struggle and unfortunately we haven't, I think we've obfuscated the issue by suggesting that you can do this, this and this after clozapine, when we should have been a bit more frank and honest and said there really isn't any evidence and we need to be devoting a lot more resources to what do I do when Clozapine fails from a research standpoint. So at the very least, we don't expose people to all these trials of compounds that clearly have no evidence for working. Interesting, I mentioned the ECT story. Very nice paper came out of New York in 2014 indicating that ECT might be a useful strategy in people with clozapine partial response but having said that there is only the one RCT to this point and that's probably enough, not enough and that was our position when we put the guidelines together to advocate, well, this is compelling evidence that ECT should be your treatment of choice.
Lucy: [00:40:54] Do you think in ten years that that's like in terms of ultra resistance, like ECT is going to be a part of the guidelines?
Dr. Remington: [00:41:01] I certainly could imagine if somebody could replicate that particular trial. As you can imagine how difficult it is to do a blinded, controlled trial with ECT in a clozapine partially responsive individual. But having said that, that's the kind of evidence we need. Or conversely, we need serendipity once again to step in and I think that's probably how the next major breakthrough will occur in terms of moving us beyond clozapine. It won't be through a hypothetical deductive strategy. It'll be somebody, by chance, tries something that doesn't really make sense, but translates to opening up a door that we just didn't know existed.
Lucy: [00:41:48] And I guess pragmatically, from your clinical practice, how likely is it that a patient stays on clozapine once they've started?
Dr. Remington: [00:41:56] Oh I just found out some data on that in the last month. So about half of people will stop clozapine in the first 12 months after they're started. So many people refuse clozapine and unfortunately, in many ways that's a kiss of death inasmuch as we just don't have another drug that's clozapine-like. We have olanzapine, interestingly, which was shown in the Catie trial and which was shown in a couple of other projects to maybe be the next best choice. And there was a nice blinded study done with olanzapine 30mg suggesting it might be an option for people who say no, I don't want to take the clozapine. But beyond that, we really don't have any other options for the clozapine story. So for those who say, no, I don't think then what we do as clinicians is, because we are in the business of selling hope and trying to give people every opportunity to improve, is we generally do move through all these hoping that at least you'll have that maybe 1 in 10 chance of responding to a drug that that they haven't yet been tried on. So generally what we advocate is that if you want to continue with strategies in a person who's proven to be clozapine partially responsive or chooses not to take clozapine, that at the very least you be cautious. So what you do is you you choose a drug based on what existing evidence there might be and then circumscribe the trial. That is, make the trial 12 weeks. But rather than just leave that drug hanging, as we so often do in this population so that they end up on 4 or 5 different medications, instead what you do is you quantify outcome. So we strongly advocate using scales rather than just your personal judgement as to whether that added drug helped and then at three months, if there's no compelling evidence to indicate that it's improved, then discontinue it and move to the next trial. I would also point out that when I'm talking about this, I'm talking about psychosis and I underscore that because I'd said earlier on that clinical recovery and functional recovery are independent of each other. And I say that because we only have a drug for one domain in this illness and it's the positive symptoms. So our drugs are antipsychotics, they're not anti-schizophrenia drugs. So we get the people better in terms of their psychosis but what we don't see is that translate to functional recovery. So they follow independent courses and the thinking is that even with resolution of the positive symptoms, the rate limiting steps that account for why functional recovery doesn't fall on the heels of the improvement in psychosis is that you have these other domains, the negative symptoms and the cognitive symptoms that aren't treated by the current medications that we have available. And consequently the individual, because of the resolution of positive symptoms, isn't in the same position to return to their level of functioning that they saw before the onset of the illness.
Alex: [00:45:38] I don't know if this exactly segues because I don't know the answer to this but do we have, outside of medications, treatment for those functional outcomes, like do our psychosocial treatments, do they touch on that? Can we touch on those topics, how they work?
Dr. Remington: [00:45:53] Sure. And I will say I'm not the resident expert in non pharmacology, so I start by that caveat. But obviously we've always needed to look for strategies that would take us beyond just medications and you see it in the most recent guidelines, now embedded in the guidelines now are CBT, for example, they're in the NICE guidelines they're in our guidelines. And we recognise that a lot can be done with non-pharmacological strategies and certainly in terms of strategies to help deal with the trauma of having this illness, trying to work with the symptoms that might persist and understanding the illness, an intervention like CBT can be extremely useful. The psychoeducation for the family, ensuring that the families involved, because one of the problems we struggle with is that many individuals, it's just so hard for them and their families to embrace the illness that as soon as we see resolution of the symptoms, there's talk of discontinuing the medication and not requiring further treatment. Supported employment from the standpoint of functioning, for example, is proving to be probably more effective than many of the old rehab strategies that we embraced for a number of years. So there's increasing evidence that and efforts, I think, to look at more innovative strategies that would allow us to improve in these other areas that take us well beyond the medication. Because, again, the medications have not been useful at all. It's not that they don't effect some changes, but the magnitude of the effect size is so modest that it doesn't translate to clinical improvement or functional improvement, as the case may be. So you can imagine, as is the case, that there's lots of interest in coming up with now new classes of medications that would address the cognitive symptoms and the negative symptoms. But at the same time, those are the kinds of domains that can very likely be enhanced with non-pharmacological strategies as well.
Alex: [00:48:22] Right. So there's no medication that will increase your likelihood of finding a job but if you help someone out with supportive employment, you can potentially increase their level of functioning.
Dr. Remington: [00:48:33] And indeed, you know, we now, even with cognition, for example, we used to just talk about cognition and in fact, when I trained as a resident, we didn't even bother talking about cognition. We only talked about positive symptoms. But then along came this concept called cognition and by 1990s, it really had gained legs in terms of its potential impact on the illness. Well, even subsequent to that, we now have that further subdivided into neurocognition and social cognition and that opens the door for not only developing unique strategies that are specific to improving people's neurocognitive abilities, executive function, verbal recall, those sorts of things, but we're also now much more sensitive to some of the social cognitive deficits that people struggle with, that are seen from a clinical standpoint in the form of symptoms like social withdrawal, anxiety, social anxiety, those sorts of things. So we have a number of doors now open to opportunities for non-pharmacological strategies that can hone in on these other domains.
Alex: [00:49:53] Right, it's not just about medications, it's about building our other resources, psychotherapy, CBT and family interventions and all of that is part of the treatment as well. Up until now, we've spoken about this as if Muhammad is nodding his head to all of these treatments and agreeing. But I think we all know around the table that with schizophrenia often comes a lack of insight into the illness itself. These patients can often not realise what's going on or not be agreeable to starting a treatment. How do we help someone who is not having much insight into their illness?
Dr. Remington: [00:50:35] Again, we certainly want to keep the families involved as much as possible. I don't think there's a single instrument that's as powerful as having the family on board in terms of of trying to to engage individuals. And then, of course, education around what this illness is, and it's such a foreign concept to most individuals, the whole idea of hearing voices or believing that people in the next room are talking about you, those sorts of concepts, it really requires a lot of education around two things. One is the symptoms that constitute this illness and the symptoms that take us certainly beyond the psychosis per se, but also the stigma of the illness. So for all the gains that we've made in mental health, and you can see just how far we've come in the last ten years with major industry embracing support for mental health and so on, we still have not made robust gains in the area of serious mental health issues like schizophrenia. It's still an illness that's stigmatised. It's stigmatised in the literature, it's stigmatised in social media and the movies. And so we have a considerable ways to go in terms of destigmatizing it for individuals who have the illness and for their families and supports as well. So there's a lot of work that needs to be done in that area. But to your point, and it's an excellent one, many people who, and it takes us back to something we talked about at the outset, as soon as their symptoms resolve, the next point to be made is, well, I don't need these medications anymore. And unfortunately, the reality clinically is that you will have to see people through perhaps several episodes or relapses where they've chosen to stop their treatment before they recognise that, from a cost benefit standpoint, they're probably much better off taking the medication. And again, we've tried to to certainly be more comprehensive in offering treatment beyond medication and in addition to that, be much less confrontive around the medication in terms of, you know, the history of using excessively high doses and multiple medications and so on.
Alex: [00:53:22] I know we're a little over time here. I don't know if we have time for one more question or...
Lucy: [00:53:30] So concluding question?
Lucy: [00:53:32] Yeah I guess there's been a lot of public discourse now in the domain of like the effectiveness of antidepressants in treating depression and like it's been on the agenda recently. And I'm wondering what your stance is on antipsychotics and schizophrenia, kind of like one concluding statement about that and then maybe transitioning that to your thoughts about the future of treatment of schizophrenia and what that would potentially look like.
Dr. Remington: [00:54:00] I would argue that the evidence remains compelling that antipsychotics work for psychosis. But having said that, I would also, touching upon several points we made in this talk, would argue that the current antipsychotics we have falls short of treating the full forms of the illness that we now recognise. I would conclude by saying that schizophrenia is not a single illness. It's a heterogeneous group of disorders that require different treatments and that I think going forward the next big breakthrough that we have will be very much a personalised medicine sort of strategy whereby we acknowledge that there are these different forms of illness, and this is actually where we spend a lot of our time now, and that if we had the capacity, as we do in other areas of medicine, to say, well, this is the form of cancer you have or this is the form of illness you have, that we will do much better in terms of overall outcome by being able to say, well, schizophrenia is not a single entity. You have this type of psychosis and this seems to be the best strategy for this type of psychosis as compared to that or so on. So to your point around the drugs we have, dopamine blocking drugs, which is the prototype of an antipsychotic work for one form of the illness. But we clearly have other forms of the illness that require other strategies, clozapine-responsive patients being one such example. And then those who fall in the non-clozapine response population have to have a different underlying pathophysiology, just by definition.
Lucy: [00:55:49] Any kind of advice that you have for future sort of potential medical students interested in the field of psychiatry and maybe convincing Henry to go into psychiatry. And what's so special about the practice for you?
Dr. Remington: [00:56:01] Well, psychiatry in and of itself kind of interested me but schizophrenia interested me a lot. And so I would argue that this isn't, psychiatry is incredibly fascinating, but schizophrenia is even a notch above. I would advocate strongly that if you have an interest in psychiatry, test the waters with schizophrenia and see it, it's so interesting on so many different levels and it's such a disenfranchised population.
Alex: [00:56:33] Well, thank you so much, Dr. Remington, for sharing your interest and passion about schizophrenia with us and our audience. It was quite the tour, all the way from chlorpromazine, clozapine up until the future, what the future holds in terms of maybe individualising these treatments and not thinking just about the antipsychotics, but also thinking about the other ways we can help people with schizophrenia. I think it was terrific. So thank you so much for being with us today.
Lucy: [00:57:00] Thank you so much. Thanks.
Lucy: [00:57:02] Psyched is a resident driven initiative led by residents at the University of Toronto. We are affiliated with the Department of Psychiatry at the University of Toronto, as well as the Canadian Psychiatric Association. This episode was produced and hosted by Lucy Chen, Alex Rabin and Henry Barron. Our theme song is Working Solutions by Olive Musique. A special thanks to the incredible Dr. Gary Remington for serving as our expert for this episode. You can contact us at info@psychedpodcast.com or visit us at psychedpodcast.org. Thank you very much for listening.