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Alex Raben: [00:00:08] Welcome back to PscyhEd, the Educational Psychiatry Podcast for Medical Learners by Medical Learners. I'm Alex Raben and I'll be your host today. This episode is the second of four in our series on schizophrenia treatment. If you haven't listened to episode nine, the first episode in this series, I would recommend you go back and listen to it because this episode builds on ideas that are in that episode. For this episode, we sat down with Dr. Albert Wong, a psychiatrist and research scientist who is an expert in schizophrenia. He is also heavily involved in our education at U of T and is known for challenging our views on psychiatric illnesses in a way that I believe gives us a deeper conceptual understanding. It is my hope that we have replicated some of that experience for you in this episode. This episode also uses a slightly different format than past episodes, in that I was joined by three medical students in their first, second and third year. The intention of this format was to provide the medical student perspective, but I think in that aim we failed somewhat. Partly because the conversation became pretty high level and partly because I just wasn't used to balancing such a large group. I really wish we could have had more of the medical student voice in this episode, and I apologise to my colleagues for that. But either way, I think there's some great information that you guys can benefit from in this episode and I hope you'll enjoy it. And please let us know what you think of this format so that we can continue to build and learn with you. So there is some overlap between this episode and the last one, but I think it takes a deeper dive in a number of the concepts.
Alex Raben: [00:01:47] So by the end of this episode you should be able to, number one, conceptualise antipsychotic drug categories in an unconventional and clinically relevant way. Number two, have an approach for choosing an antipsychotic medication for a patient and be able to consent that patient to treatment. And number three, understand the limitations of our understanding of schizophrenia and our current treatments and some of the problems that remain to be solved in this area of psychiatry. There is also one concept I'd like to clarify before we jump into the interview, and that is extrapyramidal symptoms or EPS. So these are side effects that can occur with antipsychotic medications and they're essentially disruptions in motor functioning due to the global dopamine blockade caused by antipsychotics. In other words, these are involuntary muscle movements that happen because of the medications. There are three main types that happen acutely or more acutely. These are dystonia, Parkinsonism and akathisia, and then one that occurs months to years after treatment has started called tardive dyskinesia tardive because it happens late. So I'll go through each of these in turn. Dystonia is a sustained involuntary muscle contraction. So the muscle essentially gets stuck and it can be quite painful. It can happen to any muscle group, but often involves torticollis of the neck. Second is Parkinsonism, and this is similar to in Parkinson's disease. So there's rigidity, limited arm, swing tremor, masked face. However, it's usually symmetrical because the drugs affect both sides of the brain, unlike in idiopathic Parkinson's disease. And then there's akathisia, which is a subjective restlessness that will often occur with also a physical restlessness, but not always such as pacing or not being able to sit still.
Alex Raben: [00:03:50] So for this one, you need to ask about the patient's subjective experience, because if they don't have that, it's not akathisia. And finally, there's tardive dyskinesia. This is the late occurring one, and it's a hyperkinetic movement, usually jerky, rhythmic or slow and sinuous. And this can also involve any part of the body, but often will involve the face and tongue muscles. We also need to briefly review the case of Muhammad because we use it again in this episode. So recall from last time that Muhammad is a 19 year old man who lives in his parents house and was brought to the emerged by them for acting bizarrely, he was admitted to the hospital and received a provisional diagnosis of first episode psychosis, likely related to schizophrenia. He was showing signs of psychosis both at home and in the hospital and had delusions that people were spying on him. And this had something to do with the electrical wiring in his home. At one point, he even tried to tamper with the wiring in his home, and he has no training on how to do that safely. Okay. So that's all the background you guys need. So without further ado, let's jump to the interview. I'm just going to introduce everyone who's in the room today. So as you know, I'm Alex Raybon. I'm a third year resident at the University of Toronto. And our expert guest today is Dr. Albert Wong, and I'll have him introduce himself to you.
Dr. Albert Wong: [00:05:35] I'm a psychiatrist at Camh, and I also have a lab. I do some neuroscience research.
Alex Raben: [00:05:39] Great. Thank you. I'm also joined by three medical students here at U of T, and I'll have them introduce themselves as well.
Sabrina Agnihotri: [00:05:47] I'm Sabrina Agnihotri, a CC3 at U of T.
Yunlin Xue: [00:05:50] I'm Yanlin Xu, and I'm a second-year medical student.
Theresa Park: [00:05:55] I'm Theresa, and I'm a first year medical student.
Alex Raben: [00:05:59] Great. Thank you all. So as before, we're going to sit down together as a treatment team and discuss antipsychotic medications for the treatment of schizophrenia, and especially as they apply to the case of Mohammed. So why don't we start with general principles of antipsychotic treatment for schizophrenia? Whoever would whoever would like to jump in.
Sabrina Agnihotri: [00:06:32] So there are so many medications that you could choose to start for a first episode of schizophrenia. Where do you even start?
Dr. Albert Wong: [00:06:42] Okay. I mean, I think a few things here. The first thought that I would have is that it doesn't really much matter in first episode which antipsychotic you pick because all of them will be likely to be effective. Any of them will be likely to be effective. So first episode, schizophrenia, for whatever reason, probably because it's at the beginning of the illness, it responds very quickly and very easily to most antipsychotic medications at fairly low doses. And I think but, you know, one of the reasons why you're having this educational session is because it's unclear if it was very obvious which medication to pick in this instance, then we wouldn't be having this conversation. So what is the controversy, do you think? I mean, you all have said the same thing. So what's the controversy then? Why are we having this session?
Yunlin Xue: [00:07:35] Um, potentially the side effects. Okay.
Dr. Albert Wong: [00:07:38] So that doesn't really affect the choice of antipsychotics. I mean, they all have side effects. So what do we. I'm just trying to clarify what it is that is the subject of debate, really. What is the controversy that's in this field that we really need to talk more about? I mean, in the end, we have to choose one medication. But in getting there, we might think a lot in the background about the issues at hand. So from my standpoint, I think there's it's confusing because there's a significant mismatch between treatment guidelines and the literature. You know, there are a number of studies, very well conducted studies comparing various typical and atypical antipsychotics, and they typically find no difference among these two categories. So why is it that we keep on saying that we should pick atypicals? That's one question. And so, you know, I think it's hard for people because the treatment guidelines say atypical. But then if you asked what is the advantage of an atypical antipsychotic, then I think it's difficult to say. And even more upstream question is what is it that distinguishes typical from atypical antipsychotics?
Alex Raben: [00:08:46] So I think there's even controversy about around that. But it would be the different receptor profiles. So a typical is more purely D2, whereas an atypical has the five H to a blockade as well.
Dr. Albert Wong: [00:09:04] So I think that's one criteria. A common one that's been advanced to categorise antipsychotics into typical versus atypical. And I would argue that that makes no sense. So the reason I would say that is because there are so every antipsychotic has only one therapeutic target, and that is the dopamine D2 receptor. And so far there has been no medication that's been discovered that has antipsychotic effects that we use clinically that does not bind significantly to the dopamine D2 receptor. So that's the first thing. If you then look at the dose of antipsychotic that's used clinically, that reflects only one physical property, which is the affinity for the dopamine D2 receptor, which is just another way of restating what the earlier statement was. So there is, of course, a dose response curve here. And in order to achieve the same response with a different drug, you need to occupy the same number of dopamine D2 receptors. So because of that, I think really there's no it doesn't make any sense to talk about typical versus atypical because there are some drugs which are considered typical because they're old drugs like chlorpromazine or clozapine, which are given in fairly high doses, you know, in the hundreds of milligrams. And these medications are given in that dose because they don't have a very high affinity for the dopamine D2 receptor, whereas other drugs, old drugs that are considered typical, such as Haloperidol or drugs that are considered atypical, such as risperidone, are given in very low doses somewhere, you know, under ten milligrams.
Dr. Albert Wong: [00:10:37] So at least an order of magnitude lower, in some cases two orders of magnitude lower than drugs that are given at high doses like quetiapine and chlorpromazine and clozapine. So in my mind, the the low potency drugs such as Quetiapine, chlorpromazine and Clozapine share much more in common with each other versus the drugs that are high affinity such as haloperidol and risperidone that are given in fairly low doses because they have very high dopamine D2 affinities. And the reason I'm making this point is because while some of these drugs may bind to other well, all of these drugs bind to other g-protein coupled receptors that are evolutionarily related to the dopamine. Dopamine receptor system. They do so in proportion to their affinity. So if a drug has got a low affinity for dopamine D2 receptors, in order to achieve therapeutic occupancy, you have to give a whole bunch extra, which will then end up binding to histamine receptors, adrenergic receptors, serotonin receptors and so on. And so the side effects from low potency drugs mostly come from these off pharmacological target effects. So for example, the sedation comes from histamine. Sexual side effects can come from the serotonin, cardiac effects come from alpha adrenergic. In contrast, the high potency drugs like Haloperidol and risperidone, because they bind so tightly to the dopamine D2 receptor, there may main side effects come from a pharmacologically on target, but anatomically off target effect.
Dr. Albert Wong: [00:12:08] In other words, they bind to dopamine receptors, the D2 receptors wherever they are, including parts of the brain and body where we have unintended effects for the purpose of antipsychotic use for the treatment of psychosis. So the obvious one is extrapyramidal symptoms that come from binding to the dopamine D2 receptors in the nigrostriatal tract. So you really can't get out of this. The drugs that are high D2 potency are going to have side effects that relate to D2 occupancy in areas other than what we intend for therapeutic effects. Whereas the drugs that bind to receptors other than the dopamine receptors are going to have their side effects from that and they will include sedation, weight gain, sexual dysfunction, etcetera. So in my mind, this distinction between typical and atypical, at least based on off target binding to the serotonin receptor, whichever subtype including the 2A1 really has nothing is not useful as a category because again, there are drugs that have almost no binding to this serotonin receptors that are considered typical or there are drugs like that that are considered atypical and vice versa, drugs that don't bind very strongly to D2 and bind to a whole bunch of other receptors, some of which are classified as typical and some of which are classified as atypical. So I don't see that there is any pharmacological basis for that notion.
Alex Raben: [00:13:26] Right. So you're saying that rather than distinguish antipsychotics based on first and second generation or atypical versus typical, you would rather categorise them as low potency and high potency because that is more useful in figuring out what their side effect profiles are going to be.
Dr. Albert Wong: [00:13:45] Exactly. So I think the first and second generation category is based on the time at which the drugs were first brought to market. So that's perfectly reasonable way of looking at drugs. There are old drugs and there are new drugs. And that is, you know, I'm not sure how clinically useful that is, but that's certainly something that people think about. It's certainly important to drug companies in terms of which drugs are making money or not. So there is that first generation, second generation idea, and that's not a problem. But I don't think that it matches with typical versus atypical. I think that's part of the problem that atypical drugs really are marketed as such, but they don't necessarily have anything pharmacologically different than drugs, which are so-called typical. So to me, it's a conflation of a number of ideas, which is quite confusing. And this is what is partly why we're trying to clarify this today.
Alex Raben: [00:14:34] Right? So I agree. It's it is a confusing subject. I wonder if we might turn to the medical students because I know that's a lot to kind of all take in at once. Are there any questions you guys have about what was just discussed?
Sabrina Agnihotri: [00:14:51] I think the way that they package antipsychotics to us as CC threes is exactly like that. The atypical versus typical and the side effect profiles and. One of the things that they stress to us is that Atypicals are superior because they don't cause movement disorders. And I've actually heard that that phrasing used. And so as a CC3 going through psychiatry, the rotation, like I was surprised to learn that it's not that they don't cause movement disorders, that the risk is lower. So I wonder like why it gets packaged to us like that.
Dr. Albert Wong: [00:15:29] Yeah. So I think there's a number of issues here. I think there is. So to to borrow from Donald Rumsfeld, there are known unknowns and there are unknown unknowns. What we. What we don't know for sure is what the long term risk of all of these drugs is in terms of causing tardive dyskinesia, the long term movement disorders. And part of that is because we don't prescribe antipsychotics the same way now as the as they used to be. So there used to be prescribed in much higher doses generally, not always, but generally. So we see a lot more patients today, older patients who have been on antipsychotic medications for decades who have tardive dyskinesia. We think, again, we don't know for sure because we can't do you know, we can't do a randomised clinical trial and prospectively assign someone to a very high dose versus low dose antipsychotic and see how they do in 30 or 40 years. That wouldn't be ethical and we wouldn't we're not interested in doing that. But it means that there's a gap in our knowledge. So it's hard to compare what the risk of long term treatment with antipsychotics is between the older and the newer drugs. So if we want to consider first injection second generation simply as a time category. Time on the market kind of thing, it's hard to compare. So the older drugs will look worse for sure because they were given in a higher equivalent D2 occupancy doses. So that's a fundamental problem with our data. However, what we can do is, look, there are many good clinical trials looking at active treatment of different antipsychotics in a patient population that are part of a clinical trial.
Dr. Albert Wong: [00:17:11] So that is a prospective, randomised controlled type of study. And in those cases we don't see differences in tolerability or efficacy. So that's, that's sort of the bottom line. You know, the reality is that unlike other areas of medicine, there have been really no new targets. Well, for for antipsychotic treatment. There has been no new targets since the original antipsychotic, which was chlorpromazine, that was developed in the 1950s. It binds to D2 receptors, and every antipsychotic that's come out since then also has dopamine D2 receptors as the target. Now, there's nothing necessarily wrong with that, except if you compare that to other areas of medicine. So if you imagine, say, in cardiology, so I'm not sure exactly which were the first category of Antihypertensives was it beta blockers or diuretics? But certainly now we have, you know, many, many different categories of cardiac drugs that work on different biological targets in the treatment of schizophrenia. We have still only one target. So I think it's really important to keep that in mind. We're not talking about the choice between an ACE inhibitor, calcium channel blocker, a diuretic, a beta blocker. Et cetera. In the treatment of hypertension, we're talking about the selection of an antihypertensive just within the category of, say, beta blockers. Which beta blocker should we try? So in other words, the, the the choice we have is very limited and we're looking at very, very fine distinctions between drugs that have the same pharmacological target.
Alex Raben: [00:18:43] Right. So what I'm hearing a lot of is that these are all equally effective with the exception of clozapine for treatment resistant schizophrenia, which we'll get to in another segment.
Dr. Albert Wong: [00:18:57] But I agree. I mean, just, you know, just as a quick point, you know, I only I think the only atypical antipsychotic is clozapine. Right? So if we want to talk about differences in efficacy, that's the only one, right?
Alex Raben: [00:19:10] So then we are forced to make decisions based on side effect profiles, which, as we were talking about, is more a low potency, high potency question. I know that the CPA guidelines at least used to recommend starting with a second generation for the reason of avoiding the EPS, the Extrapyramidal side effects, because people who are first episode are at a higher risk or people who are naive to antipsychotics are at a higher risk of developing EPS symptoms. So would you like is it better to pick a low potency antipsychotic first based on that principle?
Dr. Albert Wong: [00:19:51] I would say that it's best to choose a drug based on an individual patient's symptoms and their complaints. Right. As we said earlier, if you give risperidone at higher doses, people will get EPS versus an atypical such as with a typically classified as an atypical like QUETIAPINE, for example, it's a fairly new drug compared to Haloperidol. And Quetiapine never causes EPS because it causes sedation before it causes EPS, which is the same for the drugs, other drugs that are high given in high doses. So I would say you should choose a drug based on the patient's symptom profile. So if the patient, for example, is complaining of insomnia, then you would choose a low potency antipsychotic. It will because it will most of them bind quite a bit to histamine H1 receptors and like Gravol, like Benadryl, they make people really drowsy. And that's. A bad thing if you don't want to be drowsy, but if you're having trouble sleeping, that's great. Also, if that person happens to in addition to their psychotic symptoms, has a lot of anxiety, primary anxiety or secondary to psychotic symptoms doesn't really matter.
Dr. Albert Wong: [00:20:54] All of these treatments are symptomatic. So I think it's important to keep that in mind. We don't know what causes schizophrenia or any other kind of psychosis except in some very rare examples when people have some structural disorders, structural brain disorders. But because we don't know that, we're just treating the symptoms. And so if there's a side effect which happens to also mesh with a patient's complaint that actually improves one of their complaints, then you would choose that. And conversely, of course, if somebody, for example, already has a problem with being overweight, you would try to avoid a drug that increases their weight further, for example. So, you know, you can't. But because each drug just comes the way it does and it has its pattern of side effects, we may not be able to find the best drug for everybody. And we still pick the best drug for everybody. But it may not be optimal for some people. They might just have a combination of symptoms which fits perfectly with a particular one particular antipsychotic, and that's great. But that may not be the case for everyone.
Alex Raben: [00:21:54] Great. Sabrina, you look like you have a question.
Sabrina Agnihotri: [00:21:57] Does the fact that some of them have injectable forms come into play at all with your decision?
Dr. Albert Wong: [00:22:02] Absolutely.I think, you know, the discussion here, you know, we started with some sort of more basic pharmacological ideas. But really clinically, I think the the considerations are just pragmatic, very practical. And so that's a good that's one, you know, area that has a practical aspect to it. So if somebody has a problem with compliance or some people like having depots instead of taking pills every day, you know, it's just like with birth control, you know, some women don't like to take a pill every day. They want to have an injection. You know, it depends on the patient. So it could come from the patient. You know, they prefer a pill versus an injection. They prefer, you know, once a month or once every two weeks. That's it. Or it could come from, you know, the family who are concerned about compliance and convince the patient or perhaps from the treatment team as well.
Alex Raben: [00:22:51] One question that comes to my mind, especially for our audience members who are trying to remember all the side effects of these drugs for later consenting patients. To them, how do we keep how do we remember those in a way that makes sense?
Dr. Albert Wong: [00:23:11] Yeah, I wish I could draw something because when we have this discussion in a clinical situation, I usually draw a picture. So if you imagine a spectrum from left to right and on the left side, we can just doesn't matter. Arbitrarily. We can say the left side are high potency drugs that are given at low doses and on the right side are drugs that are low potency, that are given at high doses. So the ones on the right side are the ones are going to have sedation, sexual side effects, weight gain, cardiac effects from all of the non dopamine g-protein coupled receptors that the drug will bind to. Conversely, the drugs on the left side, like Haloperidol and risperidone, are mostly going to cause the dopamine related side effects. So prolactin elevation from the tuberoinfundibular system and extrapyramidal symptoms acutely from nigrostriatal tract and tardive dyskinesia in the long run from also from the nigrostriatal tract. So I would just sort of put drugs into three categories low, medium and high dose or in other words, high, medium and low potency. So basically the drugs that are given in the hundreds of milligrams, those are the ones that are low potency and those are the ones that are going to cause sedation and cardiac effects and so on. And those are the ones in the middle that are given somewhere between 10 and 100mg. So things like olanzapine, for example, loxapine, they fall in that category. And then there's the drugs that are high potency that are given at less than ten milligrams. So just sort of really three orders of magnitude and the ones the tens and the hundreds of milligrams. And so I would just I think that's enough of a of a guide for a clinical scenario because there's enough interindividual variability and people have idiosyncratic responses. You can't predict those things. They have changes, differences in metabolism, differences in illness and so on. So I think that level of general categorisation is enough, basically low, medium and high, and from that you can get a good idea of what the side effects are that the patient is likely to experience.
Alex Raben: [00:25:07] Great. Thank you. I'm wondering, maybe we could touch a little like drill down a bit more into the high potency side effects so the D two related side effects, because they are, as you put it, are anatomically more anatomically related. Could we go into that a little bit how how those relate to the anatomy? Because I find that helpful.
Dr. Albert Wong: [00:25:34] So, you know, we don't know how antipsychotics work, so we don't know for sure where the therapeutic effect is, but we think. That it's got to do with. But we know we can infer that it's from the dopamine D2 receptors. So there are four main dopamine tracks in the mammalian brain. There's there are two tracks that originate in the ventral tegmental area, which is just ventral to the substantia nigra and that's in the midbrain. So that's why it's called. So these two tracks are called the Mesocortical and the Mesolimbic dopamine tracks. So they project from the ventral tegmental area in the midbrain. They project forward into parts of the cortex and the limbic system. The second tract is the tuberoinfundibular, which is the one that goes from the hypothalamus pituitary and regulates prolactin secretion in an inverse way. So more dopamine, less prolactin. And then there's the Nigrostriatal tract, which is the track that degenerates in Parkinson's disease. It originates meaning that the neurones in this track live in the substantia nigra and they send their axons into the striatum. So that would mean that the caudate, the Globus, the Globus, Pallidus and the Putamen.
Dr. Albert Wong: [00:26:46] So, you know, so that's the list. So if you go back, you know, the mesocortical dopamine tract is one that we think is involved in higher thinking, obviously because it involves the cortex, the mesolimbic tract, it's mainly a projection to the nucleus accumbens, which is the track that we think is involved in reward. And this is the tract in which, for example, cocaine and amphetamine act on to prevent the uptake re-uptake and sometimes promote the release of dopamine. And so that's why drugs like cocaine and methamphetamine are so addictive because they derail the brain's mechanism for determining what is rewarding and what is not. And that helps to guide behaviour with normal physiological inputs. But if you take a drug that just specifically activates the reward pathway, then of course this drug will be highly addictive and of course it'll distort behaviour. And then the tuberoinfundibular tract, of course prolactin is involved in lactation and if you block dopamine D2 receptors with antipsychotic, then you will increase prolactin.
Alex Raben: [00:27:47] Because you're cutting that dopamine break.
Dr. Albert Wong: [00:27:48] You're blocking the right and you're blocking the receiver for that break. And then the nigrostriatal tract, you know, the, the Corticospinal voluntary movements tract, you know, the pyramidal tract, so-called, it originates in the cortex, of course, and the motor cortex, and it goes through the internal capsule which flows through the globus pallidus the bottom and the caudate through the striatum before descending into the spinal cord to control voluntary movement through skeletal muscle. The fluency of normal voluntary movement comes from essentially motor subroutines that are stored in the striatum. So when you learn a new activity like playing a sport, at first it's very stilted and awkward because one is thinking consciously using the cortex about every small movement. But when somebody gets good at a sport, then of course they don't think about these things. They think about more advanced things like the strategy, you know, what kind of move they're going to use to fool their opponent. They're not thinking about the individual movements that you do when you start off. And that's because those automatic motor programs are now stored in the striatum. So that's why when people get Parkinson's disease, when their nigrostriatal tract degenerates, they become so awkward. They have difficulty initiating movement because that those those motor subroutines are lost. And that's why they seem so that's why their movements are so impaired. So. So you wanted to drill down into each system, Is thatwhat you're thinking?
Alex Raben: [00:29:08] Yeah. No, that's great.
Dr. Albert Wong: [00:29:09] Um, maybe just one point. As I was just thinking about it, you know, part of the reason why antipsychotics are so unpopular among patients, why it's so difficult to get people to take them and why compliance is so bad is because they're blocking the mesolimbic cortical, the mesolimbic dopamine tract. So many of the drugs that we prescribe in psychiatry have some street value, especially the benzodiazepines. Even sometimes the anticholinergic drugs. People abuse these drugs. They find them, they like to take them on their own and you can buy them on the street. There's a price for them. You can't sell antipsychotics on the street. That tells you something about them. These drugs are profoundly unpleasant to take because they block the very system that's rewarding. So not only do they themselves are not rewarding, but they make everything else in life not so rewarding as well. So it's kind of like an anti-cocaine. It's like not fun to take.
Alex Raben: [00:30:03] Right. So that's part of the side effect profile as well.
Dr. Albert Wong: [00:30:04] Right. And it's unavoidable that, you know, we have found a system in the brain which is very effective for modulating psychosis, but it's also the same neurotransmitter that's used for signalling reward expectancy. And so when you block the system, it has this very unpleasant side effect, which is there's no way to get around it.
Alex Raben: [00:30:26] Because that's where we think the target is.
Dr. Albert Wong: [00:30:29] For because the dopamine D2 receptor is found in these different anatomical tracts and it has different roles in each tract. The brain doesn't have this problem because when you release dopamine in the reward pathway, it doesn't it can't get to the other parts of the brain. I too, can't find its way to the pituitary. It doesn't get to the cortex. It doesn't go to the striatum. So the body is fine because it can segregate these neurotransmitter signals in different pathways. And this is a common problem in pharmacological and pharmacology in the treatment of illness. You know, we can, even if we have a very good target for treating that illness, if that target is found in other parts of the body or brain, then you're going to have side effects because you can't Right now, we don't have the technology to get that drug only to one brain area and not the others.
Alex Raben: [00:31:16] To summarise again, low potency, you're going to have those off target side effects.
Dr. Albert Wong: [00:31:23] Yeah so I think the main off target side effects would be from the other g-protein coupled receptors. So there's the muscarinic acetylcholine receptor. So that's where people get dry mouth, blurry vision, they can get constipation, that kind of thing. Histamine H1 receptors are the main origin of sedation. The serotonin receptors, the, you know, that are the off target targets of the antipsychotics cause, you know, a bunch of changes in neurovegetative functioning, including sexual dysfunction, perhaps also dysregulate appetite. And then the adrenergic receptors are where the cardiac side effects mostly come from. So, I mean, this is a broad generalisation, but I think for the purpose of this and you know, at this level of training and trying to understand where the clinical, you know, to organise things clinically and to think of where side effects come from, that's where they're coming from.
Alex Raben: [00:32:11] And how do we mitigate some of those side effects?
Dr. Albert Wong: [00:32:16] Well, there's really no way to directly mitigate them.
Alex Raben: [00:32:22] Like, um, I guess what I was thinking is, um, like we do a lot of investigations for, for the low potency. Like we will monitor weight gain and metabolic parameters. And then for EPS we'll do scales and that kind of thing.
Dr. Albert Wong: [00:32:41] Yeah, I mean, I think but in the end we have no real way of treating these. I mean, the only side effect that we have a good treatment for, I would say maybe there's two with akathisia. We can give benzodiazepines, but that's not a great long term solution. And with extrapyramidal symptoms, we can give an anticholinergic drug. Benztropine benztropine procyclidine sufentanil. So, you know, just as a connect this back to what we're talking about earlier with the high potency drugs because they're purely D2 drugs, you get the EPS, you get the Parkinsonism. The reason that low potency drugs don't give you Parkinsonism even at the same level of D2 occupancy is because they also bind to the muscarinic acetylcholine receptor. So they have like a built in side effect pill that you're taking with it. It's like a, you know, like a combo. It's not. But you know, and you can think of it that way. So but, but your point about, you know, how can we mitigate these side effects? I don't think you can. You can choose a drug that has less of the side effect. That's a problem. But in the end, we really have no treatments for any of these side effects. I mean, you know, you can think of symptomatic things. I guess you could, you know, for erectile dysfunction. There's Viagra, which, you know, I'm sure you get all kinds of spam every day. So if you want to buy some cheap Viagra, you know where to get it. But, you know, in terms of things like EPS, you know, you can give anticholinergics. So that's that's probably the only one we can really treat. But things like sedation, I mean, we have no treatment for that. Definitely wouldn't use some kind of stimulating or activating medication in the context of psychosis.
Dr. Albert Wong: [00:34:07] So that's out. And then the weight gain, I mean, the majority of the population doesn't exercise already and has, you know, problems. You know, in North America obviously has a very high proportion of people who are overweight and obese. So it's already a problem in general in society for which there is no good solution. So in somebody who's got schizophrenia, who may be having metabolic side effects from the antipsychotics, you have obviously added a whole other layer of problems. Somebody who has negative symptoms and has problems with motivation and may have difficulty organising their behaviour in the first place. Plus they may have psychotic symptoms. And then now you also want to try and get them to exercise and watch their diet. Plus they're usually in a lower socioeconomic strata. You know, that's a really big challenge. So that's why it is a serious problem. But, you know, we have really not a lot we can do about it. I think, you know, the, you know, one, you know, to step back for a minute, what we really need are is a is a better understanding of the illness and better drugs, like a different category of drugs. Like we're still stuck with beta blockers for treating hypertension kind of thing. We need to go beyond the beta blocker. We need to go beyond the D2 receptor. We need new treatments for schizophrenia. And then we would have options because if you hit a completely different receptor system, then you're going to get completely different side effects. Maybe, maybe not be completely different, but they will be definitely from a different cause. And then you have something that you can you can do, you have something to play with. But right now, we've basically we don't have much.
Alex Raben: [00:35:32] Sabrina, do you have a question?
Sabrina Agnihotri: [00:35:34] Well, it sounds like a lot of these drugs are targeting the positive symptoms in schizophrenia. What about the negative symptoms? What is like are there pharmacological treatments for the negative symptoms of schizophrenia?
Dr. Albert Wong: [00:35:46] Not really. I mean, I think sometimes I mean, there are studies that show that there are some effect on negative symptoms. But I would say that overall, it's either very weak or nonexistent. The bottom line is that we don't do very well at changing the course of illness and schizophrenia. We're very actually not too bad at treating psychotic symptoms. Of course, here, you know, there are many patients who are refractory and who, you know, are noncompliant. But for the majority of patients, most of the time, antipsychotics do have an effect on reducing their symptoms. But what we aren't able to do is change the overall outcome of the illness, and that mostly has to do with their cognitive and cognitive symptoms and negative symptoms for which we really don't have any good treatments. And just to point out that we don't have a good way of treating cognitive symptoms in any disorder, in any context, really, whether it's schizophrenia or not. So, you know, think broadly back to the original conception of schizophrenia by Kraepelin as dementia praecox. You know, that highlights the fact that even 100 years ago it was noted that the primary feature of this disorder that gave its name was actually the dementia. It's just that it was a kind of dementia that came on earlier in life than senile dementia, which was obviously the other main kind of dementia. So it's been well known in some ways it's been kind of I wouldn't say it's forgotten, but it's been overlooked. It's been de-emphasised in this quest to come up with a really effective treatment for the psychotic symptoms. I'm not saying that psychotic symptoms are a great thing to have. It's just that. It's only a it's only part of the picture. And in fact, the psychotic symptoms are not the main determinant of outcome.
Yunlin Xue: [00:37:29] So can you go through the pathophysiology of negative symptoms and why it's hard to treat them compared to the positive ones.
Dr. Albert Wong: [00:37:38] You know, I don't think we know. Well, first of all, we don't know what causes anything in in any major psychiatric disorder. Right. So we don't know what causes psychotic symptoms, nor do we know what causes negative symptoms. I think this is a great this is a major challenge for our field. It's very difficult to develop rational treatments without knowing the cause. All of the you know, there are many cases in medicine where treatments are discovered by accident. And then from that, something more is learned about the illness for which that treatment is usually given. So, I mean, we do we have learned a lot about psychosis in the sense that we now know how important dopamine is. Dopamine is clearly a modulator of psychotic symptoms. And we know that people can get psychotic sometimes when you overstimulate the dopamine system, when there's too much signalling to the dopamine system, say with crystal meth, methamphetamine, that's sort of a common clinical presentation. And conversely, of course, if you block the dopamine D2 receptors, you can reduce or get rid of psychotic symptoms in regardless of the original cause. But that's not really that's just a proximal cause. We don't know what the upstream distal cause is. And schizophrenia is likely not to be an illness per se, but it's a collection of different things that end up with the same presenting symptom.
Dr. Albert Wong: [00:38:54] It's a very crude way of categorising things in medicine, you know, in terms of just looking at symptoms. So in psychiatry, we do not yet know what the cause of different types of psychosis is. Mostly, you know, occasionally again, if somebody has a stroke with a sudden onset of psychosis or they have a space occupying lesion or, you know, something like that, then we can presume that the psychosis originated from that etiology. But it still doesn't really tell us what the pathophysiology is because brain lesions in many different brain areas can cause psychosis. So there is no sort of psychosis area. It's not it's a non-localising, non-localisable abnormality. And that's partly what puts it in the realm of psychiatry. Some people would argue that that's what distinguishes neurology from psychiatry and neurology. They have focal localising symptoms and therefore there is a lesion somewhere. Even if there's more than one lesion, say, in multiple sclerosis or, you know, some kind of autoimmune other autoimmune disorders. But still there are lesions that can be identified in psychiatry. We don't have that. Two people can have what seems like a similar presentation and they may have, you know, lesions in different parts of the brain or no lesions that are discernible at all. So the answer is we don't know. I don't know and we don't know.
Alex Raben: [00:40:05] I'm thinking about Muhammad, our patient. If he were here in the room or his family, you know, given the conversation so far, he may not be too thrilled about being on a medication like this. What are the ways we can how do we frame this to patients to help them with that?
Dr. Albert Wong: [00:40:24] I don't know if I would try to frame it for them. I would be straightforward with the patients. It's not a good option. We don't have good options. We need better treatments for schizophrenia. I would be frank about that. I am frank about that with my patients.
Alex Raben: [00:40:35] And yet it's necessary. Is that fair to say?
Dr. Albert Wong: [00:40:42] Well, I don't know, you know. There are patients who I mean, I think, you know, we see psychosis as being something which is abnormal. And I think that it is a reflection of some brain dysfunction. But, you know, we have trouble framing the situation and selling this treatment to patients because we know we're not selling them a great deal. If this drug was going to make their life better and and have, you know, not that many side effects, then we wouldn't have this discussion. It would be simple. But the fact is that it's not a great option. We don't have a great treatment. Again, if you have if you have transient psychosis for some reason, then it's different because the drug these drugs are good for treating psychotic symptoms. So if you show up in the emerge and you've been smoking a whole bunch of crystal methamphetamine and you're super psychotic, and for the day or two that it takes that to clear, you get some antipsychotic and then you're much calmer and, you know, then that's, I think, a great outcome. But if you have schizophrenia, if you have this chronic psychotic disorder, you know, it's not again, the antipsychotics do not improve the outcome overall. At least not very much. So I think it's a difficult sell. Now, there are cases where there are patients who are otherwise fairly high-functioning. If their psychosis is controlled, they can do well. And I have some of those patients who I first saw in first episode, and I've been following them for many years now, and they're doing quite well. They're the exception. So there are cases like that. So it's not hopeless. But these patients also have very good insight about their symptoms and they're able to comply. And all these other factors are there as well. But in terms of like when you have somebody who is in a first episode like this, this case we're talking about, I think you have to be honest. And for them to be prepared for the likelihood the outcome is going to not be so good. You should be truthful about it.
Alex Raben: [00:42:41] Sure. Yeah. What would you say if Mohammad said he only wanted psychosocial interventions and he was not interested in trying medication? I'm just thinking about the guidelines. Like I think NICE says that you should recommend you should strongly recommend medication or something along those lines because therapy alone is not as effective.
Dr. Albert Wong: [00:43:14] I don't think therapy is going to do anything for the psychotic symptoms as bad as they are. I think that's a treatment we've got. But I very I understand why patients don't want to take them at the outset and also why they don't comply with them after they've even started on them. You know, it makes sense to me why they're doing this. You know, there are some drugs which people really want to take which we never have to convince people to take. And actually, we have to try and convince people not to take like opiates, like benzodiazepines. There's a number of drugs in medicine like this. And then there are drugs which people really don't want to take that we have to convince them that they should take. And then there are drugs that people don't want to take, but they take because they know that they have to in drugs that have unpleasant side effects like chemotherapy and cancer. This kind of thing. So, you know, we have the unenviable position of trying to push treatments which are fraught with bad side effects and which have a really limited spectrum of efficacy. They treat part of the illness, but not actually probably the most disabling part of it. So it's difficult. So again, I don't try to sell them. I'm honest about it and make people let people make their own choices.
Dr. Albert Wong: [00:44:22] You know, there's also this idea of which, you know, I think the evidence is still kind of indeterminate about whether chronic antipsychotic treatment is really the way to go. You know, people could say that, for example, if there are other examples in medicine where there are illnesses that have relapsing-remitting course, in which case we treat just the relapses and when the symptoms remit, we also stop the treatment. So for example, autoimmune disorders are a good example where we might use intermittent steroid treatments. So knowing that our treatments are symptomatic, you know, this is a bit of a heresy. But, you know, because all the treatment guidelines say you must use antipsychotics and you must keep keep patients on these antipsychotics. And it's true that sometimes when patients get psychotic, then they lose the insight about their symptoms and then don't comply with antipsychotics. So certainly you would lose you know, you would you wouldn't be able to treat those patients. You would lose those patients. But there are you know, the question in my mind is for an episodic illness, you know, so some people have chronic psychosis. It doesn't really seem to go away. But other people seem to have episodes of psychosis that come and go. Why? We're using a treatment that's there all the time for symptoms that are not there all the time. I'm not sure that there's a good rationale for that, but that's not the orthodoxy.
Dr. Albert Wong: [00:45:43] And we say, you know, we should always keep patients on their on their medications, but I'm not sure that that's the way we should be doing it. So in some ways, you know, we could reduce a lot of the concerns about antipsychotics if we weren't giving them all the time. You know, the issues about metabolic side effects, for example, are not such an issue if the patient is not on it for their entire life, if they're only on it sometimes, obviously that makes it a lot better. Same thing with the tardive dyskinesia, you know, so there is the clinical problem of getting somebody who has become psychotic to restart their antipsychotics. But, you know, we don't really try and address that problem. We don't try and come up with ways to have people on and off antipsychotics just when they're symptomatic. We just try and get them treated with it all the time. So that's why, you know you know, I know you're just phrasing the question in the vernacular way, but that's why we have this feeling that we're trying to sell these drugs to people because they're you know, they do have all these problems. And especially the way that we give it, I think is it just it's not a it's not a good for the side effects.
Alex Raben: [00:46:41] That kind of leads into my next question a little bit. Time of treatment. I know there's an orthodoxy and then there's, you know, potentially some wiggle room there for the field to try some other approaches. Is there for a first episode, Is there a recommended amount of time someone should be on this to avoid a relapse? Is there what is the orthodoxy and what is maybe the wiggle room?
Dr. Albert Wong: [00:47:08] Yeah, I mean, the people say, you know, something like a year, but you know, why is it a year? Why is it not 11 months and why is it not ten months? Why is it not 13 months? You know, there's no real rationale for it being a year. Yeah, I would say it depends on the patient. You know, many patients will want to stop their medications after their first episode. Even if they're successfully treated, they will think, and I think reasonably so, that maybe it's just happened once and it will go away. And it does sometimes happen that it's just a single episode. So I think it's reasonable. But at the same time, you know, sort of the flip side of this is that I don't think that being psychotic is good for the brain. And I think that the longer that somebody is psychotic, the harder the more entrenched those symptoms become and the harder they become to treat. And I don't know if that's partly an illness factor. Again, I don't think schizophrenia is an illness. It's a heterogeneous collection of all kinds of different pathologies.
Dr. Albert Wong: [00:48:04] But in some cases, there may be some kind of disease progression that occurs. Or maybe it's not that. Maybe it's simply a question of memory, that, you know, the longer somebody does something, whether it's playing basketball or the violin, the more entrenched that that activity, that experience is going to be. So the longer somebody spends being psychotic, I think the harder it is for those, especially the delusions, the harder it is for those delusional beliefs to be kind of squared properly with reality. So I don't think it's good for someone to spend a lot of time psychotic for that reason. So, you know, this goes against what I'm saying earlier, but, you know, the point is that there's obviously two sides to this and it's very difficult to decide for each given patient without having any kinds of real predictors of outcome. We don't have any biomarkers, any ways of really predicting how things are going to go, how long someone's episode is going to last, how long they should be on treatment, all these types of things we just don't know.
Alex Raben: [00:49:03] So yeah, another thing that's on the top of my mind, having just come off of inpatient psychiatry is that, as you were pointing out, this illness or collection of illnesses can often come with a lack of insight and can present safety issues to the patient as well as those around them. So I think that's that's almost like a third factor for why treatment may be important. I'm wondering your thoughts on that.
Dr. Albert Wong: [00:49:36] So patients who are you know, so for example, you know, you mentioned sort of safety risks. I mean, the majority of people with schizophrenia are not violent. And I think that the main determinants of violence in schizophrenia are the same as they are in people who don't have schizophrenia. And those are for the demographic factors are the obvious ones age, sex, substance abuse. So it's the young drunk man who you worry about punching you. You don't worry about the elderly, sober woman, whether either of them have schizophrenia or not. So, you know, yes, schizophrenia in some cases, especially when delusions involve a specific person and so on, there is an increased risk for violence. But I think it has more to do with the person and how they react to things as opposed to the delusions. Somebody can have the same delusion. They just don't think that violence is a good way of dealing with it. Some people, you know, one patient could think of it that way.
Alex Raben: [00:50:29] Right. And bringing it back to our case here, Mohammed has delusions around the electrical wiring in his house. Some patients may not even react to that necessarily, whereas he's going around and digging in the walls and grabbing these wires.
Dr. Albert Wong: [00:50:44] And that's exactly that's that's a perfect way of tying it to this case. And a perfect example that it's an interaction between the patient's symptoms and their personality and their environment. Yeah. So, you know, if Mohammed did not have schizophrenia and he was, you know, it was, you know, kind of handy, it might be good, you know, that he would actually fix some of the wiring problems in his house. But if his psychosis happens to involve something to do with the wiring and he's not trained and in the midst of psychosis in a disorganised state, he decides to rewire the house. And obviously that's super dangerous.
Alex Raben: [00:51:20] Right. So many, many factors to think about here in terms of outcome, um, not just of positive symptoms, but overall quality of life safety, patient preference, lots of different factors.
Dr. Albert Wong: [00:51:35] So, you know, you're asking earlier about the, you know, the sort of mandate for treatment. And so, you know, I think you've sort of summarised it well that it depends on the situation. You know, if a patient's delusions involve something that leads to a dangerous behaviour, whether it's electrocuting himself while rewiring the house or something to do with, you know, something violent about targeting somebody else, then these patients, obviously it's a much higher priority to get them treated, whereas somebody who's maybe psychotic and may have no insight, but if they are a gentle, pleasant, calm person, they could be very, very psychotic. You know, I have obviously, we all have patients like this, too, who are kind of quietly psychotic. And although we may try to convince them to take antipsychotics because it relieves their distress, because it takes away the, you know, the bothering symptoms, it's less of a priority, obviously, than somebody who's going to do something that's physically dangerous. And unfortunately, sometimes, you know, patients end up in the forensic mental health system because of the fact that they're doing something that's dangerous to somebody else. Right.
Alex Raben: [00:52:39] Great. Yeah. I think that nicely highlights the nuances to when to start this treatment in the first place. I want to turn back over to the medical students and see if you guys have questions or things you want clarified because we've spoken about a lot here.
Sabrina Agnihotri: [00:52:56] Well, I'm actually curious from this discussion, it sounds like our current treatment options, there's a lot of room to grow. And you mentioned that, you know, we're targeting dopamine and why aren't we sort of targeting other areas of the brain, other receptors? Do you have any ideas of like the future of antipsychotic research and use and where we could be going?
Dr. Albert Wong: [00:53:19] Yeah. So I mean, I'll start off by some shameless self-promotion. You know, I've done some work with Fang Lu, who's my lab neighbour and colleague, and she's a protein biochemist and recently published a paper showing that in a protein-protein interaction between the dopamine D2 receptor and another protein called disc one, that this complex between these two proteins, it's elevated in schizophrenia and that in animal models, if we disrupt this protein complex, it has antipsychotic like effects. Other people have explored, for example, the cannabidiol as one of the cannabinoids. That is not the one that people want to use when they want to get high, but it actually has some anti-anxiety antipsychotic properties. There have been some clinical trials with the Mglur2 three receptor, which didn't work out, but that seemed like a promising avenue, and it may be that there's something there as well. We know that drugs that block the NMDA receptor, which is a kind of glutamate receptor, can cause psychosis. Drugs like PCP and experimental drugs like MK 81 are used as models of psychosis in animals, actually. So there may be something. So we know in other words, there are other receptor systems that also modulate psychotic symptoms and also the GABA system. It seems that, you know, this is partly work that's done by that's been done by Karl Deisseroth, the one of the inventors of optogenetics, showing that it is the GABA receptors in Interneurons that set up the gamma synchrony across the cortex that you see in the EEG that's disrupted in schizophrenia.
Dr. Albert Wong: [00:54:47] And this may have something to do with the binding of different aspects of experience. And when this doesn't happen properly, then people can start to have psychotic symptoms. And we know that, you know, there's good evidence that benzodiazepines also have some antipsychotic effects, especially when they're combined with dopamine D2 and, you know, the conventional antipsychotics. So I think there are other transmitter systems. So I think that's one promising avenue that could have you know, that could produce some drugs within the next decade or so. I think that that's likely. I hope so anyway. But I think even that's not that would be only a sort of modest goal, I think a bigger ambition. And the ultimate goal would be to figure out what the causes of some of these types of psychosis are and intervene to prevent them. I think especially with brain disorders, ones that are developmental, but even degenerative brain disorders, once you know, the brain does not repair itself very well, it's not like a bone or the liver. So once we start to have problems with the brain trying to ameliorate those symptoms after the fact, I think is always going to be limited in its success. I think the best way of doing this would be to figure out what the cause is and then stop it in its tracks before the symptoms actually start. That would be the ultimate goal.
Alex Raben: [00:55:59] Great. We're almost at time where we are. At time. I'm wondering if maybe Teresa could ask a question before we wrap up, if you had one.
Theresa Park: [00:56:09] So you mentioned quetiapine has sedative effects and I've seen Quetiapine used in like young adolescents for sleep issues. So could you talk about the off label uses of antipsychotics?
Dr. Albert Wong: [00:56:22] Yeah, I think that's a that's a terrible idea. That's a simple answer. Don't do it. Yeah. You know, there are many causes of insomnia, none of which are worth the risk of tardive dyskinesia. It's the I think it's a it's a class-action lawsuit waiting to happen. So just don't do it.
Theresa Park: [00:56:43] Use antipsychotics only for psychotic symptoms. Nothing else.
Dr. Albert Wong: [00:56:47] Very simple. Psychiatry is like, you know that joke? Psychiatry is like dermatology. There's a thousand rashes, but only three creams. So that's the way it works. If you're psychotic, you get an antipsychotic. If you're depressed, you get an antidepressant.
Theresa Park: [00:56:59] So what about like antipsychotic use in general in the adolescent child population?
Dr. Albert Wong: [00:57:08] Yeah, again, I think if somebody, you know, if there's an adolescent who very clearly has psychotic symptoms, then antipsychotics are a reasonable choice. They're the only choice. So yeah, again, antipsychotics should be used when somebody is psychotic and never when they're not. Okay. And that includes in other areas of medicine. You know, when somebody is delirious in the ICU. Yes, you should give them I.V. Haloperidol. There's no question. Don't don't hesitate in doing it. The chance of them getting tardive dyskinesia is not, you know, not a consideration at that point because the acute delirium is so much more problematic for the brain and for the rest of them, the rest of the body. But, you know, the converse is that if somebody is not psychotic, do not use an antipsychotic. There are many medications you can use for sleep, many of which are quite benign. Quetiapine is the worst choice, especially because the sleep promoting effect of the quetiapine is not coming from the D2 receptor blockade. So that's even worse because you're giving them the risk of TD without even requiring that the target that's going to produce the TD, you know, potentially in the future is not even necessary for the therapeutic effect you're going for here. If you're going for the treatment of insomnia and you're going to use Qeutiapine, you're basically targeting the histamine receptor. So you might as well just give somebody Gravol, which is perfectly which people use for sleep. It's perfectly fine and they won't wake up nauseous either.
Alex Raben: [00:58:34] Right. But I think we I think we've all I think that's a great question because I think we've all seen off label uses of antipsychotics. And just to that point, choosing wisely for psychiatry came out with a list of guidelines. And that was one of them was a recommendation not to use antipsychotics for sleep until everything else has been tried. Um, so I think we will wrap up, but I think that was a terrific conversation around the use of antipsychotic when to use it, when definitely not to use it, what the side effects are, what the benefits are, and how that maps onto different people in different situations. So thank you very much, Dr. Wong, for joining us and thanks everyone who's come today.
Theresa Park: [00:59:19] Thank you.
Alex Raben: [00:59:21] Thank you. And we'll sign off until next time. Thank you.
Alex Raben: [00:59:34] PscyhEd 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 Alex Rabin, Yunlin Xue, Sabrina Agnihotri and Theresa Park. Henry Barron and Lucy Chen were also involved in producing this episode. Audio editing was by Alex Raben. Our theme song is Working Solutions by Olive Music. And we'd like to give a special thanks to the incredible Dr. Albert Wong, who served as our expert for this episode. Of course, we'd also love to hear from you and you can contact us at any time at info@pscyhedpodcast.com or on Twitter and Facebook at PsychEd Podcast. As always, thank you for listening!