Cram The Pance - S1E59 Antipsychotic Drugs (Typical vs Atypical)

Episode Date: July 5, 2026

High Yield Antipsychotics Pharm Review: Typical or 1st generation antipsychotics (Haloperidol, Fluphenazine, Loxapine, Perphenazine, Pimozide, Thiothixene, Trifluoperazine, Thioridazine Chlorpromazine) Atypical or 2nd Generation Antipsychotics (Aripiprazole, Asenapine, Brexpiprazole, Cariprazine, Clozapine, Iloperidone, Lumateperone, Lurasidone, Olanzapine, Paliperidone, Quetiapine, Risperidone, Ziprasidone) Mesolimbic, Mesocortical, Nigrostriatal, Tuberoinfundibular dopamine pathways Schizophrenia, Bipolar disorder Extrapyramidal symptoms: Dystonia, Rigidity, Akathisia, Tardive Dyskinesia, Oculogyric crisis Neuroleptic malignant syndrome Hyperprolactinemia Agranulocytosis Review for your PANCE, PANRE, Eor's, Physician Assistant exams, USMLE, NCLEX, nursing exams.►Support the channel by joining and becoming a member! (Thank you so much!)►Paypal Donation Link: https://bit.ly/3dxmTql (Thank you!)►INSTAGRAM: https://www.instagram.com/cramthepance/►YOUTUBE: https://www.youtube.com/channel/UCZCILePJ-E17txF-ObXlFKwBecome a supporter of this podcast: https://www.spreaker.com/podcast/cram-the-pance--5520744/support.

All right, so we're going to be doing a farm review for our antipsychotic medications. Thank you so much for the support of the channel. Let's go ahead and get started with the basics. So we're going to be going over our first gens, aka our typical antipsychotics and our second gens known as atypicals. If you ever forget which generation is typical and which is atypical, you hold two fingers up for your second generation meds, turn those two fingers upside down and it turns into an A for atypicals.

Now, when we're talking about our antipsychotics and the conditions they treat, most notably schizophrenia, the leading theory, although still an active area of research, is that dopamine plays a central role. Disregulation of dopamine signaling is thought to contribute to disease and many antipsychotics exert their therapeutic effects by altering dopamine signaling in the brain. So to understand these meds, we got to learn a little bit more about our friend dopamine and four specific dopamine pathways in the brain. Let's first talk about what they're supposed to do, which will help us understand what happens when things go wrong, as well as where our meds exert their therapeutic effect. So for dopamine pathways, you need to know, mesolimbic, mesocortical,

Niagara striatal and tuberal infidibular. Let's first start with the mesolimbic pathway. So the mesolimbic dopamine pathway is a little pathway between the ventral tegmental area and the nucleus accumbens of the brain. This is our reward center. So things like motivation, desire, pleasure. It's actually the primary area cocaine targets. So something feels good. This area of your brain motivates you to do it again. For exam purposes, I like to remember one word to associate each of these, which helps to remember key components. For mesolimbic, it's going to be motivation. And it's also important to know that excess dopamine here is thought to contribute to the positive symptoms we see in schizophrenia, like hallucinations and delusions. So the next area we're going to be talking about is our mesocortical pathway.

This connects the VTA to the prefrontal cortex. Dopamine here regulates emotions, cognition, executive function, etc. The one word association here is mood. And schizophrenia, dopamine here is thought to be low or hypofunctioning, contributing to our negative symptoms, flat affect, emotional withdrawal, anhedonia, aka, inability to feel pleasure. The next two pathways, understanding their normal function is key because it's going to help us understand many of the adverse effects associated with the medications that will discuss shortly. So first starting with the Niagara striatal, which originates in the substantia nigra. Dopamine in this pathway plays an important role in movement and coordination.

You can probably see where this is going. If dopamine promotes movement in this pathway, what might happen when an antipsychotic blocks too much dopamine here? We'll talk more about that in just a moment. The one key to remember for the Niagara striital pathway is going to be movement. And then finally we have the tubero infidibular pathways, which connects the hypothalamus to the pituitary gland. Dopamine in this pathway inhibits the release of prolactin. And prolactin, as we know, promotes lactation, among other things. Again, think about what might happen here if we block dopamine with our antipsychotics and more about that soon. So your one word association for tubero infidibular is going to be milk, and that's your dopamine pathways.

Mesolylylymetic equals motivation, mesocortical mood, negrastriatal movement, and tubero infundibular milk. Now that we have our framework, let's talk about our meds, starting with our typical or first-generation antipsychotics. So these are the OGs first developed in the 1950s with the first antipsychotic drug being chlorpromisein. Interestingly enough, we still use chlorpromisein today, but not so much for its antipsychotic properties, but actually for severe hiccups. It's true. So the use of first gens has declined over the years, not due to lack of efficacy, but due to their poor side effect profile compared to the newer second generation anti-sacartic. psychotics. Still got to know them, though, so this class includes a number of different medications,

which are classified by how potently they block D2 receptors. Our high potency meds being haloperidol, flufenazine, perfenazine, pimozide, thiothixine, and tri-fluparazine. And then we have our low-potency meds, which are going to be thyridazine and chlorpromazine. There's a whole lot of meds here, and if you just want to remember one by all means, let it be haloperidol. This is what will likely be tested on, as it's one of the most commonly used first gens. If you want to remember most of them, remember Halloparadol and your Aesines. The Azeen suffix is seen in a majority of the first-gen antipsychotics, chlorpromasein, flu-fen-A-Zene, et cetera.

I used to have this visual of the first edition of Halo magazine, like Halo the video game, because I'm a nerd and I used to play a lot of Halo when I was younger. So Halo helps you remember Halo Peridol. Magazine helps you remember your A-Zin meds, and first edition helps you remember that these are your first-gen-gen-sacotics. So those are your meds. Let's talk about the mechanism of action next. Now, all antipsychotics, whether it's first or second gen, are going to mess with dopamine in one way or another.

Depending on the med, different strength of dopamine manipulation and varying methods. But in the case of first gen, the primary mechanism is through inhibition of D2 dopamine receptors in the brain. The therapeutic effect of these drugs is by post-synaptic blockade of dopamine D2 receptors in the brain. So blocking dopamine receptors, how does that help a patient with schizophrenia, for instance? And to answer that, we need to revisit the dopamine pathways we discussed earlier. Specifically, the mesolimbic pathway. Our motivation center where excess dopamine here is thought to contribute to the positive symptoms of schizophrenia as we went over, hallucinations and delusions, et cetera.

So if we block dopamine receptors in this pathway with a first gen, theoretically we can reduce the symptoms, and there is a therapeutic window for the number of D2 receptors blocked. Typically around 65 to 70% D2 blockade is the sweet spot. You block less decrease efficacy, you block more, you have more adverse effects. Now, what about the mesocorcercer. pathway. Remember mesocortical equals mood where dopamine is already thought to be low in schizophrenia causing our negative symptoms. And since first gen's further block dopamine in this pathway,

it's thought that they have little effect on negative symptoms and potentially, potentially may worsen them in some patients, although evidence for this remains limited and a lot of this is still being researched. So for the exam, focus on first generation antipsychotics, blocking D2 receptors in the brain, reducing positive symptoms for your mechanism of action. Let's move to indications for these meds. Of course, schizophrenia and schizoaffective disorders, acute mania, severe episodes of bipolar mania that is usually combined with lithium, major depressive disorder with psychotic features, and severe agitation, plus a number of other conditions. And like we discussed before, first generation antipsychotics can treat these conditions, but they have largely

been replaced by second generation or atypical antipsychotics, particularly in the treatment of schizophrenia due to their higher risk of movement or extraperimital side effects. So I wouldn't focus too much on the indications as you won't use these that often, except in the case of severe agitation in the inpatient or emergency setting where they're still pretty commonly used. This will usually be with a rapid acting first-gen like Halloperidol combined with the Benzo. All right, the next part is the most important, and that's the adverse effects. There are many adverse effects associated with antipsychotics, and I can easily spend an entire lesson covering all of them, but for this review, we're going to focus on the highest yield effects for your exams,

especially those that are more commonly associated with your first gen antipsychotics. So for adverse effects, I want you to remember to dread neuroleptic malignant syndrome. You dread neuroleptic malignant syndrome. You'll know the highest yield adverse effects for your first gens. And also know to dread neuroleptic malignant syndrome, which is the most feared adverse effect of this class as it can be fatal. So let's start with the dread portion of the mnemonic, which helps us remember our extraperaminal side effects. These are our movement disorders, which are more common in first genes. Let's first start with why this happens, then we'll talk about which specific movement disorders to know for the exam.

So let's go back again to the dopamine pathways. Which pathway do you think contributes to our movement disorders with these meds? That's right, the nigrostriatal pathway, the dopamine highway that control movement and coordination. So if this movement pathway is fueled by dopamine, what do you think will happen when we throw a first gen in there, which we know blocks dopamine? Not surprisingly, movement disorders develop. In fact, blocking dopamine in the nigrostriidal pathway creates a situation similar to part. Parkinson's disease, which is why antipsychotic-induced movement disorders closely resemble Parkinsonian symptoms.

So now let's talk about the specific extraparaminal symptoms you need to know using the Dred mnemonic, D-R-E-A-D, starting with D, which stands for dystonia. Acute dystonia is one of the earliest adverse effects, peaking at around 24 to 48 hours from the initiation of therapy, and it involves involuntary muscle contractions or spasms of the face, neck, eyes, back, and muscle stiffness and contractions, which can actually be quite painful. Next, the R is going to stand for rigidity, so rigidity of the limbs resistant to passive movement, which is one of the most obvious features of drug-induced Parkinsonism. We can see in these patients, it may present as lead pipe or cogwheel rigidity.

Next, the E stands for eye deviation. Now, this is related to the acute dystonia and is formally called oculogyric crisis, where there is this spasmodic deviation of the extraocular muscles causing the eyes to look upward. Not super high yield, but just be aware of it. Next, the A stands for acathesia. This uncontrollable inner restlessness and compelling urge to move the body, tapping, rocking back and forth. And it can be one of the most distressing side effects of these drugs. So I do not intend to make light of this with my silly pneumonic. This is just how I remembered it. Acathia. I used to think of a cat and acathesia, a restless cat that can't sit still, constantly pacing, scratching and tapping its paws like

most cats do to help remember the compelling urge to move the body, tapping, etc., seen in acathia. And finally, the D stands for dyskinesia, as in tardive dyskinesia. Tardive dyskinesia is a late manifestation usually occurring after months of being on the medication. The word tardive actually is derived from the Latin term Tardis, meaning late or tardy, which makes sense as this is a late manifestation occurring after many months. So while the arms, legs, and trunk can be affected with this condition, tardive dyskinesia mainly targets the tongue and mouth, leading to these unique manifestations with twisting of the tongue, chewing, grimacing movements of the face.

The word tar and tar dive dyskinesia would always make me think of what your face would look like if you were chewing a piece of sticky, chewy, tar. All right, so those are your extra pyramidal symptoms, very high yield for our first gens. Again, remember dread, dystonia, rigidity, eye deviation, acathesia, dyskinesia. Next, let's talk about neuroleptic, malignant syndrome, or NMS. Why do we dread NMS with our first gens? Well, that's because this complication, while rare, can be fatal. NMS is a neurologic emergency associated most commonly with the use of first-generation antipsychotics,

and that's why you dread NMS with the first gens. Manifestations of NMS are fever, muscle rigidity, autonomic instability, usually accompanied by rabdo and creatine kinase elevation. Treatment is fairly high yield and easy to remember as you treat with the four Ds. The four Ds are discontinuation of the offending agent. In this case, it would be antipsychotics. Next D is for dantraline, a muscle relaxant. Next is your D2 agonists like Bromocrypte.

and finally, diazepam or other benzos to mitigate agitation. Now, there are, of course, a number of other adverse effects, QT prolongation, prolactin elevation. Since they're non-selective, they also may block histamine alpha-1 in muscarinic receptors so there can be sedation, hypotension, urinary retention. But for the exam, I'd stick to DRED NMS, as that's the highest yield ADRs for this class. And that brings us to our second generation or our atypical antipsychotics. So first, why are they called atypical?

What makes them atypical, well, primarily because of the lower propensity to induce EPS or movement disorders like we just talked about with our first gens. And it also originally implied that these newer drugs were fundamentally different than first gens, but not all second generation antipsychotics behave the same way. So the naming system, it's not perfect. But with that being said, let's first talk about what medications are included in this class. So the meds included in this class include Eripprysol, acetypene, acetypricene, klexeperone, eloparidone, lumeteperone, Petepirone, luresadone, olanzapine, paloparidone, quaterypine, cypidone, and zoprasidone. Like, seriously, are you kidding me?

Who's going to remember all of that? So here's the good news. From an exam standpoint, there's really only four to focus on. The four that are always tested on due to their adverse effects are clasopine, rsapine, olanzapine, and quittapine. So you need to know those. Clauseapine, risperidone, olanzapine, quittipine. I used to remember the sentence, crocs are atypical shoes.

Crocs are atypical shoes. Crocs are spelled CROQ. The first letters of clozapine, rsapine, olanzapine, and quatypine are atypical shoes. Atypical helps you remember that these are atypical antipsychotics. And no offense to anyone wearing crocs, but they kind of are atypical shoes. So again, clausapine, rospadone, olanzapine, quatyapine, aka Crocs are atypical shoes. Next, let's talk about how these meds work, which is by inhibiting D2 dopamine receptors plus serotonin 5H2A receptors. Now, before we dive deeper, I want to point out that second-generation antipsychotics are a diverse

group of meds, and not all of them follow this exact mechanism. For example, Erippipersol, Brexpiprazol, and Carriparzine are sometimes referred to as third-gen-gen-an antips by some sorts, because they act as partial dopamine agonist rather than pure dopamine blockers. But with that being said, the general mechanism you should focus on for your exam for most of these meds is that second-generation antipsychotics affect both dopamine and serotonin signaling. So like first-gen antipsychotics, they block post-synaptic dopamine D2 receptors, but it really sets them apart as their additional blockade of serotonin receptors, particularly the 5HT2A receptor. In many of these meds, the serotonin blocking effects are relatively greater than their dopamine blocking effects.

Additionally, some second-gen agents will exhibit lower D2 receptor occupancy or more transient binding to these dopamine receptors, a distinction that will become important when we discuss adverse effects later. Now, initially, it was thought that this additional serotonin blockade made them more effective for treating negative symptoms of schizophrenia, but the evidence really has been mixed, and many studies have found similar efficacy between first and second generation antipsychotics. So the key distinction to remember for the exam, first gens primarily block dopamine. Second gens generally affect both dopamine and serotonin. All right, indications, of course, we are going to have schizophrenia with our second gens, which are going to be preferred over the first gens for this condition due to the lower incidence of

extra pyramidal symptoms, acathia, dystonia, et cetera. Bipolar disorder is another one, and major depressive disorder as adjunctive therapy. There are others, Korea and Huntington disease, postpartum psychosis, but focus on those three with schizophrenia being at the top of that list. Next, let's talk about the adverse effects, which is probably the most commonly tested on component. So let's start with what we've already touched on previously. Second genes can cause extraparaminal symptoms, but less often compared to our first gens. So why do these movement disorders occur less often with second gens? Well, back to the MOA.

These drugs are still dopamine blockers, but they're also serotonin blockers. And comparatively, their serotonin receptor binding exceeds their dopamine receptor binding, which varies by the specific drug, but as a general principle, second generation antipsychotics bind more loosely to D2 receptors compared to first generation agents. The theory is weaker D2 binding allows more dopamine activity to be preserved in pathways like the nigrostriatal tract, which translates to a lower risk of movement disorders. So know that they still can cause them, but less often, most importantly. Next, let's talk about the other adverse effects, starting with the most important and prominent

for your second gens, which is going to be metabolic syndrome. So think weight gain, diabetes, dyslidemia, as a class, this is the most important adverse effect for you to know. For first genes, it was your extraperamidal. For second gens, it is metabolic syndrome. It's so prevalent with this class, it's recommended to actually monitor weight, BP, fasting, glucose, and lipids when patients are started on these meds. Now, when we're talking about weight gain, even though all of the second genes can cause weight gain,

there's one that you need to know that causes it the most, and that's going to be olanzapine. Olanzapine is the second generation antipsychotic most commonly associated with significant weight gain and other metabolic complications. Clausapine causes a similar degree of weight gain, but it's got way other high-yield associations will go over shortly. So for exams, think olanzapine equals obesity. Luckily, it's the only antipsychotic that starts with an O. The O in your mind should stand for obesity when you see this on your exam. Next is going to be hyperprolactinemia. So elevated prolactin levels.

Now, this can, of course, happen with our first genes like haloperidol. But I wanted to wait to speak about this until we got to our second genes because there's a second gen med, notorious for this. And therefore, the one you need to know for your exam. Before we get to that, why do we have prolactin elevation and development of things like lactoria in the first place? Well, back to the dopamine highway again. Remember the tubero and vindibular track or dopamine travel to the pituitary to inhibit the secretion of prolactin. Well, when we blocked dopamine here with our anti-scentia, psychotics, we remove prolactin inhibition, and prolactin levels were therefore rise,

and patients can develop hyperprolactinemia with adverse effects like galactoria, among other things as well. So the one drug you have to know that is notorious for this is Resperidone. Now, we just went over the MOA of second gens, and I made a point to mention that second gens are generally weaker D2 blockers. So why does Resperidone a second generation drug cause hyperprolactinemia so frequently, which is a side effect driven by dopamine blockade? And the answer to that is, Resperidone is somewhat of an outlier among the atypicals. Unlike many other drugs in this class, it functions more like a first-gen and that it's a more potent D2 blocker. And that's why we see dopamine blockade mediated adverse effects like hyperprolactonemia, as well as more extraparaminal symptoms.

So while there are other drugs that can cause hyperprolactinemia, do not forget Resperone, as it's one of the most common to cause this and it's always tested on. The way that you can remember, Resperone is linked to hyperprolactinemia and galactorea. is by instead of remembering risperidone, remember it as risperi-dairy. Not a very appropriate mnemonic, and I apologize, but risperi-dairy, dairy, dairy, D-A-I-R-Y, instead of risperidone, helps remember the galactoria, aka milk discharge from the breast associated with this medication secondary to hyperprolectenemia. So again, remember, instead of resperidone, remember it as rispery-dairy. Next is going to be Q-T prolongation, so your antipsychotics can cause QT prolongation,

but there's two second gens that cause it the most, and these are going to be quatyapine, and Zeprasidone. And it's easy to remember that quatyapine causes Q-T prolongation because the Q is far from the T in quatyapine. The Q is far from the T in the spelling of quatyapine, Q, U-E-T-I-A-P-I-N-E, which helps remember this medication, along with Zeprasidone, have the highest risk of Q-T prolongation compared to the other meds in this class. Next we have dund-dun-dun-a-granulocytosis.

This is a dangerous and potentially deadly drop in white blood cells, more specifically neutrophils. and when you hear a granulocytosis on a psych exam, clausopine is the answer that you are looking for. Clausapine is a second generation antipsychotic, but it's quite different than all of the other drugs in this class. It's actually way, way more effective, arguably the most effective antipsychotic we have, especially in the treatment of resistant schizophrenia.

So if it's so damn effective, why isn't clausopine first line for everybody with schizophrenia? Well, a granulocytosis. When this medication was initially tested in patients in Finland in the 1970, they found great efficacy, but people started dying secondary to a granulocytosis. So clausapine is still used in treatment-resistant schizophrenia, and it's actually first line for this specific indication, of course, after patients have tried many other meds in the class, but it requires frequent labs to assess the absolute neutrophil count as frequent as every week during the first six months, and then less so thereafter. So you have to know this association

with this medication. It is super high yield. So remember, clausapine is a white cell fiend. Clausapine is a white cell fiend. Clausapine is, I don't know, snatching up all of those white cells, all those neutrophils, and maybe like eating them or something, the visual in your head. But clausopine is a white cell fiend,

which helps you remember the super high-yield adverse effects of agranulocytosis associated with this medication. You cannot forget that. So those are your adverse effect for your second gens. There are, of course, plenty of others,

neuroleptic malignant syndrome, although this is more common in first gen, so focus on it for that class. Sedation, hypotension, urinary retention, thyroid abnormalities, among others, but the focus should be first and foremost on metabolic syndrome with weight gain, diabetes, etc. Remember, the O and Olanzapine stands for obesity, Resperidone associated with hyperprolactinemia and galactoria, aka Rospheri Dairy,

QT prolongation with saprasidone and quatyapine. Remember, the Q is far from the T in quatyapine, agrilylyocytosis with clazepine because clazepine is a white cell fiend. And of course, remember your extraperaminal symptoms happen, but less frequent compared to first genes. And that is your antipsychotics. I hope that was helpful. Thank you so much for listening and as always best of luck in school