DIP Episode 451 - Serotonin Syndrome (with integrations)

Okay, welcome. My name is Devine. Welcome to episode 451 of the Devine Intervention Podcast. In today's podcast, we're going to be discussing a topic. But before I discuss that topic, I need to give a vignette first. What if they give you a question about a 25-year-old male? They tell you that he has a history of multiple mental health problems. And he has a history of depression and anxiety. And he is currently on pharmacotherapy. Although he has not seen his primary care physician in a few months. And then you're told that he comes into the emergency room because for the past few days, he has been having fevers. He has been having chest pain. He has been feeling short of breath. He has had like some mild weight loss. And then they tell you that there are track marks on his skin. And they tell you that a new murmur is heard at the left upper sternal border. And sorry, at the left lower sternal border. And then you're told that blood cultures are obtained. And the patient is started on empiric antibiotic therapy. Now, they didn't tell you that results of blood cultures show that, show gram-positive cocci that do not respond to vancomycin therapy. That are not susceptible to vancomycin. So that the patient is switched to another therapy. And then you're told that about 24 hours later, this patient starts becoming more and more febrile. So, you know, they say maybe when he came into the hospital, his temperature was 102 Fahrenheit. But now it's 104 degrees Fahrenheit, 105.

They tell you that he has like some muscle rigidity. And they tell you that he has like four plus deep tendon reflexes. And they tell you that a urine bag has become red. And they tell you that he has these hyperkinetic movements of his extremities. And then our friends at the USML Es will then ask, what is the next best step in management? And they can put Dantrol in as an answer. They can put many different options. Or they can even ask which of the following is the most likely diagnosis. Again, I know some of you may say, Devine, this is a really long vignette. But this is a very classic example of a question you could get in the HPI format. We know that the HPI format is something that's used by the USML Es these days. Where they'll give you a medical history. They'll give you a HPI. Give you a bunch of histories. And then they'll give you one or two questions afterwards. So just something you kind of want to keep at the back of your mind for exams. Don't blow this stuff off. So what's the most likely diagnosis? Again, what does it make sense for the USML Es to throw in? Well, it makes sense for them to put anticholinergic toxicity as an answer. It makes sense to put malignant hyperthermia as an answer. It makes sense to put neuroleptic malignant syndrome as an answer. It makes sense to put heat stroke or heat exhaustion as an answer. And it also makes sense to put serotonin syndrome as an answer. But if we put it all together, the right answer here is serotonin syndrome.

So that's the topic of today's podcast. Serotonin syndrome. So let's discuss the facts of the case and how serotonin syndrome makes sense as the right answer. So we see that this person has a history of multiple mental health problems, has a history of depression. Well, if a person is depressed, chances are they are getting some kind of agent that can jack up your serotonin. You can either be getting an SSRI, a selective serotonin reuptake inhibitor, an SNRI, a serotonin norepinephrine reuptake inhibitor, an MAOI, a monoaminoxidase inhibitor, or TCA, a tricyclic antidepressant. Although I would imagine that a physician, seeing that a person is an IV drug user, I would really hope that they don't start off with an MAOI or a TCA. Because again, if a person has multiple mental health problems and they have IV drug use, again, you're already seeing some suicidal antecedents in that circumstance. So it wouldn't make much of any sense to start giving drugs that could be pretty dangerous when you take them. And by the way, I was just throwing one other answer the MB Ms could put in there. They could put like antidepressant toxicity, or they can put like, you know, MAOI toxicity or whatever, just to kind of convolute things a little bit. So the person had drugs that could boost serotonin.

But then this person, obviously, sounds like they had endocriditis, IV drug user. And if you notice, they had the MBM at the left rostromal border. Because IV drug users, they typically tend to have endocriditis on the right side, tricuspid valve endocriditis. Well, why is that? Well, again, if you're an IV drug user, that means you're a drug user that injects drugs into your veins. Literally, that's what IV means, intravenous. Where do the veins in the body drain into? They drain into the right side of the heart. They drain into the right atrium. So that's going to cause problems with the right-sided. So this person has infectious endocriditis. And typically, when a person has endocriditis, the smart first thing to pretty much always do is to get a blood culture. You need to get blood cultures before you start giving the person antibiotic therapy. That's pretty high yield to know, actually.

So they got blood cultures, but they started empiric therapy. But they then, and you know, typically when a person has endocriditis, the most common cause of infectious endocriditis, especially acute endocriditis like this person, is staph aureus. So it's reasonable to start with vancomycin. Vancomycin is a very good empiric therapy. Although many times people also started on rifampin, gentamicin as well. But that's not the main point of this podcast. But the person was starting on vanc. And then, you know, you do blood cultures. Many times when you do a blood culture, you're also going to do susceptibility studies. You're going to do susceptibility studies. So you found gram-positive coxine. You know, probably gram-positive coxine in clusters, which is staph aureus. And you were told in the question that it was not susceptible to vancomycin. So since it wasn't susceptible to vancomycin, it would then make sense that we'll have to institute a drug that can cover... So the person had disease that was resistant to vanc. So what's a good option there? Well, a good option there is going to be a drug like linazolid. Don't get me wrong. There are many other drugs you can use for vancomycin-resistant staph aureus. But if the NBM Es were to pick a drug, it would make sense that they would pick linazolid. Because linazolid is something you expect them to know about. It's a protein synthesis inhibitor. It's a 50 S inhibitor.

So this person got linazolid. And then you'll notice that after they got linazolid, things got bad. So they started getting more febrile, became hyperkinetic, had hyperreflexia, increased deep tendon reflexes, and things like that. So that's serotonin syndrome. So how did the linazolid contribute to their problem? Well, the thing about linazolid is that linazolid is also a very good monoamine oxidase inhibitor. It's a very good monoamine oxidase inhibitor. So because linazolid is a monoamine oxidase inhibitor, it can, because remember, monoamine oxidase breaks down not just catecholamines, right, but it can also break down serotonin. So that can raise your levels of serotonin. And then you combine that with a double whammy of taking some serotonergic agent like an SSRI or an SNRI. And you can see yourself getting into trouble with serotonin syndrome. So that's why this person got in trouble.

So how do we fix this person's problem? And then I'll go into some more pathophase. Well, the way we can fix this person's problem is typically, first, you want to withdraw the offending agent. You want to withdraw the offending agent because serotonin syndrome can be fatal if it's not treated properly. So you want to withdraw the offending agent. Number two, if that's not, and you know, supportive care, you know, but number two, if that doesn't work, then the second thing you need to spring for is a benzodiazepine. Benzodiazepines are very good for treating serotonin syndrome. They tamper down many of the hyperadrenergic effects that you see associated with serotonin syndrome. But if that doesn't work, then your next option is to consider ciproheptadine. Ciproheptadine is an antihistamine, but it's a very powerful inhibitor of serotonin receptors. It's a very powerful serotonin receptor antagonist. So it's very helpful in that circumstance.

So I know some of you may be like, Devine, why would we choose a benzo first over ciproheptadine? Well, again, look at the particulars of the problem. A person that is undergoing serotonin syndrome is probably not the most stable human being around. There are probably people that may not be particularly willing to tolerate PO intake, oral intake. So it would make sense in those circumstances to give something that is a little more rapid acting like a benzo. Because one, a benzodiazepine is very rapid acting. And two, you can give a benzodiazepine intravenously. Ciproheptadine, as far as I know, is not something that can be given intravenously. It's something that you give orally. So just imagine a person going through serotonin syndrome, feeling very crappy, trying to get them to take an oral medication. That doesn't seem to make much sense, does it? Or alternatively, you can give it through, I think, like a gastric tube or whatever. But again, think of all those things. And then, in addition to giving it orally, I think you have to deal with the problem of first-pass metabolism through the lever and all those things. Reabsorption through the GI tract, reduced bioavailability. You don't have any of those problems with benzos. So, benzos, you're giving them IV. So, the bioavailability is 100% for the most part. Has a more rapid onset of action. It's probably going to be better tolerated by a person that does not have good oral intake. So, you want to go to benzodiazepine. Again, if you've tried supportive care, it doesn't work. So, it's something you kind of want to keep at the back of your mind, for example. And one other thing I want to say here that may be helpful is, if the person is very hyperthermic, you can also consider active cooling. You want to consider active cooling. So, at least people do not die.

So, that's serotonin syndrome. So, you know, what are the things that, how does serotonin syndrome work? Basically, anything that can jack up your levels of serotonin can cause you to have serotonin syndrome. Many times, you're going to get this problem from combining two agents that raise people's levels of serotonin. So, what are some of these agents? Again, there's a very varied number of questions they can write on this stuff on exams, right? So, they can give you an SSRI question. That's pretty easy, right? You know, most people can maybe catch that on exams. An SNRI, serotonin or epinephrine reuptake inhibitor can jack up your serotonin. An MAOI, a monoamine oxidase inhibitor. Again, it can be the classic monoamine oxidase inhibitors that we see in psychiatry like phenylzine, tranylcepromine or isocarboxazid. Those are MAO Is. But they can also give you the non-classic MAO Is like linazolid. Linazolid. Again, the thing is, our friends at the USML Es, they love to integrate things. So, if they can give you a question that combines multiple things together for you to arrive at the right answer, that's almost like the path of least resistance for the USML Es because it will force you to think. And it's also a good way to see if a person truly understands the concepts because there are many people these days, they just blindly memorize things with zero understanding or zero context. Or they just say that this one factoid means it's always this. That's not a smart idea at all. Context kind of drives a lot of things.

So, they can give you something like linazolid. It's a 50 S inhibitor. It's a protein synthesis inhibitor, which we can use for MRSA or you can use for Versa, vancomycin-resistant staph aureus. You can also use it for VRE, vancomycin-resistant enterococcus. It's a very effective drug. But again, it's also a monoamine oxidase inhibitor. Now, they can also give you a TCA question, a tricyclic antidepressant question, especially imipramine or clomipramine. Those are two of the TCA's that have, I believe, the strongest associations with serotonin syndrome. So, the thing is, some of you may be like, well, you know, I can catch a TCA. Well, they can give it to you in an unusual setting. For example, they can give you a question about a person that has OCD and the person's symptoms are not responsive to SSR Is. And then they tell you that the person starts on new pharmacotherapy and then for their disorder. And then they start having these antecedents of serotonin syndrome. That's going to be clomipramine. Clomipramine is a second-line agent for the management of OCD. You know, probably remember the C in OCD as the C in clomipramine. Also, meth, methamphetamine, can cause a person to have serotonin syndrome because these things raise the amounts of serotonin that you have in your adrenergic synapse. So, they can give you a drug user question, methamphetamine, or they can give you a question about a person that is being treated for ADHD with a drug like dextramphetamine. Dextramphetamine is a methamphetamine derivative.

Or they can even give you a question about a person that starts becoming febrile after getting treatment for methemoglobinemia. Well, methemoglobinemia, remember, is treated with methylene blue. Methylene blue is going to convert that ferric iron, Fe3+, to ferrous iron, Fe2+. Methylene blue can raise your levels of serotonin. Also, they can give you a question about a person that's taking pain medications, right? Like meperidine, we like to use meperidine for pancreatitis pain. Because technically, as far as I know, it does not cause spasm of the sphincter of OD. So, it doesn't worsen pancreatitis. If anything, it actually keeps the sphincter of OD open so that the pancreatic ducts can drain well. Well, meperidine is associated with a serotonergic effect. It can cause serotonin syndrome. They can give you a question about a person that's taking pain medications, things like tramadol. Tramadol, yes, it's a weak opioid, but it can also trigger serotonin syndrome. Dextromethorphan. Dextromethorphan, we find it in many cough syrups. You see a person, you know, they have a history of depression. Again, many times, you cannot get serotonin syndrome. Let me not say you cannot. But you generally should not get serotonin syndrome from just taking a cough medication. And please, by the way, none of this podcast or any of my podcasts are for medical decision-making. They're mostly for test prep purposes. Actually, they're entirely for test prep purposes. That's it.

I'm just doing this for personal interest. I'm not trying to get your medical decision-making. But dextromethorphan, taking that alone should not cause a person to have serotonin syndrome. But when you combine it with another serotonergic agent, that's where you get in trouble. So if you see many cough syrups, they have like something-something DM. What do you think the DM stands for? It stands for dextromethorphan. Dextromethorphan is a weak opioid. But again, it has those serotonergic properties. And then cocaine. Cocaine also has serotonergic properties.

So these are just all things you want to keep in mind. They can even give you a person taking a herbal supplement. But that's going to be St. John's Wort. St. John's Wort is absolutely associated with serotonin syndrome. It actually has weak SSRI activity. And many of these unusual drugs that you see me mentioning, you know, I talked about inizolid. And how it's an MOI. Many of these other drugs that you're like, man, these drugs kind of break the norm. That can cause serotonin syndrome. Many of them in general are drugs that inhibit the reuptake of serotonin. So you have like some SSRI or some SNRI activity. Just something you want to keep in mind. Even there's migraine medications like sumatriptan. Remember, sumatriptan is a serotonin receptor agonist. It can cause serotonin syndrome. Or the drug we use as second-line treatment for generalized anxiety disorder. Buspirin. Buspirin is a partial agonist at the serotonin 5-HT1 E receptor that can cause serotonin syndrome. So again, these are just all the things that they can give to you where a person can have serotonin syndrome.

So what are the classic features of serotonin syndrome? The thing is, classic features of serotonin syndrome, these people can be tachycardic. They can have mydriasis. Because many times when your serotonin is elevated in the central nervous system, it also elevates other catecholamines. It also elevates norepinephrine. Because if you also think about it, if something is probably like preventing the reuptake of serotonin, it's probably also preventing the reuptake of other catecholamines like norepinephrine. So it makes sense that mydriasis can be part of this. It makes sense that tachycardia can be part of this. But the classic, classic thing I'll see you should keep in mind with serotonin syndrome are reflexes. The person is going to have hyperreflexia. They're going to have hyperkinesia. Hyperreflexia, hyperkinesia. But the thing is, many other findings in other diseases like malignant hyperthermia or NMS, like rhabdomyolysis, muscle rigidity, all those things, you can absolutely find them in serotonin syndrome as well. Again, that's why I scratch my head when people say, oh, that muscle rigidity is NMS, malignant hyperthermia, but there's no muscle rigidity in serotonin syndrome. You're kind of deceiving yourself. The NBM Es, they know that people deceive themselves that way. So you can throw all these things in. Just kind of keep these things in mind. Kind of keep these things in mind. And by the way, some other things that I maybe forgot to mention that can cause serotonin syndrome, don't forget MDMA/ecstasy can absolutely cause serotonin syndrome. Metoclopramide, which we use for, it's an anti-medic, it can absolutely cause serotonin syndrome as well.

So just the critical things you see is like, oh, hyperkinesia, hyperreflexia, think of serotonin syndrome. People that have neuroleptic malignant syndrome or malignant hyperthermia, yes, they'll have muscle rigidity, but typically those people are going to have hypokinesia. They're going to have hypokinesia. Usually they're going to have hypokinesia. So if you see cloners, if you see a person just having a lot of reflexes, you see a lot of reflexes, always, always think about serotonin syndrome. Always, always think about serotonin syndrome.

Okay. And again, I've kind of talked about the management. I've kind of talked about the treatment. In fact, I'm really hoping that I can make a separate podcast, honestly, on malignant hyperthermia and NMS so that you can see those for what they are. I think kind of having a complete understanding of both is going to be pretty, pretty, pretty helpful here. But just, again, kind of keep these things in mind as you study.

And one other veneer I guess I want to throw in here with this whole lenezolead business. Again, remember, the same advice that applies to MAO Is should apply to lenezolead with tyramine rich foods. You can already, I can already see that our friends at the USMD is writing a question about a person that's taking cheese or whatever. And they're taking a long course of lenezolead because, you know, they have like endocrinitis. Many times when people have endocrinitis, they're on pharmacotherapy for about six weeks. That can cause a hypertensive crisis. Just something I want to recognize. That's a very, very beautiful integration you could see on exams.

So, again, I think you should kind of keep these things at the back of your mind and we should maybe go ahead and stop here. So, for those of you that are taking any of your USMD exams, I have classes that are coming up. Starting this Friday, actually. I have a test-taking strategies class starting on Friday. For step one to step three, I have a biostatistics class taking place on Saturday for step one to step three. I have a step one class taking place next week, Monday, Tuesday, Thursday, Friday, and Saturday. And then the week after that, I have a step two, step three class. It's a 20-hour class. It's taking place on Monday, Tuesday, Thursday, and Friday of the last week of the month of April. And then on the 29th of April, which is, I believe, the last Saturday in the month of April, I do have a social sciences and ethics class. That's a five-hour class. Again, many people have taken these classes and they found it to be really helpful. I've had people say, wow, most of the, I took your biostats and your ethics classes and every biostats, every ethics question, every QI question, every social sciences question I saw on my exam, I got everything right. And again, I've had many people that have failed USMLE exams. They've taken these classes. They've passed. I've had people get very high scores, 260s, 270s, even in the 280s from taking these classes. So again, if you're interested in any of these classes, I think you're going to find them to be helpful.

If you're a person that is looking for a lecture, then you probably shouldn't attend. That's not what I do. I do these classes like I do my podcast. I love scenarios. So most of these classes are like 95, 97% scenarios. And then, and they're interactive. I also spend time taking questions from the audience and answering people's questions. So if you're interested in any of these classes, shoot me an email and I'll give you some more information. I also offer one-on-one tutoring for step one to step three, preclinical med school exams, third year shelf exams. And I also have these podcasts on Apple Podcasts, Google Podcasts, and Spotify. I have a You Tube channel, Divine Intervention, USMLE Podcasts and Videos, where I post the videos that I make. And then finally, I also have a new website called divineinterventionlifelessons.com. Many of you know I'm a Christian. So using the Bible, I post two podcasts every week where I address a life lesson, something that probably applies to most people, usually about 10 to 20 minutes long. I post on usually on Fridays and Sundays. And from a biblical perspective, I address a life lesson. There's actually an Apple Podcast associated with that, the Divine Intervention Life Lessons Podcast. So thank you for listening to me today. I'll see you in episode 452. Have a wonderful rest of your day. God bless you. Bye for now. Thank you.

Hyperreflexia, hyperkinesia (clonus/hypermovement), and autonomic instability (e.g., tachycardia, mydriasis).

Linezolid.

Intravenous Benzodiazepines (e.g., Lorazepam).

Tricyclic Antidepressants (TC As).

It acts as a Monoamine Oxidase Inhibitor (MAOI), preventing the breakdown of serotonin.

Neuroleptic Malignant Syndrome (NMS) or Malignant Hyperthermia (MHD).

The right side of the heart/Tricuspid valve.

Tramadol, Dextromethorphan, St. John's Wort, or Metoclopramide.

It is a powerful serotonin receptor antagonist (antihistamine).

Benzodiazepines are IV-administrable, rapid-acting, and bypass issues of poor oral intake or first-pass metabolism.

SS typically presents with hyperkinesia/hyperreflexia (clonus), whereas NMS/MHD typically present with severe muscle rigidity and often hypokinesia.

The right side of the heart/Tricuspid valve.

Tramadol, Dextromethorphan, St. John's Wort, or Metoclopramide.

It is a powerful serotonin receptor antagonist (antihistamine).

Benzodiazepines are IV-administrable, rapid-acting, and bypass issues of poor oral intake or first-pass metabolism.

SS typically presents with hyperkinesia/hyperreflexia (clonus), whereas NMS/MHD typically present with severe muscle rigidity and often hypokinesia.