Pharmacodynamics of Antipsychotic Medications PDF

Pharmacodynamics of Antipsychotic Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... Pharmacodynamics of Antipsychotic Transcript All right, so this slide set, as I was looking through it, making some edits before I recorded it for you, I realized there appears to be a lot of repetition. I guess it's not that there appears to be. There is a lot of repetition. But I guess it's mostly because there are some things that I think it's just helpful to hear a few times to make them really sink in. And so I !gure too much is better than not enough info. So if you look at things and think she said this in the last video, she said this earlier in this video, you're probably right. And so I'll try not to proliferate endlessly. But there are just some things that we want to be really clear to-- like I keep saying-- roll o" your tongue without thinking twice about it. So we're going to start with the Pharmacodynamics of Antipsychotic Medications. And in the world of antipsychotic medications, as I mentioned to you before, even the oldest ones work. Working was never the problem. The problem was the adverse e"ects. So the !rst generation antipsychotics, also referred to as typical or conventional antipsychotics, these are, of course, the oldest group around. You won't see a lot of people on them anymore depending on where you practice. Now if you wind up practicing in an inpatient setting, where sometimes you get the most complicated or poorly controlled patients, you will see !rst generation antipsychotics used. And even in the outpatient settings, sometimes people's disease is just so complex that it is the best way to get control and then we do what we can to mitigate the adverse e"ects, but they de!nitely are the exception rather than the rule in a traditional outpatient setting these days. And so they are classic D2 antagonists. They block the activity of dopamine D2 receptors in the mesolimbic pathway, and they are exceedingly e"ective for psychotic symptoms. Now you're going to remember this. We've looked at this picture a few times, and we'll probably look at it a little bit more. With the !rst generation antipsychotics, the positive symptoms of schizophrenia, or psychosis for any reason, will improve. When you antagonize D2 binding here, this is the therapeutic goal, and 1 of 22 6/26/24, 9:23 PM Pharmacodynamics of Antipsychotic Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... we get it. Now remember the problem in schizophrenia is that we have the mesocortical pathway in which dopamine binding is ine#cient or suboptimal anyway. And when we give those !rst generation antipsychotics, we just step on dopamine binding everywhere. So now this symptom, this patient while there are positive symptoms will improve, while the psychosis will improve, the negative symptoms get worse. And when you think about it-- or you could even Google it. Some of the old school, there's old school video from inpatient facilities where people are running or not running around on Thorazine. They're walking around on Thorazine like zombies. They're not hallucinating anymore, but they appear to have no range of emotion, no a"ect, no complex cognitive skills at all. They really do just walk around like a zombie. It's almost, in those old school ones where they just tanked them up with these drugs, it's almost as if they have had a chemical lobotomy. And then, of course, the story gets worse that massive impact on the dopamine pathways period takes what was a normal pathway, the nigrostriatal and makes it worse, and it takes what was a normal tuberoinfundibular pathway, the prolactin control one, and makes that worse at two, makes it worse also. And so while you control those positive symptoms, really nothing else is any good. So that's the !rst generation. Thorazine is the prototype one. The brand-- their generic name is chlorpromazine. As you can see, it is very rarely used now because it just has such a strong suppression on those other dopamine pathways, profound anticholinergic properties, profound antihistamine properties. So it really does put people to sleep. So I guess back in the day when people with psychosis presented as hugely agitated and they didn't have any other options, this was the one that shut people down fast. Now, one that you might be more familiar with is haloperidol, or marketed as Haldol. This one is one of the !rst generation antipsychotics that we see, that we continue to see used today. It is much more selective for D2 as compared to Thorazine. Thorazine just puts a lid on dopamine all over the place. But this one is a bit more selective for D2 binding. And so it does have a signi!cantly less o"ensive adverse e"ect pro!le as compared to Thorazine. It does still however, have a signi!cant adverse e"ect pro!le. It is far, far from perfect. It's just the lesser of the two evils when you compare it to Thorazine. And we see it 2 of 22 6/26/24, 9:23 PM Pharmacodynamics of Antipsychotic Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... used today a lot in the inpatient setting as a sedative-- and use it for its sedative properties, not just for people who are psychotic but sometimes just for people who are profoundly agitated. So if you have to pick between Thorazine and Haldol, you'd pick Haldol, but you still try to stay away from !rst generation antipsychotics when you can. It is available in an IV formulation, which has made it especially useful in the acute inpatient setting. And for patients that present as really agitated violent, dangerous to themselves and others, IV Haldol is-- rather parenteral Haldol is often combined with lorazepam and diphenhydramine or Benadryl as an IM cocktail. So one injection for three separate drugs to calm people down. Patients on IV Haldol do need to be monitored for cardiac problems. It's not as overt in the other formulations, but in IV form, Haldol can prolong the QT interval. And so anyone who's got other risk for dysrhythmia, older patients, I mean just as a function of being older, a cardiac conduction is a little bit less e#cient, and the risk of dysrhythmia is higher. But even for other people who have dysrhythmic problems, or maybe they're on other medications that prolong the QT interval, and there are some people who just who have congenital long QT syndrome. We don't know why they have a prolonged QT interval, but they're born with it. Also keep in mind that women tend to have a longer QT interval than men. So just in its own right, being female or having prolonged QT, naturally isn't necessarily a contraindication to Haldol. It's a risk bene!t analysis always. But patients that do have episodes of dysrhythmia, patients who are on other medications, that can prolong the QT interval, this can be a concern. And if you have to use a !rst generation antipsychotic, this might be the one, not be the one rather. This might not be the one. Do keep in mind that this is more pronounced in the IV formulation, which let's face it in the outpatient setting most of us aren't using. And $uphenazine is the last of the !rst generation antipsychotics I wanted to mention here. This is marketed as Prolixin. And you will still see people on it. It is available in both short acting IM forms and IM depot, long acting IM. So this can be used as an ongoing control or medication, even in the outpatient setting. I actually have a patient now who is on the long haul just because her symptoms are so profound. She has no 3 of 22 6/26/24, 9:23 PM Pharmacodynamics of Antipsychotic Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... insight into her disease. And the only reason she will take medication at all is because at 30 some years old, she really can't survive independently, and her parents have required as a condition of living in their home that she has to be medicated. So we've tried less aggressive things and she really just doesn't function well without it. So she is on IM Prolixin. So we de!nitely do still use it. It is a !rst generation antipsychotic. It has the same adverse e"ect pro!le as any !rst generation antipsychotics. It is characterized by suppression of dopamine in the mesocortical pathway as well as the nigrostriatal and tuberoinfundibular. It's just that for some people, the bene!ts outweigh the risks. And like I have said a few times now, the !rst generation antipsychotics, the whole problem with them is the adverse e"ect pro!le. And every attempt to develop new antipsychotics is an attempt to minimize the adverse e"ects. And so there !nally was the birth of what we refer to as the second generation antipsychotics. So the second generation antipsychotics they are-- well, there's lots of them. And they have some di"erent features. Let's start with what your slide says. So second generation antipsychotics are also known as atypical antipsychotics. And interestingly, I guess you hear that term more than second generation. So there are several things that make them atypical, but the primary thing is that they have a lesser a#nity for D2 receptors. The goal being to minimize their impact on those other pathways. And the idea was that you didn't need this overwhelming, overpowering slam dunk of D2 pathways even in the mesolimbic system. Even in the system, which is the treatment target, we need to decrease D2 activity, we want to lessen it, but we don't have to bombard it with a cannon. So second generation antipsychotics, one of the earliest approaches to a second generation was we could make the a#nity for D2 receptors a little bit less overt. And that way, you still get some control of psychosis but lesser impact on the other dopamine pathways. Another phenomenon of the second generation antipsychotics is that they have a serotonin receptor antagonist property that serves a few purposes. We've talked before about how serotonin is all over the place in the brain. And it is also true that serotonin activity in certain pathways can ultimately result in more dopamine and subsequent pathways or downstream pathways. So the real attempt with second generation antipsychotics was to control the D2 binding activity in the mesolimbic pathway, and then capitalize on other mechanisms to try to decrease the D2 insult in other pathways. 4 of 22 6/26/24, 9:23 PM Pharmacodynamics of Antipsychotic Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... Let's see. The serotonin antagonism. Yes, theoretically leads to downstream mediation of dopamine blockade in those pathways that we really didn't want to impact in the !rst place. You see the term downstream blockade a lot or downstream impact a lot in psychiatry, and psychiatric drugs, I should say. And it just refers to the fact that one neuron communicates with another neuron, which communicates with another neuron. And so if you're ultimately trying to impact neurotransmitter at, say, neuron D, you can do that by changing concentrations of neuron A which will then impact the release of the transmitter from neuron B, which then impacts release from neuron C, and you get the idea so that even though you might be targeting one synapse, or one neurotransmitter, the real goal is to change concentrations of neurotransmitters for further down in the chain. And the end result is ideally the same level of control of psychotic symptoms with lesser e"ects of dopamine blockade in the other three dopamine pathways. And the real ambitious approach here is to try to !nd a way to not only attenuate D2 binding in the mesolimbic pathway, but to improve dopamine activity in the mesocortical pathway. That would be the ideal way to treat schizophrenia because then not only would you be controlling psychosis, but you would also be improving the mesocortical de!cits that exist in a patient that has schizophrenia. However, the second generations have their own side e"ect pro!les to consider. And so this, like how you decide one second generation over the other, is really about the adverse e"ect pro!le. Antipsychotics, like I said, virtually, all of them will control psychosis. How you decide one from the other is cost, number one. And then number two, which side e"ects are least o"ensive to the patient? Because every time science tries to take one of these antipsychotics and manipulate it so that it is more e"ective in the area we want it and less e"ective or less insulting in the areas we don't. There's always a trade o". You're always going to-- in order to gain something, you're going to lose something. That just seems to be the way it goes with drug therapy in general. So when you look at the numerous collection of antipsychotics we have when you're trying to pick one over the other, which will often be part of your graded exercises. And when you get to your graded exercises for this week, you'll !nd that you are expected to make a selection of antipsychotic medication. It's almost never about will it do the job or not. It will. The question is always, which adverse e"ect pro!le is least o"ensive or the best match to the patient? It's a pain. I 5 of 22 6/26/24, 9:23 PM Pharmacodynamics of Antipsychotic Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... mean it's why there's millions and billions of dollars going into the development of antipsychotic drugs because everybody's trying to !nd that perfect one. The perfect one will reduce D2 binding and the mesolimbic pathway, increase D2 activity in the mesocortical pathways, and leave it alone in the nigrostriatal and tuberoinfundibular. And nobody's been able to do it yet. So the second generation antipsychotics come in a couple of distinct groups. And they begin with the pines and the dones. We have a bunch of antipsychotics where the su#x is pine. Clozapine, olanzapine, asenapine, quetiapine. There's a bunch of pines, and then there's a bunch of dones. Risperidone, lurasidone, paliperidone et cetera. There's pines and dones. Now we also have the pips and the rip. There are those who refer to the pips and the rip actually as third generation antipsychotics because they yet represent another series of manipulations to try to get the best e"ect with the minimal adverse e"ect. And I mean, I don't really care if you consider the pips and the rep the second generation antipsychotic or a third generation antipsychotic. The bottom line is just understanding their strengths and their adverse e"ects, and knowing how to pick the best ones for the patient. So pines and the dones. They were the ones for the longest time. I guess about 20 years ago the !rst pip came out, and now we have two pips in a rip, and we have lots of even new and improved ones on the way. So let's see. I think !rst up are the pines. So the pines. The pines. The !rst pine was clozapine. Clozapine was the !rst second generation antipsychotic. It actually has a really interesting history. And no doubt, I will !nd a reading about it to put in your external links for this week because it is interesting. Clozapine remember, I mean, it is a hallmark drug and that it was the !rst second generation antipsychotic. It was the !rst new antipsychotic on the market in decades when it !rst come out-- came out, when it !rst came out. And it was really I mean it was highly anticipated. There was a lot of demand for it. Clozapine, I believe-- now I may be getting some of the dates wrong here. Like I said, I'm going to put a reading in your assignments about it because I think it's really interesting. I believe clozapine was actually !rst identi!ed as a molecule in the late 50s. And it was !rst marketed as an antipsychotic in what I say the mid 70s, like 1970 or '75, or something like that. It !rst hit the market in Europe in the 70s. And then because it has its own safety issues, there was this big scare with respect to neutropenia. One of the 6 of 22 6/26/24, 9:23 PM Pharmacodynamics of Antipsychotic Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... concerns with clozapine is that while it may not zinc you out like Thorazine, it does have its own safety concern and it's related to immune suppression. And there was a big scare about this in Europe. And it was pulled from the market in a couple of countries, and then reportedly like reformulated, improved, tweaked, that kind of thing. And it hit the United States on the market for the !rst time in 1990. So the drug is only about 30 some years old now. And even in the United States, when it !rst came out, it was considered controversial because while when it works, like when it works safely, it works much better than the !rst generation antipsychotics. But in the small percentage of patients who get agranulocytosis, it can cause death. So, huh. It's sort of a-- talk about a risk bene!t analysis. I mean, there are really some considerations here with clozapine. So in terms of e#cacy though, it is the gold standard. It is a highly e#cacious second generation antipsychotic. It is the only antipsychotic with documented reduction of suicidality in patients with schizophrenia. Remember when we were talking about mood stabilizers, I said there were two medications in all of psychiatry that have a clear relationship to decrease suicide ideation. And one of them was lithium and the other one is clozapine. So for this-- I mean for this, this is an important feature. Like I said, it is the safety issue. And again, the more e"ective a drug, the bigger the concern about safety pro!le. That's just always how it's going to be. Also clozapine for all of the safety issues with it, it has the greatest documented e#cacy in improvement of negative symptoms of schizophrenia, actually improving negative symptoms, improving the cognition, the executive function, the decision making, the modulation of emotion. I mean, these are a big deal. When we get into your diagnosis course, your assessment and diagnosis course, you'll !nd out that it's not the psychosis that makes independent living. So di#cult for patients with schizophrenia, it is the negative symptoms. Prognostically, the presence of negative symptoms is what really carries the poorest prognosis, the inability to live in day-to-day society and function as an adult. It's the negative symptoms that really have an impact there. Like I said, controlling psychosis is easy, but those negative symptoms really have a strong relationship to long-term suboptimal function. So a drug that could not only control psychosis but improve negative symptoms, this is enormous. It is considered highly e"ective. And damn, if it was just only a little bit safer, it would be the bomb. The biggest problem with clozapine is the risk of agranulocytosis. But look at the !rst two bullet points. This really is a big deal. Even 7 of 22 6/26/24, 9:23 PM Pharmacodynamics of Antipsychotic Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... now in psychiatry, we do not have other antipsychotics that are as good at reducing euphoria or dysphoria, that don't reduce euphoria, let's reduce dysphoria, not as good at reducing dysphoria, or improving social and occupational function. We don't have another antipsychotics that's better at this than clozapine. The downside is the risk of agranulocytosis. This can just completely suppress granulocyte production, your white blood cells, those things that you have to have to protect you from infection. And when it causes agranulocytosis, it does it really fast. So patients can go from a minor infection, minor sore throat, UTI, something like that into septic shock very quickly. So that's it. The risk of a granular psychosis in the !rst year of treatment is 1%, which means 99% of people will not, which means there is still de!nitely a role for Clozapine. But because of the safety, we just have to consider this role more strictly, more stringently. And so this is the way it has evolved now. Clozapine is not a !rst line generation for patients that are schizophrenic. There's a whole thing patients need to fail to other !rst line therapies. And not only is close monitoring an issue, but patients who are going to be on clozapine, they need to be registered. There's what's called the Clozapine REMS. R-E-M-S, Risk Evaluation and Mitigation Strategy. It's a safety program that is required by the FDA to manage the risk of severe neutropenia that happens sometimes with people on clozapine treatment. And so patients have to be enrolled. Like I said, they have to have failed two other anti- psychotic medications. It's very structured, and it is for the safety of the patient. There are strict criteria in terms of starting clozapine in addition to the fact that they have failed two other antipsychotic trials, they need to have a-- what do you call it? A neutrophil count above 1,500. And then it's monitored routinely during treatment, and it cannot fall below 1,000. There's a condition called benign ethnic neutropenia where patients-- I mean, it's exactly that they have a suppressed neutrophil count that's essentially benign. And so for them monitoring, is a little bit di"erent, but clozapine is-- I mean, it's got its real own safety mitigation strategy. It's not a !rst line drug. And you will read more about it when you do your assignments for this week. But that, it is the pine. It is a pine, it is the !rst pine, it is the second generation antipsychotic. And everything since then has just tried to !nd a way to do what clozapine does but do it more safely. And here's some of your other pines. Olanzapine is marketed as Zyprexa. Quetiapine 8 of 22 6/26/24, 9:23 PM Pharmacodynamics of Antipsychotic Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... been around for a long time, that Seroquel. Asenapine, Saphris. I mean, these all try to !nd a way to be better or safer than clozapine. And they all have their own little niches in the world. In the world of second generation antipsychotics, like I said, we have the pines and the dones. And in an e"ort to mitigate adverse e"ects, some are de!nitely better but others are not. So if you take clozapine out of the picture because clozapine because of that agranulocytosis thing, clozapine is in a class of its own. But the pines in general, they are notorious for the metabolic adverse e"ects. They are notorious for the weight gain. While they minimize the extrapyramidal e"ects, the movement e"ects that occur when you suppress the nigrostriatal, the pines are not as o"ensive for the hypo prolactin stu". They spare the tuberoinfundibular pathway a little bit more readily. But what they do do is lead to certain metabolic consequences like the ones you see on the slide. Weight gain is virtually assured on a pine antipsychotic. Very often, especially with the older ones like olanzapine and even quetiapine, hypoglycemia and dyslipidemia is a risk factor. So like the slide says, logically, these are not a great choice for patients who are already obese or patients that already have diabetes or dyslipidemia. On the $ip side, if you have a patient who is psychotic and needs an antipsychotic, and perhaps they are cachectic, poorly nourished, they need some weight, then this could actually be a good choice for them. So olanzapine, once you take clozapine out of the picture because it does have its own issues, olanzapine is an older pine. And for that reason, it does have the metabolic adverse e"ects. It also tends to be used in higher doses, which also exacerbates the adverse e"ects, but they're still much, much better tolerated, much easier on the patient than the old school !rst generations, and they don't cause the agranulocytosis of clozapine. So all in all, they are still a much better outcome. These can improve mood. They can be helpful for the negative symptoms of schizophrenia. In fact, they have been helpful enough for mood that they actually now have an indication for treatment refractory depression. So your really, really depressed patients who don't respond well to a traditional antidepressant, this might be something you try for them. They are available in early disintegrating tablets for people that don't like to swallow pills. And there's a lot of them out there. There are also-- olanzapine is also available as an IM depo injection. So it can be used for maintenance therapy. And as compared to older antipsychotics, they are well tolerated, but they have the 9 of 22 6/26/24, 9:23 PM Pharmacodynamics of Antipsychotic Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... metabolic consequences. The weight gain can be signi!cant, and they can be highly sedating, which in certain circumstances with psychotic patients can actually be a bene!t. But even for people that use them for the long haul, it is just that risk bene!t analysis. They are very e"ective, they have a lesser adverse e"ect pro!le than the older drugs, but they still can be sedating and will de!nitely produce weight gain. Now quetiapine is also an older one. This is similar to olanzapine in many ways. I mean, number one it's a pine. I think I neglected to mention it on the last slide, but while olanzapine and quetiapine, while they can be sedating and lead to weight gain, they really are sparing of the prolactin e"ects and the movement e"ects. And so that is a plus. All of the pines, really the thing they're known for is the metabolic e"ects, but they tend to be more sparing of the extrapyramidal symptoms and of the hyperprolactinemia. So that's a good thing. Like I said, for the patient who's already overweight, obese, or diabetes, or something like that, these might not be a good choice, but for the patient who is not overweight and maybe could even use some weight, or could use some calming, these can be an excellent choice. Quetiapine also has a distinct and geolytic e"ect that can really help calm down anxiety. And depending on the dose, quetiapine has several indications in psychiatry. Actually they're on the next slide. At low doses, like under 50 milligrams at night, this is used as a sleeper. It is used as a sleeping medication. When you start to escalate the dose a little bit, somewhere like 200 milligrams a day, it is considered an antidepressant. And at like 300 to 400 milligrams a day or higher, it's used as antimanic drug and an antipsychotic drug. So it's one of the few that really does have multiple approved uses, just its dose-dependent. The upside of the pines is that there do not appear to be any extrapyramidal symptoms or hyperprolactinemia at any dose. So for people that are especially susceptible to those adverse e"ects, this is a good thing. This is the drug of choice for people who need treatment with these-- who need treatment with the dopaminergic agent, like Parkinson's disease. You might remember-- I don't remember in what context I said it, but at some point, I think in the !rst slide set for this unit, I said that the problem with Parkinson's is not enough dopamine. The problem with psychosis is too much dopamine. So try treating that patient. If you have to add dopamine to mitigate Parkinson's symptoms, are you going to exacerbate your psychotic symptoms and vice versa? And so for this patient, 10 of 22 6/26/24, 9:23 PM Pharmacodynamics of Antipsychotic Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... because there are no extrapyramidal symptoms, this is an especially good choice for the patient with Parkinson's who needs to take an antipsychotic medication. It is the metabolic e"ect is the hypoglycemia, dyslipidemia, and weight gain. Now Asenapine is a much newer pine, and so again, the whole newer phenomenon is to try to !nd a way to get the e"ects of the antipsychotics without having the adverse e"ects. This one is also administered in sublingual form. So it is extremely helpful when a rapid onset is required. And look, the adverse e"ect of oral hypoesthesia really is-- it is as identi!able side e"ect that you de!nitely want to warn your patients about. Hypoesthesia, I mean, it's numbness, basically numbness of the mouth for a little while after using the sublingual form of this. So you can see no eating or drinking for 10 minutes after administration is advised. But I mean in the scheme of things, if that's the worst adverse e"ect, you just prepare for it and eat before you take it. It also, like many antipsychotics, appears to have some level of utility for depression, for treatment, resistant, and depression, but although it is better than the older pines, you do have to consider the adverse metabolic e"ects. In the world of antipsychotics, when you see it pine, asenepine, olanzapine, all the pines, just think metabolic adverse e"ects. The newer ones, not as bad as the older ones. Of course, there the problem is the newer ones are still branded. And they're pricey. So the old ones are more readily available, they're more cost-e"ective, but the adverse e"ect pro!le is more intense. And lots of times, even insurance companies, even good coverage when patients say, oh, I have good coverage usually the companies will want you to try and fail an older version !rst. And buy fail, I mean either it doesn't work or the patient is intolerant of adverse e"ects. So those are the pines. The pines, they have the metabolic issues, but not as bad with the prolactin mediated symptoms and the extrapyramidal symptoms. And then we have the dones. So the dones, you might imagine, are the opposite. These are the second generation antipsychotics that end in done. Risperidone was the !rst done. And then we have all the little new baby dones that came out after risperidone in an e"ort to minimize the adverse e"ects of risperidone. So they are di"erent from the pines, but they still have their own issues. All the dones. When you think done, think extrapyramidal symptoms and hyperprolactinemia mediated e"ects. These are not as di#cult with respect to the metabolic 11 of 22 6/26/24, 9:23 PM Pharmacodynamics of Antipsychotic Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... consequences. Now, risperidone was the !rst one. It's the oldest one. So, yes, risperidone can still produce the weight gain and stu" like that. And it will also produce-- I mean, the side e"ect pro!le is better than the !rst generations, but it's still not great because it was early in the worlds of the seconds. So risperidone is a little bit unique that way. And then all the subsequent dones really try to minimize the problems with the dones. So let's see what your slide says. Di"erent from the pines and that they can produce some of the adverse e"ects of typical antipsychotics, especially at higher doses. And that's true. But as a group, they tend to be more sparing of the metabolic stu". So risperidone, like I said, it was the !rst done. And especially in higher doses, it does act more like a !rst generation antipsychotic. Risperidone is used in lower doses a lot for-- well, it is used in many disorders for anger management, for like even in patients that are autistic and characterized by angry outbursts, we use it in more advanced Alzheimer's disease where patients will have angry outbursts. We use it in bipolar II, where patients will sometimes have exaggerated anger responses. So risperidone in lower doses is classically the anger one, and then in higher doses, it is an antipsychotic. So I mean it might come from-- rather you might see it in doses from 0.5 milligrams all the way up to 32 milligrams a day. Obviously, the higher doses for psychosis, the lower doses is for the anger stu". And in the lower doses, it actually tends to be really well tolerated. There like in lower doses 0.5, 1 milligram, 2 milligram, there might be a little bit of sedation or might not. You can often capitalize on this. If the patient has trouble sleeping, just tell them to take it at night. And some people won't notice this at all. But, yes, in appreciably higher dose as, it does act more like a !rst generation. Like I said, less major bullet point here used for irritability and agitation. It is approved for patients with autism spectrum disorder, and it is used o" label for the Alzheimer's patients, like I said, or for any patient who gets disproportionate inappropriate anger that needs to be controlled. So that's risperidone. Every other done is an attempt to do it risperidone does and not cause as many side e"ects. So we have paliperidone. Paliperidone is-- really is an isomer of the risperidone molecule. It is very similar to risperidone, but yes, much better tolerated, less sedation, and less extrapyramidal symptoms. It's just newer. Like I said, the !rst drug in class, just tries to get approved. So it'll be safe and e"ective but there may be some adverse e"ects that are di#cult. Then the newer drugs in class, the subsequent drugs, their job 12 of 22 6/26/24, 9:23 PM Pharmacodynamics of Antipsychotic Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... is to try to be more tolerable, or to !nd a di"erent delivery mechanism, or !nd some little niche in the world. And so that's what paliperidone is. You can give it every three months as a long acting injection for the maintenance of psychotic symptoms. And it's just a better tolerated done. Now another thing that's useful about paliperidone is that it is not metabolized by the liver, not in any meaningful way. It is almost exclusively excreted renally in an metabolized form. So for patients that have hepatic impairment liver disease, which many times in patients with mental health disorders there is a history of hepatitis because of exposure to certain lifestyle interactions, or drug abuse, or alcohol abuse or things like that. So it may be a signi!cant impact in any given patient that a drug that's not metabolized by the liver is a safer choice. By the same token, because it is metabolized in an unchanged form by the kidneys, a patient with advanced renal disease and an increased renal problem, or decreased renal excretion, is what I'm trying to say here, this could be a problem for that patient as well. So like I said, when you're picking an antipsychotic, it's really just about matching the patient to the pros and the cons of any particular drug. Now, ziprasidone is another done. This is marketed as Geodon. And like any other done, it's going to have a lesser metabolic e"ect pro!le. It's not huge on the weight gain or the dyslipidemia, et cetera. This one does need to be taken, it's twice a day. And so the more times a day you have to take a drug, always the greater concern about adherence to it. And it also has to be taken with a 500 calorie meal, which some of our psychotic patients unfortunately have di#cult living circumstances and don't necessarily know when their next meal is, or where much less how many calories it's going to be. So that's something else to consider here. This too is believed to have an antidepressant e"ect as many antipsychotics appear to do. And this one too can prolong the QT interval. I mean, it's not the extent of IV Haldol. That's a di"erent story, but there is a potential for QT prolongation. So you just need to consider in your patient who has other underlying cardiac phenomenon. Now lurasidone, it's funny. I still think of it as a newer done, the Latuda. And yet I understand that it loses its patent later this year, and is going to become available as generic in early 2023, which will be awesome. So again, it's a done. It shares many of the features of the done antipsychotics, like sparing the metabolic phenomenon. There is a risk of extrapyramidal symptoms and hyperprolactinemia. This too appears to be 13 of 22 6/26/24, 9:23 PM Pharmacodynamics of Antipsychotic Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... dose-related. So in the lower doses that we use for things like depression or bipolar disorder, it's not as pronounced, but in higher doses, if you're taking 160 milligrams a day of Latuda, there is the potential for the extrapyramidal symptoms. And this is another one also that needs to be taken with food. It really does make a di"erence, not just in terms of GI tolerance, but in terms of absorption. This needs to be taken with food so that you can absorb it properly. I !nd this one to be particularly useful and well-tolerated. It's not-- these newer ones, the lesser the side e"ect pro!le, you just seem to lose something in terms of e"ectiveness. So for your real, real complex psychotic patient, this might not be the most e#cacious. But for depression, bipolar, and even bipolar with some psychosis, like your schizoa"ective patients, a very good and well-tolerated choice. And this one, you just don't see any weight gain. I have some patients who are-- people actually that have eating coincident, eating disorders. And if anything puts a pound on them, they will just absolutely not take it, and they tolerate Latuda well. Iloperidone is marketed as Fanapt. So this one has pros and cons like any of them do. The lower metabolic risk consistent with the fact that it's a done. This one also has a lower incidence of extrapyramidal symptoms, which is something that we do worry about with the dones. So for your patient that has a tendency to extrapyramidal symptoms, or maybe the patient with Parkinson's disease, this might be something to consider. This does need to be administered slowly because there is a potential for orthostasis. And so this is something that needs to be started out low and slowly titrate it up. This is not an urgent drug, or an urgent situation drug. This isn't something like you put at somebody in a high dose when they are acutely psychotic. This is perhaps the patient who has been stabilized on maybe another done like a risperidone, and now that they're stable, they're becoming increasingly concerned about some of the adverse e"ects. And then you could cross titrate them. Easier for me to say cross titrate them from that to this. So that's not every pine and done on the market, but it's a representative discussion. And you will !nd that the majority of antipsychotics you prescribe in the outpatient setting for sure will be among these groups. Now, we have to talk about the two pips the rip and then we'll brie$y introduce some of 14 of 22 6/26/24, 9:23 PM Pharmacodynamics of Antipsychotic Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... the very new drugs that are on the market. Two pips and a rip. If you are reading the stall book, which are supposed to be doing as part of this course, then you're going to hit the two pips and a rip. The two pips are aripiprazole and brexpiprazole, and then the rip is cariprazine. So like I said earlier on in this discussion, there are those who refer to these as the third generation antipsychotics. And it's because there's been-- there is a real twist on their approach. These drugs, all share a feature that the other ones, even the second generation don't have of being D2 partial agonists. And you might think to yourself, what good is a partial agonist if the whole problem is dopamine activity and the mesolimbic pathway? How could we do the patient any good by giving them a D2 agonist? And the key phrase here is that they are partial agonists. They bind to D2 receptors in the mesolimbic pathway, but they don't activate them as aggressively as natural dopamine does. It's really not unlike using Suboxone to mitigate opioid e"ect and craving. And of course, if you don't know what I'm talking about, don't worry about it. We will talk about it in a section where we talk about substance use medications. And if you do know what I'm talking about, if you have any experience with management of the patient with opioid use disorder, well, then that Suboxone, which is an opioid is actually used to keep people from craving and using opioids like, well, now it's fentanyl, more than anything else. And it's because Suboxone is a partial agonist. Well, in this case, these drugs are D2 partial agonist. So you have a dopamine receptor in the mesolimbic pathway. If natural dopamine binds to it, it is going to crank it up and make the patient psychotic. But if the two pips or the rip bind to it, it doesn't crank up quite the same response. It's a partial agonist, and it keeps the natural dopamine from binding. So that's how we mitigate the e"ects of psychosis. So the mechanism of action is that they lock up D2 receptors at about 1/4 of their maximal stimulation. It is a great idea, and it is another approach. Then, of course, the idea here is, if you can activate some dopamine receptors, maybe you can activate them in the mesocortical pathway as well and actually improve some of the negative symptoms of schizophrenia. It's just another approach and it's di"erent than the second generation antipsychotics. And that's why some folks consider them a third generation. There are three of these medications. The !rst one in class was aripiprazole. Aripiprazole is marketed as Abilify. 15 of 22 6/26/24, 9:23 PM Pharmacodynamics of Antipsychotic Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... And of course, it now is also available in generic form, which makes it very cost- e"ective. And this is also very commonly used. So here's the thing. It doesn't have serotonin antagonist properties like the dones. So it is di"erent from second generations. There is some serotonin agonism at di"erent receptor sites in the brain. Remember I've mentioned before that serotonin is all over the place. And in di"erent parts of the brain, it can do di"erent things. So this combination of this new approach is that there is a reduced risk of extrapyramidal symptoms and hyperprolactinemia. Now believe me they can still do it. It's just that the risk of it is less intense and it's dose-related. There really higher doses of Abilify, there is a potential for these, but the risk is less than those than you will see with the dones. And it's because that there is lateral serotonin agonism as opposed to the antagonism of the zone second generations, and there is partial D2 activation. So di"erent mechanisms of action trying to control those psychoses while mitigating the other adverse e"ects. And these two new ways of doing it-- partial dopamine organisme and lateral serotonin agonism-- make it a di"erent mechanism of action, which is why we call them sometimes third generation. Aripiprazole, it doesn't have the metabolic risks. I mean, it does not put the big weight on people. And even if it puts a little weight on, it doesn't make you hypoglycemic and dyslipidemic. It has the lesser extrapyramidal symptoms and hyperprolactinemia symptoms of the dones, like I just said. And so at the end of the road, the adverse e"ect pro!le as compared to other antipsychotics is really favorable. But there's always a but, isn't there? Always a but. The more tolerable a drug, the easier it is to take, the lesser e"ect of it's going to be. It's just nobody's found a way around this yet. So while this drug has a better adverse e"ect pro!le than either the pines or the dones, like collectively, they have their own issues to worry about because of the dopamine agonism, even partial dopamine agonism. Now in the mesolimbic pathway, it's helpful because the problem there is excess dopamine. So partial agonism is great there, but when you start doing partial agonims where dopamine is not a problem, well, then you may have some too much dopamine e"ect, basically in other parts of the brain. And we do see a tendency sometimes to agitation, nausea, and even vomiting. Again, dose related lower doses can usually mitigate this. It's not like every patient has 16 of 22 6/26/24, 9:23 PM Pharmacodynamics of Antipsychotic Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... it. It's just that the risk is there. These are not especially great for somebody who has real comorbid anxiety, like really su"ers with an anxiety disorder as well as the psychosis or whatever we're trying to treat. And then the other thing is that they're just not as good antipsychotics. They're just not e"ective. These are not the drug of choice for the profound schizophrenic, or the person with really signi!cant psychosis. These just don't work that well. And so they have evolved into a better option for people that are depressed, maybe depressed with psychotic features, bipolar disorder, they de!nitely have a role in a very widely used. But they're not as good and the really complex psychosis because they're just a more mild drug. So as always, what you trade o" with the side e"ects, you also trade o" with the e"ects. Now, the last two are the other pip and the rip. So the other drugs, the other new drugs in category are brexpiprazole and cariprazine. So brexpiprazole sounds a lot like aripiprazole, doesn't it? It's because it is. Basically, it is new improved aripiprazole. Brexpiprazole was actually designed by the same research person that developed aripiprazole after aripiprazole hit the market. And we found its bene!ts and its limitations. The pharmaceutical house went back to the scientists who developed it and said, hey, can you do that but make it better, make it a better antipsychotic? And brexpiprazole was born. So brexpiprazole is marketed as Rexulti. And it's been around for a while now too. When I say new, I mean like not 1950, or not even 1990. Let's say 21st century drugs. Brexpiprazole is still only available as a branded drug. And so it is pricey, but it has greater D2 antagonism than aripiprazole, So it does have increased e#cacy for psychoses, it has more potent serotonin antagonism, so it has lesser extrapyramidal symptoms. And it really is an excellent drug and it has also evolved into an excellent adjunct for patients with profound depression. So just think aripiprazole but better and more expensive. That's brexpiprazole. Now, another-- the rip. It's not a pip, it's not brexpiprazole, it's [audio out 50:50]. So cariprazine, or the rip, this is the !rst antipsychotic that introduces-- and really what's the word I want? Like really capitalizes on or-- I don't want to say exploits, but it really emphasizes. That'll be a good word. Cariprazine really emphasizes its role as a D3 antagonist. And then in like little 2 point 17 of 22 6/26/24, 9:23 PM Pharmacodynamics of Antipsychotic Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... font at the bottom of the package insert, it'll say the role of D3 antagonism is clinically unclear blah, blah, blah. But at least as far as I understand it, the D3 and D4 subtypes of receptors, they are much less of them, they are much less abundant in the brain than the D2 receptors, but they have very similar function. And so I do know that D3 receptors, there aren't as many of them, but those that there are predominantly located in those parts of the brain that are considered really implicit in psychotic symptoms. Areas like the ventral striatum, the nucleus accumbens, which we think of as psychotic central, the thalamus, the hippocampus. And so cariprazine is the !rst drug that blocks D3 receptors. And in doing so-- I mean, there is also a D2 antagonist property here. But targeting D3, appears to spare some of the D2, which may make it more tolerable and have a lesser adverse e"ect pro!le. So like you can see in the last bullet point, it says, it is unclear yet what this means. I love it when a company advertises a thing and then at the very bottom in 2 point font says, the signi!cance is unclear, but it does appear that D3 receptors are much more heavily concentrated in the nucleus accumbens and ventral striatum than other areas, that those are areas where dopamine activity results in psychosis, and also in like the reward system that we associate with substance abuse. And a really interesting nuance with Ray law and its D3 binding, is that it appears that it may be a particularly useful drug in helping people get over the non-physiologic withdrawal of substance abuse. And again, we'll talk more about this. And the substance abuse medication week. But we know that there's a few drugs that cause physiologic withdrawal. Alcohol, the benzodiazepines, and opioids. When people stop using them abruptly, you have abrupt activation of the sympathetic nervous system and with opioids and benzos, and they will get agitated, hypertensive, tachycardic, hallucinate, I mean they could die. When you suddenly withdraw opioids, you wake up the parasympathetic system and get nausea, vomiting, muscle pain, et cetera. But there's lots of drugs that don't have physical withdrawal. And things like cocaine, methamphetamine, any of the stimulants really, for that matter cannabis, they don't have a physiologic withdrawal but stopping all of those, markedly reduces the concentration of dopamine in the nucleus accumbens, which is why people can't stay away from them. I mean, they get used to surviving just going through the day-to-day with huge concentrations of dopamine in the nucleus accumbens. And when they stop using the drug, they don't have it and they need it. I mean it's why people-- methamphetamine is 18 of 22 6/26/24, 9:23 PM Pharmacodynamics of Antipsychotic Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... the biggest o"ender. People when they stop methamphetamine, there's no physical withdrawal symptoms. And yet they keep going back to it regardless of the fact that they might lose their job, their husband, their wife, their kids, et cetera. They could lose everything about their life to get the Meth. And there's no physical withdrawal. The problem is that when you stop using stimulants, you abruptly drop dopamine concentration in the nucleus accumbens. So anyway, bringing it back to cariprazine, cariprazine as a D3 antagonist really appears to help attenuate that abrupt cessation of dopamine that you see in substance users, and appears to be an especially good choice for people that have both psychosis and substance use disorder, which shocking no one at all often coexist. For many people, long before they actually see a psychiatric mental health provider and get a diagnosis, they try to self-medicate their symptoms. They medicate their psychosis by getting involved in drugs. And so then when they stop using-- even when they stop using drugs and get on medication for their psychosis, they still have to deal with this sudden cessation and dopamine. So anyway, cariprazine appears to be especially e"ective for that. I have a patient right now who's got a very complex history. It's been a really unusual, like several psychiatrists have said over the years. We're just not sure what to do with this. This is a very unusual and complex situation. The guy had psychiatric diagnoses and just got heavily, heavily involved in methamphetamine, and now he's o" the methamphetamine. But even that in its own right years of using Meth, can make you psychotic. So nobody's exactly sure what's wrong with him, but now he's just trying to come o" Meth and dealing with all sorts of physical depression and anxiety. And cariprazine is the !rst drug he's ever tried that has made any meaningful di"erence in how he adjusts to stopping substance use. So anyway, I digress just a bit. But this is one of the advantages of this D3 binding. We don't exactly know yet the real signi!cance, but we do know that D3 is heavily concentrated in the nucleus accumbens. And that's a big o"ender for psychosis. And so it's good that we have a drug that will target D3 receptors. All right, so as we wind down the conversation, those are the drugs that I wanted to introduce to you. There's a couple of very, very new ones that will do some readings about in your lecture. I mean really just approved in the last six months or so. So I have some good readings for you and exercises in your lecture. But the last thing I wanted to 19 of 22 6/26/24, 9:23 PM Pharmacodynamics of Antipsychotic Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... talk about with you here are some of the safety issues. I've alluded more than once to the extrapyramidal e"ects, very pronounced in the older drugs. And we still have a bit of a concern here with the done second generation antipsychotics. But extrapyramidal can mean many things. The !rst one is acute dystonia. And like the slide says, this is typically about the face or the neck. This can occur within hours of taking the !rst dose, or even subsequent doses. So it's not just a !rst dose thing. This needs to be treated very acutely with Cogentin and Benadryl. And I do have a good video for you of what this can look like in the external link section of your course. So please do be sure to check that out. Akathisia is di"erent. Akathisia is, well, like the slide says, constant restlessness or jitters. This doesn't necessarily look like unintended movement, but the patient just can't seem to sit still. They also do report like an internal sense of just being agitated, just can't calm down. And this very often is reversible when you stop the medication. Although depending on the level of involvement, we may need to treat it with propranolol, a beta blocker, or a Cogentin in an anticholinergic, or even a benzodiazepine to chill people out while we stop the medication. And every once in a while an extrapyramidal symptoms develop, they don't stop when you get rid of the medication. And while these are more of a concern with antipsychotics, they can occur with just about any psychiatric medication, even with antidepressants. Another set of links that I have for you in the external readings for this weak, link you to a YouTube of-- gentlemen, I forget his last name. His name is Josh. And Josh was being treated-- was either an SSRI or an SNRI? I think for anxiety. And he developed a really profound agastya that did not reverse when it was discontinued. And I mean, it's so bad he can't even work. His Akathisia is just all consuming. And he's actually found a way to make a living with it and educating people by developing these YouTube videos that are of course now-- they're supported and they show you what Akathisia is and how it can impact your life and coping with it and things like that. So be sure to check out those links. And then Parkinsonism is that classic, the classic triad-- bradykinesia, rigidity, postural instability. These are most overt with the !rst generation antipsychotics. It's sometimes referred to as the Thorazine shu%e. We don't see a lot of people on Thorazine. And like I said, in your inpatient settings and the more acute complex patient, yes, it's still out there, but fortunately, because of adverse e"ects like this, we don't have to use it as 20 of 22 6/26/24, 9:23 PM Pharmacodynamics of Antipsychotic Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... much anymore. This can take weeks to occur, and yes, it does stop when you stop using the drug. Tardive dyskinesia. So these are your involuntary movements. Part of dyskinesia usually does not resolve. So if this happens, the patient's got it this evolves slowly. This is most common with !rst generation antipsychotics, and it's about constant involuntary movement of the perioral muscles. If you have any older patients that have been on !rst generations for a while, sometimes their disease is so profound, and they just accept that they have to tolerate this as a consequence of treatment. And I believe also in your external links, there's a link to a gentleman who tells his story, his struggle with schizophrenia and the trials of treatment. And now he tolerates this because overall for him, the bene!t outweighs the risks and he just had to do it. And at least now he has a life in which he is connected with reality and independent, but he has tardive dyskinesia. And then !nally, the last two slides, neuroleptic malignant syndrome, is something we have to talk about because it's a safety issue, but it really isn't very common anymore. In fact, I was at a live seminar. I forget what the main topic was-- obviously it was pre- COVID. I was at this live conference and the speaker started to talk about neuroleptic malignant syndrome, and said, OK, anybody here under 50 who's ever seen it raise your hand. And of course, nobody under 50 raised their hand. Maybe one or two, and then all of us over 50 raised our hands because we've seen it because it is more common with the older antipsychotics. But what neuroleptic malignant syndrome is a neuroleptic remember. That's the old school terminology for antipsychotic. We called them neuroleptics. And there is a phenomenon called neuroleptic malignant syndrome, and it is a consequence of use of a !rst generation antipsychotics. It can happen with older second generations as well. It's just not as common, and it is very acute in onset patients develop, just what you see here. High fever, delirium, and muscle rigidity. And this can be fatal. Depending on the level of muscle rigidity and breakdown, these patients can develop rhabdomyolysis and renal failure and death. So it can be fatal. The treatment for it is immediate discontinuation of the antipsychotic. They need immediate cooling. Sometimes we have-- depending on how bad the symptoms are, they get Dantrolene, Dantrium, or Parlodel. And this is the mnemonic for it, F-E-V-E-R. So patient-- even older patients. High fever, 21 of 22 6/26/24, 9:23 PM Pharmacodynamics of Antipsychotic Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... encephalopathy, they are confused, their vital signs go way out of whack. And it's the elevated white cells and creatine phosphate kinase that can be dangerous. The CK is directly correlated to the rigidity and the muscle rigidity. And when it gets high enough, like I said, the patient can die. So hopefully you will never see that, but if you do, see a patient who is on an antipsychotic and they developed sudden unexplained high fever, muscle rigidity, and confusion. Number one, stop the antipsychotic immediately. Number two, cool them o", and then, of course, you will-- this is typically in an inpatient setting, they will decide if Dantrolene is necessary or not. And that's it. That's what I have to say about that. Took just over an hour. So I'm getting a little bit better with terms of my-- with respect to my time here. And this is the last lecture for this week. So do be sure and check out those external links. There are some really good ones there. Print this page 22 of 22 6/26/24, 9:23 PM The Physiology of Psychosis Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... The Physiology of Psychosis All right, well, welcome to week 4. As usual, I want to take just a moment in the !rst slide set of this week to say hello again, still Sally Miller. I guess I will be for the entire semester. But I wanted to introduce the topic, which is psychosis. And the primary topic is the pharmacology of psychosis or pharmacologic management of psychosis. And, as always, I feel like before we talk about the pharmacology, we need to have a little bit of an understanding of the physiology. So unlike mania and mood disorders-- you might remember last week when I was talking about the physiology of mood disorders, I said it was one of the most poorly understood in all of psychiatry. Conversely, the physiology of psychosis is one of the best understood. We really do understand a lot about the neural pathways involved in psychosis. And that's what we're going to talk about in this slide set. So here I introduce the physiology of psychosis so that in the next slide set the pharmacology of managing psychosis, the antipsychotic medications makes more sense. So without further ado, we will jump right into the physiology of psychosis. All righty, so this relatively brief slide set will really lay the foundation for the discussion of antipsychotics that we have in this week's material. And it really is fairly straightforward. I mean, I'm sure a neurophysiologist or someone who has devoted their entire professional career to studying neurophysiology would cringe at the simplistic way I'm presenting this. But as our foundation for selecting drug therapy and understanding what our medications do to, people this really is-- and this is the way that this topic is typically presented. Unlike some of the other pharmacodynamic foundations that we talk about, this one is actually very straightforward. There are four pathways, there are four neural pathways that are implicit in schizophrenia symptom presentation and pharmacotherapy. And so I do want to take a minute here to make sure we separate schizophrenia, which is one very speci!c disorder with diagnostic criteria. And one of those diagnostic criteria typically include psychotic symptoms, hallucinations or delusions. But I do want 1 of 11 6/26/24, 9:23 PM The Physiology of Psychosis Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... to make the distinction here, and I'm sure I've done this in other weeks, and I will continue to do it in other weeks, not all psychosis is schizophrenia, but all schizophrenia does at some time manifest psychotic symptoms when the patient is not well controlled. And the reason I keep harping on this is that people can become psychotic for many reasons. There are lots of other conditions that can be characterized by psychoses. It can be drug induced. There is depression with psychoses. There is generalized anxiety disorder with psychoses. Sometimes mania is evidenced or is characterized by psychoses. There's lots of things that can present with psychotic symptoms. And so that's psychosis as a symptom. But schizophrenia is a speci!c disease with speci!c diagnostic criteria. And one of those criteria is psychoses. So it is one of the most common, if not the most common disorder that is characterized by psychotic symptoms. But I just do want to make sure that we're all really clear that not all psychoses is schizophrenia. And sometimes that will make a di"erence in the medications that we choose. And so the reason I say that is because when we look at these four pathways, here we're looking very speci!cally at the four pathways that, just like the slide says, they are implicit in the symptom presentation of schizophrenia, as well as its treatment. And hopefully this will be a little bit more clear a few slides down the line. There are four pathways of interest. These are all dopamine pathways. When you think psychotic disorders, think dopamine. It is excess dopamine activity in one of these pathways that produces psychosis. So we have four pathways of interest, the mesolimbic pathway, the mesocortical pathway, the nigrostriatal pathway, and the tuberoinfundibular pathway. These are all pathways in the brain where messages are communicated by way of dopamine. OK so let's look at !rst the mesolimbic dopamine pathway. So all of these dopamine pathways originate in roughly the same subcortical area of the brain anatomically. It's referred to as the substantia nigra. And if you Google it and Google images for substantia nigra, you can visualize where it is in the brain. It is subcortical. It's very subconscious. But it's called the substantia nigra because it's an area of the brain anatomically that is very dark in color. If you looked at a cross-sectional slice of a brain, the substantia nigra is darker than other parts of the brain, hence the name, substantia nigra. The reason 2 of 11 6/26/24, 9:23 PM The Physiology of Psychosis Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... it's so dark is because of all the dopamine that's concentrated there. Dopamine is a dark chemical. And when you put a bunch of it in one space, the area looks dark, substantia nigra. So the mesolimbic dopamine pathway is one of the four pathways that originates in the substantia nigra. And it extends to, well, the limbic system, hence mesolimbic, right? So the thing about the mesolimbic dopamine pathway is abnormalities here is where psychoses comes from, psychoses for any reason-- psychosis in schizophrenia, in mania, in depression, in drug use and stimulant use, cocaine, excess methamphetamine, hallucinogens, whatever. A psychosis occurs when there is too much dopamine activity in the mesolimbic pathway. And the limbic system, remember, the limbic system is very important with respect to our emotions. Emotions like love and feelings and a"ect, all of that is driven largely by the mesolimbic pathway. And so we have to have some activity in the mesolimbic pathway. That's the way it's supposed to be, right? We're supposed to feel certain emotions in certain circumstances that would be considered a normal emotional response. When you have excess dopamine activity in this pathway, then you are going to have excess physiologic responses that can result in delusions or hallucinations. Remember that delusions are !xed beliefs that the patient has, despite the fact that everyone around them knows that the thing they believe is not true and there is no evidence that it's true. When people believe that the FBI is in their attic watching them or they believe !rmly that the world is going to end next Tuesday at 8:00 PM or they believe that-- I'm just thinking of some of the things I've had patients believe-- that they believe that they are the second coming of Christ, that they may believe that there is some agent or some entity that is listening to them through microphones in their house or things like that. These are all examples of delusions. Hallucinations, on the other hand, is a perception that the patient has from one of their senses and it's not actually there. So most commonly in psychotic disorders, patients will hear things that aren't there. They hear auditory hallucinations, very often voices, voices talking to them, voices that clearly are not their own voice, like in their head. They hear an external voice. That's the most common. Visual hallucinations are the second most common type of psychotic hallucination. And there are people that have psychoses that is manifest of gustatory hallucinations-- they taste things that aren't there-- or olfactory hallucinations-- they smell things that aren't 3 of 11 6/26/24, 9:23 PM The Physiology of Psychosis Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... there-- and tactile hallucinations-- they feel things that aren't there. But I will take this opportunity to point out, and I'm sure you'll hear me say it again, that if the hallucinations are olfactory, gustatory, or tactile, you really have to very strongly consider that there is a physiologic abnormality, like a brain tumor. Or even people will get olfactory hallucinations with certain things, like nasal polyps and weird sinus disease and stu" like that. So you really want to consider physiologic reasons if it's any of those other three. But auditory and visual hallucinations are more likely to be psychoses. Now, that's not say that people don't have visual hallucinations from a physical. There are other reasons why people will see certain things that aren't there, see patterns of lights and things like that. So whenever somebody presents to you with a hallucination, if that's the reason they make the appointment, you should always stop to think, is this psychosis or is there-- is this the type of hallucination that there might be a physical physiologic cause for? It's just part of your di"erential. But anyway, I digress just a minute, just a moment here. Here we're talking about the mesolimbic pathway. And the mesolimbic pathway is the one that is implicit in the development of delusions and hallucinations. And that's really the takeaway point. I just !gured it was a good time to mention that there are hallucinations that occur for very physiologic reasons. And we will talk about, when you get to your !rst didactic course in assessment, we will talk a whole lot about how to form the di"erential diagnosis. For right now, the thing that you really most want to take away from this particular slide is that of those four dopamine pathways, the mesolimbic one is the !rst one we're interested in. And it is the pathway that is characterized by dopamine activity and in the healthy patient regulates emotional responses, emotional behaviors. Yes, it is important for motivation, pleasure. If you're doing something that feels good, whether it's eating or really great meal or having an amazing, oh, cocktail, or, oh, I don't know, hugging somebody that you haven't seen for a long time, when your doggy jumps on the bed and lays down with you. These are all positive things. And that positive feeling that you get, that minieuphoria is a consequence of dopamine in the mesolimbic pathway. So we want to have it to some extent. But when it goes out of control, that's when you can get psychoses. And it is the D2 receptor. If you haven't heard a whole lot about the D2 receptor yet, 4 of 11 6/26/24, 9:23 PM The Physiology of Psychosis Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... don't worry, you will. D2 receptor, dopamine 2 receptor is a very popular topic of conversation in the world of antipsychotic medication. It is the primary treatment target for virtually all antipsychotic medications. So all neurotransmitters have multiple receptors and receptor subtypes. In the world of dopamine, we have dopamine 1 receptors, dopamine 2 receptors, 3, 4, 5. And then in those we have subtypes, like D2a, D2b, D2c, et cetera. So the dopamine 2 receptors in the mesolimbic pathway, those are the ones that are being hyperstimulated in the patient who is having a positive-- was having a psychotic episode of some sort. And so this is just a natural anomaly in schizophrenia. It's not the consequence of drugs or anything like that. We don't know why it happens. We just know that it does. This can also happen when patients take drugs that increase dopamine concentration in the mesolimbic pathway. And mind you, any substance of abuse really will increase dopamine concentration in this pathway. It's why people keep abusing them. They get a sense of reward from it. But the stimulants, like cocaine is one, but methamphetamine is a really big. These just so hugely increase dopamine in the mesolimbic pathway that psychosis is very common. Methamphetamine really is the worst. So mesolimbic pathway, because excess dopamine activity at the D2 receptor in this pathway is the reason that people get psychotic, this was the !rst treatment target in the world of !rst-generation antipsychotics way back in the day, things like Thorazine, Prolixin, et cetera. And all antipsychotics since then have D2 receptor activity. They will actually decrease activation of D2 receptors, or a.k.a., they will be D2 receptor antagonists, blocking the action of dopamine at these receptors. And so I got excited and said it too fast. This slide says exactly what I just said. All antipsychotics that treat not just positive symptoms of schizophrenia, but antipsychotics that treat psychoses for any reason, the way that they can reduce psychotic symptoms is by blocking dopamine activity at D2 receptors in the mesolimbic pathway. This is the foundation of the mesolimbic hypothesis or the mesolimbic dopamine hypothesis of schizophrenia that we will look at the end of this slide set. But I do want to be clear, again, that there is psychosis and then there is schizophrenia. Excess D2 activity in the mesolimbic pathway will produce psychosis for any number of reasons. When the patient is having psychoses and a series of other symptoms and diagnostic criteria that meets criteria for schizophrenia, then we make a diagnosis of 5 of 11 6/26/24, 9:23 PM The Physiology of Psychosis Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... schizophrenia. So I'm guessing that's probably pretty clear at this point. Too much dopamine in this pathway, going to make you psychotic. OK, that's that. Now, the second one, the mesocortical dopamine pathway, mesocortical, so this is another dopamine pathway that begins in the substantia nigra and it terminates in the prefrontal cortex, in the cortical structures and prefrontal or precortical structures. So this isn't really an issue in most psychoses. It's really not an issue in the patient who's psychotic because of methamphetamine use or psychotic like for any other reason. But in the patient with schizophrenia speci!cally, it also appears that not only does this schizophrenic patient have excess D2 activity in the mesolimbic pathway, but they have decreased dopamine activity in the mesocortical pathway. So the mesocortical pathway is a really critically important pathway that helps regulate cognitive function. It helps to maintain normal range of a"ect, like !ltering, not responding necessarily to things the way you might want to. I'm trying to think of a good way to say this. Sometimes you might see a stimulus of some sort. You might see, oh, I don't know, your relatives or friends doing something or wearing something or looking a certain way. And your immediate response might not be the most favorable one. But then you !lter it. You recognize at this time in this place, that is not the time to say that. You know what I'm trying to say here? When somebody walks out and says, oh, I love this out!t. I just bought this dress. Doesn't it look great? And your !rst thought is, no, it doesn't. But you recognize that this might not be the time to say that. So it's your cortex and it's your prefrontal cortex that allows you to recognize that that's not the appropriate answer for this situation and to give you the appropriate response to that situation. So regulating a"ect, regulating emotion, helping you respond appropriately to e"ective stimuli, helping you multitask, multiproblem-solve, !lter multiple stimuli at the same time and prioritize, problem-solve, think things through, these are all things that happen in the mesocortical dopamine pathway. And so again, in the patient speci!cally with schizophrenia, not only do they have psychosis because of too much dopamine activity in the mesolimbic pathway, but these patients typically have suboptimal dopamine activity in this pathway. Therefore, not only do they have periods of being psychotic, but even if they're not overtly psychotic, schizophrenics do have negative symptoms. 6 of 11 6/26/24, 9:23 PM The Physiology of Psychosis Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... Remember, the psychosis is the positive symptoms. Negative symptoms of schizophrenia are things like #at a"ect. It looks depressive. They have no range of emotion. They don't appear to have any extremes. They don't cry. They don't laugh, just tend to be sort of a #at a"ect, not really capable of complex problem-solving. The majority of patients with schizophrenia do need help interacting in an adult independent functional way. I mean, some of them really can live independently in the adult world. But many, many don't. Many need some level of support, will live in a group home or have a caseworker who works with them, things like that. Anyway, when that's the case, that's because of the suboptimal activity of dopamine in the mesocortical pathway. This is actually the thing that really leads to long-term dysfunction, long-term disability in terms of interacting in the day-to-day world. Like I said, psychoses, we can control that pretty e"ectively. But the negative symptoms of schizophrenia that result from suboptimal dopamine activity in this pathway, that's really the long-term consequence. And so, again, I get excited and I say things too fast. The current theory of schizophrenia is that you have a de!cit of dopamine in this mesocortical dopamine pathway. And that's what produces the negative symptoms of schizophrenia, which is part of the requirement for diagnosis, right? We can't just diagnose schizophrenia because somebody's psychotic. We see the psychotic patient. We get the psychosis under control. And then we do a history. We do a good history of present illness. We get a history from the patient. We get a history from the family. And in the schizophrenic patient, we will virtually always !nd that there is a more remote history, a longer-term history of negative symptoms. You will hear about the college students who were !ne all through high school, but then they went to college and just started to withdraw, couldn't function in their classes, started failing, started staying in their dorm rooms. And that type of thing, those are your negative symptoms. And that's the problem in schizophrenia. So those are the two dopamine pathways that there appears to be a natural imbalance that causes symptoms. The other two pathways, they're just innocent bystanders. The nigrostriatal dopamine pathway, there's nothing wrong with it in schizophrenia or any other psychotic disorder. The nigrostriatal dopamine pathway is the pathway where dopamine communicates with your movement centers, your pyramidal and extrapyramidal tracts, 7 of 11 6/26/24, 9:23 PM The Physiology of Psychosis Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... right? This is the beginning of the motor responses in the central nervous system. The extrapyramidal tracts control involuntary movements. The pyramidal tracts control your voluntary movement. And in the healthy patient, an appropriate balance of dopamine helps us to move when we need to move and not move when we don't need to move. And it's your normal day-to-day movement. This requires a normal dopamine balance in the nigrostriatal pathway. So, like I said, this isn't abnormal in schizophrenia or any other psychotic disorder, for that matter. The problem is, next slide, the problem is that when we treat schizophrenia, or any psychoses for that matter, any antipsychotic that we give is going to suppress dopamine activity. It's going to block dopamine activity because that's how you control the psychosis. The problem, one of the many problems that leads to side e"ects of these medications is that when we purposefully block D2 activity in the mesolimbic pathway, we inadvertently block dopamine activity in the nigrostriatal pathway, where there was nothing wrong to begin with. So now what happens is we create a de!ciency in dopamine activity in this pathway. And that's what leads to the extrapyramidal symptoms, the involuntary motor movements. That is one of the side e"ects of concern, the extrapyramidal, the tardive dyskinesia, the dystonia. This is because when we give drugs that block dopamine in one pathway, the mesolimbic, we will unintentionally or involuntarily block it in this pathway as well. And it can lead to that side e"ect pro!le. And as we will discuss in the next slide set where we talk about speci!c antipsychotic medications, every antipsychotic that's developed from the beginning, from the times of Thorazine, all the antipsychotics block psychoses. That's not a problem. It's just they create these adverse e"ect pro!les because of their action on other innocent bystander pathways. And every antipsychotic that has ever been developed from, I don't know, the '40s or '50s, whenever it was till now, the goal has been to try and !nd a way to block D2 activity in the mesolimbic pathway but spare these other pathways. And that's the challenge. That's the $30 million question. If we could block D2 in the mesolimbics and leave the other pathways alone, we'd have the perfect medication for schizophrenia. Yep, so when we suppress dopamine activity, when we involuntarily suppress it in this 8 of 11 6/26/24, 9:23 PM The Physiology of Psychosis Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425025-dt-... pathway, that's where you get these movement disorders-- akathisia, dystonia. And tardive dyskinesia gets the asterisk because that's the one that classically is not reversible. Right, once it happens, it happens. And some people have it and still make the determination that the bene!t of the medication for them is worth the movement disorders that occur. So it's not that it's a #at-out contraindication to using certain agents. It's just-- and again, we'll talk about this more in the next slide set-- always the decisions when you're trying to decide one antipsychotic from the other. And it is a big decision, because every time you turn around, some drug company's putting out a new one. There's a lot of them to choose from. And it always comes down to !nding the drug that has the best symptom control that has the least o"ensive adverse e"ect pro!le for that patient. And for some patients, the least o"ensive adverse e"ect pro!le is that they su"er with the movement symptoms. And then the last innocent bystander pathway is the tuberoinfundibular pathway. So tuberoinfundibular is another dopamine pathway. It originates very close to the substantia nigra and terminates in the hypothalamus. And the hypothalamus is the area that synthesizes prolactin and then transports it to the posterior pituitary, where it is stored and then released when stimulated. And so you know that prolactin is a critically important hormone in reproduction. I mean, yes, it's the one that stimulates lactation so that breastfeeding, women who have had babies can breastfeed. But there's a lot more to prolactin than that in the cycle of reproduction. And so dopamine is an import

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