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Dr. Lucy Chen: [00:00:05] Okay, we're rolling. All right. Hey there, podcast listeners. Firstly, we'd like to apologise for the delay in releasing this episode on the treatment of schizophrenia. We kind of went down a rabbit hole after our episode on diagnosing schizophrenia. We basically interviewed multiple experts who elaborated on multiple facets of schizophrenia treatment, and we realised really we kind of needed the basics. So that's what we're going to give you today. And we're here and we're back with our two favourite inpatient staff psychiatrists, Dr. Andy Lustig and Dr. Jason Joannou. Welcome back to the podcast!And I'm Lucy Chen, and I'm joined by Alex Raben.
Dr. Alex Raben: [00:00:44] Hello.
Dr. Lucy Chen: [00:00:45] And Henry Barron, our trusty fourth year clinical clerk who is multifaceted and talented and has been instrumental behind the scenes in our editing process.
Henry Barron: [00:00:53] Hey, guys.
Dr. Lucy Chen: [00:00:54] So we're going to cover three broad objectives and basically they're summarised as the following. So the first thing we're going to have a basic understanding of the psychopharmacology of antipsychotics. We're going to have a clinical approach to treatment based on the 2017 guidelines for pharmacotherapy of schizophrenia in adults. And we're also going to have an idea about the longitudinal treatment of schizophrenia, which will include a discussion about treatment-resistant schizophrenia and psychosocial approaches to care. So let's just start off very openly what are medication treatment options for schizophrenia?
Dr. Andy Lustig: [00:01:30] Okay. Well, really, the mainstay of treatment for schizophrenia and all of the other psychotic illnesses is antipsychotic medication. Surprise, surprise. So when we meet somebody who has schizophrenia or related condition, we try and get consent and commence an antipsychotic medication.
Dr. Lucy Chen: [00:01:53] Anything else down the pipeline or is this all we got so far?
Dr. Andy Lustig: [00:01:56] Well, they are trying to do something. No antipsychotics have been available in Canada since the 1950s. Chlorpromazine was the first antipsychotic medication and there's probably upwards of dozens of different antipsychotics. They all work basically in the same way and down the pipeline then there's been a lot of research in this. They're trying to find a novel mechanism for antipsychotics. A lot of research into glutaminergic modifiers. But there's nothing in the market right now. And, you know, it's been about 60 years. And so far dopamine blockade is the only thing that we've found that reliably is what causes antipsychotic effects.
Dr. Lucy Chen: [00:02:35] Great. So we'll focus on that for this episode. So specifically dopamine blockade and then all the sort of effects and side effects that happened. So let's start with just talking about the basic mechanism of action of antipsychotics.
Dr. Andy Lustig: [00:02:53] Sure. I mean, the interesting thing is like, you know, all antipsychotics that are licensed have an indication for this and have shown effectiveness share. One common thing, and that is they're they block D2 receptors. So but these drugs are actually quite messy drugs. So for instance, chlorpromazine, which was the first antipsychotic medication ever that we discovered is actually not very potent at the D2 receptor. It's much more potent at, you know, adrenergic receptors or other things like that. And that's where you get all these side effects from. So what they all share in common is and that's why we talk about high potency, mid potency and low potency medications. So high potency antipsychotic medications are much more specific to the D2 blockade and might have less ancillary side effects for like, you know, anticholinergic effects and things like that. But they also might have more intense D2 blocking side effects. Yeah. So that's kind of the basic pharmacology that it needs to block D2 in order to be an antipsychotic as of today in 2018. And they're actually messy drugs, a lot of them. So they block a whole bunch of other things. And that's where a lot of the side effects arise from.
Dr. Lucy Chen: [00:04:01] Great And a lot of medical students are going to be exposed to this concept of typicals versus atypicals. Can we kind of summarise what that means for them?
Dr. Andy Lustig: [00:04:11] Yeah. So, you know, people have hypothesised on what gives antipsychotic agents typicality versus atypicality. I think from a practical point of view, the kind of bottom lines are one that initially there was a belief that atypicals which were newer were better, and there was an early hope and belief that they would target the negative symptoms of schizophrenia, things like decreased energy, decreased affective expression. Those have been very difficult to treat symptoms of schizophrenia. And the initial hope was that Atypicals would target those symptoms as well as the positive symptoms of schizophrenia, by which we generally mean delusions and hallucinations. And unfortunately, that really has not proven to be true. The Atypicals are really no better than the conventional agents for treating any symptoms of schizophrenia, either positive or negative. So the way in which they differ substantially are that the atypicals are more expensive because they're still on patent for many of them. And also the side effects are different. And generally speaking, it's helpful to think of the atypical agents as causing primarily metabolic side effects. So we talk about weight gain, hypoglycaemia, which down the road can lead to diabetes and so on. And for the conventional for the older antipsychotics, we think of more like neuromuscular side effects. So like Parkinsonism stiffness, tremor, tardive dyskinesia, much more common in the older conventional antipsychotic medications.
Dr. Jason Joannou: [00:05:41] Maybe if I could just add to Andy's response for the typical Stu, I guess they've also been a lot of fierce debate in the literature about what causes that different pockets of psychiatry like Toronto versus other places in the world have competing theories, and the two main ones are that 5 HT 2A antagonism really confers the atypicality to atypical agents. And there's a whole reasons why that's done. But I'd say that's one theory. And the other theory is about a fast of a fast dissociation constant, which is the one that's preferred in Toronto, which has a whole body of literature behind it and reasons. But that would get really complicated going to those. But that's also kind of just the underlying theories behind that. But neither has been proven to there's no consensus there yet. Yeah.
Dr. Lucy Chen: [00:06:27] Thanks for that clarification. So we're basically talking about side effect profiles being the result of either like fast or kind of binding strength at the D2 receptor versus its kind of dirtiness or rather like hitting multiple different receptors as being the cause of side effects?
Dr. Andy Lustig: [00:06:44] Pretty much.
Dr. Lucy Chen: [00:06:45] So I think one thing that also helps with our understanding is the dopaminergic pathways in the brain. So where dopamine exists in the brain and how antipsychotics affect that. So maybe Dr. I'll turn it to you and maybe you can summarise for us the four dopaminergic pathways and how anti psychotics affect each schizophrenia.
Dr. Jason Joannou: [00:07:08] Nobody knows what really causes it. It's not just as simple as saying it's a defect in dopamine. What we do know is that when we block the D2 receptor, we get some anti psychotic effects. It's a lot more complicated than that. It's not like we know where the lesion is. Like if we were in neurology, we'd be like, where is the lesion? Right? We don't have that clear cut thing. So we're just kind of targeting the whole brain with this. And it would be nice if there was a more targeted treatment and then we maybe wouldn't get all these side effects. So it's important when you think about the pathways that this is really how you get the different side effects that occur and then maybe propose kind of mechanisms of action of anti psychotics as well. So the first kind of classic one that most medical students learn is the substantia nigra pathway, which is related to Parkinson's disease. And it's kind of clean cut and people it's been well delineated. So that's basically just where most of your dopamine neurones in your brain are actually reside in the substantia nigra, about 90% of them or so, and that's in your midbrain. And then they have projections out to your caudate Putamen we call the basal ganglia.
Dr. Jason Joannou: [00:08:08] That's where you get the tardive dyskinesia, the tremor, the rigidity, the kind of, you know, trap the classic stuff in Parkinsonism, and you start getting symptoms in Parkinson's when you kind of lose about 90% of those neurones. So you can kind of think about blockade as well. The other pathway that's kind of very kind of clean cut and clearly delineated is the tuberoinfundibular pathway. I was nervous about pronouncing that properly, and that's basically the projections from your hypothalamus to your pituitary gland. And another name for dopamine is prolactin inhibiting factor. So what happens here is that by blocking dopamine, it's kind of disinhibition and that can cause breast development or lactation or what we call galactorrhea in men and women actually. So it can be quite a disturbing side effect when you are prescribing this. If you know, men or women are all of a sudden having breast development and are lactating. So that's a common reason for discontinuation with these high potency medications such as Risperidone or Haldol, which are kind of the worst offenders. So that's related to side effects. The other two pathways, really, that's where people postulate a lot of maybe the origins of schizophrenia arrive, as Andy was saying, talking about negative and positive symptoms.
Dr. Jason Joannou: [00:09:32] That's basically saying that the Mesolimbic system is maybe where the positive symptoms of schizophrenia come because it has to do with your emotional brain. It's very primitive part of your brain. So it deals with emotion, motivation, long term memory, and that is projections from your midbrain. Again, your ventral tegmental area to your limbic structures. And different people have included different structures in the limbic system. Depending on where you read it. It's kind of an old concept, and some people say we should just get rid of it, but common ones. These are the most accepted ones, I would say are things like your cingulate gyrus, your hippocampus, your amygdala, so emotional brain, deep brain, and they think a lot of things, positive symptoms, may derive their origins there. And the fourth one is the Mesocortical system. Again, from the ventral tegmental area to your prefrontal cortex. And people think that's perhaps where the negative symptoms are originated because your prefrontal cortex has a lot of things like working memory and attention. It's a newer part of the mammalian brain. And so this postulated that a defect in that would kind of fit well with negative symptoms of schizophrenia.
Dr. Lucy Chen: [00:10:45] Great.Thanks for that. It must have been exhausting to kind of go through that. Just to summarise very quickly, the Mesolimbic pathways thought to be relevant to the positive symptoms of schizophrenia. So in our previous episode on diagnosis, that's the hallucinations and the delusions and antipsychotics are thought to reduce the positive symptoms of schizophrenia by blocking dopamine in the mesolimbic pathway. The other pathway was the mesocortical pathway, which is more so relevant to the cognitive symptoms of schizophrenia. When antipsychotics act on this pathway, they can worsen the negative symptoms of schizophrenia by blocking dopamine there. The nigrostriatal pathway is involved in motor planning and dopamine stimulates purposeful movement. So blocking dopamine in the nigrostriatal pathway can be responsible for the Extrapyramidal symptoms or Parkinsonian symptoms that you can see with antipsychotics. And then the final pathway is the tubulo infundibular pathway. When antipsychotics block this area can worsen symptoms like prolactin, anaemia or galactorrhea.
Dr. Jason Joannou: [00:11:49] Very articulate Lucy Very.
Dr. Lucy Chen: [00:11:51] Okay. So I think that'll I think that we'll stop there in terms of talking about kind of the psychopharmacology and maybe Henry, if you want to take the lead on kind of asking questions about the clinical aspects of starting an antipsychotic.
Henry Barron: [00:12:05] Sure. Yeah. So I wanted to talk to you guys a bit about the actual use of antipsychotics in practice and how we go about treating people with them. So now that we know a little bit about antipsychotics and how they work and also what their side effects are, let's sort of turn to how we would treat someone who comes in, for example, in a first episode of psychosis, maybe to the emergency department, maybe to a first episode psychosis clinic. What antipsychotic would you choose and how do you come to that decision?
Dr. Andy Lustig: [00:12:34] So as Jason mentioned earlier, there are a lot of different antipsychotics available on the market in Canada, and so they don't tend to differ much or at all really in terms of their effectiveness. So we're primarily driven by considerations around practical matters like route of administration, whether or not the medication is available by long acting, injectable, antipsychotic, side effect, profile, cost availability, things of that nature.
Dr. Jason Joannou: [00:13:02] Nowadays, actually a lot of them are off patent like olanzapine risperidone and there's generic forms, so they're cheap. So cost isn't as much of a consideration as it used to be. But you know, long term use with typical antipsychotics, first generations, they do have a higher incidence of tardive dyskinesia, which can be irreversible. That's like involuntary movements, usually oral buccal, it can be anywhere in your body. It can be quite stigmatising and debilitating. We're trying to avoid that. Often these people are going to be on medications for years and years and years and the risk goes up with every year up to 50% if you stay on your medication. So that's serious. But also serious is, you know, if you're having, like Andy was saying, like diabetes, high cholesterol for years of your cardiovascular risk is huge. And you're talking about people who usually start their illness in their early 20s. So the full impact of really atypicals we haven't quite seen yet in terms of the long term. So we're trying to I think, you know, again, it comes down to side effects. Like you said, there's no real superior efficacy other than clozapine in treatment refractory psychosis, which I think we're going to talk about later. That's the only one with any kind of superiority in the subset of people with schizophrenia. But the efficacy is all the same. The other problem what I think about is compliance. And so when I was a resident, people said, "you don't prescribe people depo medications until they've failed two oral courses." And nowadays there's several RCTs And we just recently did this in our little journal club here on the at the GPU about the evidence of depo medications in first episode psychosis. And there is some good evidence showing that it improves compliance and outcomes. So I'm very if people are on for it and I say, you know, "you can take this medication once a month, you don't have to worry about remembering it". This might reduce future hospitalisation. That's a good thing and we shouldn't be shying away from it like we used to or like I was taught when I was a resident. You know, some people might argue that it's paternalistic to kind of give an injection and say that you can't make the decision to stop doing it as well. And I can see from that point of view, if someone's willing to do it, I think it's good to offer it to them. I wouldn't, you know, subject somebody to like if it's their first episode of, you know, illness and they don't want an injectable medication, I typically wouldn't pursue that too strongly. But if there's a pattern of non-compliance, rehospitalization and people don't really appreciate that if they don't stay on these medications, things are likely to get worse for them and they are found incapable under the law. Then that's when I would think about, you know, strongly consider a depo medication.
Henry Barron: [00:15:44] Now let's turn to sort of the actual specifics of starting and maintaining someone on an antipsychotic. So how long would you keep someone on their first antipsychotic before you decide that you want to try a different one?
Dr. Andy Lustig: [00:15:59] Generally, I'd say several weeks. So you want to get them to a therapeutic dose of the antipsychotic, and then adequate duration is somewhere in the neighbourhood of 4 to 6 weeks In practice on the inpatient unit. We tend to accelerate that time course a bit, but on an outpatient basis, I think that's what you'd be looking at.
Dr. Jason Joannou: [00:16:20] We're a little more aggressive with the. Yeah, with the dosing schedule for sure.
Dr. Lucy Chen: [00:16:24] You guys are more so seeing them in the acute phase of illness where they're very actively psychotic and we need to control symptoms as quickly as possible.
Dr. Andy Lustig: [00:16:32] That's correct, Yeah.
Henry Barron: [00:16:35] Okay. And then so if you did decide to switch, for example, because you're not getting the response that you're hoping for, do you have any strategy to switching like, do you choose a typical antipsychotic after trying an atypical or does it not really matter?
Dr. Andy Lustig: [00:16:51] I would say generally no. I tend to stay within the atypical class. I could see the rationale for switching from atypical to conventional, but I think we tend to be pretty wedded to our atypicals. So yeah, we would we would simply usually choose another one and design a cross titration schedule. Again, I think the rapidity of the schedule would depend on on how unwell the person is so and therefore how urgent it is to complete the cross titration rapidly. And whether you're doing it on an inpatient basis where you have access to them on a daily basis and you can monitor closely for side effects or whether you're doing it on an outpatient basis and you're maybe only seeing them like once a week or once every couple of weeks, which would kind of slow it down. But typically we would just choose another agent and then cross titrate.
Dr. Lucy Chen: [00:17:44] Can I just ask a quick question about antipsychotic withdrawal? Does that exist? Does it happen? What does it look like?
Dr. Jason Joannou: [00:17:50] So it's not necessarily withdrawal due to like the antipsychotic effects, though. It's withdrawal due to your all the receptors that antipsychotics are affecting and the rapid discontinuation and your body's homeostasis with that. So the worst offender is Clozapine. If you just stop clozapine right away, it can be quite uncomfortable for people. They can have jitteriness, irritability, problems with their sleep, differences in micturition, things like that. And that's due to it's very anticholinergic medication that you develop tolerance to quickly and lose quickly when you stop it. So it can be uncomfortable. And then when you start it again, it's kind of like methadone or an opioid. You can't start at the same dose. So you have to start from early. So there are withdrawal syndromes and it can be quite uncomfortable for people to stop right away.
Dr. Lucy Chen: [00:18:40] So therefore the importance of kind of cross titration, which is slowly decreasing the dose of the drug that the patient was on and slowly increasing the dose of the drug that you're switching to.
Dr. Jason Joannou: [00:18:49] Depends on the setting you're in too, because sometimes if people say, for instance, leave an inpatient unit and the cross titration hasn't been done yet, that may not happen for weeks, months or years afterwards. And then people are on to antipsychotics, which is really not, you know, kind of evidence based or good for them and might have more suffer more side effects. So I actually do that fairly rapidly in hospital and try to minimise the discomfort, but it could be a real problem and I try not to when I'm cross titrating leave it for so long because I don't want that to kind of just inadvertently cause some harm. I would say not in terms of just generally what agents you choose after one's failed. I think, again, it just comes down to side effects and not all atypicals or typicals are created the same. Some have worse or less favourable profiles, like for instance, Olanzapine is a wonderful antipsychotic and works very well. And it just this is anecdotal. There's a great article. It was like, why olanzapine is better than risperidone, is better than quetiapine, is better than what have you, and there's no known efficacy difference. But in practice you will see psychiatrists say like, I like this or I like that.
Dr. Jason Joannou: [00:19:58] For instance, no one uses Ziprasidone very much anymore because you had to have it with food twice a day, which may decrease the efficacy and it might in a randomised controlled trial be the same, but maybe in real life not quite the same. And there's these other new ones, Lurasidone and Asenapine. And I always say to residents, I say be wary of new things, try them out, learn about it, but like tried and true things that have been on the market 5 to 10 years at least like that have gone through the wringer in clinical practice usually are a bit safer. Yeah. So I mean I try to when I'm doing things, I try to use like less metabolically heavy things. So like risperidone and paliperidone are better than, you know, clozapine or olanzapine in terms of those risks. So I try to, you know, especially in first episode psychosis like Abilify or Risperidone Paliperidone are kind of like of the atypicals, kind of the less burdensome ones. So I try to see if hopefully somebody has a positive response to those before I move to other ones.
Dr. Lucy Chen: [00:20:56] So you've treated someone in the acute phase, you've kind of gotten them better on the inpatient unit and they're stable. What does it look like for them in the maintenance period when you're discharging them from hospital? Do you keep them at the same dose? Do you reduce the dose and how long do you keep them on that medication for?
Dr. Andy Lustig: [00:21:13] Yeah, I think it's a matter, again, of weighing risks and benefits. And essentially there's kind of a safe option and a, you know, riskier option with potential for gain. So essentially, you know, the safe option is to maintain them on the dose of antipsychotic that initially led to the response and the recovery. And generally if you do that, you. I think you have the lowest chance of seeing relapse of symptoms, but that's typically a robust dose that may come with robust side effects. And most people are invested in decreasing the dose of the antipsychotic medication after they're out of the hospital. And as you probably know, many people want to get off the medication as soon as possible. So I kind of have this conversation with them and I say, you know, we can certainly try dropping the dose and we need to be vigilant for the re-emergence of symptoms. I find that most people can come down on the dose, realistically speaking, that the dose necessary to stay well is typically less than the dose that was necessary to get well.
Dr. Lucy Chen: [00:22:15] And how long do they have to stay on it on that dose?
Dr. Andy Lustig: [00:22:18] Well, it's controversial. So so I think typical recommendations. People say after a first episode, it should be somewhere like either like a year or 18 months or something like that. But we just recently read a paper and I think this is borne out by clinical experience, too, that says basically, you know, more is better. You know, unfortunately, schizophrenia does not typically go away. And people with schizophrenia who stop their antipsychotic will typically experience a relapse at some point. So I would say after a first episode, again, like somewhere around a year or 18 months, if the person is amenable to stay on the medication, I think that's the safer and frankly, the wiser option. And after a second episode, I think it's a lifetime of treatment is recommended.
Dr. Jason Joannou: [00:23:03] Yeah. And Andy's referencing a recent American Journal article with a big Finnish cohort. And basically there's no safe time to discontinue. They have all this great registry data in the Scandinavian countries. And, you know, from one year to five years, they're high relapse rates if you stop the medication. So despite many guidelines saying somewhere between 18 months to two years or three years or what have you, I mean, that's more expert opinion than kind of great science behind that. I usually tell patients, I was like, look, if you're tolerating this, well, your life is a lot better. We can try to reduce the dose, but like, if I were you, I'd probably you're most likely going to have a relapse if you stop this medication. So you got to weigh that.
Dr. Alex Raben: [00:23:48] And for sure, that's good advice. I want to turn now towards Clozapine, which is something we've alluded to a little bit already as being a bit more effective than the others for a subset of people with schizophrenia, at least in the new guidelines. And I think a lot of guidelines would say this as well, that if someone fails two treatment trials with other antipsychotics, that in those cases you should move to using Clozapine because it's shown to be more effective for what we would label as treatment resistant schizophrenia. So these are assuming that it's two good trials of a number of weeks at an adequate dose and that kind of thing. However, Clozapine is an interesting medication for many reasons, and I'm wondering, practically speaking, how that works out in real life, or what's your clinical experience with starting Clozapine?
Dr. Andy Lustig: [00:24:37] Yeah. So Clozapine has higher efficacy than the other antipsychotics. It's the one notable exception to the previously stated rule of thumb that there's no real significant difference. And unfortunately, that greater efficacy comes at a greater cost in terms of the side effect burden. And so Clozapine has a lot of side effects and it's frankly quite a toxic drug. And so, I mean, typically after someone has two failed trials of antipsychotic medication, we would recommend and propose Clozapine as a third agent. And it's also important to be explicit about the side effects that the person is signing up for. So so Clozapine is kind of the quintessential atypical antipsychotic, and it has the attributes of Atypicality in kind of like in extremis. So so in terms of, you know, we talk about atypicals, we talk about metabolic side effects. And Clozapine has really severe metabolic side effects and it's variable. Some people don't seem to gain a lot of weight on clozapine. But I have seen people that have gained like £80 on clozapine. And in addition to that causes it causes constipation, which in some cases can be fatal.
Dr. Jason Joannou: [00:25:55] I know that sounds weird, but it's true. You can get a ileus, like your gut just stops working. So you have to it's actually really important to monitor people's poops.
Dr. Andy Lustig: [00:26:03] You have to be very vigilant about bowel motility for people on Clozapine, it causes myocarditis. It has been linked to sudden death. And as you know, it causes agranulocytosis, which is a precipitous decline in the neutrophils. And so people on Clozapine have to be enrolled in a national registry of everyone on clozapine and they have to be monitored with a complete blood. Cbc's, which have to happen weekly for six months and then bi weekly for six months and then in perpetuity for the rest of the time that the person is on the drug. And so in order to get somebody on clozapine, effectively you really need some buy in from the person because remember, it's an oral agent. It doesn't come in in any injectable or long acting injectable form. So the person has to take it on a daily basis. They have to have the blood work. And if they don't have the blood work, you have to stop the medication. And if you stop the medication, you can't after several days, you can't just restart it. You have to re-titrate it again, which takes some time.
Dr. Alex Raben: [00:27:11] Right. So I it's obviously the most effective, as you're saying, but comes with all of these side effects and practical limitations that make it quite hard to not convince but it's not an easy drug for someone to decide to go on, essentially. And what I'm also hearing is, although we kind of are in medical school, we all learn about agranulocytosis associated with Clozapine. There's also these other quite significant side effects which are constipation, which again may not think but can cause a deadly ileus. And then I also heard myocarditis. Can you speak a bit more to that? Because that can be scary as well.
Dr. Andy Lustig: [00:27:48] Yeah, absolutely. So that's, you know, inflammation of the heart muscle and it's often associated with kind of like a flu-like illness and oftentimes pain. And so now here at this hospital, we monitor people with we do their TROPONINS and CRP to monitor for inflammation of the heart muscle. And so we can stop the medication if they're developing that side effect.
Dr. Jason Joannou: [00:28:14] Yeah. And it's actually no, no one told me about myocarditis again when I was even a resident, no one really talked about it. And then all of a sudden, you know, people were having these sudden deaths and they kind of the myocarditis story has been coming more and more. Australia has really good guidelines on what to do and the timeline and usually happens within the first month of initiation. So you don't have to if you've been on Clozapine for six months or a year, you don't really you're kind of past that window for the most part. And you know, the Australian numbers say something like I think 4% or something like that of people initiation get myocarditis, which is huge. 4% is you know we talk about everyone knows that agranulocytosis that's more like 1 to 2%. And we've been tracking this at CAMH and apparently, like the numbers here are like 7% and that just might be a cohort difference or what have you, but it's not insignificant and not uncommon. So it's actually a super important issue with Clozapine.
Dr. Andy Lustig: [00:29:13] It also causes sialorrhea like excessive salivary production, which is a nuisance side effect for people, especially at night. People will describe waking up in their pillow is soaked with saliva very commonly.
Dr. Alex Raben: [00:29:26] And then I'm just using my cheat sheet here. A few other kind of more nuisance side effects would be the anticholinergic and the side effects that come with other antipsychotics. But because it's the prototypical atypical antipsychotic, it tends to be quite extreme in clozapine. So like drowsiness, orthostatic hypotension, those kinds of things. And then also, as with other antipsychotics, there's a seizure risk, which I think is higher in clozapine. But I could be wrong about that.
Dr. Jason Joannou: [00:29:55] It's very high in clozapine dose dependent, and you really start getting risky once you get above kind of 450, 500mg. Most people, when you're starting Clozapine, if you're doing a first trial, kind of get to 300mg, sit there for a while, see if there's a partial response or a full response, you have a partial response. You might want to increase the dose. Really therapeutic range is from 3 to 900mg. But once you start getting to the 500 milligram range, people really start considering adjunctive, maybe antiepileptic medications like Epival, which has some evidence about efficacy and augmentation, not great, but if you have to choose an anti-epileptic, might as well choose Epival because that's a mood stabilising properties as well. But yeah, seizure becomes a very big issue, one in high doses and obviously in overdose. If people were to kind of overdose on their medications, it can be quite dangerous.
Dr. Alex Raben: [00:30:53] We've learned that it's clozapine is substantially more effective in treatment resistant schizophrenia. However, it doesn't work all the time. The new Canadian guidelines don't comment actually on what to do after Clozapine if it doesn't work. I'm wondering when you're faced with this clinical dilemma, what do you guys tend to do in practice?
Dr. Andy Lustig: [00:31:17] That's a tough situation. You know, it depends how they got there, basically, and how much it's not working. If it's doing nothing, then really you can stop it. You should stop it. And if they've been on two other antipsychotics, well then there's lots of other untried antipsychotics. And so you can do trials of other antipsychotics that you haven't yet tried. In some instances, rarely ECT has been used for the treatment of refractory psychotic symptoms. And, you know, some people have psychotic symptoms that don't respond to medication management. That's the case. Then you want to help them move forward with their recovery, given the symptom burden that they're experiencing. And so, you know, we have other modalities which are not the cornerstone, but there is cognitive behaviour therapy for psychosis and other kind of like recovery tools and approaches to help them live the best life. They can with psychotic symptoms.
Dr. Jason Joannou: [00:32:14] Another strategy. But you've got to tell people what the numbers are or they're not that great once you've failed. Clozapine in terms of a robust response with something else. But people do have idiosyncratic reactions to individual antipsychotics, and we don't know why. Right. Just like we were talking before, if you fail one trial, you go to a different one. We don't know why they fail the first one and they might respond to the second antipsychotic. And the earlier you are on in your illness, the more responsive that seems to be. But that doesn't mean that you can't have an idiosyncratic reaction to another antipsychotic. So I just recently had an experience where I was cycling through antipsychotics for another person who was failing them. He tried clozapine and actually got myocarditis twice. So he had two failed failed trial because of the myocarditis, not because of efficacy, failed a couple of other antipsychotics. We said we're going to retry him maybe on a slower titration schedule that might help. Still happened. And then Haldol, for whatever reason, he's doing really well now. But that's the patient's decision because the numbers aren't great there. And if someone's like, I get all these side effects and I rather just do what Andy said, I think that's a very reasonable course to go. But I also think it's very reasonable to say, look, we don't know why these individual superior effects with these medications happen, but we can just try to find the one that works best for you. Just being upfront again about like what the odds are is is important.
Dr. Alex Raben: [00:33:44] Dr. Lustig, you you commented on CBT for psychosis and we spent almost all of our time today talking about antipsychotic medications as the cornerstone of treatment and certainly for positive symptoms like hallucinations and delusions. It is. But I'm wondering more now about the psychosocial aspect of the treatment and how that plays into things. The guidelines, again, we'll talk about everyone should get CBT for psychosis, everyone should get a family intervention. How often is this happening? When does this tend to be introduced to treatment and why is it necessary above and beyond antipsychotic treatment?
Dr. Andy Lustig: [00:34:24] Well, yeah. I mean, essentially the antipsychotic medications are rarely a cure for for schizophrenia. And although there are some instances where people take the medication, have total resolution of their symptoms and just go about their life, that's the exception, not the rule. Most people don't have 100% reduction in in their positive symptoms, and most people have negative symptoms, which again, make it hard to go about doing the things that people want to do in their life. Those things are like, you know, going to school or going to work, cultivating healthy relationships with their family, cultivating romantic relationships, friendships, pursuing extracurricular interests and hobbies, fitness. Those are all the things that healthy people want to do as a part of their life. And those are hard to do with schizophrenia. It's just hard to it's just hard to get out of bed and hard to get ready in the morning and attend to your hygiene and get dressed and and call people and follow up and go to interviews and prepare your CV and all those things that we kind of take for granted become a kind of an extra effort in recovery from schizophrenia. And so a part of cognitive behaviour therapy for it is, I mean, you know, and it's not just cognitive behaviour therapy, it's just a part of recovery is structure and, you know, giving people like structured scheduling and prompts and encouragement and motivation to go about doing these things in their life.
Dr. Alex Raben: [00:36:01] Right. So there's so much more to the illness that the antipsychotics don't really help with. That's right. And these psychosocial interventions, including CBT and helping with finding a vocation or other things like that, are essential for helping people with just going on with their lives and recovery, essentially.
Dr. Andy Lustig: [00:36:19] That's right.
Dr. Jason Joannou: [00:36:20] Yeah. I mean, there's a real risk of kind of isolation, marginalisation with this diagnosis and anything you can do to increase people's supports, their circles, it's going to be not only good for their illness, but just for their lives. And there's a lot of evidence behind that in terms of, you know, people are generally maybe do better in non-urban environments because they're more likely to have friends or neighbours that know them, care for them, check in on them, friends circles, their behaviours a little bit more accepted. Sometimes we know people in kind of developing countries actually are more likely to have a job, more likely to be married, more likely to be part of a community. And those are really important things not to forget. You just can't simply prescribe an antipsychotic and say, Here, that's all you need. See you later. These are the sorts of things that are going to help with all the things that Andy were saying that are really important not only to people with schizophrenia, but just healthy. Controls. Yeah.
Dr. Lucy Chen: [00:37:14] Yeah. So I guess right now I'd like to just tie everything in together and, like, really kind of maybe provide the context of a case and then maybe have you guys use your clinical expertise in guiding this patient through a first episode of psychosis and how you'd counsel them on really the course, the trajectory of their illness and kind of maybe some counselling around medications and providing them with some guidance around what their life is going to look like.
Dr. Alex Raben: [00:37:42] Okay. I'll read the case off here. So you are working on an inpatient psychiatric unit and are admitting Mohammed, who is a 19 year old male who was brought to the emerge by his family after two months of acting increasingly more bizarre. He is talking to his parents about Russian spies and has been tampering with the wiring of his home. He was placed on a form one for physical impairment. He almost electrocuted himself and harm to others. On one occasion, he elbowed his father in the nose while his father was trying to prevent him from touching the wiring. He has been relatively calm in the emergency room, but continues to feel like his home is bugged and is wanting help to deal with the spies. He appears unkempt. His speech is somewhat monotone, but otherwise normal. His affect is intense and constricted. He appears to be talking to someone at times when no one is around. He is tangential but coherent. He denies any drug use and his urine drug screen is negative. Basic blood work wasn't impressive and he has no significant past medical history. After a thorough history, including collateral from family doctor and his family, you find out that he has been hearing voices when no one is around and that his uncle has schizophrenia. Also, Mohammed has been followed for a year by first episode schizophrenia clinic for prodromal symptoms, but has never shown true psychosis before now. He has been managed conservatively up until this point. Your team concludes that Mohammed's most likely diagnosis is first episode of schizophrenia with Schizophreniform on the differential. Mohammed does not believe he is suffering from any illness and does not want treatment. So this is something that we haven't touched on too much. But how do you broach a situation like this with someone who doesn't have insight into their illness and doesn't actually want to be on medication at all?
Dr. Andy Lustig: [00:39:33] Yeah, it's a it's a great case. So as you know, quite typical of the stuff we would see here, I would say. So I think you want to remember that. I think where this conversation is going, I think, is that we're going to talk about a variety of coercive tools that we have at our disposal. But but it's also important to notice that you want to avoid using those if you can. And this is going to be, you know, potentially a lifelong engagement between this person and their team and the system. And we want to work as collaboratively as possible with them. Having said that, so you basically what you would want to do in this instance is there's the two primarily kind of medicolegal issues that that have to be addressed. One is the issue of certify ability. Is this person sufficiently dangerous to justify detaining them in the hospital against their will? And the second is the issue of capacity. You know, here in Ontario, there's a test of capacity that we apply. And is the person able to understand the information relevant to making a decision? Are they able to appreciate the reasonably foreseeable consequences of a decision or lack of decision? We call that the two branch test with understand being one of the one of the branches and appreciate being the other one. And so you want to assess for this guy, should he be here in the hospital? And we would recommend an antipsychotic medication to him. We would work with him to to educate him about our concerns and educate the family and educate him about psychosis and schizophrenia and the medications and try to get him to take the medication.
Dr. Jason Joannou: [00:40:58] Yeah. And I would just say in Ontario and he said the two decision points are, you know, involuntary detention or capacity. I would just add on the involuntary detention, you can't treat someone who is incapable and doesn't want treatment unless they're detained in hospital. I mean, initiating treatment is very difficult. You could be on a CTO and do it in the community, but like practically speaking, initiating treatment on somebody who doesn't want a treatment if they're not involuntarily detained is most likely not going to happen. The criteria for involuntary detention are safety ones, generally harm to self, harm to others, serious physical impairment, which basically means you don't want to hurt yourself, but you're just behaving in a way that is likely to occur.
Dr. Alex Raben: [00:41:40] Harm like tampering with electrical wiring in your house?
Dr. Jason Joannou: [00:41:43] Yes, exactly. Not dressing appropriately for the weather, being disorganised, walking into traffic, those sorts of things. The other criteria is benefit from treatment in the past. And different jurisdictions in Canada have different thresholds for this. Some don't have it. Ontario does, but it's only based on a previous treatment response. So if you're in a first episode psychosis, you can't say that you've had a previous response and we can hold you in hospital because you're going to benefit from this versus if someone's had multiple admissions and tried treatment, then basically if they've deteriorated and lost their capacity, you can treat them in the future, which is, you know, that's a whole podcast on its own about why you would do that. And one of the most frustrating things for I think, providers who want to help people and families who really are seeing their family members suffer, you know, part of the illness is a lack of insight into being ill. So it's very hard to explain to someone like they're very unwell, they're super. We have a treatment that we could do for them. But because there's no like 50% chance in a short period of time, they're going to hurt themselves seriously, someone else or die. They can just be, you know, deteriorating. And you say, I can't do anything. That's a very difficult conversation that we have to have many times with families.
Dr. Lucy Chen: [00:43:01] So with like maybe Muhammad and his father in the room and his father is extremely concerned, very tearful. How do you talk about treatment? How do you talk about the course? How do you talk about what's going on and make sense of it for very like distressed family?
Dr. Jason Joannou: [00:43:16] Yeah, I would say. I mean, the first thing is talking to Muhammad and telling him what you think is going on, that basically, you know, your brain is misfiring right now. There's there's actually not all these threats out there. Unfortunately. You have this illness called schizophrenia, psychosis, whatever. You're going to label it that just talking more about the symptoms and the diagnosis and saying we have this medication doesn't come without side effects, but it can make you feel more at ease, get you back to where you were. And we can monitor it closely, especially in hospital, and then support you when you leave with it. That's kind of the general conversation. And sometimes people, you know, even if they're incapable, will go along with it and kind of just do what doctors do. And sometimes people are very vehement. They don't want treatment. So that's kind of where you start. And then when you talk to the family, you know, you sympathise with them, you educate them about the limits of what you can do in hospital under the law, you problem solve with them in terms of what to do. If this were to happen, they can go to the doctor, they can get a form to if there are safety issues, all those sorts of things, and then you try to provide them with any support you can. So there's, you know, a lot of family support usually are very good social workers here on the fifth floor work with families. So and this is a journey they're going to be taking together for a very long time, even though you can't give them what they want, you want to make sure that they feel heard and listened to share their concerns with them as well. The other kind of stumbling blocks sometimes is people say, I don't want you to talk to my family. And then there's a limit about information that can be shared and that that can be very frustrating for families as well.
Dr. Alex Raben: [00:44:52] So thank you guys so much for that. I mean, just summarising that last piece, I think something I take away is just how important those moments can be for the longer term trajectory, because it is often a life long illness and you have to be cognisant of that while you're giving all this counselling in those early days and moments.
Dr. Jason Joannou: [00:45:09] Setting the stage.
Dr. Lucy Chen: [00:45:11] For sure. So thanks so much again for sharing your time guys. We'd love to have you back on the show.
Dr. Andy Lustig: [00:45:16] Thanks for having us again!
Dr. Lucy Chen: [00:45:18] But for now, we're going to wrap up, I guess, any closing remarks or just some advice or kind of insight to give to young learners in the scope of pursuing a field in psychiatry and especially in the context of your practice.
Dr. Jason Joannou: [00:45:30] Just like any area of medicine, there's going to be challenges and limitations to what you can do. But we I think we do really good work. And even when we're having to use these coercive tools and doing what we think is in our patient's best interest, I think we do make an impact on people's lives. And I feel very privileged to be in the position I am in every day to work with these families going through this and the kind of courage and strength that they show the patients and the families and just trying to help and be part of it is can be a really wonderful experience. It can be very taxing and difficult experience as well. But most things in life that are worth doing can be difficult as well.
Dr. Andy Lustig: [00:46:13] Yeah, I agree. And I think it's important to celebrate small victories when working with people with chronic psychotic illnesses.
Dr. Alex Raben: [00:46:21] Great. Thank you, guys.
Dr. Lucy Chen: [00:46:22] That's a wrap.
Dr. Alex Raben: [00:46:23] 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, Henry Barron and Alex Raben. Special thanks to Yanlin Zhou and Theresa Park for help with research. Henry Barron provided the audio editing. Our theme song is Working Solutions by Olive Musique. A special thanks to Dr. Jason Joannou and Dr. Andy Lustig for serving as our experts on this episode. You can contact us at info at psychedpodcast.com or visit us at Psyched podcast.org. Thank you for listening!