Understanding Dopaminergic Pathways and Antipsychotics

So in today's video, again, we're going to be talking about a very broad and comprehensive topic. First, we're going to talk about the different dopaminergic pathways, specifically the mesolimbic pathway, mesocortical pathway, tubero-infandibular pathway, and nigrostriatal pathway. Then we're going to get into antipsychotics. So we're going to cover the first generation and the second generation antipsychotics, aka the typicals versus atypicals. And then we'll wrap up by talking about extrapyramidal symptoms, also known as EPS. and neuroleptic malignant syndrome. So a lot of stuff to cover today. We're going to move through it. It's going to be high yield, concise. There's going to be great explanations of pathophysiology and where appropriate, I'll throw in a little bit of memory hooks so that you guys can try to boil this down and get some free points on test day. So the first thing I want to do is start with the dopaminergic pathways. And we're just going to have to go through these. Now the dopaminergic pathways are, they do show up on USMLE and COMLEX. But it's really important that you understand this for in class exams. And when you get on your rotations, this will be really useful in psychiatry, neurology, and occasionally internal medicine. But this has been known to show up. So we're going to go through it. So we can really increase the yield that you get from this video. So let's start with the mesolimbic pathway. So in the kind of the floor of the midbrain, you have an area called the ventral tegmental area. And I'm pretty sure tegmental just means to cover. So this is the ventral covering area, this area covers the base of the midbrain. And I've shown it there with that orange circle. The way that I remember the ventral tegmental area is VTA. I say this is where the trouble arises. So if you have schizophrenia, this is where the trouble arises. This is the VTA, the ventral tegmental area. Now, this is going to project to an area shown at the second orange circle there called the nucleus accumbens, a.k.a. the NA. So we have a ventral tegmental area to nucleus accumbens. And these... Pathways are connected, shown there with that black line. So this is the mesolimbic pathway. Dopaminergic cell bodies are rising in the VTA, projecting to the nucleus accumbens. So you see that written there, that is the pathophys. Now, in somebody with psychosis, typically schizophrenia or schizoaffective disorder, you have positive symptoms. And positive symptoms are hallucinations, delusions, etc. And positive symptoms result from an overactive mesolimbic pathway. And I've shown that there. by thickening that black line. So when you're dumping dopamine from the VTA to the NA in excess, you're gonna get positive symptoms. So that's an overactive mesolimbic pathway due to too much dopamine. Now how do we treat this? Well, we're gonna get into this later in the video when we touch on the antipsychotics, but if you know that antipsychotics treat psychosis by decreasing dopamine, we change that thick black line now to a thinner green line because we've decreased dopamine. which means we're decreasing the dopamine in the mesolimbic pathway, and therefore we're decreasing positive symptoms. So what's high-yield? Let's take a step back here. The mesolimbic pathway is the projection from the VTA to the nucleus accumbens via dopaminergic neurons. The mesolimbic pathway is responsible for the positive symptoms of schizophrenia, and this is due to an increased level of dopamine. Antipsychotics treat positive symptoms, by decreasing the amount of dopamine that's released in the mesolimbic pathway. So all that stuff I just said is very, very high yield. That's the mesolimbic pathway. So now let's switch gears and talk about the mesocortical pathway. So don't confuse the two because they both start with meso. But the mesocortical pathway, as you may have guessed, is going to go from the same area, the VTA. But this time, it actually projects to the cortex. So again, don't forget the VTA, where the trouble arises. But this time, as the name implies, mesocortical. we're projecting to the cortical, aka the cortex of the brain. So you see that here shown in blue, and of course the pathway is connected with our black lines. So normally dopamine goes from the VTA to the cortex, but it's a very well regulated system. In schizophrenia, there's a decreased level of dopamine going from the VTA to the cortex. Now this may be confusing for some medical students and a lot of people get tripped up here. And this, this is a really good pimp question when you get into your clerkships. that neurologists and psychiatrists and neuropsychiatrists love to pimp you on. So let's really, really emphasize this. I want to make sure that you understand this. In the mesocortical pathway, the reason that you have dysfunction in schizophrenia, and specifically now we're talking about the negative symptoms of schizophrenia. So, you know, anhedonia, flat affect, poverty of thought, all the things that you don't have that you should have, that's due to mesocortical pathway having decrease levels of dopamine. So in the normal brain, we need dopamine to go from the VTA to the cortex to kind of light up our mood. You know, I'm going to simplify this as best I can, but without dopamine going from the VTA to the cortex, nothing really makes us happy. Nothing really gives us facial expression and emotion and pleasure. So in the case of a schizophrenic, there's decreased levels of dopamine going from the VTA to the cortex. And as a result of this, depicted there with very, very thin black lines, there's decreased levels of dopamine. So they have negative symptoms. So let's take a step back. And I really want to make sure that you understand this. Positive symptoms such as hallucinations and delusions come from too much dopamine in the mesolimbic pathway. Negative symptoms of schizophrenia, a.k.a. things that you don't have that should be there like pleasure and... facial expression and emotion, that's due to decreased levels of dopamine in the mesocortical pathway. So don't mix those up. That's very high yield. Everybody always thinks that schizophrenia is due to too much dopamine everywhere, but that is not the case. Decreased levels of dopamine in the mesocortical pathway are responsible for the negative symptoms of schizophrenia. Now let's talk about our next pathway. So now we're talking, we're going to start with the new dopaminergic cell body that actually starts in the substantia nigra. So basically, what we're talking about now is the nigrostriatal pathway. The nigrostriatal pathway is responsible for the coordination of movement, and there are dopaminergic cell bodies arising in the substantia nigra that project to something called the striatum, and the striatum is composed of multiple structures, but specifically we're talking about the caudate and the putamen. Now this pathway, the nigrostriatal pathway, I told you, is responsible for the coordination of movement. So this is the intricate involvement of something called the basal... ganglia. Now normally the dopaminergic neurons project from the SN to the striatum but what happens in a patient with schizophrenia who has way too much dopamine in its mesolimbic pathway causing positive symptoms and not enough dopamine in its mesocortical pathway causing negative symptoms you should know and we'll talk about this later in the video but you should know that we treat them with antipsychotics that decrease levels of dopamine. When this happens the decreased levels of dopamine not only affect the mesolimbic and mesocortical pathways, but also this nigrostriatal pathway. So with that in mind, what happens when you decrease levels of dopamine from drugs is that you cause Parkinsonism. Now, Parkinson's disease, organic to the brain, is due to decreased dopaminergic activity coming from the substantia nigra. But we can functionally cause Parkinson's, which is called Parkinsonism, by decreasing levels of dopamine by something like antipsychotics. So that's exactly what happens when we treat schizophrenics with antipsychotics. And that is depicted here in the diagram with the very, very thin black line showing decreased activity in the nigrostriatal pathway. So again, mesolimbic causes positive symptoms due to too much dopamine. Mesocortical causes negative symptoms due to too little dopamine. The nigrostriatal pathway... doesn't cause schizophrenia or any symptoms of schizophrenia, but when we decrease levels of dopamine by treating patients with antipsychotics, we induce Parkinsonism. So high yield, know the symptoms of Parkinsonism because when you do it, when you induce it with drugs versus when it's organic to the brain, the symptoms are identical. So cogwheel rigidity, mask faces, resting tremor, shuffling gait, don't forget all that stuff. The fourth and final dopaminergic pathway that we need to talk about. is the tubero-infundibular pathway. So that starts in the hypothalamus, shown there with the green circle. The hypothalamus communicates with the pituitary gland, shown there in the second green circle. And under normal circumstances, dopaminergic cell bodies from the hypothalamus go to the pituitary gland, which cause the release, well, or which modulate the release of prolactin. Now, something that's extremely high yield for USMLE and COMLEX is to understand that the platelet-rich plasma, the relationship between dopamine and prolactin. And this is an inverse relationship. So increased levels of dopamine from the hypothalamus will cause decreased levels of prolactin. And consequently, decreased levels of dopamine will cause increased levels of prolactin. And increased levels of prolactin do two things. They cause galacteria and amenorrhea. The relationship, this is also high yield, the relationship between prolactin and FSH is also inverse. So test writers love to ask, you know, what happens if you have decreased levels of dopamine from giving somebody an antipsychotic? How does that affect prolactin? How does that affect FSH? They, you know, the charts with the up-down arrows, it's such a high yield question. It shows up all the time. So be really, really comfortable with this. When you decrease levels of dopamine with an antipsychotic, you're raising levels of prolactin. Prolactin will inhibit FSH, which causes amenorrhea. And increased levels of prolactin will cause galacteria. So classically, there's a classic side effect from antipsychotics where patients are decreasing their levels of dopamine and all of a sudden they have milk coming through their body. And this is due to hyperprolactinemia. So very, very high yield. Understand this pathway. But again, inverse relationship between dopamine and prolactin. And then again, inverse relationship between prolactin and FSH. Very, very, very high yield. Now, here's a review of everything we've talked about so far. The four different pathways color coded for your studying pleasure. The mesolimbic mesocortical, nigrostriatal and tubero-infundibular pathway. Remember, guys. Anti-psychotics decrease levels of dopamine. So when we treat schizophrenics or someone with psychosis with an anti-psychotic, in the mesolimbic pathway, we're going to improve their positive symptoms because we're decreasing the two high levels of dopamine. In the mesocortical pathway, we have the potential to worsen negative symptoms because we're further decreasing already decreased dopamine. In the nigrostriatal pathway, we're risking EPS or extrapyramidal symptoms because we're going to induce movement disorders. We can cause Parkinsonism, among other things. And we'll get into that later in the lecture. And in the tubero-infundibular pathway, we risk galacteria and amenorrhea. So amenorrhea and galacteria are coming from the increased levels of prolactin because of the decreased levels of dopamine. So this is all very, very high yield. Now, I want to pause for one second. In the mesocortical pathway, you know, and I told you that it causes negative symptoms. And when we treat someone with an antipsychotic, you might be thinking, you know, are you always going to worsen negative symptoms? If that's the case, how do we ever treat schizophrenics and fix their negative symptoms? And the truth of the matter is, is that positive symptoms will go away before negative symptoms do. And negative symptoms really, really tend to stick around. So if you've ever had an interaction with anybody who's experienced psychosis, like in the hospital or anything like that, you know that even when we start treating them and their hallucinations and delusions get better, they still have that look on their face where you can tell that they are still experiencing. negative symptoms. So truth be told, in the mesocortical pathway, the negative symptoms do tend to stick around. But it would be technically incorrect to say that we're definitely going to worsen them by treating them with antipsychotics. That was just a little clinical aside. But these are the four pathways. And I think with all of that said, now we can move on and talk about a little bit of pharmacology with antipsychotics. So the first generation antipsychotics are also known as typical antipsychotics. The biggest one that you'll be tested on is haloperidol. That's why I put it in red text. But the other ones that you may see are flufenazine, chlorpromazine, and theoridazine. So recognize the names because when they're multiple choice, you should identify them as first generation antipsychotics. The mechanism of all these drugs is that they are D2 receptor inhibitors. So they block the dopamine receptor. The receptor profile, however, in addition to dopamine receptor inhibition is that they block the histamine alpha and muscarinic 1 receptors. So They are anti-HAM1. They are anti-HAM. So the way that I remember all this is I go through, first of all, I go through each of the individual receptors. So when you block the H1 receptor, you cause weight gain and sedation. When you block the alpha-1 receptor, you cause orthostasis, hypotension, and sexual dysfunction, occasionally priapism. And when you block the M1 receptor, dry mouth and visual changes. So anti-HAM, anti-H-A-M. Anti-HAM, I remember this because these patients gain weight because of inhibition of that H1 receptor. So anti-ham, I think of like eating a lot of ham and getting fat. These patients get fat, just helps me remember. So anti-ham, anti-H-A-M-1, that's the receptor profile for both first and second generation antipsychotics. And again, I'll bring this up when we talk about the atypicals or the second generation. But the high yield point to know really for the first generation antipsychotics is that they have the greatest incidence of... extra pyramidal symptoms, and potentially neuroleptic malignant syndrome, which is an emergency, a life-threatening condition. And I'll talk about all this stuff at the end after we go through the atypicals, but high yield is that the first generation antipsychotics, specifically haloperidol, cause so much dopamine receptor inhibition that they really cause a lot of EPS and can cause neuroleptic malignant syndrome. They are anti-ham, weight gain sedation, orthostasis, hypotension, and dry mouth. anti-ham, remember an actual ham, eating too much, getting fat, that's kind of what those receptor profiles lead to. So that's the first generation antipsychotics. Now the second generation antipsychotics, aka atypicals, do everything that the first generation does, but they have one little difference, and that's that they block the serotonin 2A receptor in addition to the dopamine receptor. So let's take a little aside here and talk about why this is important. So imagine that there's a spectrum. from 0% to 100% of dopamine receptor blockade. At 60%, if you block 60% of the dopamine receptors, you fix or, you know, you make better the positive symptoms. You get rid of hallucinations and delusions. But if you block 80% of the dopamine receptors, you cause the patient to have movement disorders and EPS. So normally, if you just block dopamine to receptors in like the case of a first generation antipsychotic, you would have over 80% receptor occupancy. And therefore, the person would have their hallucinations and delusions be gone because you pass 60%. But they would also have EPS because you passed 80%. And we don't want patients to get extra pyramidal symptoms. So because we're also inhibiting the 5-HT2A receptor, that leads to a little bit of increased levels of dopamine, but just a little bit. So we move that red line back between 60 and 80%, and we're actually right there where the orange line is, smack in the middle of 60 and 80, and that is the hot spot for the atypical antipsychotics, because we're getting rid of the positive symptoms. We've got at least 60% D2 blockade, but we have not yet hit 80% because That little bit of 5-HT2A inhibition gives us a little baby bit of dopamine back, which helps avoid the EPS. So that's why atypical antipsychotics are really, really heavily used today in psychiatry. It's because they have a lower incidence of extrapyramidal side effects. And the list of those drugs shown there on the right of the slide include risperidol, olanzapine, zaprazidone, clozapine, quetiapine. aripiprazole, and loracidone. There are of course more that I'm not listing on the slide, but these are the ones that you may see on USMLE and Comlex, so you should definitely recognize the names. Now, the second generation antipsychotics have decreased incidence of extrapyramidal symptoms, but they have other side effects that occur more often that aren't found in the first generation, so we need to talk about them now. The big one is weight gain slash metabolic syndrome. So all of these drugs, unfortunately, cause patients to gain a lot of weight. spike their cholesterol, type 2 diabetes, and the risk is really, really high, like way more so than first generation antipsychotics. These second generations are also anti-ham, so they do all that stuff that I mentioned on the first slide, but the weight gain in the second generation is way more than the weight gain in the first generation. Specifically, we should talk about risperidone and clozapine because they have two very, very high yield adverse drug reactions. Now, technically, all of these drugs can do hyperprolactinemia or cause hyperprolactinemia because they are decreasing dopamine. However, the drug risperidone has the highest incidence of this side effect. So if on your exam, you have some patient with a psych history and all of a sudden they have milk coming out of their breasts, the answer is risperidone. So just know that risperidone specifically is the one that has the highest incidence of hyperprolactinemia. Um, clozapine causes the adverse drug reaction agranulocytosis. So because of this, um, the, the mnemonic is that you monitor clozapine closely or clozly like clozapine because you need to have like routine, um, complete blood counts done to look at the patient's cells to make sure that they're not experiencing agranulocytosis. Now, the funny thing about clozapine, little clinical aside here is that it is the most effective antipsychotic that we have. But because of its... side effect of agranulocytosis, it's often reserved for refractory cases. So that's sort of high yield. You might get pimped on that when you're on your clerkships. But for you, assembly and complex know the agranulocytosis. Sometimes they like to ask you like what test you need to order. If you're going to start them on this drug, the answer would be a complete blood count, a CBC. So those are the second generation antipsychotics, aka the atypical. So what's high yield? What should you remember? Dopamine. and 5-HT2A blockade, just enough to squeeze between that 60 to 80% window. That's where we want to be. That's the hotspot. Metabolic syndrome and weight gain for all of these drugs, hyperprolactinemia for risperidone, agranulocytosis for clozapine. That's high yield. Now let's talk about the extrapyramidal symptoms. So this is where we're going to wrap up today. The four that you need to know are dystonia, akathisia, Parkinsonism, and tardive dyskinesia. Now let me pause for a second. In all of the review books, there's this BS about like oh this one happens at four hours and this one happens at four days and this one happens at four weeks That is all bullshit. You don't need to know that in reality. That's really not the case The only thing that I'll say is that dystonia typically happens first But there's like there really is no timeline for this stuff And I don't believe that it's high yield for you as some of your complex I've never seen a question where they're like you're four weeks in and the answer had to be deduced because it's four weeks in so You know take that for what it's worth, but I think that it's your time is way better served if you just understand what these are, as opposed to the timeline of when they occur. So dystonia is a sustained muscular contraction. And that includes two things that show up on exams all the time. The first is oculogyric crisis. Now, that is when the eyes have this like stuck up fixed upward gaze and the muscle The muscle of the eye is literally pulling the eyes up. And because it's a sustained muscular contraction, the eyes are stuck looking up. And the reason that this is really, really high yield is because when people think of dystonia, they classically think of like a bicep contraction or something in the arms. But in the eyes, you can have the same muscular sustained contraction. So look for the oculogyric crisis. The other big one is torticollis. So in the neck, your head gets... bent towards the side and rotated away from the muscle that is in sustained contraction. If we're talking about the ipsilateral sternocleidomastoid. So that's dystonia. Typically the first to occur, but again, don't really worry about the timeline. The next is akathisia. And this just simply put is restlessness. So like the patient that is pacing and tapping really, really quickly, that's akathisia. And this is, these are all due to decreased levels of dopamine as the result. of anti-psychotic use. So when you deplete those dopamine levels, all of a sudden the patients get really, really restless. They start pacing, they start tapping, they like literally can't sit still. And it's not like a normal patient who just, you know, likes to fiddle with a pen. This is like true restlessness. Knees are flying a mile a minute. You know, they're tapping their feet on the ground really, really quickly. They are absolutely restless. The next is Parkinsonism. And this is identical to organic Parkinson's disease of the brain. So again, you're going to see their cogwheel rigidity. The mask face, shuffling gait, resting tremor, all of the stuff that you expect the Parkinson's disease. Parkinsonism is the same exact thing. The ism just represents that this was induced by something not organic to the brain. So like antipsychotic use, decreasing those levels of dopamine in the nigrostriatal pathway, causing Parkinsonism. The last one is tardive dyskinesia. And tardive dyskinesia are repetitive and uncontrolled movements of the lips, tongues, and neck muscles. So patience. will move and smack their lips. They'll wiggle their tongues in very like serpent-like motions and their neck muscles will twitch a little bit. This is tardive dyskinesia. If you've ever seen somebody who doesn't have teeth, their mouth sort of moves like those people. So people without teeth tend to open and close their mouth and smack their lips a lot because of the way that their gums feel. Tardive dyskinesia looks very, very similar. So lip, tongue, and neck smacking. These are repetitive uncontrolled movements. So what's really, really high yield. is to not only understand what all of these different EPS are, but to know the treatment for them. So I'm going to break this down and make this as easy as possible because people always get caught up on the different treatments. For dystonia and Parkinsonism, the treatment is anticholinergic medication like benztropine or even Benadryl. You should know that Parkinson's disease, one of the treatments for Parkinson's disease is benztropine, and that's an anticholinergic. So it shouldn't surprise you that the treatment for Parkinsonism, which again is the same exact thing, same exact... physiology as far as the neurotransmitter dopamine is concerned, we're going to use anticholinergic medications. For dystonia, for sustained muscular contractions, we treat it with anticholinergics. Same thing, benztropine or Benadryl. For akathisia, we're going to use a beta blocker. Again, these people are restless. They're walking around, they're pacing, they're tapping. So we want them to chill out. We're going to give them a beta blocker. Really, really high yield. If people have some anxiety about speaking in public, a lot of times their prescribed beta blockers to help them relax before addressing a large crowd. And that sort of restlessness and anxiety is very functionally similar to akathisia. So it shouldn't surprise you if you understand that first point, that akathisia is treated with a beta blocker. The last one is tardive dyskinesia. And this is probably the highest yield here because its treatment is interesting. There really is no treatment. The first thing you do is you discontinue the antipsychotic that's causing it. The second thing you do is you... may or may not give them clozapine. So like if you ever look in a textbook, the answer is always discontinue the antipsychotic. And then literally, it usually says clozapine may help. So if you have to pick a drug, the answer is clozapine. If you have to pick an answer, the choice is discontinue the antipsychotic. That's always first. So again, these are the four EPS. Don't worry about the timeline, understand what they are individually, and know the treatment for each of these. The last thing I want to talk about today is neuroleptic malignant syndrome. So, neuroleptic malignant syndrome, which is technically one of the EPS, but I give it its own slide because it's life-threatening, is a life-threatening situation that can occur when too much of an antipsychotic is taken. Now, classically, this will occur secondary to having taken a typical or first-generation antipsychotic, but you technically can get this from a second generation as well. So, how this looks is originally the patients will get fever, tachycardia, muscular rigidity, and confusion. And if it progresses, it will turn into rhabdomyolysis. So rhabdomyolysis, the muscle will break down and you'll have increased levels of CK, potassium, and white blood cells. Now this is life-threatening because you know that rhabdomyolysis can put you into kidney failure, which can lead to heart failure, which can lead to death. High fevers can lead to death. You can get septic. This is just... an absolute mess. So this needs to be treated and identified promptly. So the treatment for neuroleptic malignant syndrome or NMS is first you discontinue the antipsychotic, you give them dantrolene, and then if needed, you give them a dopamine agonist. So think about it. The reason that this occurs is that there are decreased levels of dopamine and this causes neuroleptic malignant syndrome. So you want to give them back dopamine. So something like bromocryptine, a dopamine agonist, can be given. in addition to dantrolene, which is just protective for the autonomic nervous system in the body, but you have to discontinue the antipsychotic. So the neuroleptic malignant syndrome is treated with the three Ds. You discontinue, you give dantrolene, you give dopamine. That's it. The way that I remember this is I say NMS kidney disease. So neuroleptic malignant syndrome, kidney disease. The NMS reminds me that we're talking about NMS. The K and the D remind me of two things. The K, that we're going to have increased levels of the three Ks. K for potassium, K in CK, and K for killer cells, aka white blood cells. The D reminds me of the three Ds, the three treatments. Discontinue, give dantrolene, and give dopamine. So that's neuroleptic malignant syndrome, and it is an extrapyramidal symptom, one of the EPS, but it is the super life-threatening acute condition that needs to be promptly identified and treated. I know that we sort of flew through this video, not that many mnemonics today, but very, very high-yield material. know the four different dopaminergic pathways, understand how increased or decreased levels of dopamine cause either positive or negative symptoms, movement disorders, and hyperprolactinemia, understand the difference between first and generation antipsychotics, remember really, really high yield, first generations cause more EPS and just block dopamine, second generations cause less EPS and block both dopamine and 5-HT2A receptors, but because of this, there are some very, very unique side effects. namely the metabolic syndrome, agranulocytosis for clozapine, and hyperprolactinemia for risperidone. Understand the different EPS. Don't really worry about the timeline, but know the difference between dystonia, akathisia, Parkinsonism, tardive dyskinesia, and the treatment for each. And lastly, know how to spot neuroleptic malignant syndrome. Remember the three Ks, what it looks like, what's rising, and the three Ds, how you treat it. Good luck.

and neuroleptic malignant syndrome. So a lot of stuff to cover today. We're going to move through it.

It's going to be high yield, concise. There's going to be great explanations of pathophysiology and where appropriate, I'll throw in a little bit of memory hooks so that you guys can try to boil this down and get some free points on test day. So the first thing I want to do is start with the dopaminergic pathways. And we're just going to have to go through these. Now the dopaminergic pathways are, they do show up on USMLE and COMLEX.

But it's really important that you understand this for in class exams. And when you get on your rotations, this will be really useful in psychiatry, neurology, and occasionally internal medicine. But this has been known to show up. So we're going to go through it.

So we can really increase the yield that you get from this video. So let's start with the mesolimbic pathway. So in the kind of the floor of the midbrain, you have an area called the ventral tegmental area.

And I'm pretty sure tegmental just means to cover. So this is the ventral covering area, this area covers the base of the midbrain. And I've shown it there with that orange circle. The way that I remember the ventral tegmental area is VTA.

I say this is where the trouble arises. So if you have schizophrenia, this is where the trouble arises. This is the VTA, the ventral tegmental area.

Now, this is going to project to an area shown at the second orange circle there called the nucleus accumbens, a.k.a. the NA. So we have a ventral tegmental area to nucleus accumbens. And these... Pathways are connected, shown there with that black line.

So this is the mesolimbic pathway. Dopaminergic cell bodies are rising in the VTA, projecting to the nucleus accumbens. So you see that written there, that is the pathophys. Now, in somebody with psychosis, typically schizophrenia or schizoaffective disorder, you have positive symptoms. And positive symptoms are hallucinations, delusions, etc.

And positive symptoms result from an overactive mesolimbic pathway. And I've shown that there. by thickening that black line. So when you're dumping dopamine from the VTA to the NA in excess, you're gonna get positive symptoms. So that's an overactive mesolimbic pathway due to too much dopamine.

Now how do we treat this? Well, we're gonna get into this later in the video when we touch on the antipsychotics, but if you know that antipsychotics treat psychosis by decreasing dopamine, we change that thick black line now to a thinner green line because we've decreased dopamine. which means we're decreasing the dopamine in the mesolimbic pathway, and therefore we're decreasing positive symptoms.

So what's high-yield? Let's take a step back here. The mesolimbic pathway is the projection from the VTA to the nucleus accumbens via dopaminergic neurons.

The mesolimbic pathway is responsible for the positive symptoms of schizophrenia, and this is due to an increased level of dopamine. Antipsychotics treat positive symptoms, by decreasing the amount of dopamine that's released in the mesolimbic pathway. So all that stuff I just said is very, very high yield.

That's the mesolimbic pathway. So now let's switch gears and talk about the mesocortical pathway. So don't confuse the two because they both start with meso.

But the mesocortical pathway, as you may have guessed, is going to go from the same area, the VTA. But this time, it actually projects to the cortex. So again, don't forget the VTA, where the trouble arises.

But this time, as the name implies, mesocortical. we're projecting to the cortical, aka the cortex of the brain. So you see that here shown in blue, and of course the pathway is connected with our black lines.

So normally dopamine goes from the VTA to the cortex, but it's a very well regulated system. In schizophrenia, there's a decreased level of dopamine going from the VTA to the cortex. Now this may be confusing for some medical students and a lot of people get tripped up here. And this, this is a really good pimp question when you get into your clerkships.

that neurologists and psychiatrists and neuropsychiatrists love to pimp you on. So let's really, really emphasize this. I want to make sure that you understand this.

In the mesocortical pathway, the reason that you have dysfunction in schizophrenia, and specifically now we're talking about the negative symptoms of schizophrenia. So, you know, anhedonia, flat affect, poverty of thought, all the things that you don't have that you should have, that's due to mesocortical pathway having decrease levels of dopamine. So in the normal brain, we need dopamine to go from the VTA to the cortex to kind of light up our mood. You know, I'm going to simplify this as best I can, but without dopamine going from the VTA to the cortex, nothing really makes us happy.

Nothing really gives us facial expression and emotion and pleasure. So in the case of a schizophrenic, there's decreased levels of dopamine going from the VTA to the cortex. And as a result of this, depicted there with very, very thin black lines, there's decreased levels of dopamine.

So they have negative symptoms. So let's take a step back. And I really want to make sure that you understand this. Positive symptoms such as hallucinations and delusions come from too much dopamine in the mesolimbic pathway.

Negative symptoms of schizophrenia, a.k.a. things that you don't have that should be there like pleasure and... facial expression and emotion, that's due to decreased levels of dopamine in the mesocortical pathway. So don't mix those up. That's very high yield.

Everybody always thinks that schizophrenia is due to too much dopamine everywhere, but that is not the case. Decreased levels of dopamine in the mesocortical pathway are responsible for the negative symptoms of schizophrenia. Now let's talk about our next pathway. So now we're talking, we're going to start with the new dopaminergic cell body that actually starts in the substantia nigra. So basically, what we're talking about now is the nigrostriatal pathway.

The nigrostriatal pathway is responsible for the coordination of movement, and there are dopaminergic cell bodies arising in the substantia nigra that project to something called the striatum, and the striatum is composed of multiple structures, but specifically we're talking about the caudate and the putamen. Now this pathway, the nigrostriatal pathway, I told you, is responsible for the coordination of movement. So this is the intricate involvement of something called the basal...

ganglia. Now normally the dopaminergic neurons project from the SN to the striatum but what happens in a patient with schizophrenia who has way too much dopamine in its mesolimbic pathway causing positive symptoms and not enough dopamine in its mesocortical pathway causing negative symptoms you should know and we'll talk about this later in the video but you should know that we treat them with antipsychotics that decrease levels of dopamine. When this happens the decreased levels of dopamine not only affect the mesolimbic and mesocortical pathways, but also this nigrostriatal pathway. So with that in mind, what happens when you decrease levels of dopamine from drugs is that you cause Parkinsonism. Now, Parkinson's disease, organic to the brain, is due to decreased dopaminergic activity coming from the substantia nigra.

But we can functionally cause Parkinson's, which is called Parkinsonism, by decreasing levels of dopamine by something like antipsychotics. So that's exactly what happens when we treat schizophrenics with antipsychotics. And that is depicted here in the diagram with the very, very thin black line showing decreased activity in the nigrostriatal pathway. So again, mesolimbic causes positive symptoms due to too much dopamine.

Mesocortical causes negative symptoms due to too little dopamine. The nigrostriatal pathway... doesn't cause schizophrenia or any symptoms of schizophrenia, but when we decrease levels of dopamine by treating patients with antipsychotics, we induce Parkinsonism. So high yield, know the symptoms of Parkinsonism because when you do it, when you induce it with drugs versus when it's organic to the brain, the symptoms are identical. So cogwheel rigidity, mask faces, resting tremor, shuffling gait, don't forget all that stuff.

The fourth and final dopaminergic pathway that we need to talk about. is the tubero-infundibular pathway. So that starts in the hypothalamus, shown there with the green circle.

The hypothalamus communicates with the pituitary gland, shown there in the second green circle. And under normal circumstances, dopaminergic cell bodies from the hypothalamus go to the pituitary gland, which cause the release, well, or which modulate the release of prolactin. Now, something that's extremely high yield for USMLE and COMLEX is to understand that the platelet-rich plasma, the relationship between dopamine and prolactin. And this is an inverse relationship. So increased levels of dopamine from the hypothalamus will cause decreased levels of prolactin.

And consequently, decreased levels of dopamine will cause increased levels of prolactin. And increased levels of prolactin do two things. They cause galacteria and amenorrhea. The relationship, this is also high yield, the relationship between prolactin and FSH is also inverse. So test writers love to ask, you know, what happens if you have decreased levels of dopamine from giving somebody an antipsychotic?

How does that affect prolactin? How does that affect FSH? They, you know, the charts with the up-down arrows, it's such a high yield question.

It shows up all the time. So be really, really comfortable with this. When you decrease levels of dopamine with an antipsychotic, you're raising levels of prolactin.

Prolactin will inhibit FSH, which causes amenorrhea. And increased levels of prolactin will cause galacteria. So classically, there's a classic side effect from antipsychotics where patients are decreasing their levels of dopamine and all of a sudden they have milk coming through their body. And this is due to hyperprolactinemia. So very, very high yield.

Understand this pathway. But again, inverse relationship between dopamine and prolactin. And then again, inverse relationship between prolactin and FSH.

Very, very, very high yield. Now, here's a review of everything we've talked about so far. The four different pathways color coded for your studying pleasure.

The mesolimbic mesocortical, nigrostriatal and tubero-infundibular pathway. Remember, guys. Anti-psychotics decrease levels of dopamine.

So when we treat schizophrenics or someone with psychosis with an anti-psychotic, in the mesolimbic pathway, we're going to improve their positive symptoms because we're decreasing the two high levels of dopamine. In the mesocortical pathway, we have the potential to worsen negative symptoms because we're further decreasing already decreased dopamine. In the nigrostriatal pathway, we're risking EPS or extrapyramidal symptoms because we're going to induce movement disorders.

We can cause Parkinsonism, among other things. And we'll get into that later in the lecture. And in the tubero-infundibular pathway, we risk galacteria and amenorrhea. So amenorrhea and galacteria are coming from the increased levels of prolactin because of the decreased levels of dopamine.

So this is all very, very high yield. Now, I want to pause for one second. In the mesocortical pathway, you know, and I told you that it causes negative symptoms.

And when we treat someone with an antipsychotic, you might be thinking, you know, are you always going to worsen negative symptoms? If that's the case, how do we ever treat schizophrenics and fix their negative symptoms? And the truth of the matter is, is that positive symptoms will go away before negative symptoms do.

And negative symptoms really, really tend to stick around. So if you've ever had an interaction with anybody who's experienced psychosis, like in the hospital or anything like that, you know that even when we start treating them and their hallucinations and delusions get better, they still have that look on their face where you can tell that they are still experiencing. negative symptoms. So truth be told, in the mesocortical pathway, the negative symptoms do tend to stick around.

But it would be technically incorrect to say that we're definitely going to worsen them by treating them with antipsychotics. That was just a little clinical aside. But these are the four pathways.

And I think with all of that said, now we can move on and talk about a little bit of pharmacology with antipsychotics. So the first generation antipsychotics are also known as typical antipsychotics. The biggest one that you'll be tested on is haloperidol.

That's why I put it in red text. But the other ones that you may see are flufenazine, chlorpromazine, and theoridazine. So recognize the names because when they're multiple choice, you should identify them as first generation antipsychotics. The mechanism of all these drugs is that they are D2 receptor inhibitors. So they block the dopamine receptor.

The receptor profile, however, in addition to dopamine receptor inhibition is that they block the histamine alpha and muscarinic 1 receptors. So They are anti-HAM1. They are anti-HAM.

So the way that I remember all this is I go through, first of all, I go through each of the individual receptors. So when you block the H1 receptor, you cause weight gain and sedation. When you block the alpha-1 receptor, you cause orthostasis, hypotension, and sexual dysfunction, occasionally priapism.

And when you block the M1 receptor, dry mouth and visual changes. So anti-HAM, anti-H-A-M. Anti-HAM, I remember this because these patients gain weight because of inhibition of that H1 receptor.

So anti-ham, I think of like eating a lot of ham and getting fat. These patients get fat, just helps me remember. So anti-ham, anti-H-A-M-1, that's the receptor profile for both first and second generation antipsychotics. And again, I'll bring this up when we talk about the atypicals or the second generation.

But the high yield point to know really for the first generation antipsychotics is that they have the greatest incidence of... extra pyramidal symptoms, and potentially neuroleptic malignant syndrome, which is an emergency, a life-threatening condition. And I'll talk about all this stuff at the end after we go through the atypicals, but high yield is that the first generation antipsychotics, specifically haloperidol, cause so much dopamine receptor inhibition that they really cause a lot of EPS and can cause neuroleptic malignant syndrome.

They are anti-ham, weight gain sedation, orthostasis, hypotension, and dry mouth. anti-ham, remember an actual ham, eating too much, getting fat, that's kind of what those receptor profiles lead to. So that's the first generation antipsychotics.

Now the second generation antipsychotics, aka atypicals, do everything that the first generation does, but they have one little difference, and that's that they block the serotonin 2A receptor in addition to the dopamine receptor. So let's take a little aside here and talk about why this is important. So imagine that there's a spectrum. from 0% to 100% of dopamine receptor blockade. At 60%, if you block 60% of the dopamine receptors, you fix or, you know, you make better the positive symptoms.

You get rid of hallucinations and delusions. But if you block 80% of the dopamine receptors, you cause the patient to have movement disorders and EPS. So normally, if you just block dopamine to receptors in like the case of a first generation antipsychotic, you would have over 80% receptor occupancy. And therefore, the person would have their hallucinations and delusions be gone because you pass 60%. But they would also have EPS because you passed 80%.

And we don't want patients to get extra pyramidal symptoms. So because we're also inhibiting the 5-HT2A receptor, that leads to a little bit of increased levels of dopamine, but just a little bit. So we move that red line back between 60 and 80%, and we're actually right there where the orange line is, smack in the middle of 60 and 80, and that is the hot spot for the atypical antipsychotics, because we're getting rid of the positive symptoms. We've got at least 60% D2 blockade, but we have not yet hit 80% because That little bit of 5-HT2A inhibition gives us a little baby bit of dopamine back, which helps avoid the EPS.

So that's why atypical antipsychotics are really, really heavily used today in psychiatry. It's because they have a lower incidence of extrapyramidal side effects. And the list of those drugs shown there on the right of the slide include risperidol, olanzapine, zaprazidone, clozapine, quetiapine.

aripiprazole, and loracidone. There are of course more that I'm not listing on the slide, but these are the ones that you may see on USMLE and Comlex, so you should definitely recognize the names. Now, the second generation antipsychotics have decreased incidence of extrapyramidal symptoms, but they have other side effects that occur more often that aren't found in the first generation, so we need to talk about them now.

The big one is weight gain slash metabolic syndrome. So all of these drugs, unfortunately, cause patients to gain a lot of weight. spike their cholesterol, type 2 diabetes, and the risk is really, really high, like way more so than first generation antipsychotics. These second generations are also anti-ham, so they do all that stuff that I mentioned on the first slide, but the weight gain in the second generation is way more than the weight gain in the first generation.

Specifically, we should talk about risperidone and clozapine because they have two very, very high yield adverse drug reactions. Now, technically, all of these drugs can do hyperprolactinemia or cause hyperprolactinemia because they are decreasing dopamine. However, the drug risperidone has the highest incidence of this side effect. So if on your exam, you have some patient with a psych history and all of a sudden they have milk coming out of their breasts, the answer is risperidone. So just know that risperidone specifically is the one that has the highest incidence of hyperprolactinemia.

Um, clozapine causes the adverse drug reaction agranulocytosis. So because of this, um, the, the mnemonic is that you monitor clozapine closely or clozly like clozapine because you need to have like routine, um, complete blood counts done to look at the patient's cells to make sure that they're not experiencing agranulocytosis. Now, the funny thing about clozapine, little clinical aside here is that it is the most effective antipsychotic that we have. But because of its...

side effect of agranulocytosis, it's often reserved for refractory cases. So that's sort of high yield. You might get pimped on that when you're on your clerkships.

But for you, assembly and complex know the agranulocytosis. Sometimes they like to ask you like what test you need to order. If you're going to start them on this drug, the answer would be a complete blood count, a CBC. So those are the second generation antipsychotics, aka the atypical. So what's high yield?

What should you remember? Dopamine. and 5-HT2A blockade, just enough to squeeze between that 60 to 80% window. That's where we want to be.

That's the hotspot. Metabolic syndrome and weight gain for all of these drugs, hyperprolactinemia for risperidone, agranulocytosis for clozapine. That's high yield. Now let's talk about the extrapyramidal symptoms. So this is where we're going to wrap up today.

The four that you need to know are dystonia, akathisia, Parkinsonism, and tardive dyskinesia. Now let me pause for a second. In all of the review books, there's this BS about like oh this one happens at four hours and this one happens at four days and this one happens at four weeks That is all bullshit. You don't need to know that in reality.

That's really not the case The only thing that I'll say is that dystonia typically happens first But there's like there really is no timeline for this stuff And I don't believe that it's high yield for you as some of your complex I've never seen a question where they're like you're four weeks in and the answer had to be deduced because it's four weeks in so You know take that for what it's worth, but I think that it's your time is way better served if you just understand what these are, as opposed to the timeline of when they occur. So dystonia is a sustained muscular contraction. And that includes two things that show up on exams all the time. The first is oculogyric crisis. Now, that is when the eyes have this like stuck up fixed upward gaze and the muscle The muscle of the eye is literally pulling the eyes up.

And because it's a sustained muscular contraction, the eyes are stuck looking up. And the reason that this is really, really high yield is because when people think of dystonia, they classically think of like a bicep contraction or something in the arms. But in the eyes, you can have the same muscular sustained contraction.

So look for the oculogyric crisis. The other big one is torticollis. So in the neck, your head gets...

bent towards the side and rotated away from the muscle that is in sustained contraction. If we're talking about the ipsilateral sternocleidomastoid. So that's dystonia.

Typically the first to occur, but again, don't really worry about the timeline. The next is akathisia. And this just simply put is restlessness. So like the patient that is pacing and tapping really, really quickly, that's akathisia. And this is, these are all due to decreased levels of dopamine as the result.

of anti-psychotic use. So when you deplete those dopamine levels, all of a sudden the patients get really, really restless. They start pacing, they start tapping, they like literally can't sit still.

And it's not like a normal patient who just, you know, likes to fiddle with a pen. This is like true restlessness. Knees are flying a mile a minute. You know, they're tapping their feet on the ground really, really quickly. They are absolutely restless.

The next is Parkinsonism. And this is identical to organic Parkinson's disease of the brain. So again, you're going to see their cogwheel rigidity.

The mask face, shuffling gait, resting tremor, all of the stuff that you expect the Parkinson's disease. Parkinsonism is the same exact thing. The ism just represents that this was induced by something not organic to the brain.

So like antipsychotic use, decreasing those levels of dopamine in the nigrostriatal pathway, causing Parkinsonism. The last one is tardive dyskinesia. And tardive dyskinesia are repetitive and uncontrolled movements of the lips, tongues, and neck muscles.

So patience. will move and smack their lips. They'll wiggle their tongues in very like serpent-like motions and their neck muscles will twitch a little bit.

This is tardive dyskinesia. If you've ever seen somebody who doesn't have teeth, their mouth sort of moves like those people. So people without teeth tend to open and close their mouth and smack their lips a lot because of the way that their gums feel.

Tardive dyskinesia looks very, very similar. So lip, tongue, and neck smacking. These are repetitive uncontrolled movements. So what's really, really high yield. is to not only understand what all of these different EPS are, but to know the treatment for them.

So I'm going to break this down and make this as easy as possible because people always get caught up on the different treatments. For dystonia and Parkinsonism, the treatment is anticholinergic medication like benztropine or even Benadryl. You should know that Parkinson's disease, one of the treatments for Parkinson's disease is benztropine, and that's an anticholinergic. So it shouldn't surprise you that the treatment for Parkinsonism, which again is the same exact thing, same exact... physiology as far as the neurotransmitter dopamine is concerned, we're going to use anticholinergic medications.

For dystonia, for sustained muscular contractions, we treat it with anticholinergics. Same thing, benztropine or Benadryl. For akathisia, we're going to use a beta blocker. Again, these people are restless. They're walking around, they're pacing, they're tapping.

So we want them to chill out. We're going to give them a beta blocker. Really, really high yield.

If people have some anxiety about speaking in public, a lot of times their prescribed beta blockers to help them relax before addressing a large crowd. And that sort of restlessness and anxiety is very functionally similar to akathisia. So it shouldn't surprise you if you understand that first point, that akathisia is treated with a beta blocker. The last one is tardive dyskinesia. And this is probably the highest yield here because its treatment is interesting.

There really is no treatment. The first thing you do is you discontinue the antipsychotic that's causing it. The second thing you do is you...

may or may not give them clozapine. So like if you ever look in a textbook, the answer is always discontinue the antipsychotic. And then literally, it usually says clozapine may help.

So if you have to pick a drug, the answer is clozapine. If you have to pick an answer, the choice is discontinue the antipsychotic. That's always first.

So again, these are the four EPS. Don't worry about the timeline, understand what they are individually, and know the treatment for each of these. The last thing I want to talk about today is neuroleptic malignant syndrome.

So, neuroleptic malignant syndrome, which is technically one of the EPS, but I give it its own slide because it's life-threatening, is a life-threatening situation that can occur when too much of an antipsychotic is taken. Now, classically, this will occur secondary to having taken a typical or first-generation antipsychotic, but you technically can get this from a second generation as well. So, how this looks is originally the patients will get fever, tachycardia, muscular rigidity, and confusion.

And if it progresses, it will turn into rhabdomyolysis. So rhabdomyolysis, the muscle will break down and you'll have increased levels of CK, potassium, and white blood cells. Now this is life-threatening because you know that rhabdomyolysis can put you into kidney failure, which can lead to heart failure, which can lead to death.

High fevers can lead to death. You can get septic. This is just...

an absolute mess. So this needs to be treated and identified promptly. So the treatment for neuroleptic malignant syndrome or NMS is first you discontinue the antipsychotic, you give them dantrolene, and then if needed, you give them a dopamine agonist.

So think about it. The reason that this occurs is that there are decreased levels of dopamine and this causes neuroleptic malignant syndrome. So you want to give them back dopamine. So something like bromocryptine, a dopamine agonist, can be given. in addition to dantrolene, which is just protective for the autonomic nervous system in the body, but you have to discontinue the antipsychotic.

So the neuroleptic malignant syndrome is treated with the three Ds. You discontinue, you give dantrolene, you give dopamine. That's it. The way that I remember this is I say NMS kidney disease. So neuroleptic malignant syndrome, kidney disease.

The NMS reminds me that we're talking about NMS. The K and the D remind me of two things. The K, that we're going to have increased levels of the three Ks. K for potassium, K in CK, and K for killer cells, aka white blood cells.

The D reminds me of the three Ds, the three treatments. Discontinue, give dantrolene, and give dopamine. So that's neuroleptic malignant syndrome, and it is an extrapyramidal symptom, one of the EPS, but it is the super life-threatening acute condition that needs to be promptly identified and treated. I know that we sort of flew through this video, not that many mnemonics today, but very, very high-yield material.

know the four different dopaminergic pathways, understand how increased or decreased levels of dopamine cause either positive or negative symptoms, movement disorders, and hyperprolactinemia, understand the difference between first and generation antipsychotics, remember really, really high yield, first generations cause more EPS and just block dopamine, second generations cause less EPS and block both dopamine and 5-HT2A receptors, but because of this, there are some very, very unique side effects. namely the metabolic syndrome, agranulocytosis for clozapine, and hyperprolactinemia for risperidone. Understand the different EPS. Don't really worry about the timeline, but know the difference between dystonia, akathisia, Parkinsonism, tardive dyskinesia, and the treatment for each. And lastly, know how to spot neuroleptic malignant syndrome.

Remember the three Ks, what it looks like, what's rising, and the three Ds, how you treat it. Good luck.

Transcript for:Understanding Dopaminergic Pathways and Antipsychotics

Transcript for:
Understanding Dopaminergic Pathways and Antipsychotics