Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast is Narrator - ? 00:12 provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk. Episode 140 I'm your co host, Dr. Kane, and I'm Dr. Patel. I'm excited that we have Dr. Roberta Duma with us today, who is an expert in all things in the psychiatric world, but we brought her in for this episode in particular, which is entitled The Ultimate Guide to SSRIs and in depth drug class review. So Dr. Dumais, thank you so much for coming on. Do you want to just kind of introduce yourself to the audience before we jump into the episode? Speaker 1 00:58 Sure. Thank you so much for having me everybody I as a previous student listening to HelixTalk and now faculty at RFU, it's great to kind of be on as like a guest host. And my clinical area that I work in is at the North Chicago VA, next door to RFU, so I'm excited to be talking with you guys today. Unknown Speaker 01:18 Well, Dr. Dumas, it's a full circle, and we're so glad you're with Unknown Speaker 01:21 us today. Thank you. Well, Dr. Sean Kane 01:24 we'll go ahead and jump in. You know, the title, I think, speaks for itself. But today, we're going over SSRIs as a drug class, and then going through some of the nuances in terms of what makes SSRI a different than SSRI B, going through some of the clinical pearls and things like that that a practicing clinician might want to know when it comes to treating depression and anxiety with this drug class. So why don't we kind of kick it off in terms of what are the SSRIs and which ones are more commonly prescribed or less commonly prescribed? So Dr. Duma, why don't we start with that? Speaker 1 01:55 All right, so some of our most commonly prescribed SSRIs that we have, sertraline or Zoloft is one that comes up very often, another one that can be prescribed, maybe not as often as sertraline, but you see it very often, especially in the private sector. I don't see it as much in my clinical practice, but it's an escitalopram (Lexapro), and then fluoxetine or Prozac has been around for a long time that one is also very commonly prescribed as well as citalopram. Branded name is Celexa. Some of our maybe not as commonly prescribed anymore, maybe, like, less than 10% of what's available there on the market would be medications like paroxetine or Paxil and then fluvoxamine. It is technically an SSRI. Some folks may forget that, because we actually don't use it to treat depression. We'll talk a little bit about it later. It's has other FDA approved indications, and I'm Dr. Sean Kane 02:48 just going to throw it out there, fluvoxamine for covid 19, we will not be talking about at all, but it's a hot topic, and we're not touching that today, so sorry if you're hoping for that. Speaker 2 02:59 And so you know, as my patients like to call these my happy pills. You know, common use of SSRIs is it's for its treatment and depression, major depressive disorder or anxiety, and specifically the generalized anxiety disorder. There's some on label as well as off label uses that are not mainstream. And what would those be? Dr. Duma Speaker 1 03:20 so sometimes you may be able to see this in a premenstrual dysphoric disorder, or PMDD, as it's a commonly referred to obsessive compulsive disorder, as we said earlier, fluvoxamine, it's actually the drug of choice for that. It's actually high doses of these antidepressants are used to treat OCD and then just some other like specific, like more nuanced anxiety disorders, post traumatic stress disorder, I treat this, you know, daily in my in my clinical practice, there could also be some indications for panic and social anxiety disorders as well, and then moving on, maybe something that we don't necessarily think of. Some of these antidepressants specifically, these SSRIs can also be used to treat conditions like bulimia, neurosa or binge eating disorder, and then maybe some things that are much even less so related to anxiety and depression. You could see these may sometimes be used for like vasomotor symptoms of menopause, specific menopause symptoms, or even premature ejaculation, which we'll talk about when it comes to side effects later on. Dr. Sean Kane 04:20 So tons of indications here. And as we mentioned, different SSRIs may be FDA labeled or indicated for some indications, whereas other SSRIs may be off label use. So it kind of depends on the indication and the SSRI that you're looking at with that in mind, you know, in terms of the mechanism of action, one nice thing about the drug class SSRIs, it actually tells you the mechanism. So SSRI stands for selective serotonin reuptake inhibitors. So Dr. Dumais, maybe you can walk through the acronym in terms of why they picked those different words, and how that results in this improvement of primarily anxiety and depression for patients that take this drug class. Speaker 1 04:57 So SSRIs, they selective. Really bind to serotonin reuptake transporter, so they don't really focus on other neurotransmitters, or what we call monoamines, but mainly just with serotonin. Serotonin sometimes in literature or in when you're in school and you're learning about it, it's also written out as five HT. And then there's specific subtypes other drug classes when in comparison, sometimes it's easier to compare it with other drug classes. For example, tricyclic antidepressants, which have been out around much longer than SSRIs have. They're not selective at all, and it kind of goes into kind of those reasons why we may not use them as often because of the way that they block serotonin, but they also block other neurotransmitters as well, for example, norepinephrine, or if there's like some alpha activity, they're kind of just lead to more side effects, as compared to medications like SSRIs that selectively bind to serotonin only. And when you're looking at like the neuron, what it does is that they bind to these like pre synaptic nerves, which will then kind of block the RE uptake in the synapse further downstream. So they're increasing serotonin in the synapse by allowing that blockage to happen, so that there's no more reuptake happening at the synapse, at the end of the neuron, postsynaptically. And it gets a little bit hairy when it comes to the side effects versus the therapeutic benefit. So this is something that we teach very early on when and it's a counseling point that should be given to patients. Is that you may experience side effects right away, but it's going to take a couple of weeks for you to feel better, for that happy pill to work, like you said, Dr. Patel, and there's a couple of different postulated hypotheses and a great resource to utilize to kind of go a true deep dive with graphs and charts and paragraphs and paragraphs would be stalls essential psychopharmacology, if I have access to like an E version or like the actual book itself, they go into great depth about this. But what the mono amine hypothesis says is that while yes, the immediate presynaptic desensitization of the neurotransmitters, it takes a long time for that to down regulate postsynaptically, so that there is an immediate elevation in monoamines initially, that's when you get those side effects, but then it takes longer for The adaptation to down regulate postsynaptically, and that's why the therapeutic effect is delayed a couple weeks. There are other hypotheses out there, particularly one that folks may have heard of would be BDNF, or brain derived neurotrophic hypothesis. But for the purposes of today, you can definitely, again, look that up in psychopharmacology kind of textbooks to kind of get a deeper dive, but there's a couple of different hypotheses out there as to why takes longer for them to work. Speaker 2 07:47 You know, that's really interesting to know. And like you said, Dr. Dumais, it's really important to let the patients know why the side effects come before the actual benefit of the drug. And looking at the treatment of depression and anxiety, kind of focusing on the main indications for SSRIs. Where do they all fit? We discussed that. You know, these are like the first line therapies to go to, but do we pick one over the other? Is there any difference in the efficacy when we are selecting SSRIs for depression or anxiety? Speaker 1 08:19 It really does depend on patient specific factors, and when I teach this to my students in class, maybe there's an eye roll, because I always say that a lot of in general, with psychiatric pharmacy, it's like very patient specific because they all have maybe slightly different side effects. While all of them may be a first line option, there may be one that's slightly better than the other, just given some of the particular symptoms a patient may have at baseline. Dr. Sean Kane 08:44 So kind of highlighting that a little bit. If I was to go in a depiro chapter or clinical practice guideline document, we will see SSRIs as first line therapies. Is there ever an instance where one specific SSRI is preferred in depression globally, not just based on patient specific factors, Speaker 1 09:02 not for depression. There is not one that you would say you would do this one as opposed to another one for depression alone. If we're looking at specific like anxiety disorders, for example, the VA DoD guidelines that were published in 2017 I think, or 2019 I'm not sure they have four antidepressants, three of which are SSRIs that they prefer. They've shown really good data for use in PTSD, symptoms specifically, but for depression, and there's no specific patient factors that you have available to you. All SSRIs are first line. Dr. Sean Kane 09:37 I think the other question that commonly comes up is when someone does take an SSRI, if they don't have a good response, meaning that their depression, for example, doesn't get better. Is the next step that they'll try a different SSRI, or is the next step that they'll go to a completely different drug class, like an SNRI or a TCA, or something like that? Speaker 1 09:57 That's a really great question, and it depends on. If it was just they didn't find any therapeutic benefits, but they were able to tolerate it. Okay, you can definitely try another SSRI. Just because you fail one SSRI does not mean you fail the class. And if there's more of a, oh, I didn't really tolerate this medication very well, they the patient may be more hesitant to try another one from the same class. So then you may have to have a little bit more of an open conversation with them, discuss that, you know, maybe this one has higher rates of diarrhea or nausea, but you can still potentially try some of the other ones from the class. However, we could also move on to another class that's also considered first line as well in those cases, Speaker 2 10:38 and kind of going along the routes of, you know, treatment and how they're taken, kind of diving into the pharmacology a little bit. They are mostly dosed once daily, because of, you know, the half life of about one day. We're going to talk about that in just a little bit. And some of these SSRIs go through CYP metabolism, especially the CYP2D6 pathway when it comes to fluoxetine and paroxetine. So we have to look out for drug interactions with other drugs, such as, you know, codeine, Tramadol, oxycodone, tamoxifen, that comes to mind when we're thinking about CYP2D6. And then obviously, you know, looking at other antidepressants, as we talked about like TCAS, like amitriptyline and stuff. We're worried about some of the higher levels of TCAS and kind of giving that anticholinergic style side effects and stuff. But on the flip side, if you're selecting these SSRIs based on drug interactions, your citalopram, citalopram and sertraline have less significant interactions, definitely not the CYP2D6 pathway based interactions, Dr. Sean Kane 11:49 yeah, and I would say, in terms of the CYP2D6 interactions that we see, what's interesting is some of those classic examples, like you mentioned, Dr. Patel, with those analgesics, It actually makes it so that they aren't activated as well to their more potent metabolites. So it means that the analgesics, opioid analgesics, don't work as well. Tamoxifen, that's a pro drug that is activated, so you don't get as much of the active compound. So therapeutic failure potentially. And then, with things like amitriptyline and other antidepressants, you metabolize those drugs less, so the half life extends and you actually get higher levels. So the nature of the interaction itself depends on whether the two to six pathway is an activation pathway or a metabolism pathway to get rid of the drug in the body. So again, with fluoxetine and paroxetine, those are kind of our troublemakers, and then the other ones, not so much. What will Speaker 2 12:43 be some of the other maybe not beyond looking beyond the drug interactions. What will be some of the common adverse effects that we will be advising patients for us as our eyes? Speaker 1 12:54 So, as we mentioned earlier, the side effects, unfortunately start right away, and therapeutic benefit, like the ultimate goal of treating hopelessness or treating that depressed mood or treating that generalized anxiety, does take weeks, we usually say at least four weeks, to kind of start to feel better. They are dose dependent, so that's why I like to tell my patients that antidepressants, SSRIs, it's like, slow and steady wins the race, just like, like the rabbit versus the turtle. These are the turtles in your treatment. They're not like your quick acting. They take a while to kind of work, and you have to be patient with them. So starting low at a low dose will help mitigate any of those side effects that a lot of people don't tolerate, and some ultimately stop the medication because of them. But we also want to counsel folks that the side effects do improve with time your body just needs to get used to them. As we continue to kind of regulate those serotonin levels on various areas in the body, there are serotonin receptors in our gut, so that's why people feel really crummy. They have diarrhea, they have nausea, they have upset stomach. That's why that happens like immediately, and a lot of folks don't like it. But just generally speaking, some other side effects that we can occur with SSRIs is sexual dysfunction. It's something that I feel like maybe a lot of providers don't want to talk about, because then maybe the patients don't want to take these medications. And it may be a sensitive subject to some, it is highest with sertraline and paroxetine, and it is lower if you start off with maybe fluoxetine or escitalopram, in particular, with men, what you'll notice is erectile dysfunction is probably the highest rates and then delayed in ejaculation as well, and then in both women and men, there could be some inorgasmia or inability to orgasm, or just decreased libido. It's interesting, though, because sometimes untreated depression or untreated anxiety can also exhibit decreased libido or inability to orgasm, things like that. So. Yeah, potentially for some folks, when they start a medication, some of this may improve over time, too. Dr. Sean Kane 15:04 And I know you mentioned the gastrointestinal side effects, like nausea, vomiting, diarrhea, anorexia, is there an SSRI that's worse or better for that particular side effect? Speaker 1 15:14 Clinically, I've noticed it the worst with sertraline for whatever reason, however, they all have this as a side effect profile in folks who you are starting sertraline instead of starting it at like 50 milligrams, or they have a history of having really bad GI issues with other medications, you can start even at small dose of 25 milligrams with those folks. Speaker 2 15:35 So Dr. dimay learning SSRIs back in school, you know the word activating or kind of deactivating came to mind, and that has to do with how much of these SSRIs triggered the nervous system. So those that are activating can cause insomnia or agitation, and those would be SSRIs such as fluoxetine or sertraline. However, the sertraline can kind of cause both the insomnia or hypersomnia, which is sedation, and then paroxetine is kind of more common to be causing sedation. Are they still using that kind of a terminology? Dr. Dumais, and that's how these three are categorized? Speaker 1 16:14 Oh yes, most definitely. This is where you can sort of see now when I would choose one over the other, of somebody who is has depression is very fatigued, really tired throughout the day, I'm going to probably start them on fluoxetine. On the flip side, you also want to make sure that you're educating them, because maybe they also have some insomnia. That doesn't mean that they can't try Prozac or fluoxetine, but you just want to make sure to tell them not to take it close to bedtime, or if they forget their dose, their morning dose, not to take it in the afternoon. Just skip it. Move on. Take it tomorrow's dose in the morning, because it does really affect people's sleep. And I can't count the number of times I ask folks, you know, I've seen them for a couple of visits, and they ask them, when are you taking your fluoxetine? And they tell me they're taking it in the evenings after being counseled on it even, and it's affecting their sleep, and when they switch back to a morning dose, they have energy during the day. They can sleep okay at night. So yeah, we kind of try to educate folks and say words like activating or sedating or it makes you sleepy, to kind of help them take it at the appropriate time of day so it doesn't interfere with their day to day activities. Dr. Sean Kane 17:24 Now, Dr. jume Kind of along the same lines, I know that, given the activating nature, if you will, that that could have implications when treating patients who have anxiety. Even though these SSRIs are commonly used to treat anxiety, the more activating they are, potentially that could worsen their anxiety, if not kind of titrated appropriately. Is that correct? Speaker 1 17:45 Yeah, it is kind of ironic how we can induce anxiety, but we're using them for anxiety. It's more of that long term goal of decreasing overall generalized anxiety and your baseline anxiety, or having less panic attacks, let's say so it starting on a low dose, not starting on a too high of a dose, and titrating up slowly will help mitigate some of those worsening anxiety like symptoms, and then having something like a short acting as needed anxiety medication could be really beneficial for some folks who are maybe still feeling like Okay, starting a new medication like this will worsen my anxiety Speaker 2 18:22 and the weight gain is also another chicken or the egg situation. I've had some patients, in practice, they say that, you know, please don't put me on anything that would make me gain weight. Which ones are more on that line? Dr. jamaya, especially when somebody is depressed and, you know, their maybe lifestyle is a little bit more sedentary and stuff. It's harder to give them medication that can, you know, make them gain more weight. Speaker 1 18:48 Yeah, in general, I do think that SSRIs, when you compare them to the larger class of other psychotropic medications, even other antidepressants that we used to treat depression are pretty weight neutral and are not a big culprit. And we're not kind of like, you know, pointing our fingers at them for weight gain. However, there is still potential for weight gain. I think paroxetine is probably the one that is associated with the most weight gain. It's the most sedating, so it is something that you may want to educate your patients on. And fluoxetine is probably the most weight neutral of our SSRIs, but generally speaking, SSRIs don't have terrible weight gain as you compare it to other drug classes that we use for other mental health conditions. Dr. Sean Kane 19:31 So Dr. Dumais, we've kind of talked about some of these larger categories of side effects, but anytime you watch a drug commercial, you hear like 10 other side effects as well. What are the other common side effects that maybe don't fit in these logical buckets in terms of the side effect profile of SSRIs in general, right? Speaker 1 19:50 A big one, I think, would be headache. That's pretty common with a bunch of oral medications that are taken, and SSRIs also could potentially cause headache. Could also notice some dizziness. Maybe initially dry mouth, some blurred vision, and then also hot flashes. I've noticed more recently with a lot of my folks who started antidepressant especially SSRI, notice it as well, like some heat intolerances Speaker 2 20:15 and so so far, the side effects we discussed were kind of like common, but not as severe side effects. There are some rare, however, serious side effects associated with SSRIs. You know, the first one that comes to mind is suicidal thoughts, and that's kind of part of the box warning on all the antidepressants. However, this warning is somewhat age specific. Can we expand on that? Dr. Dumais, yeah, so Speaker 1 20:43 there is an increase of suicidal ideation and suicidality in general in those who are 18 to 24 years old. Why this particular group most likely? It's because folks in this group are more likely to be impulsive, as compared maybe to an adult who's a little bit older. So when you look at the therapeutic effects of SSRIs, one of the first things that kind of start to improve is maybe energy, you're sleeping better, and also motivation. So now that you have somebody who's motivated but they're still depressed in those first two weeks of starting an SSRI, maybe they're more likely to act on some passive suicidal thoughts that now become more active. Maybe there wasn't a plan before, but now there is a plan, because that motivation is starting to improve. So that's why, in those first two weeks when you start an antidepressant, is really when you want to check in and assess and do a suicidal assessment on folks in particularly in this group. So it's not really seen with those who are older, like 25 to 30, and it continues to, you know, this risk is lower as you increase in age. Dr. Sean Kane 21:51 Now, Dr. Duma, is this an SSRI specific warning, or are all antidepressants falling in this similar pattern or category? Speaker 1 22:00 Yes, I would definitely say that it's not just SSRIs, it's it's all antidepressants, just on the way the therapeutic effects of the medications, they all kind of take longer to work, and motivation comes back first, so it's something that you want to assess in those first two weeks of starting therapy with any antidepressant. Speaker 2 22:21 Yeah, that's great to know, and I guess I do not work with particularly younger patient population as much. But the one that another serious side effect that comes in my discussion all the time, it's because these epic drug interaction flag warning left and right, and it's Qt prolongation, especially with citalopram, but it does flag it with a citalopram as well. So what's the data there? What's the deal there? Right? Speaker 1 22:49 So citalopram, it's what they've noticed, is that at higher doses of citalopram that were maybe initially approved, they noticed a QTC prolongation. So when you're older, you may be more prone to QTC prolongation given other conditions that you may have, other medications that you may be on that can prolong the QTC interval. So there is actually something that in the in the actual drug monograph, that they recommend folks who are six years or older to the max dose is half of the regular maximum dose for other adults. So just as a way to kind of, you know, think of when you're thinking of citalopram, I don't like using it in older adults in general, because you're limited for how much you can titrate the medication because of that potential for that QTC prolongation. It is, you know, it's not something that is like a huge warning, but it is something to, you know, really be mindful of when you're on this medication, to maybe be a little bit more vigilant and do an EKG a little bit more regularly than you normally would. But there really isn't any evidence of like arrhythmias or started sudden cardiac death with this medication. Dr. Sean Kane 24:00 And I would just add to that that with QTC prolongation in general, you know, if you look up a list of meds, you're going to come up with 500 meds probably that have a potential for QTC prolongation. What we found in the literature for arrhythmia specifically, is that there are plenty of meds that prolong QTC but don't cause things like Torsades or other arrhythmias. Then there are other meds that do prolong QTC and definitely cause arrhythmias, like the anti arrhythmics, especially class three anti arrhythmics. Dr. Duma in your practice, at least, are you getting 12 lead EKGs on everyone before you start citalopram? Or is this kind of on a case by case basis? Or how do you kind of risk assess a patient before starting any SSRI, but especially citalopram. Speaker 1 24:41 First of all, I look at their age. I look at what other medications they're on, just like you said that laundry list of 500 plus medications that can prolong the QTC, and I look to see if they're on any other medications that can increase that risk. And then I just also you most folks have an old EKG. On file. And I'm lucky to work at a facility where I get access to all their labs while also working in like an outpatient type of setting. So I look at previous trends to see if they pretend if they have potentially a longer QTC, and then, typically, I don't do a baseline just for starting citalopram. There are other medications out there within mental health that you want a baseline EKG prior to starting this isn't one that I'm super vigilant about, to be quite honest. It's a case by case basis. Speaker 2 25:28 Well, that's helpful. And the other kind of rare issue that we potentially see with SSRI, it's probably more in your nook of things. Dr. Kane is drug induced si ADH. And when we think about drug induced si ADH, you know, we normally think diuretic like diazide or an SSRI or SNRI, but in the early days of starting an SSRI, there could be a patient who may come up with symptoms such as, you know, nausea and vomiting, which are kind of common side effects, as we talked about of SSRIs, perhaps even altered mental status, such as confusion or increased, you know, somnolence or sedation, potentially even seizures, if, if their sodium has dropped to dangerously low levels, yeah. Dr. Sean Kane 26:16 And I would say, every year, I see a handful of these patients that come in that started an SSRI, and they come in with a sodium of 115 I actually don't know. Dr. Dumais, maybe you have a better sense of how common this is. I know it's uncommon, but is this one in 1001 in 10,000 Do you ever do follow up sodium checks just for this particular side effect, or is it so rare that really the symptoms are going to prompt additional lab monitoring for these patients, Speaker 1 26:43 I most definitely think it's more symptom driven. You know, if they're if they're vomiting, they're becoming dehydrated, you would just do like a BMP or a cmp, and just see what it is, and then take it from there and see what other medications like you mentioned earlier, Dr. Patel, like starting a thighs, I will induce some of these symptoms, not something that I necessarily will be vigilantly looking out for. When it comes to, yes, hyponatremia, we need to, like, do a full workup for that. It's pretty rare. Dr. Sean Kane 27:12 Dr. Patel, I feel like the next side effect is something that you kind of already mentioned in terms of drug interactions and epic alerts and things like that. I think many people have worked in facilities where an SSRI is prompting some interaction with an anti platelet therapy, you know, suggesting a higher risk of bleeding. Have you seen that your practice, Dr. Patel, and can you tell us a little bit more about that? Speaker 2 27:36 All the time, I actually put my students to task and figure out what this drug interaction is and what the what the baseline mechanism is all about. And so, yeah, we get those flags. And obviously there is sometimes overabundance of these flags, and avoidance of the flags too. But this, this is something kind of going back to the previous one looking at patient specific risk for bleeding. Obviously, you know if the patient is on other anticoagulants, like warfarin or doac or anti platelets, you do want to monitor the risk for bleeding. But the mechanism is that the SSRIs could inhibit serotonin uptake into the platelets and kind of decrease the platelet aggregation. And so when it times to come and create a platelet plug, the platelets don't kind of connect with each other, and so it could be prolonged bleeding. So that's a theory. However, if you look at some retrospective studies, kind of have said that the quality of the data that we have looked at for the increased risk of bleeding is not really great, and so if the patient is starting SSRIs by themselves, probably not a big deal. However, if they're on other medications that can increase the risk of bleeding, plus their inherent bleed risk is high, then you might want to suggest that they keep an eye on any abnormal bleeding or bruising Dr. Sean Kane 29:04 to follow up on that. Dr. Dumais, is there ever an instance in your practice where you would not give an SSRI to a patient, let's say, with a high fall risk because of the bleeding concern, or is this a small enough or more theoretical risk that it wouldn't necessarily prohibit you from starting an SSRI and someone who would, let's say, be at a high fall risk. Speaker 1 29:25 That's a great question. I would definitely avoid maybe more of like a sedating antidepressant to promote that fall risk. But I would, I would maybe go more towards an activating antidepressant. I wouldn't not treat somebody with an SSRI, because if they have a higher fall risk, I have patients in my practice that are in their late 80s and early 90s, and while, yes, we, you know, they have depression, we started them at very low doses, but not necessarily, not utilizing these medications because of their age or their risk for falls, definitely. Still something to pursue and continue to educate like Dr. Patella said about if they are just at an increased risk for bleeds in general, Speaker 2 30:08 and the last but not the least, and we can't complete this episode without mentioning is, it is serotonin syndrome. We loved serotonin syndrome so much that we created an entire episode. We had the discussion for it. So if you want to listen to it in depth, you know, go back to our episode number 63 for it. But in general, serotonin syndrome, as the name sounds, there's just too much serotonin in those synapses. It could be idiopathic, even at usual doses of SSIs. It could be at higher doses, or when you're combining medications that work in the serotonin system, such as, you know, augmenting drug interactions could lead to that. And obviously, you know, intentional overdose, which could be a situation in this patient population, can cause that too. Having said that, Dr. Dumais, how many actual cases of serotonin syndromes Have you seen in your practice so far? Speaker 1 31:07 This is probably more a Dr. Kane question, when he when he may see the patient? I don't really see it. Some patients may not even know that they're having serotonin syndrome, and they just may have mild symptoms. It's really the more severe cases when and Dr. Kane, if you use a different scale, you know, please share. But usually it's like the hunter criteria, because some of these are very nondescript symptoms, and we'll go over them. And they may kind of blend and may mimic other acute situations. For example, one that comes to mind. There's a lot of data out there, and like how to differentiate between serotonin syndrome and another kind of acute case of what's called NMS, or Neuroleptic Malignant syndrome, and things like the hunter criteria help that. Dr. Kane, do you see a lot of this in your practice? Dr. Sean Kane 31:53 No, I don't. You know. A lot of what we see in the ICU, at least, are patients, let's say, on fentanyl drips, because fentanyl has a potential for serotonergic property to it. So high doses of fentanyl drips, and they're also taking an SSRI, because that's what they're on at baseline. Then they start developing, you know, fever and some of this muscle rigidity. But it's not completely clear if it's definitely due to serotonin syndrome or not, most of the time, even with something like a hunter criteria, it's not clear enough to us what the culprit is, and it's pretty easy in most cases to stop the SSRI. So for that reason, usually we don't have a firm diagnosis. The only exception I can think of are cases in which someone intentionally overdoses on an SSRI, and it's pretty clear that they did that and that the symptoms that they're having is because of their overdose. That's kind of a layup shot. You don't even really need 100 criteria for that. But at least to my practice, one, really, really rare, and two, usually it's not clear enough that you can definitively say if that was the problem or not. Speaker 2 32:57 Yeah, I think talking about the rarity, you know, in my practice, I've seen it all but once, and there was some, a patient who was on 150 milligrams of amitriptyline, and then an SSRI was added on top of it, and ended up showing these, some of these symptoms, such as, you know, altered mental status. Patient had high temperatures or hyperthermia, hyperreflexia, muscle rigidity, which is what causes that hyperthermia, myoclonus, as well as, you know, maybe sweating, palpitation, tachycardia, high blood pressure. My patients had some of this, and the PCP was hyper vigilant and kind of noticing that, you know, the only thing that had changed recently was the addition of SSRI to the amitriptyline therapy, and that's how we had caught it. Yeah, these are normally the symptoms. And like you said, Dr. Dumas, these are probably hard to catch unless you're being hyper vigilant Exactly. Speaker 1 33:56 I think that, you know, there are some things we do want to kind of keep out for. And you know, Dr. Kane, you mentioned one, for example, fentanyl, some other synthetic opioids that could potentially trigger serotonin syndrome, especially at higher doses. Could be Tramadol, stimulants, you know, like medications we use to treat Attention Deficit Disorder, ADHD, even dextromethorphan has kind of like a serotonergic moiety, which is available over the counter. And then some of the ones like off the beaten path, like linezolid is the antibiotic that we know has interactions can increase risk for serotonin syndrome, probably the worst one, and is actually one that you do need to be very vigilant for. And it's actually in the drug monographs would be MAOIs, MAOIs monoamine oxidase inhibitors, they're antidepressants that are last line. You look at all the guidelines, they're last line for many reasons, lot of drug interactions. It interacts with foods. People have to limit what foods they take, and the biggest one is having serotonin syndrome with MAOIs if you're starting an MAOI. You can't really do a lot of cross tapering. You have to stop the previous antidepressant before starting an MAOI because it has such a high risk for serotonin syndrome. So yeah, that's kind of some things that come to mind when it comes to increased risk of serotonin syndrome with SSRIs and Dr. Sean Kane 35:17 Dr. jumay. Just to kind of wrap that up before we move to our next section. Can you give a couple examples of Maoi drugs, like their drug names, because I think a lot of people don't see these, and if they were to see one in clinical practice, they may not know that it's an Aoi drug class, right? Speaker 1 35:33 They're, they're so we don't see them very often at all. And they're also used to treat potentially like other conditions. So one that comes to mind is like selegiline. Patches are approved for depression. Oral selegiline is used for Parkinson's disease. And then another one that we could potentially use to treat depression is phenolzine. These are old drugs that have been around for a long time and very vigilant when it comes to being on those medications and some of these other ones that we mentioned for drug drug interactions with serotonin syndrome. Dr. Sean Kane 36:04 So Dr. Duma, I thought it'd be kind of neat if we could go through some of the specific SSRIs, and we've kind of, as we've gone through the episode, talked about some nuances with QTC prolongation with citalopram as an example. But maybe we could have like, a little lightning round here where Dr. Patel and I just give the brand and generic name of an SSRI, and you can tell us what are some unique things just about that one particular SSRI. Okay, so why don't we start with the most commonly prescribed SSRI, which is sertraline or Zoloft. What is its claim to fame, or what is it notorious for? Speaker 1 36:38 A sertraline? It's most commonly prescribed, as you had said, probably the one that causes diarrhea the most. So definitely counsel your patients it's activating or sedating. So it could actually be dosed at bedtime or in the morning. You just got to check with your patients and see how they feel when they're on it. Speaker 2 36:55 All right, I think you're ready for me. Dr. Dumais, we're gonna let's go with a citalopram, the brand name Lexapro. What is something special about that? Speaker 1 37:04 So it's in the name. And I really like when the generics kind of include this. I'm a chemistry major at heart. So when you see s citalopram, it's the s enantiomer of citalopram. That's why it's pronounced s citalopram, and it's not there's not like a hard C, it's like, not esque citalopram. It's just like the letter S. They say that the S enantiomer of citalopram is more therapeutic, maybe less side effects, because it's not the racemic mixture, as you notice in citalopram. But in my clinical practice, I really don't see much better benefit with s citalopram as compared to when patients had tried citalopram previously. It's more it's more costly. It's only, I think, been around generic, you know, not that long ago, as compared to citalopram. So if you've had, you know, like somewhat therapeutic benefit with citalopram, trying this, just at the higher cost, may not be worth it. So just something to keep out in mind with that one. It's also its max dose is pretty low, so there's not a lot of room for dose adjustments. You start at five or 10 milligrams, and then the max dose is 20. Not a lot of room to kind of dose adjust and fine tune. Dr. Sean Kane 38:11 So then the next one is the OG of the SSRIs fluoxetine, or Prozac, first came on the market 1987 what do we need to know about fluoxetine, Speaker 1 38:22 fluoxetine, it's probably our longest Half Life SSRI. Typically, it's one to three days, versus one day in general, for some of the other SSRIs, it's probably also the most activating out of all the SSRIs that we have available. And it's the only SSRI with an active metabolite that is potent. The active metabolite of fluoxetine is called norfluoxetine. So what we want to keep in mind with fluoxetine, take it in the morning, and then if you forget to take it that morning, just take tomorrow's dose and skip today's dose. If it's usually, I say, around four or five in the afternoon, just skip it because it's so long acting, you won't have any of these off effects, as you may feel with some of the other SSRIs, because it's so long acting, so it's okay to skip a day's dose, because your body probably won't feel it coming down as quickly as maybe something like paroxetine, for example. We also mentioned this earlier. There is some CYP2D6 inhibition that's going on with fluoxetine as well as paroxetine, as we mentioned. So you kind of want to keep that in mind when you're looking at other medications that are metabolized by CYP2D6. Additionally, fluoxetine has another CYP interaction to CYP2C19, which can potentially have some complications with the patients on clopidogrel and antiplatelet. And then additionally, it's actually also probably the best choice for renal impairment, because it's kind of like that's half life is so long can potentially be used, and those who have decreased renal function and even end stage renal disease, other medications may need to be dose adjusted. For any sort of renal complications. Hence why I probably also use this a lot in my older adult population, and we have Speaker 2 40:07 discussed this further in our episode 83 so if you are interested in learning more about drugs used in renal impairment, take a listen. The next one on the list is the citalopram, Celexa. We kind of discussed this earlier, about but what one thing we need to take away Speaker 1 40:25 risk for QTC prolongation. There's a max dose for adults older than 60 that's decreased. It's half the regular Max dose, but that's 20 milligrams for those who are 60 or older, and Dr. Sean Kane 40:38 then another agent is paroxetine or Paxil. We've talked about this a lot because it's pretty different than a lot. Than a lot of the other agents. What are some of the key facts that come to mind with paroxetine? Speaker 1 40:48 There's definitely some anticholinergic burden associated with this medication. So you want to keep in mind that this medication may not be tolerated, as well as some of the other SSRIs in its class, dry mouth, very sedating so and also some constipation can be seen. I don't like to use this in older adults, because of the risk for increased anticholinergic burden. Also, if somebody is already having trouble with fatigue during the day, this medication needs to be dosed, usually twice a day for therapeutic benefits, and they have to take a morning dose, and they don't like the side effects of being even more sleepy and tired when they're taking this in the morning, and it's also weight gaining too. So a lot of folks don't like this one, but it does have some unique like FDA approved indications that may warrant its use in certain patients. Speaker 2 41:36 And the last one, which is not something that we mentioned too much earlier, except just mentioning it's interesting indication, but fluvoxamine, or brand name Luvox, is our least prescribed SSRI. Anything special about that? Dr. DeMay? Speaker 1 41:55 It's the only SSRI that's not approved for depression. It's It's actually one of the first line options and drugs of choice for obsessive compulsive disorder. It also has the shortest Half Life After paroxetine. Usually also needs to be taken twice a day, and it's associated with one of the Columbine mass massacre shooters back was it was that the late 90s? I think, yeah. Dr. Sean Kane 42:18 And I think that, in addition to many other reasons why it fell out of favor, because it was associated with this massacre, any patients that were taking fluvoxamine probably thought about not taking it anymore because of that association. So probably not a deserved Association, but it's something that has come up and certainly decreased the use of that agent after that, that news came out of that shooter taking fluvoxamine. Speaker 2 42:44 So Dr. DeMay here, you know, we kind of discussed about how to select SSRIs for depression and anxiety. What kind of common side effects to watch out for drug interactions? What are the uncommon side effects and the specifics of it, but something that also comes along with medications that treat such mental health concern is the withdrawal. And I know it's important counseling point that there is withdrawal that could occur with SSRIs, and so let's talk more about it. What are these withdrawal symptoms? What could you be doing as a clinician to avoid such withdrawal symptoms occurring, especially if somebody is on it for chronic use? Speaker 1 43:31 Yeah, that's a great question. Dr. Patel, and I think the first thing I would say, and I'm a big proponent for destigmatizing mental illness in general, and the word withdrawal, unfortunately these days, is associated maybe with addiction. And while withdrawal is an okay term to use, another term that we could use and is probably more accurate and will be less stigmatizing, would be discontinuation symptoms or discontinuation syndrome. And just by changing that one word, one, you take away the stigma that antidepressants or SSRIs are considered addictive, because if your body is getting used to them, and if you suddenly stop them, you feel a certain way, doesn't that mean I'm addicted? No, it doesn't. It's just like at the chemical level, you need to kind of taper off of them. Is the same reason why it takes so long for them to work. Maybe so definitely something that when I use the word discontinuation symptoms or syndrome, there's no stigma, and then folks are less likely to be like, I don't want this medication anymore. But having said that, there is some nuances in particular with SSRIs that we want to kind of keep in mind when it comes to those withdrawal or discontinuation effects, and it's mainly based on the half life. So, as we said earlier, multiple times, fluoxetine probably has the lowest risk of discontinuation syndrome because of its long Half Life. There's an active metabolite that hasn't even. Longer half life. Back when I was talking about MAOIs, there's very specific directions. If a patient's on fluoxetine, there needs to be five week washout period before starting an Maoi after finishing fluoxetine, because it just sticks around in the body so long. It's also known in clinical practice to be the self tapering antidepressant. So you don't actually have to do a tapering schedule, like take a certain dose for this many weeks, then decrease for another weeks. If you just stop the medication, it'll just self taper, which is pretty cool. Paroxetine and fluvoxamine, as we said, the shortest acting or shortest Half Life SSRIs, are the ones that most likely trigger these symptoms, especially if folks miss a dose or two, then they'll really start to have some of these kind of discontinuation symptoms Dr. Sean Kane 45:47 related to that. What are some of those symptoms that a patient might watch out for if they do plan to taper down or stop that would be associated with this discontinuation syndrome? Speaker 1 45:57 The first one, I would say, is they just feel really crummy or have flu like symptoms. So you're just having a headache, feeling really tired or fatigued again, nausea comes back again now that you're kind of disrupting the serotonin kind of receptor activity, feeling dizzy, chills, sweats and just feeling like myalgias, like body aches, basically all the flu like symptoms that we think of, additionally, there could be just changes in their mood or sleep. They could feel more anxious, a little bit more agitated or irritable, or just like dysphoric in general, and then also potentially worsening of their sleep, so kind of like a reversal of some of those effects that they had prior to starting medication. Some of those may kind of come back or act up a little bit, and one that's really less common, but it's really notable, and it's not something that I really see with anything else is electric like shocks or brain zaps in the brain if they just suddenly stop their antidepressant or their SSRI. It's very cool, and I want to learn more about why that is, but that's something that a lot of folks just say they can't better explain it, better than just being just being a brains app. Speaker 2 47:04 And you know what? Interestingly enough, I would be surprised to know that right now. However, I actually know somebody who had gone through this withdrawal symptom itself. So definitely it's true, but probably rare on the whole scheme of withdrawal symptoms, but definitely true that it can happen. Dr. Sean Kane 47:23 And then, of course, in patients where they're switching from one SSRI to a different SSRI, if you don't do that kind of appropriately, Dr. Duma, I assume some of these symptoms could happen even though you're switching from one SSRI to another. What are some strategies to avoid this from happening when SSRI number one doesn't work and you're going to number two. Speaker 1 47:45 So there's probably two different approaches to switching antidepressants, and they're just based on, like, your own clinical experience. And you know your approach, maybe somebody who is a psychiatrist working for 50 plus years in their practice will do a little bit more of an aggressive approach, whereas somebody else may kind of do a little bit more conservative to avoid symptoms, or to avoid withdrawal or the opposite serotonin syndrome symptoms. So what I like to do is cross tapering, so you slowly go down on one of the medications while you start at a low dose of another, and then you follow up a little bit more frequently than you just would if you just started somebody on just monotherapy. SSRI, you follow more closely if we're tapering too fast, or maybe the doses are both a little bit too high right now they're we're at a point where maybe we do need to decrease one a little bit faster, because patient may be having some mild serotonin syndrome, like symptoms, so definitely cross tapering is what I do in my practice, some folks will do a direct switch, and it's not something I'm very familiar with. In my particular practice, they'll go from one therapeutic dose of one medication to another. I think it depends on the class you're switching from. If you're switching in between classes, it may make more sense, but if you're going from like an SSRI to like Bupropion, where has works on different neurotransmitters, not sure if it will really work that well, and they could potentially have side effects, those are the two different ways you can switch antidepressants. Well. Dr. Sean Kane 49:16 Dr. Dumais, first of all, thank you so much for coming on today's episode. This has been a really good overview of the SSRI drug category and the individual agents. One key concept that I think is worth mentioning is that these are selective serotonin reuptake inhibitors, so the mechanism is built into the drug class, which is cool, and they're literally the drug of choice for depression, many different anxiety disorders and a variety of other psychiatric indications, one is not better than another one per se, but patient specific factors is the primary driving force for which agent to pick Speaker 2 49:51 and out of all the commonly prescribed SSRIs, the two that have CYP interactions are fluoxetine (Prozac) and paroxetine (Paxil), which end up inhibiting the CYP2D6 pathway, which is also the metabolic pathway for agents such as opioid analgesics like Tramadol, tamoxifen and many other antidepressants. So we got to have to watch out for these drug interactions and educate patients accordingly, Speaker 1 50:20 and something as pharmacists that are bride and butter are patient counseling, we want to counsel our patients on some of the adverse effects of SSRIs that can immediately happen, but the beneficial outcome of the reason why we're on them for depression anxiety, can take up to two months for some folks. So it's really important that we counsel on that to ensure that they give these medications a fair trial and not sabotage their therapy preemptively, without giving them a fair shot. Something else to keep in mind is SSRI should not be abruptly discontinued to avoid discontinuation or withdrawal symptoms that we previously mentioned. These can include flu like symptoms, changes in your mood or sleep pattern, or even rarely, some electric like shocks or brain zaps. If you want to stop an SSRI, they should be tapered slowly over several weeks, and you should tell your doctor or your provider that you want to stop a medication, and they'll help you taper off of it. Dr. Sean Kane 51:18 Well, I think that wraps up everything quite well for the listeners. If you want to see show notes, we're at HelixTalk.com this is episode 140 we're also on Twitter at HelixTalk, and we love the five star reviews in iTunes, so keep those coming. So again, Dr. Duma. Thank you so much for your assistance in today's episode. And with that, I'm Dr. Kane Speaker 2 51:38 and I'm Dr. Patel, and to our audience, study hard. Narrator - Dr. Abel 51:42 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there to Narrator - ? 51:53 suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.