saying thank you so much for coming today. Of course, you need a presenter, but presenters need an audience. And you're getting here at eight o'clock today. We appreciate the effort and planning that went into doing that. I'm now gonna turn it over to Dr. Osser. Thank you. Well, good morning. You must be the larks that are all here this early. I guess the owls are gonna struggle to make it for this early session, but the larks are here. So today our topic is psychopharmacology of acute agitation in psychosis and mania. And I'm thrilled to be here with Sean Stetson, who is the first author of our paper on this subject that came out about a year ago. And we'll be updating it in this meeting. We have no financial disclosures. So, I'm sorry. You can't hear? Oh. Okay. Is it better now? That's better? Okay, thanks. Okay, here's a summary of what we're going to cover in today's talk. We'll explain our approach for how we construct these guidelines or suggestions or review of the literature that we're going to present. And then we're gonna discuss each of the medication options that are being used, have been used for treating acute agitation and psychosis and mania one by one, just sort of in a slide or two going over the evidence-based pro and con for each option. And then we're going to have some comments on route of delivery and what the evidence is on whether things work better PO, sublingual, liquid, and IM. And then we'll give you our qualitative review, opinion-based way of organizing those options that we will have presented you the data on, and show how we think they might appropriately be employed among the top choices, second line, third line. We call them tiers. For the PO administration route, if your patient can handle that, or the IM route. Then we're also gonna add a few extra material for you. There's a drug or two that are not mentioned in any of the other discussion that we will bring up at the end and explain why they're at the end. And then we'll have a few conclusions, including how we're planning to have this, it's not really an algorithm, but we're going to have it up with our other algorithms on our website of algorithms. And I'll be showing you that website and how you can access this particular sequence of recommendations along with the other 13 algorithms that are up there right now. That'll be at the end of the talk. So let's start by discussing the process we used for assessing the evidence on how to use these treatments. And I should underline that we're trying to be evidence-based, go as best as we can with what the evidence suggests. This is not meant to be, nor are we proposing it as an opinion-based approach. We're trying to be as close to the evidence as we can, but not basing it on our experience, which of course would be limited to the few people we've treated. So we're trying to bring in what the science has as best we can. But it turns out to be very difficult. This area of endeavor has very few good quality studies, a tiny number. And if we limited ourself to just those high-quality studies we'd have hardly anything we can reasonably say. We had to go beyond that and look at the observational studies, even case reports in some instances might be of importance in determining what the evidence seems to say. So we tried to comprehensively review what's out there and put it together in, as I said, an opinion-based distillation of all this information. Another problem with the studies is when there are studies that are carefully done, controlled studies, they tend to enroll subjects with fairly mild agitation, the kind of people that can consent to such a study. And if there's a placebo control in particular, it can't be a very severely ill person. If they're really psychotic, they can't consent. So that limits the evidence base, at least in the controlled studies, to people that are more mildly ill when most of the time we're concerned with much more severely ill people and we have to look at what other evidence there is to help us with them. Another problem with the studies is the treatment settings are so different where people are getting this treatment. It could be on inpatient units. It could be in emergency rooms. It could be in different countries where they have different rules and regulations regarding consent. So looking at the international literature, which we tried to do, reveals a very disparate group of settings and it's hard to combine them. We're definitely combining apples and oranges and doing network meta-analyses is just not gonna be a useful endeavor in this area, although people have attempted it with the small number of high-quality studies, but we've gone beyond that. The other thing is the small sample sizes in so many of these studies that limits their usefulness. So then there's the heterogeneity of the patients in these studies. For example, they may take people with schizophrenia, but they could have mania patients in the same study. They could have agitated, even a few agitated patients with dementia that wind up getting treated in some of these studies. Personality disorders possibly could be mixed in a few of them or organic problems of other sorts. So they're rarely very pure samples in any of the studies. Then the outcome measures are also extremely different. So again, making it hard to compare the results of one study with another. And then which medications are used. It's remarkable how many different medications are used for this indication, these indications that we're discussing today. And you'll get a sense of that when we go over a whole list of those meds one by one and summarize the data on each individually, which Dr. Stetson is going to do as soon as I finished these first few slides. And then of course the delivery routes vary. Some are oral, some are IM, some use the rapid dissolving products. So anyway, the way we went about it is we collected as many papers as we could. We looked certainly at the meta-analyses that have been done. Cochrane reviews are out there. We reviewed them. We looked at published guidelines. And then we looked at individual studies. We looked at the lists of references in some of those studies to find more studies that would be worth looking at. And then what we tried to do was summarize the evidence pro and con for each of those products and combinations of products and looking at the most recently published interpretations of those studies. And then as I said before, we did at the end present our distillation of that information into our tiered rankings of the drugs for use in these different situations like oral versus IM. So we're going to present the meds in alphabetical order when I turn over the chair to Dr. Stetson. It's not meant to suggest any order of preference when we're going through them one by one. You'll see our order of preference in the second part of the presentation. Thank you. Okay, so without further ado, Dr. Sean Stetson who's Director of the Psychiatry Emergency Room in the VA Boston Healthcare System, Brockton Division. And he's the first author of our paper on this subject and he's now going to go through the options one by one. Dr. Stetson. Thanks for getting us started, David. We can talk at you for about an hour. However, I'd like to have people ask questions as we go. I think that's a more engaging way to do this. So if anybody has a question now they'd like to ask of Dr. Osser, please raise your hand. Thank you, David. Questions? No, all right. I'd just like to expand on a couple of things that David just mentioned, specifically the difficulty of studying this topic. We've relied rather heavily on several of the more recent meta-analyses. And to give you an idea of how difficult this is, one of those meta-analyses that had a pretty stringent criteria. The patient needed to be agitated enough to require IM medication. This was done by D'Souza. They started out with over 5,000 studies and winded it down to 11 that made the cut for inclusion in their analysis. So looking at this literature requires, I think, an extra level of vigilance on the part of the reader. What is being studied? How severe is the agitation? What's causing the agitation? I don't mean to imply cynicism because this is such a difficult thing to study. And for anybody who's curious about that, there's a study done by Klein's group, and I believe he's in Minneapolis. This was a few years ago. He describes in great detail their efforts working with the FDA to get approval for the study and the FDA's requirements for informed consent were such that they were only able to enroll patients mostly with mild to moderate agitation. So again, as many of our drug studies include young healthy men primarily with no comorbidities, and then we have to extrapolate that to real life, the same is somewhat true for this topic as well. Any questions? All right. As David said, these medications are presented in alphabetical order rather than order of preference or recommended hierarchy. That will be done later on in the talk. So starting with the centipede, there is one randomized placebo-controlled trial. It is industry funded, it utilized a single dose. It was performed in the ED. It was kind of an all comers study, so it was not confined to just mania and psychosis. It did include some patients with intoxication. The subject's average rating was moderately agitated, and the response rate was compared to placebo at two hours. As we know, it's great if a medication works prior to two hours. So take that finding with a grain of salt. The study's other weakness was no adverse effects reported. That seems unlikely. However, that's the information we have. There was no provision for a second asenipine dose in non-responders, and 7% of the patients did require a unspecified rescue medication in order to achieve adequate control of their agitation. Asenipine is sublingual, so that's a delivery route that's appropriate for fairly cooperative patients. And at this point, we regard it as promising, but in need of replication and comparison with other oral agents. Does anybody have a question about asenipine? Incidentally, I noticed a few people taking photos of our slides. That's great. Again, we're gratified by your interest. We've also uploaded the talk to the APA meeting site, so if you'd like to obtain the slide deck there, that's another option. Next up, we have chlorpromazine. This may be given oral or IM. Frankly, it's been considered obsolete for decades, although we know many colleagues who still favor it. The logic is it's low-potency and thus sedating. It's low-potency, and thus you don't need to provide a medication for EPS, and neither of these things turn out to be correct. Well, the sedating part is correct. However, it has a remarkably high level of EPS for a low-potency medication. It's no more effective head-to-head with haloperidol, which is a safer medication if you're gonna use just a monotherapy approach. And again, it's less safe than haloperidol. It has a risk for causing severe orthostasis. It has significant effect on the QT interval, and it has a significant rate for lowering the seizure threshold. Any questions about chlorpromazine? We did come across a more recent study. This was done a few years ago in Italy. The efficacy was good, but we don't consider this a sufficient rationale for including this less-than-safe medication in our recommendations. Next up is droperidol. For the younger folks in the audience, you may not be familiar with this. The older folks in the audience remember when this was a fairly popular medication for this indication, and then it got a black box warning in 2001 due to its risk for prolonging the QT interval. The data for that risk are now considered controversial, possibly even spurious. As an aside, cloak and dagger, a lot of that data came in in a very short period of time and from one or two sources. So that raises my suspicion level a little bit. The risk was only seen at doses well above those usually employed for agitation. So a prominent investigator in this area, Calver, did an observational study of over 1,000 patients in the ED. The initial dose and median dose was 10 milligrams, I should say modal dose was 10 milligrams, and all the subjects had an EKG within two hours of dosing, which was an impressive feat considering the circumstances under which EKGs must be obtained for this patient population. They found that only 1.3% of patients had QTC prolongation using their nomogram. If they excluded other causes, that reduced the rate to 0.6%, and none suffered torsade de pointe. As you can see, my emphasis here is less on efficacy and it's more on safety because of the history for this medication. We don't quite have the courage to push it up to the top of our rankings, but I am hopeful that this medication will be restored to its former place in our choices. It appears to be an effective and fairly safe medicine. And in fact, a Cochrane review about seven or eight years ago addressed Droparadol's cardiopulmonary adverse effect profile and efficacy in six comparative studies. And found that it was as effective as Haloperidol, Midazolam, and Olanzapine in comparison with placebo. The cardiopulmonary adverse effects were no greater than other active agents, and EPS occurred in only 1% of patients. This medication has been re-released in the United States as of 2019. Are there any questions about Droparadol? Next up, we have the old war horse, Haloperidol. It's been extensively investigated. It's as effective as monotherapy, I'm sorry, it is effective as monotherapy, but it really should not be used alone without an EPS agent, unless literally no other medication is available or an option for that patient. The reported frequency of EPS when given IM ranges widely, but up to 50%, especially the specific symptom of, or adverse effect of acute dystonia. And my colleague, Dr. Osser and his collaborator 20 years ago, Dr. Sigodal, is responsible for advertising that finding. One Cochrane review considers the use of Haloperidol alone to be unethical due to these very high rates of EPS. Haloperidol monotherapy has more adverse effects than our second generation antipsychotics, and it compares rather poorly for efficacy and speed of onset when compared with most options other than placebo. By the way, I'll mention, this is from a paired set of articles from Leslie Zun and her team. They looked at efficacy and adverse effects for these medications, and she's speaking to this topic on Tuesday, if anybody has some open time in their coursework while they're here. She's done some terrific work. We have a question. Actually, Dr. Zun is a he, but I wanted to ask if it's possible, because if we work in emergency rooms and with tight margins and everything, everything has a cost. I just wonder if, as you're going through the meds, you are able to make a comment about relative cost of each agent, is that possible? Most of these medications are available generically and the cost is rather low, but I will speak to that specifically for Loxapine, which has, the inhaler has the eye popping cost of about $160 per dose. Thank you for the question, and thank you for notifying me about Dr. Zun's gender. I appreciate that. Let's see. Are there other questions? QTC prolongation is a concern with Haloperidol alone or in combination with other medications, but high quality evidence regarding the severity of QTC prolongation when used briefly for rapid sedation is scant. Some authors do recommend requiring a baseline EKG or avoiding Haloperidol when the medical history is difficult to obtain or of concern. However, others have concluded that there is no significant difference in incidence of QTC prolongation among the current commonly used IM treatments. Question. The question is, is there any difference on the impact on the QTC when Haloperidol is administered IV, IM, or oral? And I do not know for sure. I could speculate, but I'm not sure. Does anybody in the audience know? Yes, the comment from the audience is that when Haloperidol is administered that the EKG does need to be monitored. That does seem to be the standard of care. Frankly, we aren't speaking to IV administration in this talk because it's so difficult to achieve in the ED and really not an option on an inpatient unit, but thank you for your question. Any other questions or comments about Haloperidol? Question. We have a comment from the audience. The doctor's experience with haloperidol IV is that it has a low rate of causing EPS given via that route. Can anyone else speak to that? Yes. Yeah. Actually, that's a pretty long comment. Would you mind repeating it to the microphone here? So, I'm from Germany, and in Germany, Haloperidol IV was basically withdrawn by the manufacturer, and now we don't know. There are some situations where you want an IV version, and I don't know how people in the U.S. handle that. So, to summarize, this doctor is from Germany, where Haloperidol IV has been withdrawn, and as one of the few IV options, that's a considerable loss to the armamentarium. And then you had a follow-up comment? Yes, it does remain available in this country. Thank you. Question? I'd like to just comment about working in the CL setting is not what we're addressing in this algorithm, this discussion today. We're talking about acute agitation in mania and schizophrenia on inpatient. So we haven't even addressed IV heliperidol because one wouldn't use it in those settings. It would be a whole other literature to be looking into the IV heliperidol in the medical setting. So I think we should move on from that subject. Yes, just a question. If it's possible at all, could you address the relative response rate of these different molecules? Because I don't know if you have that data. I'm sure it's quite heterogeneous, but. So that data is generally expressed as very effective, moderately effective, or modestly effective. It is, and compared to a placebo or head-to-head. As far as, for example, 63% of patients had a PANS EC score drop of X percent. It's generally not expressed that way. I have an interest in heading that direction myself. Thank you for your question. Halodol has stirred up a lot of interest, hasn't it? Oops. Lorazepam. So there are no large-scale studies of oral lorazepam for this indication. There's at least one major prescribing guideline that recommends oral use for comparatively — I'm sorry, for cooperative and moderately agitated patients, and using it IM for uncooperative patients. The safety findings when administered IM are somewhat mixed. It is quite safe as far as causing deadly side effects, such as cardiac conduction, respiratory suppression, or airway management issues, and it has a low rate of causing EPS. However, it can over-sedate patients, and in the ED, this is a problem because we're often still in the process of evaluating the patient, and if they're zonked, it's difficult to complete that evaluation. The evidence that it puts patients to sleep faster than haloperidol may be considered an advantage on the inpatient unit, where, again, practically speaking, you have someone who is disturbing the entire milieu at 3 a.m., and you know what their diagnosis is. You know they're not having a PE, so getting them to sleep so everybody else can get to sleep is desirable. The bulk of the evidence suggests that the efficacy of IM lorazepam alone for agitation is moderate, considering its relative safety advantages, it's a reasonable option for some patients. Any questions about lorazepam? All right. Loxapine, which is available via a handheld inhaler device, it's FDA-approved for this specific indication of acute agitation in patients with schizophrenia and bipolar mania, I'll go off topic here a little bit and say it also looks like it has fairly good efficacy in the personality disorders, specifically borderline personality, where it's been studied in, I believe, two or three studies. It looks to be effective. Again, as with our earlier question, unlike many of these medications, which are pennies per dose, this one started out, I think, north of $360 per dose and now is down to $160 per dose. It is impractical for severe agitation due to the delivery mechanism, which requires a level of cooperation similar to someone with asthma using an inhaler for the first time. However, it does look to be effective, and it looks to be effective quite rapidly. We have a question. Yeah, no, I just wanted to know, in Canada, and our go-to is IM-Loxapine, and I'm not clear why it's not available in the U.S., so we have Haldolatibin as the first option, together in the same syringe. The difference with Loxapine is that it can't be given in the same syringe with the lorazepam, but because it's a mid-potency antipsychotic and very quick onset of action with the IM route, it's our first line for severe agitation when you need an IM. And I'm wondering if you can, we don't have the inhaler for the reasons you mentioned, the cost as well as the lack of appropriateness with this patient population, but I'm wondering if you were going to mention, if you know anything why the U.S. doesn't have the IM route available? I do not know. We have another question or comment coming. To answer your question, a lot of, you know, because I'm kind of old and pasty, I remember when all of our antipsychotics were available as either oral liquids or injectables, including Loxapine, it was available. I think these drugs have been orphaned in the U.S. because of lack of use. I think a lot of the controversy about Halval is because it's the most widely used one and, you know, things can happen with them, much like Zolpidem is no different than the others, but because it's so widely used, it has a reputation of causing all the problems of, you know, sleep eating, things like that. So I think back when the notion of rapid tranquilization in emergency departments for psychosis and mania was more popular, I think that all of the medications we had at the time were available as an injectable, except, I think, thioridazine, but basically most of the others were available. So then they were orphaned. Yeah. They're still, yeah, I know, still orphaned. And it wasn't the doctor's decision. It was, it's economics, got to use it. Thank you. So side effects are generally pretty mild if the subjects or patients are chosen properly. However, asthma, COPD, and other acute or chronic airway abnormalities are contraindications and, as we know, these are pretty common conditions for our patient population, which is another reason that makes this a bit of a niche option. Further study with an active comparator would help establish its place in the armamentarium. Midazolam, this is available in many different preparations, and there are numerous study of its use off-label, IM, for acute agitation in the ED setting. Reviews of these studies come to similar conclusions that, compared to most other options, it's faster than most of our other choices, its duration of efficacy is shorter, and thus repeat dosing is required more often than with most other medications. Respiratory suppression is a considerable risk, and up to 30% in some studies had this as an adverse effect. I will comment here that that Isbister study seems to be primarily with fairly intoxicated alcohol in intoxicated patients, and so that respiratory suppression rate may not extend to the bipolar and schizophrenia population. However, airway management is required in about, again, comparing apples to oranges, it appears that overall airway management is required in about 5% of patients, and this profile makes it appropriate in the ED, but we cannot recommend it for use in an inpatient unit where access to respiratory support is far less rapid. Any questions about midazolam? All right. Oops. Olanzapine, this is available in tablets, rapidly dissolving form, and IM. The meta-analyses that we relied on most heavily in the Cochrane reviews rate its efficacy and evidence as being high quality. A major prescribing guideline also recommends it based on efficacy comparisons. The onset is generally within 15 to 30 minutes, and IM, and within 15 to 120 minutes orally. This time to onset is equal to haloperidol plus promethazine, but with a shorter duration of effect. It is well-tolerated. The specific adverse effects are over sedation seen in roughly 1 in 10 patients. It has a low rate of orthostatic hypotension and a low to nonexistent rate of QTC prolongation. However, olanzapine causes significant insulin resistance and raises metabolic parameters and inflammatory markers after just a single oral dose. These effects have not been demonstrated with other medications, although not many have been studied in this way, so it's hard to know if this is unique to olanzapine or can be seen in many agents. The package insert advises against co-administration of IM olanzapine with benzodiazepine due to the potential for excessive sedation and cardiopulmonary — I'm sorry, cardiorespiratory suppression. That evidence is controversial, but the manufacturer itself recommends waiting at least one hour after olanzapine is given before giving IM benzo if that is needed. Questions about olanzapine? Question? Well, just a comment. Recently, olanzapine has become — IM has become almost unavailable in our region, secondary, I think, to manufacturer delays and things. I don't know if that's been happening with other people. No. Well, that's good. Quetiapine, which may be given via the oral route, it appears to have some efficacy for agitation, and it is recommended as a second-line option in at least one major guideline. However, it's lightly investigated, and thus the appropriate dosing strategy is unclear. And multiple studies demonstrate orthostatic hypotension at a high rate. We have a comment about dementia here, although we've generally steered away from that. But there's no efficacy shown in three studies for agitation and dementia, although it is often used for this. Questions about quetiapine? Okay. Risperidone, oral and ODT, is considered effective in recent meta-analyses. It's also recommended in a major prescribing guideline. Despite its high-potency D2 receptor blockade, the frequency of EPS is attractively low, less than 5%, with or without co-administration of a benzo. There's no information about QTC prolongation in this setting, but no serious adverse effects have been recorded. However, a recent Cochrane review excluded many studies for low evidence quality and concluded that the main outcomes of the included research suggested no real benefit for risperidone as a treatment for acute agitation. Thus, more studies are needed with and without co-administration of a benzo to see if the benefits are additive, synergistic, or indistinguishable. Questions about risperidone? Ciprazidone. This may be given IM in this setting. The oral delivery has not been studied because it's rather poorly absorbed when administered without food, and that, again, is impractical to insist on with an agitated patient. The IM is well-tolerated with low rates of over-sedation in EPS, but the efficacy results are uneven and generally modest, and it is not recommended in a major recent prescribing guideline. Due to the potential for QTC prolongation, the manufacturer themselves recommends consideration of other medications first. Questions about ciprazidone? We have a few medication combinations to discuss. Haloperidol plus lorazepam. This may be given orally, but there are no major studies of that. The IM combination had proponents due to positive older studies, which suggested that the combination was more effective than either alone. The rate of EPS was low in these small studies, approximately 5%. However, more recent studies conclude that the combination is more likely to produce sedation rather than tranquilization and does not improve the rate of EPS compared with haloperidol alone. Other relatively recent reviews found this combination to have a relatively slow onset of action and be slightly or no better than monotherapy with either agent alone. Questions about that? Haloperidol plus midazolam. Using different time intervals, this combination was judged effective in two studies. As it turns out, both were performed in Brazil, and we are grateful to them. And there are more flexible regulations around informed consent. In one of these studies, it was considered the least effective compared to haloperidol, both with and without promethazine, and less effective than ciprazidone and less effective than olanzapine. In the other study, it was the most effective compared with olanzapine, compared with haloperidol plus promethazine, and compared to ciprazidone. Harkening back to what we discussed earlier with midazolam alone, this combination is not suitable for use on an inpatient unit. Questions about that combination? The question, correct me if I misheard, I'm having a little trouble hearing, but the question is because agitation and the treatment of agitation can be a traumatic and anxiety provoking event for the patient, does midazolam help address that? Did I hear that correctly? Yes. I don't know what the studies are on that. Again, I can speculate that the benzos, both lorazepam and especially midazolam, may cause some memory impairment for the event, which could be beneficial in this setting. But I'm not aware of any specific studies of that. Haloperidol plus promethazine, this combination may be given orally and one major prescribing guideline includes it as an option, but the major studies are IM. A rigorous IM study found this combination to have a higher rate of EPS and inferior efficacy compared with haloperidol plus midazolam or lanzapine. And that's the study that I cited in the prior slide. But a study with similar methodology, which I also just cited, one recent meta-analysis and two Cochrane reviews rate it as the most effective option as measured by reduction in the PANS excitation score. These reviews report EPS for this combination to occur in about 5% of subjects. Both agents can prolong QTC and promethazine can inhibit haloperidol metabolism. In theory, this could increase its effect on the QTC interval and repeat dosing could amplify that risk. Diphenhydramine is often used instead of promethazine in clinical settings in this country, but there are no major studies of that. And the three-ingredient combination of haloperidol plus promethazine, I'm sorry, plus lorazepam plus diphenhydramine is commonly used, but we could find no studies of it. There's a theoretical potential for added benefit, but also for added risks. And I'm going to step aside now and turn it back over. I'm going to step aside now and turn it back over to Dr. Osser. Okay, I'm back. I'm going to make a few comments on delivery issues, the different forms of these products, and then show you what we came up with for our preferred first tier, second tier, and third tier choices. So you've all seen in the discussion so far the evidence on which we did our distillation. So you can decide if you think we did a good job on that or if you think we should have ordered them differently based on the evidence. Our reviewers, at least, our peer reviewers, blinded peer reviewers, thought that we did a good job, but you may feel differently. So we'll see what you think. Anyway, let's do a few interesting slides on the ways of delivering these products. So first of all, the question of oral disintegrating agents, often abbreviated ODTs, are commonly used with the drugs that have a version of that available, and that includes arepiprazole, olanzapine, and risperidone. Of course, the patient does have to be sufficiently cooperative to hold the tablet in their mouth. The absorption is not transmucosal. It still occurs in the stomach. And in the studies of olanzapine in particular, goes by the brand name Zytus, the onset of action is actually equivalent to the tablets. So there is no more rapid response with this agent. And then there was a large observational study of olanzapine ODT showing no advantage in reducing emergent IM use or seclusion or restraint. So in short, we don't see a lot of use for the ODTs in general. Now some of the meds are available orally and IM. That's an advantage if you require a second dose and a change in delivery type is desirable. So at least you're staying with the same medication when you give the second dose by a different method of delivery. So it adds flexibility when the product has two forms. As far as onset, IM delivery may be no faster or better than oral, at least in cases of moderate agitation. The notable exception, as Dr. Stetson pointed out, is in the evidence on midazolam. That may work faster. And droperidol possibly works faster than the oral version. Oral risperidone has had three studies. Two of them compared risperidone oral concentrate plus oral lorazepam, the two combined, to IM haloperidol and lorazepam. And then a third study compared olanzapine IM with oral ODTs risperidone and olanzapine. All three studies showed no significant difference in onset or efficacy. A recent meta-analysis also found rapid onset for oral olanzapine, risperidone, and loxapine. So considering both ethics and safety, we generally recommend that IM should be used only if the patient is too agitated and uncooperative to take medication orally across the board. All right. Now we're ready for our qualitative distillation of all this evidence we've just presented you. And I think you clearly have the impression from the discussion so far that each med has its advantages and disadvantages. And it's got generally variable evidence regarding efficacy and safety. And we're going to offer you our opinion-based qualitative distillation, as I've said several times. Now the people who reviewed our paper had some comments, and we made some changes in the original draft to accommodate to the reviewers so we could achieve consensus with them. And so that adds a little validity to what we've come up with in that we had these reviewers that also went over it, and we reached consensus with them. So it's more than just our own opinion in that sense. Anyway, in the absence of a clear winner, what we have is descending tiers. We group meds that seem roughly equivalent, balancing their benefits and risks. And then we suggest that you use your clinical judgment to select within those tiers, based on various considerations. It could be their past response, if that's known. If something clearly worked before, that would lead you to favor it within the same tier. They may have some history suggesting allergies or severe adverse reactions to some members of the tier. It may be important to consider what they're currently on, if they're already on some medication, so that you're not giving anything that would be incompatible with that or cause side effects. Any medical comorbidities that you might have to take into account could help you in choosing. And then if you can know the patient's preference, that would be a factor. So these all help you decide within each tier. So let's start with our distillation of the oral choices. We have three first tier oral choices. And again, this is not an order of preference. These three options have their pluses and minuses. And you should pick the one, we think, that seems to fit best for your patient with all those considerations I just mentioned. So the first one is haloperidol plus lorazepam. The usual dose is 5 milligrams of the haloperidol plus 2 of lorazepam. And it may be given every 30 minutes. Maximum dose, 4 in 24 hours. Another option is just lorazepam alone. We don't recommend haloperidol alone, as indicated earlier. But lorazepam alone could be used as a first tier oral choice, 2 milligrams every 2 hours. Maximum 12 in 24 hours is recommended in the various guidelines that we considered. And your third choice would be olanzapine, which could be given 5 to 10 milligrams every 30 minutes. Maximum of 20. That is the PDR max of olanzapine in any form in 24 hours. One might note, though, that olanzapine is metabolized slower in women, according to the package. 30% slower. So consider spacing your olanzapine doses a little longer, especially in non-smoking women. Smoking increases metabolism of olanzapine some 40 or more percent. So if it's a non-smoking woman, this is a person who needs significantly less than, let's say, a smoking male. That would be a fairly large dose difference, certainly more than 2 to 1 dosing difference. So this is the first tier for oral. Now the second tier, if for some reason you don't want to use any of those first tier options, or they don't work well for this patient, or they have unacceptable issues, then we have haloperidol plus oral promethazine. You saw that that has respectable data. Five milligrams of the haloperidol is combined with 25 of promethazine. Every 30 minutes, maximum four doses in 24 hours. Loxapine inhaler device, we're putting in the second tier category for the reasons explained earlier. It has its problem with the method of administration, and the patients studied tend to be less severely ill. Can also be used orally, two milligrams every 30 minutes, maximum of six in 24 hours. That's the second tier options. And we have some third and fourth tiers that we think are further down in your options in case all of those don't seem appropriate. And that would be the asenapine, sublingual, 10 milligrams. It's only been studied in a single dose in 24 hours. We don't know when you would give a second one for many evidence. And then quetiapine, which has a very uninspiring evidence base. Commonly used orally, but not studied. So we're suggesting 50 to 100 every hour, maximum 400 in 24 hours. And our last tier, our least desired, would be haloperidol monotherapy. Interestingly, many of the studies of the second generation antipsychotics in IM form used haloperidol as a comparator without combining it with any anticholinergic or lorazepam. So it was really a straw man comparator. In all of those studies, the FDA thought that was an OK design to use against the second generation antipsychotics that obviously would favor the second generation antipsychotics. And so we don't really think, although it's been used in studies, we think ill-advisedly. And we have put it as a fourth tier, as a monotherapy. OK, now we're getting to the IM situation, when a person cannot take oral. What would you use first, second, and third for IM? I had a question for the first tier. So are you not using it to take oral antipsychotics? Is the haloperidol the best you have here? Do you have anything like haloperidol or lorazepam? Lorazepam works very well to reduce EPS when combined with haloperidol in the studies. It's 5% or less. So it actually does effectively address EPS. In the doses described here, it effectively blocked EPS. We wrote a paper on this subject 20 years ago, which Dr. Stetson referred to. Well, 2001, anyway. And in that paper, we thought haloperidol plus lorazepam was our first choice, even for IM. But as you'll soon see, we've changed that based on newer data. But yes, it takes care of the EPS. You don't need to add Benadryl or any other EPS agent. David, you have another question? One brief question or comment. In the first tier for the oral, you note the Haldol 5 lorazepam 2. I think it's every half hour. And then you note the lorazepam 2 every two hours. It's an extremely different rate of use. In the first one, you're using the lorazepam 2 milligrams every 30 minutes. I don't know if you thought about that or discussed it or just wanted to comment. Well, lorazepam is more sedating. Well, it's a good question you've asked. We have it there because this is how it's used in the studies. Whether it could be given more frequently, I can't tell you that from evidence. Question. Sorry. Oh, another question. Question back to oral about olanzapine. My understanding was that about the pharmacokinetics is that time to peak is six hours. So I was interested in your results that there was no difference in onset of action. And we don't recommend it because you have to wait. I mean, if you're going to do Q30 minutes, then it hasn't even peaked. And then you're going to, especially with your findings about the inflammatory response and insulin impact, et cetera. But just back to the pharmacokinetics of it, from my reading of the literature, it did take longer than the others to really kick in. And you don't have that time to wait. Well, many people will get better with the first one of these and not need a second or a third. But if you think they may need a second or a third right away, I guess you would prefer option one. I see one more question. This medication, most of them first-generation antipsychotic and then the second one, they have a serious side effect, increased prolactin level. And we all know what that may lead to, even including increased breast cancer in women, according to a Scandinavian studies register. That's my first question. And the second one is – Let me answer that first before I forget it. The answer is there's remarkably little EPS from haloperidol when you combine it with lorazepam. If you use haloperidol alone, there can be a 40% incidence of EPS. So we definitely don't recommend that. The second question, what about tardive dyskinesia, which is much higher in first-generation antipsychotic in comparison to the third-generation or partial dopamine agonist? And as we know, the partial dopamine agonist has a minimal or no effect on prolactin level and less tardive dyskinesia. And the third one, Rexalti, has been just approved for agitation in Alzheimer's patients. Our algorithm is not focusing on Alzheimer's patients. This is on mania and schizophrenia. We have a whole separate algorithm for treating agitation in patients with Alzheimer's disease. We have a separate paper on that. We're not addressing that today. But as far as the issue of TD, we're not recommending you continue with the haloperidol and give them a TD. Yes, first-generation are more likely to produce TD over the long term. We're only talking about single use or a few uses for acute agitation. We don't have strong data that there's a problem with TD in this usage in the studies. So we think it's reasonably safe from the TD standpoint. But in our schizophrenia algorithms and our mania algorithms, we do not recommend long-term haloperidol. Any experience, last question, any experience with a partial dopamine agonist in agitation in manic and schizophrenic patients? I didn't understand that last point. Do you have any experience controlling agitation with a partial dopamine agonist in schizophrenia and bipolar I patients? Did you understand that? Can someone repeat that? I had trouble understanding it. He's wondering about any experience with using the partial dopamine agonists in the management of acute agitation in this setting. Like aripiprazole, brexipriprazole, those agents. Aripiprazole has no significant evidence that we found for acute agitation and mania or schizophrenia. It did have an IM product at one point that was indicated for that, but it's been removed from the market. It's no longer available. And all aripiprazole has no real evidence base for this indication. That's why we have not discussed it. Brexipiprazole? Is that a question about that? Brexipiprazole, as you know from walking around the convention center, from the heavy advertising going on, just got an indication for agitation in patients with Alzheimer's disease. And we're not discussing that in today's algorithm. As I said, that's a whole different subject. So does it have a role in treating mania or schizophrenia acutely? No data on that yet. Thank you. Just wanted to clarify, you mentioned Haldol plus lorazepam helps with EPS. Does it help specifically with acute dystonia also? Yes. It takes care of acute dystonia. That's the worst problem you can have, especially with haloperidol alone. But yes, lorazepam seems to address that in most cases. But probably it seems from the reviews that, at least with IM, the promethazine does a better job on that. But haloperidol plus lorazepam, pretty good combination for reducing even acute dystonia. Thank you. Hi there. To what extent did the algorithm focus on medications that were available exclusively within the US market? So was there evidence for IM-Loxpane, PO-Loxpane, Zuclopanthixol, things like that that might not be available here that would have changed the algorithm? Was there other evidence? Or did you focus specifically on what was available? IM-Loxpane? I don't think there's an IM-Loxpane available in the US. Is there? No, that's my point. If it wasn't available, for instance, in the US, was it excluded from the algorithm? It never got an FDA indication for acute agitation in mania or schizophrenia. Yeah. OK. The evidence we present is not confined to what's available, but confined to what's been studied. Could you comment about dexmethomidine, which was released? Yes, we will be commenting on that before the lecture's over. All right, I'll go to the IMs. How much time do we have? We've still got 20 minutes. And we're taking questions in the middle as we go along. So hopefully that works. OK, so now you're ready for it. Our first recommendation for IM use is alloperidol plus promethazine. And as the slide says, this is going to surprise some people. It seems not commonly used in the US. And some formularies don't even carry the IM version of promethazine. However, going by the evidence, we were not expecting this. As I said, 20 years ago, we wrote a paper and concluded that IM alloperidol plus lorazepam was number one. Well, we think the evidence now has displaced that with this combination. And you saw the data on it before. A number of reviews of that evidence conclude what we have here on this slide, that it is the first line choice. So probably you're not using it now. But it seems safe and effective, and perhaps better than some of the standard treatments. So this is something new that you can say you heard in this lecture. Now, another much more commonly used option in the first tier, and certainly reasonable, is olanzapine IM, which, again, is given every two hours, maximum 20 milligrams in 24 hours. And with the caveats about women and nonsmokers being slower metabolizers of it, keep that in mind to reduce side effects from it. So many people will be picking olanzapine for their first line choice, IM. But we're informing you about what the evidence seems to say about alloperidol plus promethazine. The promethazine is given in 25 to 50 milligrams. And I might add, by the way, that I work in the VA, and I do a lot of consults on treatment-resistant patients with bipolar disorder, as half of my time over there. And in reviewing people's records, I see that in the Department of Defense, Army, Navy, and so on, they actually prescribe quite a bit of promethazine for anxiety, agitation in soldiers. So whereas in civilian VA reviews, I never see it, or hardly ever see it as one of the options. So it's also big in South America. Brazil, for example, which is, by the way, the third largest market for psychopharmacology products in the world, they consume or prescribe the third most. US is number one, Japan number two, and Brazil is number three. So they like promethazine and use it quite a bit and have published some of the studies on it in combination with alloperidol. Now, our second tier, we come up with the alloperidol. Oh, sorry, question. One of the strongest arguments for the combination of alloperidol and erosopam was the protection of EPS from the oral combination. And now you are recommending the EM application, not in this combination, but together with promethazine. Why? You might think so, but it isn't turning up that way in the studies. We were surprised. You might think of a number of disadvantages of it in theory, but it has not shown those disadvantages in the study. Maybe the anticholinergic effects of it are actually effective, countering the EPS coming from the alloperidol. Yes, there was no lower rate on EPS rates in the combination. The rates were lower. Check our references and you'll see. You may not agree with, you may not like it, but we didn't like it either. Yes, okay. We're trying to go by the evidence. But you just give the controversial recommendation to inject erosopam one hour after injecting olazepine when olazepine is not really efficient. So is there any evidence to do this? Are there any cases or observation studies to recommend this algorithm in a way? Trevor, did you understand his question? I think I heard the first half, which was about... It was the first slide. You just said that it's discussed controversial if erosopam or benzodiazepines could... obligated EM after olazepine is not sufficient just to get more sedation. Oh, you're asking if one fails, would the other work? Is that what you're asking? We don't have any studies of that, so can't answer that. And no observational cases now? The studies all involve using the single product in question versus some control through a number of administrations of the matter in question, of the drug in question. We don't have any studies where they use a little of one for a while and then use another for a while to see what the safety and effectiveness of that is. It would be very hard to do because the first drug may be starting to take effect when you start the second one. So is the improvement then with the third injection to be credited to the third drug you gave or to the build-up of the first two? These would be hard things to study and have not been studied. OK. And if you change it, if olazepine doesn't work, would you switch it to the first recommendation, haloperidol plus bromazacin and not olazepine? Well, if you don't have success with the first one and you don't see any contraindication, then yes, I think it would be reasonable to try the second first-line agent. OK. Thank you. But again, we don't really have evidence that you can be successful with that. And if so, what is the reason for the success? All right. Ready to see the second tier? Well, our old favourite haloperidol plus lorazepam winds up in the second tier now for IM usage. It was first-line in our paper 21 years ago. And we also have the option of just lorazepam IM. Two to four milligrams every two hours has significant study as a second-line option. The third-line option, we have droperidol because, as Dr. Stetson was emphasizing, the black cloud over this medication has dissipated based on newer evidence regarding QTC. So it was quite popular. Even in the Boston area, certain emergency rooms were using a lot of droperidol for this indication. And it stopped completely. And then some new studies have come out showing it's effective, safe. So it may be deserving of a comeback, but we put it in the third tier. And then we have zeprazidone also in the third tier for the reasons described earlier. Okay. I think that's the end of the part where we talk about our recommendations and their tiers. Finally, we have a few extra points that Dr. Stetson will make. I just have a question. Thank you, David. One more question? Yes. So you were mentioning something about the online zipping usage waiting approximately an hour before you give the RASPA. Is that applicable to both IM injection and oral usage or does it really matter? Do you understand my question? I'm sorry. The speakers point that way, so it's a little hard for us to hear. You had mentioned earlier that when you're giving online zipping for agitation that you needed to wait another hour before you can give the RASPA. My question is, is that applicable or just injectable or is it just for injectable only and oral use? So it's oral and injectable and controversial for both. So pharmacologists who have studied this opine that there is no actual danger with that combination given together, but we're kind of constrained by the manufacturer's recommendation. So, for instance, if I give a patient 2 milligrams of lorazepam PO and they don't get better, would that be a risk if I decided in 30 minutes to give the same patient 10 milligrams of lorazepam IM? We take our recommendations for the spacing from the studies. Now, if you want to deviate from those and give it more frequently, then you're doing an experiment. It may be fine, but we're trying to go by to present to you what we have from the studies. Before you ask your question, I'm going to say let's take one more question and then I'm going to apologize and say we'll need to go through the rest of the slides and then take any further questions after that. These slides, by the way, are available. We've uploaded them, so you can get them to the place where you get them. Maybe we better just finish our talk and see how much time we have for questions at the end. We've got one person standing at the microphone. Just a short question, Thomas from Germany. Your recommendations that you talked about right now belong to the clinical practice in psychiatric hospitals or in other fields. How are the SOPs that you have for those who are in the preclinical settings and who are mostly not psychiatrists? So there are many anesthetists or surgeons who work in the preclinical setting. Do they look for all these recommendations as well, or do they have different SOPs? That is probably in the CL literature rather than what we're addressing. Thank you. Sorry. So we're going to have some comments on dexmedetomidine, as was requested, and talk about two more options for management in the ED, and then a brief but necessary reminder about non-medication management. So EGAMI was recently released. It's been FDA-approved for mild, moderate, and severe agitation in the setting of both schizophrenia and bipolar disorder. It's an orally-dissolving film which can be self-administered, a rather unique approval. It can be flexibly dosed along four different doses, and it may also be given IM. The onset of efficacy is seen as early as 20 minutes for the oral film. However, as with several other of these medications, you have to consider the patient's ability to use an oral film properly. So these studies are for mania-related agitation and psychosis. The findings were quite similar for both indications. So within two hours, the 120-microgram dose resulted in a 9.1-point reduction in the PANS-EC, 180 micrograms, a 10.4-point reduction in the PANS-EC, whereas placebo resulted in a 5.0-point reduction in the PANS-EC. You may repeat this in two hours, and you may give a maximum of three doses in 12 hours. For schizophrenia-related agitation, again, 380 subjects, and within two hours, the 120-microgram dose produced an average of an 8.5-point reduction in the PANS-EC. The 180-microgram dose resulted in a 10.3-point reduction in the PANS-EC, and placebo resulted in an average of 4.8 reduction. Rated as responders, for the 120-microgram dose, it was 79%. For the 180-microgram dose, it was 89%, and for the placebo, it was less than 40%. Again, it may be repeated every two hours for a maximum of three doses in 12 hours. The dosing recommendations are the 120-microgram dose for mild to moderate agitation and 180 micrograms for severe agitation. If the patient has hepatic impairment, the recommendation is to start with 60 micrograms. It should be noted that these studies were conducted in people with mild to moderate agitation. You should avoid using dexmedetomidine in preexisting hypotension and syncope, QTC prolongation, advanced heart block, and severe ventricular dysfunction. I see someone coming to the microphone, but I'm sorry. We're going to have to keep going and save questions for the end. I apologize. There was a review in the medical letter on drugs and therapeutics a few months ago that noted concerns about serious hypotension seen for this medication, along with bradycardia and QT prolongation, and that included finding orthostatic hypotension in about one in six patients and bradycardia in six percent of patients. So, in addition to nuisance side effects, such as oral numbness and dry mouth, stomalance and dizziness are also fairly common, and the medical letter conclusion was less expensive drugs with longer records of efficacy and safety are preferred. Hence, we do not include it in our tiered list at this time. Next, we have ketamine, and rigorous comparative studies are lacking. An analysis of heterogeneous outcomes found that the evidence quality is described as poor overall. The mechanism of action is uncertain. It may be sedation, or it may be that it causes dissociation, and it's unclear if there is a threshold effect rather than a dose-response continuum. As far as efficacy, the average dose used is five milligrams per kilogram. No consistent tools are used to assess response, but usually it produces a rapid onset of desired behavioral response very rapidly. A second dose or rescue med is needed for roughly one in four patients. With regards to safety, intubation when it's administered in ED was only around 2%. I should say, or add that when used in the field by EMTs, the intubation rate is quite a bit higher. I forget the exact numbers. I believe it was one in four or one in three patients. Really high. Other adverse effects include vomiting, hypertension, emergence reaction coming out of the dissociative effect, and transient hypoxia and laryngospasm. For midazolam in the ED, again, it's not appropriate for the inpatient unit, but it is used and effective in the ED. It's been studied for use as monotherapy, and in combination with either hiloperidol or droperidol. As usual, the study quality has been a challenge, and so it's rather difficult to rank. Used with droperidol, there's one major study. It had three arms. It was done in the ED. It was comparing droperidol alone, midazolam alone, and droperidol plus midazolam. It was an all-comers study, so again, you have to consider that in the context of our focus here. It also utilized a unique primary outcome measure, which was duration of security staff involvement. You can get a granular metric that way, but it's unique. They found no differences in efficacy for the three arms, although the midazolam was significantly less safe due to respiratory side effects. Again, I'll emphasize that most of these patients were not manic or psychotic. Many of them were alcohol intoxicated, and it's quite difficult to compare with other studies due to their idiosyncratic metrics. The final extra item before you prescribe, please match your intervention with the patient's level of agitation, and attempt non-medication management first if the patient's condition allows it. If you don't prescribe any medications, there won't be any side effects or other iatrogenic risks, and you don't have to monitor the patient after prescribing. If you don't hold the patient down and restrain them, no one gets injured, and if you don't administer IAMs, there isn't the humiliation and trauma that our colleague mentioned earlier in our talk. We recommend the Project Beta workgroup article as an excellent starting point for review of non-medication interventions. And I'm going to turn it over to David for the end here. Just for the last minute, I just want to call your attention to our website where we have 13 algorithms. The website is psychopharm.mobi. Dr. Patterson is our engineer. He did all the software to create this website. He's sitting in the audience today. We have 10 of them that have gone through peer review and published in papers, 3 that are works in progress, and we are going to have this one up there very shortly. These are the 10 peer-reviewed ones, and when you go to the website, at the top of it, there's a menu of algorithms, and when you pull that down, you just click on the one you're interested in, and we will be having this one added, and then it shows the flow chart for it, and here's the website again, psychopharm.mobi for the Psychopharmacology Algorithm Project at the Harvard Schatzer Psychiatry Residency Training Program. And in conclusion, with the proper medication, they lived happily ever after. I'm afraid we've run out of time, but please come to the front if you have some final questions. We probably could answer them there.

acute agitation

psychosis management

mania treatment

psychopharmacology

treatment guidelines

medication effectiveness

oral administration

IM administration

haloperidol

olanzapine

lorazepam

dexmedetomidine