Generalized Anxiety Disorder: Evidence-Based Approaches for Optimal Outcomes *ACPE-Accredited*

(upbeat music) - Hello, hello, what is going on everybody? How's everybody doing? We're back with another episode of the Core Consult our ex-body guest. Cole, how's everything going man? - It's going good. How about you Mike? - Good, good. I can't complain, you know, it doesn't help when I do. - But we still do it, we do it anyway. - We still do it, pretty much every episode. - What is that, have you seen that? - Video of that guy kind of singing a dance in silly and he's like, I do it said, I do it glad. - I don't think so. - I don't know I'm talking about, okay. Well, I'll send it to you if I see it and that's what I think. - He's basically saying commercial? - No, it's just like, you know, a TikTok or whatever and it's just, it's, explaining TikToks is never a good idea, but, you know, it doesn't really work out. - I'll send it to you and there's an Instagram reel that way it's more age appropriate. - There you go, Instagram reel. - There are people out there who know what I'm talking about. He's basically saying like, you know, even if I'm sad, I still have to work and do things. - That is true. - He's dancing and it's funny and yeah, that's that. - Can you imagine like, you know, people who are in their thirties and stuff, especially, you know, my age, I'm 37, like, my parents' generation when they were 37 being like, well, TikTok is the younger one, but we're more of the Instagram. (laughing) - What a stupid thing to say. (laughing) - Yep. - I mean, it was Facebook before us, you know. - That's true. - Yeah. - So now it's, yeah. - I remember Facebook. - Why aren't we the Facebook generation? - We are the Facebook generation. - I think I technically am. Because I think Facebook got popular when I was in college, like when you still had to have like a EDU email, whatever to join or whatever. - Oh, yeah. - I think earlier, that's, I remember first being like, "Oh, this is cool." - You were in college? I wasn't like, that doesn't make sense. You're not that much older than me. And I was in like middle school when it was popping around. - I mean, what, what, what, what, you were born? - 94. - Now, right now, I'm like, I'm like six or seven years older than you. - Okay, all right. - Yeah, dude, I'm almost done, dude. Come on, it's, you're almost in college. - You're almost at the end. - I almost made it. It's a lot of time. That's time for me to call it a day. - Yeah, yeah, I remember being like, this is like my space, only different. - Yeah, there's no music playing in the background on every page. - Yeah. - You can't crash the website every time you try to do something. - That guy, that guy isn't your top friend. Whatever you call it. - David or Tom? - Tom, yeah, Tom. I think it was Tom. - Yeah. - Now, all of you listening might be wondering, this is a weird way to start an episode, and it is, and it was definitely, it just happened. We didn't plan for this, but it's actually kind of fits with what we're talking today, because thanks to social media, anxiety is on the rise. I'm sure amongst other things, but social media, I'm sure plays a pretty big role in that. And so we're gonna be covering the topic of anxiety tonight. Topic that we have done in the past, and I can't say that there's anything too new as far as meds or anything like that, but definitely an important one. And something that, whether you're in primary care, working in psych, or some other specialty, anxiety is definitely something that you will run into. Maybe you won't be the one directly managing it, but definitely something you should at least be familiar with. So it figured to be a good one to cover again. - Yeah, we're tackling it in a bit of a different way this time. - Yeah, so hopefully it'll be a little different. If not, just don't go back to the one from a few years ago and listen to it, and we won't be different from that one. - You won't think it's any different. But this is an accredited episode, and so the one we had done previously expired, and so we're going back through what we're doing this one, so that you can still get credit for this topic, and like I've said many, many times, and I'm sure you'll all are sick of hearing me say, the accreditation is through our friendsover3ce.com. And if you are an unlimited member, you can get access to a continuing education credit for not only this episode, but all of the episodes that are listed as being ACPE accredited. And if you have an unlimited membership, listen closely during the episode, we'll give you a password. That password will give you access to the post activity test that is on FreeCease website, and you pass the 10th question multiple choice test, and you will get your one hour of continuing education credit. It's available for pharmacist and nurses, and so make sure that you take advantage of that. And like always, I want to encourage you to check out their website, if you are not a member, definitely consider, at least perusing the different content that they have on there. Lots of great stuff from live panel discussions and live lectures to podcast episodes, monographs. If you're more of a visual reading learner, but lots of good stuff, something for everybody. So definitely encourage you to go check them out and get your continuing education credit all in one spot. So thanks to them for continuing to partner with us. But I guess to kind of jump things off, we'll talk about generalizing anxiety disorder, 'cause there are obviously other types of anxiety. So we're going to be primarily focused on general anxiety disorder. We've been there is some overlap with other forms of anxiety, especially when it comes to the medication side of things. But JDGAD, generalizing anxiety disorder, whatever you want to call it, has some diagnostic criteria that we'll go through. But also a screening tool that is widely used in primary care, and so it's not just a psych thing, but a great tool to use. I'm sure most of you are familiar with the questionnaires, like for depression, like PHQ9. I know we've talked about that a bunch. Anxiety has its own sort of screening tool as well, called the GAD7 Anxiety Score. And it's something a patient can answer fairly quickly, but it just goes through a series of seven questions, and you get a score of either zero to three for each question. And then once you add up the patient's total score, that obviously lets you know if one, if they have anxiety and two, if the severity of setting anxiety and kind of can steer you in one direction or the other, definitely, there's more to it as far as differentiating the different types of anxiety and whether it's social or what have you. But the GAD7 nonetheless can still be a very good tool for primary care, especially if you're not working directly with a therapist or someone that's gonna make a definitive diagnosis. But the GAD7, just to give you an example of some of the questions, first one is feeling nervous, anxious, or on edge. And this is all pertaining to basically the last couple weeks and how often the symptoms bother them. And so feeling nervous, anxious, or on edge. Number two is not being able to stop or control worrying, three, worrying too much about different things for his trouble relaxing, five, being so restless that it is hard to sit still. Six is becoming easily annoyed or irritable. Seven is feeling afraid as if something awful might happen. And as a score of zero for those would be not at all, the score of one would be several days. The score of two would be more than half the days and then three would be nearly every day. And again, you give it a score of zero to three for each one of those seven questions, total it up. And if the patient is zero to four, that would be considered minimal anxiety, something that made an absolute required treatment. It could just be a part of this daily adult life. Once you hit the score of five up to nine, that is classified as mild anxiety. 10 to 14 is moderate. And then 15 to 21 would be considered severe anxiety. And not only using this as a screening tool, but if you do end up starting patient on treatment, having them repeat the GAD-7 at follow-up gives you a way of sort of quantifying the progress they're making. And making sure that we're moving in the right way, that we're getting a positive trajectory, if you will. When it comes to the true definitive diagnosis, we want to turn to the DSM-5 for that. And that's why I say that at that point, you may be referring the patient to psych, to especially if they have a therapist or anything that they're working with to give a definitive diagnosis and make sure that there's not some other type of anxiety present, but the DSM-5 describes generalized anxiety disorder as a chronic debilitating condition. And it's characterized mostly by excessive or persistent worrying that interferes with many aspects of daily life. Now, they do mention that symptoms can be both somatic as well as psychological. So somatic being like physical symptoms, where the patient may have like palpitations or tremor or something along those lines, and then psychological symptoms being obviously all the worrying and the apprehension of expectations, all that. Very common anxiety disorder, but definitely not the only one. We will kind of go through different medications and things like that as we go and then summarize at the end using an algorithm that was written by a physician that-- I believe he's out of Harvard Med still, but Dr. David Osser, he's published multiple psychology, psychopharmacology algorithms, and he has one on there for a GAD as a paper that's associated with not just the algorithm that he published, but a paper that kind of walks through the explanation for all that. And I wanted to make a note to you, because he specifically stated in his GAD algorithm when he was talking about kind of the history and changes that have happened with the DSM variations. But he mentioned the DSM-3. The anxiety, the condition itself, was predominantly a disorder of autonomic motor or other somatic manifestations of anxiety. He notes that these symptoms turned out to not be particularly specific to GAD. And that many DSM-3 GAD patients would now be classified with other anxiety disorders or somatic symptom disorders. And so the differentiation between the different types of anxiety is definitely something that has become more widely discussed and published on as the more data has come out, the DSM has been updated to now the fifth edition. But definitely a good idea if there's any doubt in your mind as far as the true definitive diagnosis of generalized anxiety disorder to have the patient follow up with a specialist that can kind of walk through an evaluation and really make sure that they're pinpointing what type of anxiety that the patient's dealing with. Typically, we consider this like we set a chronic condition. So the DSM-5 talks about the symptoms that you're evaluating being present for at least six months. And then the other thing we have to consider is does the patient have concomitant behavioral health issues? So is there depression on top of the anxiety? And that can obviously change how we end up treating the patient to some extent, or at least some of the combo drug that we'll use, but tonight we'll focus strictly on anxiety and not mention the concomitant depression and how that changes things. I can't remember how long ago it was, but I'm sure we've done episodes on depression with anxious stress and all that stuff. But yeah, so kind of jumping into the medications, do you want to start off with our good old friends, the SSRIs, Cole? Yeah, we'll start there. And we're going to hit on a number of medications that many of you are probably familiar with. I've certainly heard that and realized, of course, that we have listeners from all across the spectrum of learning and their careers and other professions as well. So for some of you, it'll be review for others. It's good to go through. But the SSRIs, the selective serotonin, reuptaking inhibitors are certainly a mainstay of treatment for anxiety and for other psychological conditions like depression. They selectively inhibit the reuptake of serotonin into the presynaptic neuron. It results in increased availability of serotonin in the synaptic cleft. The increase in serotonin leads to a rapid activation of postsynaptic serotonin receptors, particularly receptors like 5HT2 and 5HT1A. Over time, desensitization of certain receptors, including the 5HT1A autoreceptor occurs. And that leads to enhanced receptor signaling, improved efficacy, and the postsynaptic pathways. And that's critical for improving patient's mood. So we have a number of SSRIs that are out there, commonly prescribed, fluoxetine, searcholene, peroxetine, cytalapram, esitalapram, and fluvoxamine. They're all approved for depression, notably, except for fluvoxamine, which has FDA approval for OCD. And we'll kind of compare and contrast these a bit as we go. And all the depression, but only a couple of them are technically approved for anxiety, specifically. Although I will say, in a lot of cases, they are kind of used as a class effect to help with anxiety, even though they don't have FDA approval necessarily. If you start a patient on SSRI, there is a box warning that's associated with all of these. And it more so has to deal with depression side of things, and it does anxiety. But nonetheless, it's something that I think is a good idea to share with patients because as soon as they get home and start googling, seeing the box warning for any of these can be a little alarming for patients. Box warning being that the SSRIs can increase the risk of suicidal thinking and behavior in children, adolescents, and adults. So that applies for all of them. Obviously, when you're dealing with behavioral health issues, especially when it comes to things like depression, the major concern amongst all the quality of life issues and things like that, but the major concern being the risk for suicidal ideation or attempt. And you're doing a study. It's hard to differentiate. If you do have patients that do end up, unfortunately, going the route of suicide, it's not hard. It's impossible to truly, without 100% certainty, to say that it was just a patient's clinical course worsening versus the medication causing an issue. And so definitely something to at least mention to patients, but usually giving them the reassurance that if you feel like symptoms start worsening, then contact the clinic and we can make some adjustments. But also kind of talking to them about the starting into lower dose and titrating up, I think, can kind of put their mind at ease. But I do find that it's a good thing to mention to patients at least briefly just so that you don't get an angry phone call a couple days later talking about why you put them on a drug that could make them want to do something horrible and hurt themselves. But that's just my two cents. I'm sure there's plenty of people who don't go into that with patients as far as side effects and things to kind of warn patients about and as far as expectations and whatnot, some of the common side effects that are pretty similar between all the different meds in this class, some GI issues, constipation, dry mouth. Some patients may experience things like tremor, potentially even worsening anxiety. That's usually the case if you start too high of a dose and don't titrate them appropriately, and potentially slowly, if you start too high, can definitely worsen anxiety in some patients. And then sexual dysfunction is another big issue that patients will complain about. Then they do have some medications in the class that have kind of like more unique side effects that are more unique to them specifically. So for example, with Cytalapram and Scytalapram, the risk of QT prolongation can occur. And if you have a patient who is on these meds and they're titrating them up, typically we don't go above the dose of 40 milligrams with Cytalapram and then 20 milligrams with Scytalapram. And then usually that dose is cut in half with our elderly patient populations. And then in fluoxetine in particular, still for some patients will be sedating, but does have a little bit higher risk for some patients actually having the opposite effect, or they get some more of a stimulant type of effect and can cause some insomnia. So if you have a patient that's already dealing with insomnia, fluoxetine may be one that you hold off on and try an alternative. And then peroxetine is one that tends to be the most sedating as far as all the SSRIs. Again, all of them can cause sedation, but peroxetine tends to be the one that's the most likely culprit if you were going to compare all the agents in that class. The same with sexual dysfunction. peroxetine definitely tends to be the biggest cause of sexual dysfunction compared to all the other agents. And one that I will say I'm not a huge fan of personally. I think that some of the others, like, certainly in what not tend to be a little bit better tolerated, which is my anecdotal experience. I have talked to some clinicians at like peroxetine. I'm just not personally a big fan of it. As far as the sexual dysfunction, loss of libido and ability to ejaculate or have orgasm and ability to get and maintain an erection, the sexual dysfunction symptoms can be kind of all of the place in it affects guys and girls. And can definitely be problematic when it comes to patients, obviously family life and their relationship with their spouse or social anxiety, things like that. And so you do want to make sure that you're open with patients about the risk of sexual dysfunction and encourage them to let you know if those do occur. And hopefully you can mitigate that risk as best as possible. But it is one of the top complaints that you'll get from patients when it comes to the side effects from an SSRI. Yeah, and now we're good. Yeah, I was going to just add this little, too, since this is not at all pertaining to what we're talking about. But I do think it's like a weird clinical parole, if you will, that has come up. And I actually was talking with one of our family medicine residents just last week about this. So I'll mention it here, too, but I had a patient that was having anxiety symptoms. But it was more so as far as anxiety around sexual encounters and whatnot, and specifically premature ejaculation. And that was causing anxiety even, you know, when you wasn't engaging in said activities. But that was the main thing that kept coming up with the patient. And he kept me mentioned it like two or three times when the visit that he wanted something to help with that. And I've heard a psychiatrist a while ago talking about that that says go to proxene. Is this go to when there is a case of a patient who needs to be on a necessary and also is having issues with premature ejaculation that proxeteen can be effective for that. And there's a couple really small studies and things that have shown some effectiveness with there. So in the off chance here, you have a patient that is getting, you know, having issues with that, that can be a treatment option or a reason to at least go with proxeteen over the others. Sounds interesting. Something, yeah, it's something that I heard in the lecture one time a while ago and didn't think I would ever come to play and then lo and behold, ran into a situation. It was like verbatim what the guy was talking about. So figured I'd share it with you guys, too. Very interesting. Yeah, for those who have been listening to us for years, they know that I usually harp on the fact that the sexual dysfunction is a huge reason for discontinuation. So I wanted that again. We've been doing this for like eight years, by the way. She hasn't been that long. Yes, been a lot of time. But yeah, the increase in anxiety is very important to set expectations with patients for. Because even at a low dose, they can see a short term kind of increase in anxiety. So if you're giving them a new med for anxiety and then their first week, they're like, I was super anxious. So this isn't working. Set the expectation with them that that should improve. And then of course, a net benefit with their symptoms over time. But Mike mentioned that there's only a couple of SSRIs that are FDA-approved for generalizing anxiety disorder, esitalipram, and peroxetine. But of course, we pretty much use them all interchangeably. Circuline has a few studies that show that it has comparable efficacy. Peroxetine, like Mike mentioned, produces the most side effects. One observational study looking at OCD patients on long-term treatment found both esitalipram and peroxetine being associated with a 14%-- with greater than 14% of patients gaining more than 77% body weight versus less than 5% surgery, so that's notable. Studies with esitalipram have found that if response commences within two weeks, which they defined as a 20% improvement on a HAMA score, which is kind of another scoring system, then that's a good prognosis for remission. If there's no response in two weeks, the initial dose should be increased. If there's no response in four weeks, one minute analysis suggests that the patient's unlikely to respond to it. So definitely not as long of a waiting game as it is when you're treating depression. Anxiety, you should see a little bit quicker results, which is definitely nice for patients. Now, if you're on a SSRI, you're getting a lot more serotonin in your system, and so by itself, usually not an issue, other than like we've said, going too high in the dose too quickly can cause some problems, but just in general, usually the SSRI alone isn't going to cause an unreasonable amount of serotonin to be available. Now, if the patient is also on other drugs that are serotonergic, that can potentially lead to a case of serotonin syndrome, very, very rare, but definitely can occur. And so just some things to consider, you know, some meds to consider and watch out for. Obviously, a huge one, MAOIs, we would never use those in combination, or even within a couple weeks of use of the SSRI. So hopefully that's a no-brainer. But then other things, they're like a dextramethal worth. If that can actually cause an increased risk of serotonin syndrome when you're taking it with an SSRI, if they're on things like tripdans for migraines, those are serotonergic, things like lithium, tricyclic antidepressants, if they're on an SNRI, which, you know, every once in a while, you'll see patients that are on like an SNRI, like duoxetine for maybe neuropathy, but then they get put in a SSRI for their depression and anxiety. And obviously that can lead to an excessive amount of serotonin and not really a good reason to go with the combo necessarily. And then another one that I think a lot of us forget about just because it's not used all that often anymore, but I'm a parodine. I feel like if you're going to see that one nowadays, it's mostly like dental procedures, things like that. But, you know, in the off chance, you have somebody on a parodine that is also serotonergic and you need to be cautious if the patient's also on a SSRI, you know, as far as warning patients about the symptoms, if they were to start to develop serotonin syndrome, making sure that they're aware of just some of the kind of classic symptoms. So the neuromuscular hyperactivity, so it can be tremors, rigidity, things of that nature, altered mental status, agitation, confusion. You can have autonomic instability, hyperthermia, that parisis, and, you know, obviously, different varying degrees of severity of these, but just something to kind of warn patients about if you start having any symptoms, let us know. But a lot of it can be, the risk can be mitigated by just doing a thorough med rack to make sure that they're not on anything that could potentially interact. Right. So as far as their pharmacokinetics go, there is some variation. Even though we use these pretty much interchangeably, certainly there's variation between each of them and they have specific half-lifes and drug interactions to be aware of. An example is that fluoxytine has a really long half-life, six to nine days. Might be good, might be bad in some situations. Maybe good for a patient who you have adherence concerns for or they might be lost to follow up something like that. But fluoxytine has interactions with CIP-2D6, 2C19, it's an inhibitor versus peroxetine, which has a really short half-life of 21 hours, which may help explain some of the side effects that it comes along with, but it has interactions with 2D6 as well. It's an inhibitor. Yeah, I like that fluoxytine, it's got that built-in taper. If you happen to have a patient that wants to abruptly stop it. Yeah, Anna was talking to a, she was talking to a psychiatrist the other day who mentioned fluoxytine was one of the more activating ones and I forgot about that. I was like, really, I hadn't really thought about that in a while and of course that was true. And it's, it's, because the farther I get from kind of interacting with these, I start to think of the mall as like one bushing, they're just all the same. But they're certainly just between them. Definitely not. Yeah, I think it's got more alpha androgenic activity than the others. So, all of those receptor interactions and receptor signaling, it's fascinating when you really start diving deep into it. They're definitely not a, you know, one size fits all when it comes to these meds, even though they're the same class. A lot of different receptors that they interact with. I know the thing with SSRIs that may come up, especially if you're sending a prescription for one and the patient's on some kind of a medication, whether it be an interplatelet drug or maybe an anticoagulant, but you'll see an interaction with SSRI, talking about an increased chance of a bleed. The reason behind this is when you think of a platelet and all of the different things that a platelet can use to kind of signal other platelets to start the process of platelet aggregation and, you know, the part of the clotting process. A platelet has both a dense granule and then what they call an alpha granule and each of these contain different, you know, things that they can use to kind of signal and other platelets can kind of conduct that process. The dense granule in particular, one of the components of it is serotonin. And platelets aren't able to synthesize their own serotonin and so they have to get it from the surrounding environment and it gets taken up into the dense granule and stored for when they need to use it to signal for other platelets for aggregation. But when you give a SSRI the same inhibitor that blocks serotonin from being, you know, taken back up and presynaptically also will block the transporter that platelet uses in order to get serotonin into the system and are into the dense granule. And so you block that and serotonin no longer is available to platelets so it's not able to undergo platelet aggregation as effectively. Now, obviously there's other aspects to platelet aggregation more so than serotonin but it is something that can increase the risk of a bleed because platelets aren't able to aggregate as effectively. For a lot of times, a lot of patients, it's not something that we have to worry about but I will say for me personally anyway this is something that I consider to be like almost like a textbook type thing versus, you know, a true clinical concern that we should have. And that's actually one of the things that David Osir talks about in his, his paper and his discussion on anxiety and same with depression is the risk of bleed and it kind of goes through some of the statistics and it's a higher risk than I would have assumed. And so specifically with insets, right? - Yeah, and also patients that are on anticoagulation and stuff already obviously, any kind of increased bleed risk with those patients is going to be no more now. But I say all that long windedly to express that obviously that's a warning that will pop up. It doesn't mean you have to avoid SSRIs and probably still the right treatment option but just warning patients to look for signs of bleeding. You know, if they have a history of a GI bleed, something like that, then that may give you a little bit more pause. But overall it's something to at least warn patients about but you know, we say to have it on your radar not necessarily to convince you to avoid the SSRIs in those patients. But definitely higher risk than I anticipated, I think initially. - Certainly. - Before we pop into the next class, do you wanna do the password? - Yeah, yeah, good idea. We're already at the halfway mark. It's time for password reveal. Everyone's favorite section. - We need like a jingle. - We need like a jingle. - Oh, we should. - We should. - I can't believe we've never done that. - That is a sound effect or something, you know. - Of all the dumb things that we've tried with this five casts with some sound effects. - So we did wait a minute. Do you remember that? We did have sound effects for a minute. - Oh, of course. I still have them loaded up on the road to cast. - That's ridiculous ones. Like what they like. - For toilet flushing. - Oh yeah. - When we talked about a 10-a-wall, the most juvenile thing. - Yeah. But that was a long time ago. We've matured since then, basically. - Basically. - Yeah. - There's still all loaded up on my sound panel. We just don't ever need to lie to anyone. - It was easy when we had AJ and he could click a button. - AJ. - Yeah. - He's finishing up his PhD. Just can't have a two doctorates. - Yeah, so for those of you who know or remember AJ, make sure you say hey to him over Instagram or whatever. He's doing doing well and doing a lot of, we got a paper published recently and doing some cool stuff. - Congrats AJ. And then a few years will be like me and forget that he has a doctorate and realize that nobody really cares. - Yeah, well, he's got two of them. - That's it. - Maybe people will care at that point. - They'll care. They'll care. - Yeah, so anyways, the password for the post activity test, use password GAD25. So GAD25 and the GAD is capitalized and it'll be on freece.com and you go to the learning tab. Look for the sectionist's podcast and find this episode and then put that password in. Crush that test. It'll be easy for y'all. And then get you one hour of continuing education credit. - That's right. - Don't forget. - Don't forget. Or just wait 'til the last day like I do and could call you a lot better at it, but I definitely wait 'til the last minute. - I guess I am, but I am. I've got to do my diabetes one this year and I thought I had 'til the end of the year, which I technically do, but I have to pay like 200 extra dollars. It's not a penalty, but if you do it earlier, you save money and I can't not save money. So now I have like two months to do all the stuff I need to do for that. - Are you gonna do the CE for that? - Yeah, I'm just gonna retake it. - I don't like taking tests. I know you like to take the test. I just don't like to take the test. - I don't need that. I'm just lazy. That's why I like to take tests. I don't even have to go do all that maybe. I could just go take it and pass maybe. My brain doesn't work that way. So I'll have to prep and it's like I don't want to prep. So I'll do the CE, I'll do the CE. - Yeah. So the good thing is as I know myself won't enough to know, I'm gonna say I'm gonna prep and then it'll be the night before I'll be crannin' for it. - And then I will do the exact prep for my dead. - I can't not prep for it extremely long time. So yeah, I'm gonna go CE row. - Anyways, so we'll pop into the SNRIs, the serotonin or epinephrine re-uptake inhibitors. And as you can imagine, they block serotonin like the SSRIs, but they also block the re-uptake of nor epinephrine. Mike mentioned a couple before, but we have vanilla vaccine, death-fenol vaccine, deloxetine, and a branded one, fetzema, which is levomil nasopram, kind of a cousin of an older one, I guess. But they also carry a box warning for increased risk of suicidal thinking and behavior, particularly in children and adolescents, but adults as well. So they would carry that same kind of recommendation for counseling that Mike went through before. - Yeah, and technically speaking, kind of like with the SSRIs, there's only two that are technically FDA approved for generalizing anxiety disorder, those being vanilla vaccine and deloxetine. But there are instances where you can kind of use, or clinicians will use any of the available agents, but I think vanilla vaccine and deloxetine, even if you just were gonna stick with the FDA label, those are two pretty good choices if you're gonna pick of the four that are available. Efficacy as far as comparing them to like the standard SSRIs, pretty comparable. We do tend to start off with SSRIs as sort of a first-line drug, but SNRIs can be just as effective. Deloxetine in particular has been seen to, or from some of the studies have been seen to have significantly lower rates of sexual adverse effects than something like peroxetine, which, you know, peroxetine being the worst, maybe not, maybe not the biggest feather in the cap, so to speak, but at least something to consider. And then, vanilla vaccine tends to have the same rates of sexual dysfunction compared to most SSRIs. And the other thing to consider with vanilla vaccine is as the dose increases, you know, is insane with deloxetine. You sort of get this more serotonin effect, or more effect on the serotonin side at the lower doses, and then as the dose goes up, it starts to sort of shift over to the norepinephrine side of things. And with vanilla vaccine in particular, you know, we've seen as the dose goes up, the potential for a patient's blood pressure to also go up. And so if the patient has concomitant hypertension, you know, at baseline, into your planning on titrating the dose of the vanilla vaccine up, which in most cases you will, it's definitely something that needs to be monitored and make sure that we're not worsening their cardiac issues versus fixing their anxiety. We don't want to give them another problem, right? And so something to at least keep in mind and make sure the patient is monitoring, you know, at home and whatnot. Right. As far as adverse effects to be aware of, very similar to SSRIs. But there are also the adverse effects from the norepinephrine effect, like increased heart rate, dilated pupils. Also, they can be associated with dry mouth or excessive sweating. They have a couple of renal adjustments to be aware of. Levo-malnaciprium don't use if the creatinine clearance is less than 15. And deloxetine don't use if creatinine clearance is less than 30, which is certainly a good thing to know. I'm sure that pops up. There's a slight increased risk of bleeding with SNRIs due to the serotonin activity. But, you know, I'd imagine it wouldn't be as much as SSRIs because it's not as potent at an interaction with the serotonin receptor. - And vanilla vaccine does have the most effect on serotonin at lower doses. I will say that once you get to the dose of 150 milligrams or higher, it definitely shifts over to the norepinephrine side and you have to start worrying about those type of side effects. But, you know, if they had issues, you know, from a serotonergic standpoint, you know, with an SSRI, then maybe vanilla vaccines. And if you're going to start a lower dose, which we typically would entitrate up, we may want to find an alternative if they had a lot of issues on the SSRI already, at least something to consider. And then the most potent of these agents when it comes to the norepinephrine, I think inhibition is Livo melanopran. And plus, it's also metabolized through a lot of different sip pathways. So drug-drug interactions can be an issue, same with risk of hypertension and all that. And so that one is probably of the four available, that one's probably one you won't see as widely used, just because of those issues. But again, the big thing is with these SNRIs is monitoring blood pressure when the dose is on the higher side and making sure that the patient has preexisting cardiovascular issues or hypertension, especially, that we're doing very close monitoring or at least considering maybe an alternative as well. - Next drug is one that's kind of in a class of its own, boost barone or boost bar, which was approved in the '80s, based on the DSM-3, GAD criteria. It's one that has very low abuse potential, versus benzose, for example. It's not really sedating, doesn't really have sexual side effects or considerable amounts, at least. So for the most part, it's pretty benign, but its efficacy is also more benign. A made analysis in 1992 of eight placebo controlled trials involving boost barone and doses ranging from 50 to 60 milligrams a day found that the typical effect of dose was 30 milligrams, but there was a placebo controlled trial to evaluate the efficacy of boost bar as monotherapy with the DSM-4 GAD criteria. Effectively, what was found was that, or I guess this was a different study, sorry, there was another study with the DSM-4 criteria that compared boost barone, phenylfaxing and placebo and boost barone daily was no better than placebo on some measures and boost barone was inferior to benylfaxing on some measures as well. So typically, it seems to be less effective than the SNRI. - I think that the placebo controlled trial you started to talk about. That was more so to confirm that boost barone can be used as monotherapy, since obviously with depression and things, we only use it as an adjunct agent, and we don't use it as monotherapy, but then when you compare it, like you said in the other study, it may not be as effective as some of our other options anyway. So, do you ever, have you had much luck with this at all, have you done, have you had many patients you've worked with that are on boost barone? - I mean, I see it regularly. I mean, I haven't been closely involved with their treatment, so I'm not really sure how well they respond to it, but I do see it fairly often. - I haven't had much luck with it personally. I mean, not that I'm super heavily involved in mental or behavioral health side of things, but I've definitely used it a few times with some patients or followed up with patients that were put on it by somebody else, and I feel like anecdotally I haven't had too many people that are like, this was the game changer. - Yeah, no, I certainly wouldn't think it's that, but I think anecdotally, 'cause I have known some, actually some people to take it out, I think about it, and I've seen it used where somebody's like, I don't have crippling anxiety, but I have anxiety that's affecting me, and they don't want the stuff with all the side effects, and so they're like, no, it's not worth it, I don't want to deal with that, but they would accept this, I guess that's where I've seen it, pop in, whether that's right or wrong, that's just kind of where I've seen it pop in. - Yeah, that's definitely what I kind of think of it too. - And I don't even think they still fully understand like the mechanism behind it, which is kind of crazy, 'cause it's been out for so long, but hopefully the patient doesn't ask you, how does this work? - Ooh, there's a surprising amount of stuff that we don't really know, we don't really know how it has its effect on this disorder, but they like know kind of what it does, pharmacokinetically, on the body, you know? - Yeah, it's like serendipity. - Yeah, we tried this and something, we found that it helps this too. - Yep, yep. - All right, let's talk about another drug that I feel like is kind of controversial most with anxiety, and that is our dopamine, norepinephrine, we have taken Hibiter, Bipropeon. This is one that I feel like a lot of people are either widely against or, you know, very cautious at the least, you know, to use in anxiety, Bipropeon is available as a sustained release, which can be taken every 12 hours or an extended release, which is 24 hours or just once a day of formulation, and it's one of those that affects dopamine and norepinephrine, and so, you know, as far as an augmentation option, if a patient's on an SSRI, you're already covering the serotonin side of things that you can cover your other two major neurotransmitters, you know, by adding this on, but it can also be used as monotherapy as well. As far as contraindications go, there are a couple big things to assess for. Seasure disorders, you know, in a patient who is about to start Bipropeon, no good. Bipropeon can potentially lower the seizure threshold, and, you know, cause seizures if patients had seizures in the past, or, you know, traumatic brain injury or any other condition that would put them at a higher risk for seizures, then Bipropeon could increase that risk even more so. And unlike the SSRIs and SNRIs, where, you know, we do think they're either gonna be weight neutral or potentially cause weight gain in some patients, in some patients they can really cause some issues with weight. Bipropeon has the opposite effect. And so, for a lot of patients, they actually will have a decrease in their appetite with Bipropeon, especially like in the beginning. And, you know, a patient has a history of any type of eating disorder, anorexia, bulimia, anything like that. Bipropeon probably wouldn't be the best option. And, you know, it is also used as a component of a weight loss drug. Bipropeon and Naltrexone in combination is that drug contraiv, and then Bipropeon can also be used for smoking cessation as well. And so, that being said, if a patient has concomitant issues, you know, they're trying to quit smoking or they're trying to lose weight, and that may be reasons why we end up going this route or at least consider it for an augmentation option down the road. Side effect wise, though, the stimulating type effects that can happen with some patients insomnia, irritability, in some patients' anxiety, which obviously we're trying to treat here, but in some patients, we'll notice some anxiety, especially in the beginning, and especially the dose isn't tapered up, or titrated up appropriately, you know, things to consider. That because it's got that dopamine activity, it is something that we have to at least consider. I'll let Nicole talk about some of the comparative studies that justify, you know, using this in anxiety, but definitely things to consider side effect wise. And then, the increase in blood pressure is a potential as well, not nearly to the extent as an S, NRI at higher doses, but there's still a norepinephrine activity, so it's something to watch for. - Yeah, I bet that contravenufacture does not so many bottles anymore. - Yeah, no, I doubt it. - Doesn't, yeah. Hey, hey, Munjaro calls, is that, or is that bound? - Yeah, they wanted to see how you're doing with those four pounds you lost over the last 12 months. (laughing) - Yeah, so, you know, while it's controversial, like Mike said, there's a little bit of data to support it, so an example is one small trial with just 24 patients who had DSM4, GAD, randomized to receive either well, butrin, 150 to 300 milligrams daily, or esitalopram, 10 to 20 milligrams daily. They did have a difference in their mean AMA scores, which I talked about briefly earlier, that was significant in favor of buproprion. The endpoint score for the AMA was 5.3 with the buproprion versus 11.4 with the esitalopram group, low incidence of sexual side effects, like Mike said, so it can be an option to bring up with patients considering their first treatment for GAD. - Yeah, and it's something that I think that Dr. David Osser was one of the first clinicians and some of who's involved, that level is for us guidelines and things that I had heard talk about buproprion like in a positive way for generalizing side disorder, 'cause I feel like everybody always says, "Oh, stay away from buproprion," but he kind of explains, he mentioned the study that Colgis brought up versus esitalopram, and then some other small studies and stuff as well, but he does have that included in his treatment algorithm as a potential first line even, but definitely as a med to consider second or third line, our augmentation option. So, point being, don't necessarily shy away from buproprion in these patients, just because of the potential side effects with anxiety. - All right, some other alternative medications, hydroxazine is a big one that I think some people tend to forget about, it is an antihistamine, but it's not just an antihistamated. It also has some mild 5HG2 receptor blocking effects and has been shown to be efficacious compared to placebo. And a few different randomized control trials and specifically in GAD patients. Around 50 milligrams daily is usually the dose that patients will tie trade up to, and the safety profile compared to other meds that we'll talk about in a second, like benzoes and things, does tend to be pretty safe as far as this guy's a very low abuse potential. It is sedating, because obviously it's an antihistamine. But one of the pushback that I've gotten in the past, personally, from trying to go to hydroxazine route for my physician colleagues is in patients who, or maybe a little bit more chronologically gifted, and they may have concerns with the anti-colonarchic effects of hydroxazine because hydroxazine is considered to be the most potent anti-histamine. But remember, anti-colonarchic effects, it's a different receptor that it's interacting with. And so if we're talking about anti-colonarchic effects compared to other anti-histamines, hydroxazine actually is on the lower side, as far as risk compared to other first generation in histamines. The sedation probably would be the worst compared to others, but the anti-colonarchic effects specifically, so like the fall risk and all that, tends to be lower compared to like diphenhydramine or something along those lines. So I think everybody here is most potent into histamine and the automatically assume it has to be the most potent in anti-colonarchic as well. And that's not the case. There's some meta-analysies and things to show that it is on the lower side of risk compared to other first gen's. And then there's also no sexual side effects or anything like that. There was a cochlear review that came out that it was comparing hydroxazine to other anxiolytic agents, the benzoes, beesbarone, things like that. And hydroxazine was found to be equivalent and tolerability, efficacy, and acceptability among patients. So hydroxazine is a good, non-controlled medication that can be a very good treatment option. Yeah, that's right. Another one that I think may be kind of somewhat controversial is pre-gablin, Lyrica. It's not approved for generalizing anxiety disorder in the U.S., but is approved for a GAD in Europe. And they've used it for years over there. There's some studies that show a dose response relationship and anxiety disorder, and doses over 300 milligrams daily were more effective compared to lower doses. It is obviously a controlled substance, and so we have to deal with the laws and things that go along with it being a controlled substance. And side effect profiles besides the reported abuse potential, some illness, dizziness, things like that can occur as well. And then if cost is an issue, which that hasn't been as big of a problem now that I went generic, but GABAPENTAN, a very similar drug could be used as an alternative as well, but pre-gablin is more widely used in European countries and things. Even though in the U.S., it's not as widely accepted for that specific indication. - Right, okay, so the benzodiazepines, my reference those before, very effective for anxiety, widely prescribed, but to be used with caution, if not avoided for multiple reasons. But probably most notably, after treatment for a while, several months, maybe about 40% of patients develop tolerance and dependence, high risk for dependency. It's also associated with rebound anxiety. If a patient has a history of substance use disorders, they should be avoided. Long-acting benzos like clonipin may help decrease breakthrough anxiety during treatment with an SSRI. So you could use it for the first four to eight weeks while waiting for the SSRI to kind of kick in. But it might not even take that long for the SSRI to kick in. And then you would want to try to taper to discontinuate it if possible, but ideally, we've made an attempt at a number of these other medications before going straight to this, but you know, a lot of patients, a lot of patients take them. - Yeah, patients take them. - The problem is this is very hard to get off of these if you are on long term and the rebound anxiety, you can get as pretty substantial. So if you can avoid getting patients on them in the first place, or if you are doing it like Colesette, do a very short period of time, then they may have some utility. But there are cases where you have patients with refractory symptoms or very severe anxiety at baseline that they may be appropriate for. So it's not that benzos don't have their place 'cause they clearly do. - Just be the first thing. - Have to be cautious, yeah, for sure. - All right, so I wanna walk through the algorithm that Dr. David Osler had gotten published and put together and these are available. If you just Google David Osler and psychopharmacology algorithm, his website will pull up and you can see his various algorithms for different behavioral health disease dates out very, very useful website. But he says step one, obviously making sure the patient is met the criteria for generalized anxiety disorder. And then, from there, typically we wanna look at the other comorbidities. Does the patient have insomnia? Do they have history of substance use disorders? Is the patient of childbearing potential, and are they looking to potentially become pregnant? Is it an elderly patient? Do they have concomitant major depression, bipolar depression, mania, post-traumatic stress disorder, those type of things? And you're just making sure that we're getting obviously a full picture. And those, depending on comorbidities, they can definitely alter the course that we go. But typically starting patients off on a necessary ride for a lot of patients that's gonna be kind of the first line therapy. Maybe they've tried us as far as in the past and had a bad experience with them or poor response or what have you. Then it doesn't mean you have to start with a necessary ride. But it's usually for most patients kind of a good place to start. And then from there, the big question is, did they have a response, or did they have a partial response or no response? Obviously, if they've had an adequate trial, but they had no response, then we would want to kind of change course and either try a second SSRI. We could also switch to something like deloxetine. If they had a partial response after their first SSRI trial, but they're not completely in remission, then we can also consider augmenting with some of the other agents we've talked about. Hydroxazine, pregabolin, abenzo, and then the other thing is if they haven't had an adequate trial, you could, like we said, most of the patients will start with an SSRI, but it wouldn't be necessarily wrong to start off with one of the other options that we've talked about, beast-per-own, pregabolin, be appropriate on, things like that. Once you've kind of worked through the SSRI, maybe an SNRI, like deloxetine, if they're still not having a response at all, then switching completely to an alternative, like be appropriate on, beast-per-own, hydroxazine, pregabolin, any of those is like monotherapy. And again, if they've had a partial response, but not full remission, then you can add in any of those agencies as augmentation options to whatever their baseline therapy is at that point. And then if they've already tried SSRI, SNRI, maybe some of these other agents, then the other thing to consider would be a couple of the second generation antipsychotics, there are lettics that have some data, quityapine, resparadone. Dr. Osla does put a note in there that says to avoid a lens of pain just from lack of data and side effect profile and all that, but quityapine and resparadone that too he specifically mentions in his algorithm is options to consider, but he makes a note that he should be at least on your third line drug before considering to go that route. And then the other sort of mood stabilizer drug you can use is a depacote. The devil prox is another one that you could potentially try at that point. But in most patients, SSRI, SNRI, and then those other augmentation options we talked about would probably be used prior to that, unless the patient has certain comorbidities or something that would push the antipsychotic up the list. But there is some data there. Definitely encourage you to check out his algorithm and he has his papers and stuff referenced on the website as well. So you can actually find the full article that was published about the algorithm and the studies and whatnot that backed up his algorithm recommendations. It's personally one of my favorite go-to resources for working through some of these behavioral health issues from a pharmacotherapy standpoint. So we don't have any, I know we're singing his praises today, but we don't have any affiliation with him whatsoever, anything like that. But we've actually talked about getting on the podcast for a while off and on, so that'd be something we should probably try to pursue at some point. - You mean you don't work at Harvard and do research? - No, I talked to him over LinkedIn. I did do that. Yeah, it was a while ago, though, and I just my fault for not continuing to follow up with him, but he seemed like, I mean, it was a short conversation, but seemed like a very, very nice guy. So that'd be cool if we can get him on here one of these days. But in the meantime, I encourage you all to check it out and I'll put a link to his website in the show notes for this episode too, so you guys can find it easier. - Cool. - But as much as I would like to continue discussing some of these, maybe more detail, we'll have to save it 'cause I think we are out of time. Call anything else we gotta add in before we get out of here? - I think we got it. I think we covered it. - Good deal. All right, y'all, well, I hope that was helpful. Like I said, I'll put the website in the show notes, you can find his algorithms and his work, and if you'll have any questions for Cole and myself, shoot us an email or reach out to us on social media. And then thank you to FreeCE, as always, for continuing to partner with us. Make sure you get your continuing education credit for those of you who are members, and through not, go check them out and consider joining. And until next time, we will see you guys and appreciate everything that all are all this time. You guys have stuck with us and continue, as Cole mentioned earlier, eight years or something like that. I don't know, I feel like that's too long, but maybe it is, but we appreciate all of you who are still listening to us babble on about stuff. And we'll see you on the next episode. Have a good one.