So, this is an absolutely stupendous turnout, given the timing at the end of the program and the remote location that we're in here. So, thank you all for coming for this presentation, the title of which is shown up there, an evidence-supported algorithm for psychopharmacology for generalized anxiety disorder in older adults. This is the 14th algorithm that our group at the Psychopharmacology Algorithm Project at the Harvard South Shore Program, based in a VA system in Boston and Brockton, has produced. This one is brand new. We have not presented it before. We have a paper on it, which is under review. We're waiting for a decision from the reviewers, so I think we should consider it a work in progress for sure. There may be further improvements to be made, and we'd love any feedback that you have on it. But it has a slight relationship to our Generalized Anxiety Algorithm Project for GAD that we presented here at APA and wrote up about eight years ago. But this is focused only on older adults in particular, and we really started from scratch to produce it. So we're having three speakers that we're going to divide up the presentation of it into three parts, the beginning, introduction, diagnosis issues, issues with comorbidity and how that might affect the algorithm will be part one. Then part two will be discussions of the first two steps of treatment that we propose. And then the final part will be on the remaining steps into the most treatment-resistant situations. And then we'll have hopefully plenty of time for Q&A. The speakers start with myself. I'm David Ossor. I'm an Associate Professor of Psychiatry at Harvard Medical School and at the VA Boston System and have been the General Editor of our Psychopharmacology Algorithm Project over the past 30 years or so that we've been doing this. But next we have Anderson Chen, who is the first author of the proposed draft of this algorithm that we have submitted for publication. And just to say a few words about him, he'll be coming up second on the program. He's on the Geriatric Psychiatry Department at Mass General. And he got his medical degree from Temple. He completed his residency and fellowship in geriatric psychiatry at Harvard and at Mass General. And he also was the recipient of the Outstanding Resident of the Year when he was with us at the Harvard South Shore Program in Brockton. And he's also won Livingston and DuPont Warren Fellowships from Harvard. And he was Chief Resident in Geriatric Psychiatry at McLean. And our third presenter will be Aaron Metzger. And he's the person with true gravitas among the three of us in that he's been a geriatric psychiatrist for a long period of time. He is the Director of Psychiatry at Hebrew Senior Life in Boston and is an assistant professor at Harvard. That's their affiliated university. He has 25 years of experience treating the kinds of patients we'll be talking about today in outpatient, post-acute, inpatient, and long-term care settings. So that's the speakers. And I will begin with part one. And let's see if everything's working to get me to the next slide. So I mentioned the manuscript is under review. This is the citation for our previous algorithm for generalized anxiety disorder, if you wanted to look that up. I do want to disclose that all of us have no financial relationships with any pharmaceutical firms or any other commercial firms. And here's what is going to be covered. Why would we have an algorithm for generalized anxiety disorder in the elderly, specifically? How would it be different from treating younger people? We're then going to go into the comorbidities and other conditions that are practically ubiquitous in these patients who have generalized anxiety disorder. And we will then talk about the algorithm. We'll review FDA-approved treatments, off-label meds with evidence. The role of benzodiazepines is a major topic to be addressed. Then we'll get into treatment-resistant cases with Dr. Metzger's part of the talk. And we'll also make further comments on meds to generally avoid or use with great caution and say some more words about those options. Now there will be citations throughout the presentation, but they're not spelled out in detail. But if you click on this symbol, you will be able to have access to all of the references in full. So take a minute to flash on that if you're going to want to see our references in sufficient detail to find them more easily. And I will show this again at the end of the talk. All right, so people are photographing it. Okay, so generalized anxiety disorder is a chronic debilitating condition. It's characterized by excessive and persistent worrying that interferes with life. I'll show you the full DSM criteria or at least a sum or a synopsis of them shortly. The prevalence in older adults has been reported to be 6% to 9%. This could be an underestimate, though, due to underreporting. Symptoms in addition to the criteria themselves include somatic physical symptoms like muscle tension and difficulty concentrating and psychic or psychological symptoms, especially apprehension about major and minor concerns. I might throw in here that I do quite a bit of consulting in my work for the VA on patients with problems with mood disorders. We have a service of consultation for people with bipolar disorder where we see people remotely and I review a lot of charts before seeing them. And I am very impressed with how often people have diagnosed their patients with generalized anxiety disorder when they don't have it. It's not meeting criteria for it. They have some other cause of their anxiety. It might be PTSD, chronic pain, any number of other things, but they don't meet the criteria. To utilize our algorithm, you must work with the DSM criteria because that's what all of the research is connected to. If you have some other method of diagnosing GAD, then all this discussion of evidence we're going to present today will not be relevant and you'll be basically making it up as to what you are choosing for treatment. You have to start accurately diagnosing by the criteria. Some think that GAD is a condition of younger people primarily and then they get older and still have it, but actually 50% of older adults have their onset after age 50 of GAD. So this is really a problem, very much so, of the geriatric population. So just again by way of introduction, because this is a psychopharmacology algorithm, as are all of our algorithms from the Harvard South Shore program, it doesn't mean we feel that psychosocial interventions should be neglected or not be the first line or second line or included in your treatment. On the contrary, they're extremely important. They may be the preferred treatment. Many patients may prefer it. We just have not attempted the much more Herculean and we would say impossible task, based on the evidence available, to say when you should use psychotherapy first, second, or third, when you should combine it. So these algorithms, including this one today, are only to help you decide what medication to use. If you decide to use medication, you and the patient, then we're going to make suggestions about what the evidence suggests might be your first, second, or third choice and what you might do after a failed trial and so on. But not to suggest in any way that we don't encourage appropriate use of psychotherapy. Now this you probably can't see, but this is a table of the 13 studies of medication treatments for GAD in older adults that we were able to find. There's actually very few. It made our job a little bit easier to have so few, but that's such a disparate group of studies of different methodologies, different outcome measures, different periods of time that you can't really do a meta-analysis of the more mathematical, classic type. And that isn't what our algorithm is derived from. It's a qualitative analysis of this data, opinion-based, after reading and studying these evidences. And then we submit our papers for peer review and see if we can get agreement by the experts that review our papers that we did a reasonable job of synthesizing what the evidence seems to say according to their interpretation of the same evidence. If there are significant disagreements among the reviewers, the blinded reviewers when we submit, then we have to reach agreement with those reviewers if we hope to get the paper published. And that adds some validity to the final product once it's published. Anyway, this one's not published yet, so it hasn't undergone sufficient review of that kind. So take that into consideration as you hear what we have to say. Oh, it skipped a slide. Hmm. Well, I guess it didn't. All right. So here is an overview of the algorithm. I don't know how well you can see this either, but I'm just going to, in a few minutes, a minute or two, give you the bird's eye view of the whole thing. And then we're going to go into it step by step with our speakers to explain the reasoning for each of these steps and show you the evidence base and give you a sense of how we derived this flowchart that you're looking at. But it basically starts with the person meeting criteria for GAD as in the DSM-5, which is very similar, by the way, to the criteria for the DSM-4, but very different from the criteria for DSM-3 GAD. There's probably no diagnosis in the DSM that changed more since DSM-3 than GAD. They completely changed the concept of what we're calling GAD into basically a worrying disorder. Before, it was a mixture of somatic and psychic symptoms of a wide variety. Multiple symptoms were possible that could be part of the diagnosis, and they changed it to be much more closer to depression in terms of the symptoms and putting strong emphasis on worrying. I'll show you the exact criteria in a bit. But then after making that diagnosis, you also have to evaluate for key comorbidities that might be present along with the GAD because most of them would probably change the basic algorithm. I'm going to be talking about each of those a little bit in my portion of the talk. But they're listed here. They include sleep disturbance, mild cognitive impairment, COPD, neuropathic pain, active substance use disorders, major depression, bipolar, depression and mania, PTSD, and physiologic changes common in aging. A lot of comorbidities to take into account before you're ready to see if the algorithm has a recommendation for you. But then the first step is to propose an SSRI. And escitalopram or sertraline are the first choices. If they don't want to have the side effects of those drugs, maybe they don't want the sexual side effects, we think you could consider buspirone or duloxetine. But if they fail that, we would try a second SSRI. And you could also now consider an SNRI as well as buspirone, venlafaxine and duloxetine are the two SNRIs that come up. And if that trial fails, a third trial could involve the options we've already considered. But we also have the option of pregabalin or possibly gabapentin. We'll explain that later. Agamelotine, not available in the United States, but has been studied in GAD. And if we have some international attendees, you may be familiar with it. It has a possible role. And then the last step, these are the really treatment-resistant cases if you've tried three trials already. Then we add the possibility of an antipsychotic, quetiapine being the one preferred. And also we'll talk about the role of benzodiazepines and hydroxazine at this level. So that's the two-minute overview of what you're going to hear about in more detail. Now I should start by pointing out there are a number of FDA-approved medications for GAD in younger people. They aren't specifically approved in the elderly. But we have two SSRIs that have that approval, escitalopram and paroxetine. And we have two SNRIs that have FDA approval, those being venlafaxine and duloxetine. One benzodiazepine has that approval, alprazolam. And one azepurone, there is only one available, buspirone. Actually, another one just was approved for major depression, gepurone. We have two azepurones now in our armamentarium. It hasn't been approved for GAD, though. And then we have a bunch of off-label options, like other SSRIs not already mentioned, other benzodiazepines, hydroxazine, pregabalin, bupropion, lavender oil, and gabapentin. We'll talk about all of those. Now the criteria for GAD, and you may not be able to read this either very well, but it involves excessive worry most days. So excessive worry is most days for six months. So on at least more than 50% of the day, you're worrying excessively. And it's difficult to control that worry. And then you have three out of six of these additional symptoms listed here. Restlessness or feeling keyed up or on edge, being easily fatigued, difficulty with concentration, irritability, muscle tension, sleep disturbance. And it causes significant impairment is the other level of impairment of the other criterion. All right, so you've diagnosed your GAD. Now let's look into the comorbidities and see which of those you have and what their implications might be. So the first would be physiologic changes related to aging. There are many that can influence the choice of agent. Weakened ability to regulate blood pressure, for example, and to regulate temperature, electrolyte balance, weakened bladder control, reduced postural stability. These would all influence your choice of which of our options to pick for any individual. The drug half-life is also generally prolonged in the elderly. So the less efficient hepatic and renal function patients are going to influence your choice. You can still consider the medications, even if they have these impairments, but generally you want to start with a lower dose and make a slower titration. We generally prefer to avoid augmentation strategies in this whole algorithm to minimize polypharmacy and drug-drug interactions with all the other drugs they may be taking. We prefer sequential monotherapy, at least for a bunch of steps in the algorithm in older adults. And if you do try augmentation, it too should be at low dose with slow titration. Fall, by the way, is a major concern in older adults, of course, and comprehensive reviews have suggested that many frequently used medications in older adults, including many, if not most, of the drugs we're gonna be recommending at various points can cause increased risk of falls. So it's something you always have to be concerned with in treating this problem. But there's also analgesics, NSAIDs, opiates, antiepileptics, polypharmacy. They're all associated with fall risks, and as such, you have to constantly weigh the risks and benefits of meds use as you treat your elderly patient. So the next comorbidity to talk about is sleep disturbance. It's not really a disease, but sleep problems are a symptom, so you have to see what the causes are. They usually are multiple causes. And then you wanna treat each of those multiple causes with evidence-based treatments as best you can. And some of the treatments we're giving may be a cause of insomnia. SSRIs and SNRIs, for example, all have significant percentages of patients getting insomnia as a side effect. And other drugs too, if they're on, insomnia is a very common side effect for anyone on a stimulant, double or triple the rate of people not on stimulants. So in general, also, when you use these other drugs, you wanna prescribe them in the morning because that might minimize the insomnia side effect. So we recommend evaluating and managing the contributing causes of the insomnia systematically. I am always telling my residents, insomnia is not a disease for which the treatment is Seroquel. I get the impression that's what people think. Now maybe that's because they're being called in the middle of the night, and that seems like the quick and easy answer when the nurses say someone can't sleep. But you gotta try to figure out what's causing it. There could be a dozen different things. That's not the focus of our talk today, but certainly could be a whole talk. But there's things like sleep apnea, nightmares and disturbed awakenings due to PTSD, nicotine dependence, people who smoke heavily and they go into withdrawal in the middle of the night, and they have to go have a cigarette to get back to sleep. Very common problem. Having managed, then, their other causes of insomnia, you now then may consider primary insomnia. That's out there, not due to other psychiatric disorders, not secondary insomnia, but primary insomnia when there's no psychiatric or medical condition known to be causing it. We don't see that much of it in psychiatry. It's generally primary care doctors that encounter primary insomnia, but it is out there. We have a lot of FDA-approved medications for primary insomnia. By the way, that's what all the hypnotics are approved for, primary insomnia. They're not approved as a treatment for insomnia secondary to all the other diseases we treat that have insomnia as a symptom. I mean, probably the worst example, obvious example, is mania with insomnia. Are any of these hypnotics an approved treatment for that? No, you probably want to treat the mania with something known to work for mania. But that's maybe the most obvious example. Obvious as it is, I see people doing it all the time. And let's see. Now, if the insomnia is due to side effects of SSRIs and SNRIs, we suggest first dosing the med in the morning, trying a different one, trying a junk of trazodone might help. In two placebo-controlled trials in younger patients, it did help, but safety issues require caution in the elderly. We're generally trying to avoid using two or more drugs if possible. Pregabalin might be more helpful for sleep than SSRIs or SNRIs, if that's a prominent problem. It is more sedating. It's not FDA approved, but it is approved throughout Europe as a treatment for GAD. Hydroxazine, it is sedating. We do recommend it in our younger patients with GAD, but it is on the BEERS list of drugs to be avoided in the elderly, if at all possible, due to safety concerns related to its anticholinergic effects. So we think you should probably have it at the bottom of your option list for the insomnia. And with sleep apnea, you definitely want to avoid overly sedating, respiratory depression, mesocation, so be sure you've accurately diagnosed sleep apnea, that you're not missing that, because there's a lot of drugs you don't want to use for their sleep problems. Now our next quick comment to make about the comorbidity of mild cognitive impairment and dementia. Anxiety is common in these patients. The standard of care for cognitive impairment is something that's deserving of another talk, but there are approved treatments, and we suggest refer to neurology, neuropsychiatry, if they meet criteria for GAD plus have MCI and dementia, and consider in collaboration with your consultants whether you want to treat the GAD separately. Neuropathic pain. Duloxetine has indications for GAD in younger patients. Depression, neuropathic pain, fibromyalgia, musculoskeletal pain, chronic low back pain, and pain due to osteoarthritis. So it might be a good choice for those people who have those comorbidities. Pregabalin and gabapentin have similar indications for neuropathic pain, but not for anxiety. There's really been little study, hardly any, of gabapentin for various anxiety situations, and specifically GABD, there's been no studies of gabapentin, but it is very similar to pregabalin chemically, which has been extensively studied as a treatment for GAD. Chronic obstructive pulmonary disease. We want to avoid respiratory depressants like opioids, benzodiazepines. The use of benzos for anxiety in this context requires considerable caution, but could be done on an individualized situation. What if they have active substance use disorders comorbid with their GAD? 15% have that. Well, we would avoid benzodiazepines, avoid pregabalin, which is also a schedule four, and related agents. And what if they have major depression? Very common to have comorbid anxiety and major depression. It responds much less well to antidepressants than either alone. The comorbidity is associated with poor response. So what could work? Well, quetiapine can be effective, but it's got considerable side effects. Aripiprazole augmentation of an SSRI has a good study for anxiety associated with depression. Bipolar depression. Rates of GAD are higher in bipolar than unipolar. But we don't recommend antidepressants for bipolar depressed people who have GAD. We would consider that more appropriate treatments for their depression, such as quetiapine, lamotrigine, lorazodone, coriprozine, and lumateperone, all of which have FDA approval for bipolar depression. Quetiapine can work for both bipolar depression and GAD in younger patients. So those are options to think about. Bipolar mania. Manic patients have high rates of GAD, too. Response to lithium and anticonvulsants may be reduced in those patients. Valproate was effective for anxiety, compared with placebo in a small study where there was comorbid GAD, so you might think about valproate for them. Quetiapine is an antimanic agent that's also effective for GAD, probably to be preferred over valproate or lithium if the manic patient presents with mixed depressive features. And finally, PTSD. What if they have comorbid PTSD with their GAD? Well, for the PTSD, we have a very effective add-on treatment for their insomnia, nightmares, disturbed awakenings, and daytime symptoms. Prazosin has been effective in six out of nine placebo-controlled trials. I have to disagree with the speaker earlier in the week, who was very negative about Prazosin because of one negative study, but in a meta-analysis of those nine studies, it had an excellent effect size of about 0.4, better than the effect size of SSRIs for GAD, which is in the 0.3 area. So I think it's the treatment of choice for people with PTSD. For PTSD symptoms in your GAD patient, and indeed, they may not even have GAD, take a close look at whether their anxiety is all due to the PTSD. If so, they should be treated with an algorithm, your best algorithm, for PTSD, not with GAD treatments. I think I've gone over my time. I'm at the end. All right, I'm ready to introduce the next speaker. Dr. Chen, it's all yours. Thank you. Hi, everyone. Can everybody hear me? Thank you again for coming. So I have about 20 minutes. We're gonna go over the steps of first trial, and what if you want to avoid sexual side effects, and then the second trial. Before I go into that, I wanna make clear this is a first step for a patient who's developing symptoms that meet the diagnosis of GAD for the first time in older adults. Many of your patients are not going to be like that because 50% of the patients probably already had GAD when they were younger adults. So this wouldn't exactly be their first step. You might have to go to a different step. You have to tailor it to the patient's needs. But for the patient who's perhaps always been an anxious person, developed coping skills, maybe they loved working out at the gym, they loved their job, suddenly they retired. They develop a medical issue, or they lost their best friend who happens to be their spouse. And then now they develop symptoms that meet diagnosis criteria for GAD. This then would be your first step. And that is typically what we see clinically. We kind of have two types of patients with GAD. Those who's always had GAD versus those who are developing it for the first time. For those who've always had GAD, maybe they were really well-maintained on fluoxetine. And then they were able to have other coping skills and they came off of it. And then now they're coming back on something because they're developing these symptoms. Do you have to go to escitalopram or sertraline? I don't know. But you would make a better decision if you at least know the evidence supporting the use of escitalopram or sertraline. But it would still be very reasonable, I think clinically, to go back on fluoxetine if that's what used to work for them in the past. So this is not something that's really, really rigid. Just wanna make sure I emphasize that people know the evidence to guide your decisions. All right. So the first trial, we recommend an SSRI. I think that's pretty, pretty widely accepted. It's a first-line medication treatment for uncomplicated cases of generalized anxiety disorder. The FDA-approved medications are escitalopram and paroxetine. Just because it's FDA-approved doesn't mean it's the right choice or a good choice. And we'll talk more about why paroxetine is not an ideal choice, but really kind of underlying is kind of the anticholinergic effect, which if you see a lot of older adults, you're feeling it these few months with the allergy season coming up and a lot of patients taking allergy medicines, that's kind of why they're getting into trouble right now. Talk about the evidence for escitalopram and sertraline. And we'll also talk about citalopram and how the issue really is about QTC prolongation. I see it all the time. Clinically, I have a patient come in, they're doing well, they're finally getting better on citalopram, but it stopped at 20. And then you can't go further up. And the reason is usually because of the concerns of the QTC prolongation. Now it's true, one of the experts in QTC prolongation who happened to be my program director when I was a resident, Margo Funk, did kind of suggest that perhaps a QTC prolongation is kind of overemphasized or kind of overly concerned. But an older adult, I would say you have to be very mindful because even if the QTC is not prolonged right now, chances of them being on other agents in the next few months or the next few years that will prolong it is not low. So it's also kind of ideal to just have them on something that doesn't prolong that much. So frequently, clinically, what I have to do then is I have to taper it off and then put them back on something that has less, like escitalopram. SSRI in general is an effective treatment for GAD with an overall modest effect size of 0.36 in all ages. So let's first talk about some of the evidence for escitalopram. In one randomized controlled trial of 177 GAD patients over age 60, 85 patients were treated with escitalopram for 12 weeks with doses ranging from 10 to 20 milligrams. I'll take a quick pause there. A lot of times, older adults, you don't have to start right up at 10. I have seen clinically older, more frail adults, you can do 2.5, five, and sometimes you can pause there. But in these studies, it was 10 to 20. Escitalopram was found to be superior to placebo for anxiety symptom control with a robust effect size of 0.93, which is really robust. And the main adverse effect being fatigue. Escitalopram is preferred over citalopram as it has a more favorable adverse effect profile with respect to QTC prolongation, as long as the maximum dose of 20 is not exceeded, right? This is GAD, we're not talking about OCD. Now let's talk about Sertraline. What's the evidence there? In a controlled trial, Sertraline outperformed both placebo and cognitive behavioral therapy on a three-month follow-up study with a Cohen's D of 1.02 versus placebo. Response rates were 44% for CBT, 57% for Sertraline, and 11% for placebo. We're not saying CBD's bad. Definitely, if your patient has the resources and the ability to receive CBT and the medication together, that'd be great. And Sertraline also causes minimal QTC prolongation risk. In one RCT trial of 46 patients older than 60 with GAD, 21 patients received 50 to 100 milligrams Sertraline daily, and 25 received 10 to 15 Buspirone daily. During eight weeks follow-up, Sertraline was shown to be helpful for GAD symptoms as early as two weeks into treatment. At baseline, the patient's Hamilton rating cell for anxiety scores were about 30. By eight weeks, HRSA scores decreased for Buspirone and Sertraline, or 15.7 versus 13.1, respectively. This trial does seem to suggest that Buspirone is super effective, even more than Sertraline. But I will go into this study in a little bit, but this study's patient population was very healthy. Clinically, you usually would get a good effect for Buspirone for a patient who is truly developing generalized anxiety disorder for the first time. I wouldn't really go for Buspirone if this patient is also on quetiapine, plus benzodiazepines for other reasons, and then coming to you for anxiety. I would be very doubtful that Buspirone would work. As many of you probably know, Buspirone in an adult is almost sometimes known for like a placebo effect. But in older adults, it can work. Peroxetine, it is FDA approved for GAD. However, we recommend avoiding it due to its anticholinergic effects. And that's really, really important, because sometimes there are other medicines with anticholinergic effects that they can't avoid. So if you can avoid it with this one, great. It has the most sexual side effects amongst SSRIs and SNRIs, and it's among the most likely to produce waking, probably, again, tied to the anticholinergic effect. To tag onto that, it also has significant risk for drug-drug interactions. Specifically, it's P450 2D6 inhibition can lead to increased levels of many commonly used medications, including opiates. So a lot of times I have patients coming in to me on high doses of peroxetine, now also feeling like they're becoming more confused and things like that and in addition to the other workups to make sure there isn't really like an underlying neurocognitive disorder, we do have the discussion of tapering off the paroxetine going to something more evidence-based, but you just have to be mindful when you're doing that if they also have a pain issue that the pain would suddenly worsen because paroxetine was kind of giving them a higher level of their opiates. Paroxetine also presents with a high risk of withdrawal symptoms with sudden discontinuation. This is very big, especially for your patients who are older adults living at home. You shouldn't assume that they are taking medicines very consistently. It is super easy for them to miss a medicine. They didn't fill out CVS or they get it from those mail orders. What if it's delayed? Maybe it's a 91 year old taking care of an 89 year old. Those things happen. They can make mistakes, so a lot of times what if it's just they miss the medicine and they're going through withdrawal and they tell you that they have an anxiety exacerbation. You see this a lot for immediate release with duloxetine, venlafaxine, or kind of short-acting benzodiazepines as well. These are like huge reasons why you would want to avoid paroxetine in an older adult. One thing to be mindful of is all SSRIs carry a risk of hyponatremia in the geriatric population due to the risk of developing the syndrome of inappropriate antideriotic hormone secretion. The risk is really high when you just started, especially like the first two weeks to a month. If you have a patient who's been on sertraline or escitalopram for nine months now, suddenly there's symptoms of hyponatremia. You're concerned about it. The PCP is messaging you. You're like, yes, but first you want to make sure is it something new, but have I kind of conceded because they've gone through everything. They couldn't really figure out why. Yes, in those cases, sometimes we do cut back on the SSRIs. There's also a ninefold increased risk of bleeding when SSRIs are used with NSAIDs without concomitant use of proton pump inhibitors. This is really important because falls plus bleeds is significant medical trauma for an older adult that's sometimes hard to recover. So you really want to make sure if they're on an NSAID which is commonly used in older adults that it's not something NSAID PM. That's number one. Number two, that there is a PPI on board. Studies have also found that one to four weeks of SSRI use is associated with 67 to 84 percent increase of bleeding risk. And many older adults do care about bleeding risk. So let's say you mention these first-line treatments and it doesn't sound very appealing. If they go home, they Google. There's a lot of side effects. They're saying, I'm a little bit anxious. Do I really want to take something that's going to make me a lot more anxious? Okay, you have other options, especially if sexual side effect is a concern. We talked about Buspar Diloxetine. So Buspar, this FDA-approved anti-anxiety agent for GAD, was slightly superior to Sertraline on one small RCT in older adults with GAD. So that's the one I just talked about. Demonstrated effectiveness at 10 milligrams three times a day by six weeks of treatment. So if relatively healthy adult, again, this is the medication that I would lean into. If there's also concomitant pain, like Dr. Oster had mentioned earlier, then I would lean into Diloxetine. Compared with Paroxetine in younger adults, it has significantly fewer sexual side effects. So that's key. Placebo-controlled Diloxetine in older adults, in which 151 subjects received Diloxetine and 140 received Placebo, Diloxetine reduced the HRSA scores more than Placebo by 4.2 points. In Sheehan Disability Scale, global scores more by 3.2 points. And we're going to talk more a little bit about kind of the downsides of Diloxetine just a little bit. So that's the first try. Now we're going to slide into the second try. What do you do? You could try another SSRI, Buspirone, Venlafaxine, or Diloxetine. So really at this time, there are no studies to guide you kind of what to do. So you kind of rely on the evidence that you know and good communication with your patients. Since the SSRIs are not identical in their spectra of receptor activity, it may be that a different one can be effective or one could select an SNRI which presumably employs a different mechanism of action. So Buspirone. The two trials to date in older adults, these studies suggest that Buspirone is reasonable for a relatively early trial in the algorithm for GAD in a healthy older adult. There's minimal sexual side effects, lack of cognitive impairment, or psychomotor performance. Again, these are really strong risk factors you want to mitigate in older adults, which is impact on cognition and psychomotor performance. Sedative effects are more likely when the daily dose exceeds 20. You want to warn your patients about that. Although sometimes you also see insomnia, jitteriness, nausea, and headaches. In general, I will say Buspirone is very well tolerated in an older adult. In the comparative study with Sertraline, benefits were seen as early as two weeks. Venlafaxine. At low dose, it's primary an SSRI, and at higher dose, then there is a dose-related kind of relationship with hypertension. But actually, when you use a low dose, you sometimes see low blood pressure. In older adults, and I think in general, you want to use extended release as opposed to immediate release because of the quick withdrawal effect you might see if they miss it by a little bit. In a secondary analysis of the results in older adults age 60 and above, participating in five industry-sponsored studies of Venlafaxine extended release for GAD, 66% responded versus 41% on placebo. And one good thing to know is that Venlafaxine does not pose significant QTC prolongation concerns and causes minimal p450 drug interactions. A sister medication to Venlafaxine is Diloxetine. Diloxetine has a lot of GI side effects though. So if you have a patient with anxiety, and a lot of times they commonly have like GI diagnosis, irritable bowel syndrome, you might want to avoid Diloxetine. The 2023 BEERS criteria recommends avoiding Diloxetine in older adults for this reason, the gastrointestinal side effects. And despite marketing of its FDA indications for various painful syndromes including fibromyalgia, diabetic neuropathic pain, and chronic musculoskeletal pain, two meta-analyses concluded that these analgesic effects are clinically insignificant in depressed patients with pain and not greater than with other antidepressants. A more recent review found moderate certainty strength of evidence that SNRIs as a class do have benefit for pain, but this did not take into account the presence or absence of comorbid depression or anxiety. Some of the studies in the review would have excluded patients with those comorbidities anyways. If Diloxetine is being utilized for an older adult, the clinician should be aware that this medicine is a moderate p450 2d6 and 2b6 inhibitor. I will say in general uncontrolled pain is also pretty depressing, anxious, kind of inducing. But if you had those symptoms before the pain started and they were really thick and then the pain comes up, then I really think you need to take this into account and not expect too much effect from the Diloxetine itself. One placebo-controlled trial and a pool meta-analyses of several small studies with a total of 73 patients older than 65 with GAD. The RCT showed that Diloxetine reduced mean HRSA total score 4.2 points and SDS global scores 3.2 points more than placebo. Ultimately with a response rate of 71% for Diloxetine versus 46% for placebo. So it's really pretty good. The pool study used population subsets from four studies and the results suggest that patients treated with Diloxetine had more significant HRSA improvement when compared to placebo with a response rate of 48% compared to 29% for placebo. Diloxetine S60 was effective in older adults with major depressive disorder with anxious features with anxiety improvements observable at one week. So these are kind of the two options. I'll stop there and I'll pass it on to my colleague Dr. Metzger. Thank you, Anderson. So lack of response after two trials unfortunately is not uncommon in psychopharmacology and treatment of GAD in older patients is no exception. We also encounter unsatisfying or inadequate response after two trials and we'd like to present to you some options for dealing with that scenario. Just as Anderson said there are no studies to guide us for patients who have failed a trial. Similarly there are no studies to guide us for older patients who have failed two trials. Our first recommendation is to consider one of the agents that Anderson has already discussed if those agents have not been tried and one of them could be a good fit for the patient. So considering a different SRI or a different SNRI or abuse-prone for example. However there are some other agents we'd like to introduce you to and the first are pregabalin and gabapentin. As their name implies they have effects on gamma amino butyric acid however they don't unlike benzodiazepines work directly at the GABA receptor and for that reason don't have some of the adverse possible adverse effects that benzodiazepines could have that will that I'll be talking about a little bit later. Of the two as Dr. Oster mentioned pregabalin is the one for which we have the most data and it is approved in Europe for generalized anxiety disorder. One of the benefits of pregabalin is that you don't have the response latency that you see in SSRIs so you don't have to wait a few weeks for a response. There is an eight-week randomized controlled trial for gamma amino for generalized anxiety disorder of pregabalin doses 150 to 600 milligrams per day. It was a decent-sized study of 273 subjects and their age was reflective of the older population mean age of 72 years. They did have a response as early as two weeks and though there was only a two-point reduction mean reduction in the Hamilton a score it was statistically significant and the side effect profile was quite favorable. The evidence for gabapentin as Dr. Oster mentioned is much more limited really only case studies. Gabapentin is familiar to us psychiatrists because it's been used as in hypnotic, a mood stabilizer. It was even popular for a while for personality disorders. It does not have FDA approval for any of those indications and we really don't have a solid database for which to recommend it for generalized anxiety disorder. However we mention it because of its physiologic similarity to pregabalin for which there is more data. Incidentally the main side effect for pregabalin and this has occurred across all of the studies is weight gain which may or may not be an undesirable adverse effect depending on what's going on with your older patient. Agamelotine is medication not available in the United States. It's sold in Europe as Veldoxan and as its name implies is a melatonin receptor agonist but also has serotonergic effects and was developed primarily as an antidepressant but has also been studied now in generalized anxiety disorder although not in older patients. And from three trials and meta-analysis agamelotine did perform favorably for generalized anxiety disorder with a very impressive number needed to treat of 3.1. And in a head-to-head trial versus si-talipram actually performed quite well with essentially an identical response rate. It is considered to be safe and well tolerated. I will say that most of the studies of agamelotine were sponsored by the manufacturer Cervier and the meta-analysis that was written by Dan Stein also received funding by Cervier. So that's just one thing to take into consideration as you interpret that data. The side effects were fairly minor. Those include headache, nasopharyngitis, nausea. Those side effects occurred with equal incidence for placebo however. There were cases of transaminase elevations. So if you were to get hold of agamelotine we would recommend monitoring liver function tests. All of the cases of transaminase elevation did resolve without incident when the medication was discontinued. I'd like to discuss a couple of agents which would probably fall under the heading now of what we call complementary therapies or alternative therapies and those are lavender oil and kava. You've probably had patients who use lavender oil aromatherapy for relaxation or sleep induction and who like my patients probably report that it's effective. Lavender oil aromatherapy is very hard to study in a randomized controlled manner because how do you come up with a control arm for something that smells like lavender oil but isn't lavender oil. So therefore the controlled studies have actually been of the oral preparation of lavender oil which is marketed in Europe as Selexan. It's a capsule but is also available in the U.S. over-the-counter as a product called Calm Aid. The oral preparation does carry with it the risk of GI side effects which can lead to discontinuation unfortunately. But if someone did have response to the oral capsule but couldn't tolerate it that would be a reason to recommend switching to the aromatherapy. Kava is another natural occurring substance. It's a shrub that has its origins in the South Pacific and has a history of being used recreationally and for a while was completely banned in Europe because of liver function abnormalities, some very serious that in retrospect now that it's been studied more closely were probably due to impurities in the Kava product that people were using and subsequent analyses of those data have led to a decrease in the concern about Kava. Kava is now legal again in Europe and is available over-the-counter in the U.S. and there is a study with an impressive Cohen's d of 0.62 and 26% remission in the Kava group versus only 6% in placebo. Hepatotoxicity though probably should remain on your radar screen so liver function test monitoring and discontinuing the medication immediately if you do see elevations of transaminases. Even without the liver function test abnormalities it's important to keep in mind and this is a recurring theme across this talk that Kava actually does affect the cytochrome p450 isoenzyme system so it will affect metabolism of some of the other drugs that your older patient may be taking. If your patient has failed a third trial, well, then they are truly treatment-resistant. I would say they are a super-resistor, and we have some agents for your consideration for that scenario. You've heard a little bit already today about antipsychotics, and I'd like to focus on quetiapine. Quetiapine works at various receptors, serotonergic, also at the D2 receptor, but unlike other antipsychotics, it rapidly dissociates from the D2 receptor. Akathisia is probably the last thing you want to give your patient who has generalized anxiety disorder. So quetiapine, because of its rapid dissociation from D2, is less likely to induce akathisia than some of the other antipsychotics. It is frequently used in the treatment of anxiety as a monotherapy for generalized anxiety disorder in several randomized controlled trials. It has been studied in older adults in a large trial. 450 patients. And it had a very impressive response rate of 69% versus a 24% response rate from placebo. The Scandinavian countries are known for their very high The Scandinavian countries are known for their very impressive registry studies because of their socialized medicine. They are really good at tracking adverse effects. And we have from Denmark a study of a half million patients who took low-dose quetiapine for anxiety and did show a 1.7-fold increased risk of major cardiovascular events, non-fatal ischemic stroke, but also cardiovascular death. And this was more pronounced in older patients. This 1.7-fold increase in adverse effects is almost identical to the 1.7-fold increase in mortality that we see in antipsychotics used for behavioral and psychological symptoms of dementia. So it's probably a real effect at this point. But I would caution you that while a 1.7-fold increase sounds like a lot, when you talk about the raw percentage numbers, for example, in behavioral and psychological symptoms of dementia, you're talking about an absolute mortality increase ranging from about 3.9 to... going from about 3.9 to about 4.2%. So in absolute percentage numbers, that kind of risk may be acceptable when you consider the possible improvement in quality of life. Other antipsychotics have been studied for generalized anxiety disorder, but not in older adults. And these include risperidone, aripiprazole, olanzapine. Those agents would have other reasons why we wouldn't favor them as well because of akathisia, as I mentioned, but also things like anticholinergic effects. Another adverse effect, incidentally, to be mindful of for catiopine is that it does have alpha-1 blockade effects, and that can cause postural hypotension, hence the cited adverse effect of dizziness. And now to benzodiazepines. The Beer's Criteria were mentioned before. Is anyone unfamiliar with Beer's Criteria? I don't want to, because people who do geriatrics regularly live and breathe Beer's Criteria, but those who don't do geriatrics regularly may not be that familiar with them. They are based on a consensus Delphi approach to making recommendations about all classes of medications for use in the elderly, and psychotropic medications are among the classes of medications that the Beer's Consensus Panel adjudicates, and benzodiazepines have been among those medications ever since the first publication of the Beer's Criteria back in the 1990s. Since that time, the Beer's Criteria have undergone a number of revisions, and interestingly, the trend for benzodiazepines over that time has been towards more leniency, actually, in allowing older patients in some circumstances to be prescribed benzodiazepines. So that whereas back in 2017, the Beer's Criteria recommendation was a strongly avoid recommendation against benzodiazepines, they acknowledged last year in the latest edition that benzodiazepines could possibly be appropriate to consider for generalized anxiety disorder. I'll talk about in a couple of slides some of the possible rationale for this increased leniency, and it relates to the concerns about adverse effects, including falls and hip fractures. We know that benzodiazepines continue to be prescribed to almost 10% of our older patients, and of these, that about a third of them use benzodiazepines chronically, and across many studies, they have been associated with increased risk of falls, they've been associated with increased risk of fractures from those falls, they've been associated with increased risk of motor vehicle accidents, and there have been concerns about older patients developing tolerance, dependence, and rebound withdrawal when efforts are made to discontinue the benzodiazepines. We've talked a little bit already about the risk of respiratory depression. Our older patients, in contrast to younger patients, are more likely to have coexisting pulmonary disorders, such as chronic obstructive pulmonary disease, and that could be a contraindication to using a benzodiazepine. The mechanism by which benzodiazepines exacerbates respiratory failure in patients with COPD has to do with its effects on the hypoxic drive. COPD patients who retain CO2 have lost their carboxic drive, so that's why, even though they run up higher levels of CO2, they do not respond appropriately by increasing their respiratory activity. So CO2 retainers are, therefore, depending on their hypoxic drive. What benzodiazepines do is suppress the hypoxic drive so that now they've lost both their carboxic drive and their hypoxic drive, which can get them into serious trouble and respiratory failure. If your older patient, in addition, happens to be taking an opioid analgesic for chronic pain, that is a possible formula for disaster. There was a study by Helene Altman looking at benzodiazepines in conjunction with SSRIs, and her study showed, actually, that people did more poorly when an SSRI was co-prescribed with an SSRI for benzodiazepines. So that's all the bad news for benzodiazepines. But we do have some trials of benzodiazepines in older patients. Just a reminder that, as Dr. Oster mentioned, the only benzodiazepine that actually has FDA approval for generalized anxiety disorder is alprazolam. The ones that we more typically use, like lorazepam and clonazepam, actually don't have an FDA indication for GAD, and we're using them off-label. But some other agents that have been studied, albeit in relatively small studies, are ketazolam, which is not available in the U.S., oxazepam, which is available. And these trials did show that, particularly if symptoms are severe and other trials have failed, that benzodiazepines can be effective and safe alternatives for treating generalized anxiety disorder in older patients. If you are going to use a benzodiazepine for generalized anxiety disorder, there are reasons to favor lorazepam or oxazepam. These are in part due to their relatively short half-life. There are physiologic reasons why older patients tend to store up benzodiazepines in their bodies more than younger patients. These agents are lipophilic, so they get stored more readily. As our proportion of body fat increases, which is the trend as we age, but also half-lives of all of the medications increase with aging, so that's another reason to favor shorter half-life benzodiazepines like lorazepam and oxazepam. For any patient with hepatic insufficiency and possible metabolism problems, lorazepam and oxazepam don't depend on a healthy oxidative metabolism in the way that other benzodiazepines do. They rely exclusively on glucuronide conjugation, which is not affected by liver disease, so that you will not run into the risk of benzodiazepine toxicity in liver failure with lorazepam or oxazepam as you would with the other benzodiazepines. Most commonly, however, you'll encounter a patient who comes to you for the first time who's already been using a benzodiazepine, and what do you do then? We recommend that you take an individualized approach, assessing the risks and benefits to that patient of continuing versus discontinuing a benzodiazepine, and discontinuation of a benzodiazepine in an older patient is not itself without risks. There's a review of 350,000 cases that showed discontinuation of benzodiazepines actually increased mortality, increased the risk of overdose, suicidal ideation, emergency department visits, and that if the patient was already taking opioids and benzodiazepines, the risk of adverse effects was further elevated. So discontinuation itself is not without risks as well. And the risks of benzodiazepines may have been overstated because of earlier epidemiologic studies failing to take into consideration that the indication for the benzodiazepines may have itself resulted in some of the increased adverse effects that were attributed to the benzodiazepines themselves. And a very convincing thought piece just occurred a couple of months ago in the American Journal of Psychiatry by Stephen Sumerai and Carl Saltzman, making a very strong case that failure to control by indication for benzodiazepines has probably really skewed our assessment of the safety of benzodiazepines in older patients. That's not to say that they don't carry with them risks. All psychotropics do carry risks, including the risk of falls. However, I think this greater appreciation of the failure to control by indication gives us a more realistic assessment of the true risks and benefits of the benzodiazepines. If you do decide to taper a benzodiazepine, unfortunately, we don't have any studies, and certainly not for the elderly, that will guide you in this. Therefore, based on the evidence that we have, including a 2018 Cochrane Collaboration Review, we recommend a gradual tapering over several months, trying to include a psychotherapy, such as cognitive behavioral therapy. And there are some studies using a reduction of, say, 25 percent every two to three weeks, which can be thought of as a hyperbolic tapering approach versus a linear approach, which has had some success. A word about hydroxazine, which is an antihistaminergic medication. It has been studied for generalized anxiety disorder in younger patients, where it did outperform placebo. It is also mentioned among the beer medications as a medication to avoid in the elderly because of its anticholinergic effects, and it can also cause QT prolongation. Valazodone is a newer medication marketed as an antidepressant, but there are randomized controlled trials for generalized anxiety disorder, in which it did outperform placebo. It has a relatively large effect size, with gastrointestinal side effects being the most common. Probably not going to be approved for generalized anxiety disorder because the manufacturer is no longer seeking this indication. A word about cannabis. Among the studies for anxiety, there are no studies of inequality in older adults. There's a lot of self-experimentation. I'm sure that you all have patients who are using it for anxiety, for sleep. I would say anecdotally it seems to be well tolerated, although there's never been a good study for some of the adverse effects that one might anticipate with cannabinoids, for example, increased fall risk. So just a quick summation. I want to emphasize that critical to the effectiveness of an algorithm like this is first clarity about the diagnosis. This is an algorithm for generalized anxiety disorder. There are a lot of etiologies for anxiety in a patient who comes into the office. What we're proposing today is really limited to a specific etiology for those anxious symptoms, and that's generalized anxiety disorder. The main areas in which this algorithm departs from an earlier algorithm, 2016, for generalized anxiety disorder in non-elderly adults is that we are emphasizing monotherapy versus augmentation or polypharmacy, again, because, as Dr. Chen mentioned, our older patients generally are already taking a lot of medications, and the more medications we add to that list, the higher the risk of drug-drug interactions and adverse effects. Benzodiazepines and hydroxazine warrant particular caution in older patients for the reasons described, and another departure from the 2016 algorithm is that at this point we're not recommending either SNRI over the other, so our recommendations are comparable for both venlafaxine and duloxetine. As with all the algorithms, this should be thought of as a consultative guide and is best when it is applied in conjunction with thoroughly knowing your patient, their comorbidities, their preferences, and their likelihood of being able to adhere to the treatment plan that you're proposing. So I want to echo my colleagues' thanks to you all for coming to this final session of this conference, and we've allowed time for questions. Thank you. Okay, question number one. Hi, thank you for that great talk. My name is Srageet Glasman, and I'm a geriatric psychiatrist in New York and Connecticut, and I was just wondering, is there any understanding as to the mechanism of the Lavender or the Kava? Not that I know of, but clinically I've seen it work very similarly to bucephalus, kind of my expectation for it for the most part. I don't know if any of my colleagues have anything to add. I'll just say that one concern about lavender, particularly lavender aromatherapy, that it was just, and this was used in sort of a derogatory way, that it was just psychological. But actually, lavender oil has been studied in preclinical trials with mice in oral preparations, and they have been shown to benefit from its anxiolytic effects through the oral formulation. So it's not simply the pleasant sensation of lavender. And this was, of course, then supported by clinical trials in adults. But no, I can't give you a better explanation of the mechanism, unfortunately, and similarly with Kava. Thank you. I don't know if we know the mechanism of how SSRIs work either for GAD. Good afternoon. Thank you for the presentation. I just had a question about duration of treatment and what you're recommending now in terms of how long do you treat these patients? I would say first you have to decide how bad is the GAD in front of you. Is it emergent, meaning if you don't do something, the patient's going to go to the hospital today, versus urgent. If you don't do something, he's probably going to go to the hospital this weekend or the next, versus non-urgent, you have some time. Because if it's emergent or urgent, SSRIs is probably not the place to go right away. You want something to give you an impact right now, and you might have to go to GAP Penton, quetiapine, something like that. If it is non-urgent, then you could use an SSRI. And in those cases, you could wait six weeks, eight weeks, and you continue to go up. I don't know if I did a good job explaining that or. I think longitudinal studies like the Harvard Brown Anxiety Study, which followed GAD and other disorders, patients for a dozen years, they had comparison with major depression, social anxiety disorder. They found that GAD was one of the disorders that's most likely to still be there in 12 years and doesn't go away. Whereas major depression, episodes come and go, and it's more likely to remit. Panic disorder, more likely to remit. So probably you do need to continue the treatment, perhaps indefinitely. However, there have been some maintenance studies there where they move people to a placebo versus keeping them on the drug. And keeping them on the drug is always better than moving them to a placebo. However, a significant portion, 60, 50, 40 percent still do okay when switched to the placebo. Whereas maybe 80 percent do well when they stay on the drug. So that means there's a significant number of people that can go off the drug and be okay. And in other words, maybe their initial response was a placebo response. You saw from these studies that there's this difference from drug and placebo. But a fair amount of people are responding in the placebo group. And so you don't know if your patient who responded wasn't one of those people. And taking them off their drug is a good way to find out. Many of them will do okay. And of course, the drugs have side effects, sexual and otherwise. So I think it's reasonable. I don't know what my other panelists think. To try, if someone responded acutely after a year or so, especially if there are side effects that are bothersome, to see if they need it and try tapering it off. That's right. That's what I wanted to know. Because usually I would tell patients up to one year to treat the episode. But I just wanted to know if, you know, if that was appropriate or I should be advised. Well, it's an informed consent thing. They need to understand that their chances of relapse are greater if they go off it. However, they have significant chance of being able to do without it. I think clinically I consider two things. One is what else have you done in this past year while their anxiety improved? Did they develop a hobby? Do they have other non-psychopharmacological things to handle the anxiety? And number two, it's not like once you taper, you can't go back and you're not stopping cold turkey. So if you're doing a small taper and the symptoms exacerbate, then you know you need to, the next wait is going to be more than a year or two. I don't know, Erin, if you have? I'd just say the patients who do best with discontinuation are those who while they were getting pharmacologic treatment also learned, for example, CBT skills so that they can continue to use those skills after they've come off of the medication. Sure. Thank you. Thank you very much. Good afternoon. My name is George Dimitriades and I'm a psychiatrist based in Athens, Greece. So I apologize for my poor English. The question I'd like to ask is in older adults, how many hours after a PPI have to give an SSRI? Is there any difference between, because in, usually in adults we don't use them at the same time. We have to have a gap, a minimum gap. Is there any difference in elderly, in the elderly? I'm not sure I understood the question. Is it how long does it take for the drugs to work? After taking a proton pump? No. Yes. If someone takes a PPI, we don't use at the same time, I mean the morning, morning PPI with an SSRI. Okay. We have to wait for a few hours and then give the, because the absorption is different. My question is, is there any difference in the elderly, in older people who have to wait more or it's the same thing? It's the same. In fact, absorption actually is the one part of the pharmacodynamics that doesn't change that much with elderly. All the other aspects of pharmacologic physiology do change with aging, but absorption is pretty much constant. I'd like to ask a bit more about QTC and citalopram and escitalopram, specific questions. Is it dose related? Is it the same in escitalopram and citalopram? And I have this relating to Dr. Chen's mentor who didn't think it was very significant. I have this vague memory that when the warning first came out was based on one study and at the same time, there was a much larger veteran study that did not show it. So what do you actually do? Well, the FDA was getting all these reports of death from overdoses on citalopram. It seemed out of proportion to the quantity of reports. So they commissioned two studies, one with citalopram, the other with escitalopram. The citalopram study involved 20, 40, and 60 milligrams with a control of moxifloxacin, which is a well-known QTC prolonger antibiotic. And then they did a similar study with 10, 20, and 30 of escitalopram. And they found with both drugs, there was a dose-related increase in QTC prolongation. In the case of the citalopram, when they got to the 40, it was more prolongation than the control moxifloxacin. So that's when they decided that to eliminate the 60 milligram dose as approved and made it a 40 as the maximum, and for elderly, 20. For escitalopram, from 10 and 20, both of those were significantly less QTC prolongation than the moxifloxacin control. So they made no change in recommendation for the dosage of escitalopram. But at the 30 milligram escitalopram, which is greater than the FDA-approved 20, there was significant prolongation comparable, actually slightly greater than the moxifloxacin. So they didn't change the escitalopram dosing, but going to 30 puts you into the same ballpark as we used to get with the 60 that you used to have with citalopram. So that's what the data showed. And what do you do? Pardon? Oh, but the study you're talking about in the American Journal was a study of how many people had serious adverse effects on 60 milligrams of citalopram. And they didn't find any significant problems in the population that they looked at. So they concluded that it was maybe okay to be on 60. But there was a rejoinder to that from the FDA in the American Journal saying that this data with the dose-related evaluation was much more impressive to them, and they were sticking with their plan to eliminate the 60-milligram dose. So clinically, what do you do? Have an EKG? Exactly. I think, basically, you monitor the EKG. I think the guidelines, like, every six months, and then you can span it out to, like, a year. That's from the Psychiatric Times, I believe. But, you know, if the QTC is, like, 4-20, and you monitor, and it stays like that, then you document, you let the patient know, and I think that's fine. But if the QTC is now getting prolonged, it's getting really high, then I do think you need to switch. Yeah. Thank you very much. That clarifies it. Of course. All right. Oh, we have one minute left for one more question. Sorry. I'll try to be quick. Thank you so much. I really love these algorithms. I find them useful clinically. And as a geriatric psychiatrist, I love having these as a tool for when I need to recommend educational resources to general psychiatry colleagues. I just had sort of a methodological question that I was curious about, if you could entertain me. I'm wondering why the branch out, I think it was at the step 2C or something, why the branch off for folks who are wary of sexual side effects with the duloxetine and buspirone. I'm just curious why that branch off, because those are both medications that do have actually relatively high rates of sexual side effects per the PDR, particularly duloxetine. Why the branch off for that reason from other options? Well, we just wanted, you know, some patients are really adverse to getting sexual side effects. They're already having trouble in this age bracket, perhaps. And so you tell them about the sexual side effects and how common they are. They could be up to 70% in some studies. So then they want to know what else have you got that doesn't have that problem. So that's why we have a branch there for those people. And buspirone is a possibility. And duloxetine has lower sexual side effects than at least paroxetine. There was a direct comparison on that combo, but it has some. What about the rates for the other options, kind of the other arm coming off of there, like the GABAergic agents? I'm actually not familiar with the rates there. Are they significantly higher as well? Well, they're just, you know, first of all, those drugs are not approved in the United States for GAD. The effect size of pregabalin in the elderly population study that was done, as was pointed out, was only two points difference from the placebo. It was a very large study, so that was statistically significant. But clinically, it's questionable just how much better than placebo pregabalin is. And so that's why we have it at lower down. All right, well, thanks for sticking it out to the very bitter end. Thank you.

generalized anxiety disorder

GAD

older adults

Psychopharmacology Algorithm Project

Harvard South Shore

SSRIs

escitalopram

sertraline

treatment-resistant

comorbidities

monotherapy

personalized treatment

benzodiazepines