Psychiatry & Psychotherapy Podcast - How to Manage Aggression with Psychopharmacology in an Inpatient Setting

Episode Date: April 14, 2022

Violence and aggression are often used interchangeably, with subtle distinctions differentiating the two. Aggression is an umbrella term that encompasses violence and is defined as actions that lead to harm towards self, others, or objects, while violence is defined as actions that lead to harm, specifically toward other individuals (Newman, 2012). Aggression, according to the 3-factor approach initially detailed by investigators from the New York State Hospital system, is categorized into three types of assault: impulsive, predatory/organized, and psychotic. Impulsive aggression was the most common type at 54%, with predatory/organized type (29%) and psychotic type (17%) trailing behind (Quanbeck CD, 2007; Meyer et al., 2016). This episode aims to explore the management of agitation, aggression, and violence in the inpatient setting. By listening to this episode, you can earn 1 Psychiatry CME Credits. Link to blog. Link to YouTube video.

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All right, welcome back to the podcast. Before we begin, I want to make an announcement. that we are continuing to have webinars. So if you hear this a year from now, you could go on to Psychiatrypodcast.com backslash webinar and see what we have in the future. We have two currently, one April 22nd and one May 1st. The April 22nd will be going over the big five. You know, you will be able to understand your own personality. We will be sending people before the webinar a one-hour assessment where you can do the gold standard on the big five. And then May 1st, Dr. Danny is going to be doing one on racial trauma.

And she is an expert in this. And any of the proceeds for her webinar will go to support her podcast. So I'm hoping that we can raise enough funds to support her for the next year. Editing is expensive. And this will be helpful to her. So if you go to that, all proceeds will go to her. And now on to the episode. All right, welcome back to the podcast. I am joined today with Dr. Michael Cummings. He is a psychopharmacologist who has been on many times. And today we are going to be talking about how to manage aggression

with psychopharm in an inpatient setting or an emergency setting. And so Dr. Cummings, welcome to the podcast. Well, thank you very much. I'm happy to be back. And this indeed is topic that since I work in a state hospital is very apropos to essentially my day-to-day job. Yeah, so I was kind of thinking about how we could do this episode. We've talked about violence before. We've talked about psychopathy. We'll probably duplicate some of the things that we've discussed. But I was thinking about kind of like, okay, let's imagine your, let's say, a and you're seeing this, you get called to the unit and this patient is, they're asking for, you know, some sort of injectable. What is the first information that you would want to know?

Patients' diagnosis, their current presentation, i.e. is this violence or aggression due to psychomotor agitation, that's usually fairly easily essentially. assessed in the emergency room or in a hospital unit. If the patient is capable of being interviewed, then I would certainly interview them and assess them for a degree of motor activity. I'm looking to try to decide is this agitation and violence due to an underlying psychotic illness, due to drug intoxication or withdrawal or due to some other unknown cause. If the person is at risk of harming themselves or someone else in the short term,

I likely will first intervene with what has been classically used to control acute psychomotor agitation that is intramuscular administration of a first-generation antipsychotic dopamine antagonist, because most of them are both sedating and also directly inhibit motor activity. Often that is given an association with a benzodiazepine such as lorazepam. The advantage of the hydroxybenzodiazepines is they are reliably eliminated. They don't undergo complex metabolism. And in some cases, I might add to that hydroxazine, first-generation antihistamine, which crosses the blood-brain barrier, but which does not possess anticholinergic properties.

So in essence, the first attempt is simply to get the person to a calmer state to support further evaluation and definition of what is driving their agitation. or violent behavior. Okay, so let's pick apart a little bit about what you said there. So psychomotor agitation, like, how would you define that, and what do you think that is from in particular? In terms of the core underlying mechanism, and the example I often use is psychomotor agitation is very similar to what you see when you suddenly frighten a cat.

And, you know, the fur is up, the back is arched, the pupils are dilated, the cat is often striking out wildly. What's happened in that case is there is a perceived threat, the amygdala being the part involved in the perception in this case, which in turn sets off an acute, aggressive, agitated response. That is much different than violence that, for example, is predatory. If you were to look at the same cat in the context of predatory violence, it would be silent, stealthy, and other than the dilated pupils would look like a very different animal than in the agitated state. Human beings are very much the same. It is our amygdala that monitors the environment for threat, and indeed

if threat is perceived, whether it's real or not real, the typical response is fighter flight, which is often expressed as psychomotor agitation. Okay. So this is like, yeah, it's a good picture of that sort of scared cat, the cat that's going to be aggressively trying to get away from things. And you're contrasting that with the predatory aggression. And so in this first sort of assessment, you're thinking to yourself, okay, what am I viewing? am I viewing someone who's in a more predatory aggression state, a psychomotor agitation state?

I'm curious, like, what about more of a delirium, like agitation? Would you consider that the same as psychotor agitation, or would you be putting that in a different box? During the agitated phase of the delirium, again, the underlying mechanism that is activation of the amygdala and the limbic system is very much the same. The other element that occurs in delirium that is also present in many other conditions where the person is agitated is there is a deficit in the functioning of the prefrontal medial cortex, which in a healthy, intact person, if there is a perceived threat, that information is essentially transferred to the prefrontal cortex, which evaluates the risk and essentially decides on a. course of response, you know, withdraw, runaway, fight. In many of the patients that we see who are acutely agitated, whether it be from delirium or some other cause, aside from the activation of the amygdala, the other important part of the nervous system that's involved is that the evaluative function of the prefrontal cortex is impaired, which is why we often see people,

for example, in the emergency room or in a hospital unit where there is no real external threat, but they are responding as if there were. That can certainly occur in the context of delirium, where the person is confused, disoriented, and may indeed be perceiving threats that aren't there in terms of their mental state. Delirium, of course, can also present in a stupor state, and if there is time for observation, the tip-off for delirium is that it always involves a fluctuating level of alertness so that the person will transition from agitation to stupor and back again with sometimes a lucid period between those two things. Okay. So you're considering psychotic illness. You're considering drugs, either acute

intoxication or withdrawal. Those are the main two categories you kind of want to differentiate. in that initial sort of encounter. Is your treatment going to change that acute treatment based on... The acute treatment, well, the acute treatment before I know what's going on, probably will not, because the very first step is to control the person's agitation well enough to permit further evaluation. And clearly, if you have somebody who's very agitated, they may be at risk of harming themselves or harming other people unless you can make them calmer.

Once they are somewhat calmer, then you can do a more thorough evaluation and determine what's driving their psychomotor agitation. And at that point, indeed, the treatment shifts to considering what to do with the underlying cause of the agitation. You know, if they are, if it's being driven by paranoia and psychosis, then indeed getting an adequate amount of antipsychotic on board to begin to treat the psychosis along with perhaps further acute medication to keep them calm. Unfortunately, people sometimes confuse treatment of agitation and treatment of psychosis. The antipsychotics can sedate somebody and make them less motorically active within seconds to minutes, depending on administration.

But the treatment of the psychosis is going to take days to weeks before the psychosis itself gets better typically. They may need adjunctive medications initially to help keep them calm while the antipsychot has time to work. That's been one of the major uses, for example. of valproic acid in the context of people either with hypomania or mania or psychomotor agitation due to psychosis because you can load it and have an effect fairly quickly. In the case of drug intoxication or drug withdrawal, for example, we see a lot of people in

Southern California with methamphetamine intoxication who are both psychotic and very agitated because of the effects of essentially a flood of dopamine in their brain. And often the treatment for them is to sedate them along enough with an antipsychotic and benzodiazepine and in some cases, valproic acid until the acute effects of the methamphetamine begin to wear off. In the case of things like alcohol withdrawal delirium, of course, then you want to cross-taper them with a drug that will replace the alcohol withdrawal. to prevent them from developing fully evolved delirium treatments. That treatment usually involves fairly aggressive use of benzodiazepines,

as well as magnesium sulfate to decrease seizure risk, and of course support for things like blood pressure. Okay. So we have kind of phase one is the acute sort of getting something I am. So we talked about maybe I am Haldol. laurazepam and hydroxazine. Usually people say like Benadryl or cogentin. I'm curious why you would prefer hydroxazine. Because you avoid anticholinergic burden. Certainly one of the potential causes for agitation is anticholinergic delirium. So if the person is suffering from anticholinergic delirium,

I certainly don't want to give them more anticholinergic. The other reason is there is there is no reason to give them an anticholinergic until or unless they develop extra-paraminal symptoms. One of the major errors that people make is I've seen somebody, even when they have EPS, get put on Ben-Stropine, and 30 years later, they're still taking binstropine, even though the need for it is long since gone. Yeah. Yeah, I agree. That's a peep of mine as well. Yeah, I think in psychiatry, people underappreciate just how much burden the anticholinerges cause in terms of cognitive and memory deficit, increased dental carries, GI problems, urinary retention, you know, the list goes on and on. And cognitive doling, you know, it's harder to focus. It's harder to concentrate.

You know, I feel like a zombie, that kind of thing as well. Okay, so do you put the hydroxazine in the injection? Yes. Okay. Yeah, hydroxazine, of course, comes in both oral and injectable formulations. It can be mixed in the same syringe with drugs like haloperidol or flufenazine, antelorazepam, and they can all be given as a single shot. If you have a somewhat less agitated person who's willing to take oral medications,

then the oral route is also available for all three drugs, but onset of action, of course, is going to be slower. These days, you also have the option of intra-nasal loxapine, which is effective for treatment of acute psychomotor agitation if you have a patient who will cooperate with a nasal spray. Okay. So when would you choose the I.M. Flufenazine versus the I.M. Howlol. They are essentially equivalent on a milligram per milligram basis, and in terms of their dopamine

antagonism, they're virtually identical. So usually I choose halidol first just because it's more universally available in most hospitals and emergency rooms. But if, you know, basically if your pharmacy says, well, we ran out of haloperidol, flu-phenazine is essentially the same drug in terms of its activity profile. How would you choose the dose of Haldol five versus 10 are pretty normal doses? When would you choose one over the other? It usually start at the lower dose for treatment of acute psychomotor agitation. One of the errors that people sometimes make is to use a whopping dose of drugs,

but then write their orders so that the nursing staff has to wait a very long time before they can administer another dose. The problem often is that the psychomotor agitation will, in essence, rekindle, and the person will again become agitated. It's often more effective to give them smaller doses, but give them doses more frequently so that you essentially titrate against their degree of agitation so that you don't overtreat them, You don't sedate them into coma, but you don't under treat them either and allow the agitation to build up and become a storm again, if you will. Often what I'll prescribe initially for somebody is held all five milligrams with lorazepam 1 milligram and hydroxocene 25 milligrams, depending on circumstance, either orally or I am every two hours as needed to control their agitation.

and then put a cap on it, not to exceed four doses in 24 hours. Okay. So, okay, you get their psychomotor agitation under a little bit of control. You start to evaluate, you know, is this more psychosis? Is this bipolar? Is this drugs like methamphetamines? Is this alcohol withdrawal? Those are the big categories I think you said before.

Are there other categories that we're missing here? I would put delirium just because I feel like that's like something that we see a lot. Certainly delirium. And in many cases, what you're looking at, for example, with the drug intoxications or drug withdrawal is you are looking at delirium, in this case, a substance-induced delirium. Good point. Yep. Delirium also can occur, of course, in other contexts, for example, post-surgical delirium, which is a response typically to the anesthetic agents use. So in that sense, it's also a drug-induced delirium. If the person has a medical reason to have delirium, such as hepatic and sophylopathy or status epilepticus that is non-motor in nature,

that's part of the reason for getting the agitation under control is so that you can proceed with the workup of all of those things. Certainly in an emergency room setting, physical exam and laboratory evaluation are going on as soon as you can get the person calm enough to permit those things to proceed so that you can be sure you're not missing an important cause of delirium. Drug-induced delirium has typically a very good prognosis provided to control the acute signs and symptoms. Other causes of delirium, that is, non-substance-induced delirium, has a very bad prognosis. Most of the studies that have looked at that have found that about 25% of people who present to an emergency room with a primary delirium,

that is for a medical cause, 25% of those people don't survive the hospitalization. Wow. That's, wow. Because they're ill, right? Yeah, because they're ill. And essentially, delirium reflects a state in which all of the defenses that protect the brain have been overreacted. overcome. And our biology is designed in essence to essentially try to keep the brain intact at the cost of a lot of other things. So if somebody is delirious due to medical reasons, they are seriously ill, whatever the underlying causes. You know, the underlying mechanism for that is something that I and one of the people here at Patton have written about Dr. Sphira. And we looked at it, from how is it when somebody has a peripheral infection that causes inflammation, how does that result

in them becoming centrally delirious? Looking at the literature on that topic, what we discovered was that it's really an effect on the astrocytes, the glial cells, that's the culprit. If enough interleukin 6 and interleukin 8 get into the brain from a peripheral inflammatory process, it can cause the astrocytes essentially to stop their job of flushing out the toxins that accumulate in the brain, modulating CSF turnover, those sorts of things. So essentially the, what's been called the wide-scale neurotransmission, the brain goes awry and the person becomes delirious. You know, there are two types of neurotransmission. There's the point-to-point synaption. transmission that we often focus on because that's how we process information.

But there's also a general background turnover of CSF and molecules in the CSF that modulate, if you will, background brain activity. And that we most often ignore because it doesn't go wrong very often, but delirium is one of those circumstances where it has gone very badly wrong. That's good. I think when I think of delirium, I think of there's also like almost like a spectrum of total brain function, sensorium. You know, we all have a lower sensorium, you know, midday, 3 p.m., 4 p.m. You know, we're not as sharp. If we've had a big meal, maybe the blood rushes to our stomach away from our brain where we get sleepy. do you see like this kind of sensorium like and then with like it gets worse and maybe you have some hypoactive delirium and then it gets worse than you have hyperactive delirium but we all kind of can struggle with variance of sensorium like if we get ill we may not be thinking as sharp we may be

more fearful because our like parts of our brain just aren't working as well like how do you see that uh yeah formally delirium is defined as essentially a disregulation of level of arousal, which could also be stated as level of alertness. And I think that's what you're describing. In essence, the higher functions of the brain, that is, the cortical functions begin to go awry. And indeed, if you look at the electrophysiology of somebody who's becoming delirious, you'll start to see breakthrough of slower, electrophysiologic rhythms from deeper in the brain, midbrain and brain stem, down into the theta and delta bands. And what you're essentially looking at is this person is having a hard time

keeping their cortex up to a normal level of arousal. And what often happens in such individuals is that that very important top-down modulation of alertness and attention, orientation go very badly wrong, and the person then overtly exhibits either stuporous delirium or agitated delirium, often alternating between the two. One of the reasons that physicians in hospitals post-surgically don't spot delirium very often, although careful surveys suggested it occurs in about 40% of post-surgical patients is that most of those deliria are short-lived, 24 hours or less, and they're almost always stuporous. So they're just quietly confused, and people don't notice that they may not be thinking very well.

But if you actually ask people in that state, you'll find people are having all sorts of interesting experiences, for example, one of my colleagues told me that after her dad had surgery, he seemed perfectly fine until you asked him why he was staring out the window. He was seeing a pterodactyl circle the hospital in the air. Oh, man, good times. Yeah, it's evident on spelling world backward, drawing a clock. They cannot do these things normally. You know, like they just they can't process.

And I think that to an untrained eye and non-psychiatric person, it's like they know something is off, they don't know what. And sometimes they don't see it very clearly. They're expecting this person that's sick to react or behave in a certain way, and they're not. And it can be really difficult to the family to see this. Oh, yes, very much so. Very much so. I know I had one of the consults I did way, well, eons ago now, when I was. was a resident, was a woman who had come into the hospital because she was suffering from a

cardiac arrhythmia and they had loaded her with lytocaine. And unfortunately, they loaded her with a little bit more than she could tolerate. Lidicane at high concentrations can cause delirium. And indeed, a couple of hours later, she was literally wandering down the hallway in the cardiac unit chasing what she was seeing as small owls. She was literally going down the hall calling, come here little owl, come here little owl. And neither her family or the cardiac staff knew what was wrong with her. Interesting. Okay, so as we kind of progress, we're trying to assess what type of why this agitation occurred. We're trying to assess what's going on. Other etiologies of aggression.

So we have the thought that it could be psychotic aggression, it could be impulsive aggression, it could be predatory aggression. Any other sort of delineating or historical things that would help us know one way or the other? Those are indeed the major categories that were established by a very well-done study by Krakowski-E-L and the New York State Psychiatric Hospital. hospital and most persisting violent behavior or aggressive behavior fits into one of those three categories. The person is aggressive because they are psychotically misperceiving a threat that's not really there, meaning that they're paranoid in some way. Or they exhibit impulsive behavior,

which is actually the most common cause of persisting violent behavior. They're affective responses are out of control in response to environmental stimuli. And then lastly, of course, you have a predatory category. One of the major benefits of not just treating all agitation and violence, the same is in association with diagnoses, dividing the underlying cause into those categories very much helps guide treatment. If it's psychotically driven aggression, of course, then the treatment is pretty much the well-established, well-worn path for treating psychosis, starting usually with dopamine antagonists, and if the person is treatment-resistant, eventually moving on to chlozapine,

if it is predatory violence, then it becomes largely a non-pharmacological issue because there's no strong evidence except for impulsive violence and some psychopathic individuals that pharmacology can have an effect. Closopine was found in one small study, one open case series rather, to benefit that population. The treatment approach for impulsive violence is much more varied and heterogeneous, depending on diagnosis. And in some ways, that says that we don't have a lot of great data.

If you actually look at the number of well-done studies for impulsive violence, It's tiny. There's a huge amount of anecdotal data and almost no randomized control data in this area. The three most common categories, at least in hospitalized settings for persisting impulsive violence, are the people with traumatic brain injury, people with personality disorders, and people with neurocognitive disorders. If you round those people up in terms of impulsive, aggressive, or violent behavior, you've accounted for the vast majority of people who are engaging in impulsive violence. Yeah. And then, so those are the three sort of categories that you can start to sort of think about. And you can, it may help with your differential as you're sort of trying to think about

what might be going on, what's underneath this. And then we always want to make sure physical conditions contributing to violence risk are looked at. We already talked about delirium, pain, physical discomfort, aceshesia. Especially if you have a person who, for example, as in the neurocognitive disorders, has difficulty communicating. You really want to be careful to rule out pain as a cause, especially if their aggressive behavior is associated with times when they're being treated where there is external movement being imposed, they're being rolled over, they're being set up. If movements associated with agitation, one question you should always have is, are they experiencing pain because they're being moved? Yeah, that's good. And then

partial or complex partial seizures, how would that look different than other things? Complex partial seizures carry the hallmark of essentially what all seizures are like, that is abrupt onset and abrupt offset. Most of the psychiatric illnesses, deliria, psychoses, they don't start and stop abruptly. That's not true of seizures. You can be having a normal oriented conversation with someone, and if they have a complex partial seizure disorder, they may suddenly stare into space, exhibit eyelid flutter, be disoriented and start behaving bizarrely, violently.

And then a few minutes later, they're back to where they were. So it has that sudden onset, offset. And during this, they may exhibit automatisms, automatic behaviors, repeated phrases, and clearly be out of touch with the world. Now, there is also an elevation of inter-ectal violent behavior in people with complex partial seizure disorders, likely because of ongoing impairment of the limbic system. That's usually impulsive violence in response to a stimulus of some kind. But the seizure itself has that very classic characteristic of sudden onset of a change in behavior and sudden offset.

Yeah. And then sleep issues would be another thing that was on the list here from Hinkin-At-all 2011. Any comment on that? Yes. Sleep disorders, of course, sleep disturbances can also be associated with lowered seizure thresholds. sometimes people only exhibit seizure behavior in association with sleep. You can also have a host of parosomnias, somnambulism has been associated with kind of oddly violent or aggressive behavior in some cases where the person is partially in contact with the exterior world

and partially not, and they may behave in very odd ways during sleep. Yeah. So let's talk about some lab abnormalities, which may be contributing to violence risk. One board question I remember was you have a patient that comes in with history of bipolar on Deppicoat, who is now acutated. What laboratory do you want to check? Well, you want to check their plasma ammonia after you've done a mental status examination, because indeed, as you alluded to earlier, you may find that they can't spell world backwards or count backwards by a series of numbers and can't draw a clock. Because of course, one of the risks with valproic acid is hepatic encephalopathy. It is fairly rare. Almost everyone who takes valproic acid

will show some elevation of plasma ammonia, and we frankly don't recommend that people routinely measure plasma ammonia and people taking valk acid because what they'll get back is an elevated level and then they're stuck with the question of what do I do with it? If the person is not appearing to be delirious, then there's no reason to do anything. Most people who become delirious because of elevated ammonia do so when their ammonia level is well over 100. And they exhibit the classic signs and symptoms of confusion, ataxia, asterixis, often lateral astagmus, which is one of the ways you can tell if you're giving anybody too much anti-epileptic.

And this applies for all of the antipelptics, a quick and dirty test you can do in your hospital unit is simply have them do lateral gaze. if they have coarse nistagmas when they follow your finger all the way to the right and all the way to the left, you're pushing up against their tolerability threshold for the drug. That's quite the pearl. Okay, other things, plasma glucose? Yes, because, of course, people can become delirious due to hypoglycemia or hyperglycemia. Hypoglycemia being, of course, common in people who are diabetic, who are diabetic, who

may have taken their insulin and then not eaten sufficiently. That can progress all the way to coma and death if their plasma glucose gets low enough. And of course, if they've acutely increased their plasma glucose to very high levels, usually in the four to 500 milligram per deciliter range, then you may be looking at essentially what amounts to an osmotic delirium. And they may develop ketoacidosis and developed delirium and coma for that reason. So certainly one thing to always ask while you have

them still conscious is are you diabetic? Plasma calcium would be another thing to test. Yeah. And indeed that's we're touching on the reason why a general chemistry profile is essentially part of every delirium

workup. You're looking for things that are abnormally out of range that can affect the brain, calcium, sodium, acute hyponatremia, or hypernatremia also can cause delirium. And cedrate, you know, or CRP to look for if there's an inflammatory disease going on? Yes. Yeah, the ced rate is probably the cheapest, easiest test that exists in the laboratory. All you have to do is put blood in the capillary tube and let it stand there.

Now, if it's positive, they have an element. said rate, unfortunately, it doesn't tell you which inflammatory disease they have, but it tells you they have one. On the other hand, if it is negative, it's very useful because you've now excluded an entire category of illnesses. Yeah. So, okay, let's get on to treatment. And with treatment, we can start with what are maybe some of the potential issues with treatment. We're thinking dopamine antagonists maybe. And so let's say you have them on a dopamine antagonist and they're still violent. What might you think in terms of reasons why they would still be violent?

Let's say they're on a reasonable dose for what you consider a reasonable dose. Okay. One thing I would do with any antipsychotic when I put them on it and I'm not getting the response I expect is measure of plasma concentration. Dose, frankly, is a horrible guide in terms of adequacy of treatment because although people have an average rate of metabolism in the population, there's a huge amount of variation from. person to person. You may have everything from an ultra-rapid metabolizer to an extensive metabolizer to at the other end of the spectrum a poor metabolizer for a given drug. And certainly in cases where you're administering a drug and you're seeing neither benefit or side effects at a dose where you would expect to see something, measuring a plasma concentration can tell you two things. One, are they actually taking the drug? Because, of course, none of these work if they're not in the patient.

And two, if they are taking the drug, is their metabolism of the drug abnormal? And you may not be getting the results you want simply because there isn't as much of the drug as you thought, because they're eliminating it more rapidly. Certainly in the case of the dopamine antagonists, if you've treated the person for, or at a confirmed therapeutic plasma concentration for a period of at least four to six weeks, and you're not seeing the antipsychotic benefit that you want. If you do that twice, at least in the context of the psychotic disorders, odds are you're looking at a treatment-resistant psychosis, and it's time to start thinking about putting this person on chlozapine.

because in treatment-resistant schizophrenia, the response rate to all of the antipsychotics except chlospine is less than 7%, which means you have a 93% rate of failure for everything else. Closepine will give you a 40 to 60% response rate in those patients. I was looking at some odds ratios of just for more of the, aggression in like schizophrenic patients for it seemed like pretty much all antipsychotics were in one group and then olanzapine was a little bit better and then clozapine was a little bit better than that

yes and the reason we think that's the case is that one of the things that seems to be very determinant of whether the person is prone to either psychotically driven or impulsive violence is the quality of their top-down inhibition of impulsive or impulses arising, essentially, from their limbic system and ventral striatum. The antipsychotics, other than olanzapine and closopine, provides some benefit because they dampen, if you will, the impulse generation toward violence. But the Closopine and very high plasma concentration, Olanzapine, also promote glutamate signal transduction and essentially improve executive functioning. In the Krakowski study that we mentioned earlier, they had taken 37 people on Olanzapine, 37 people on Closepine, and 36 people on Haloperidol.

they randomized them, gave them all their drug for 12 weeks. These were not treatment-resistant people. All of them had a similar decline in PANS scores. So their psychosis got about equally better. The Clozapine was essentially twice as good in reducing violence as the other two drugs. And when they looked at what had changed in the individuals who were less violent, it was that their executive functions had improved significantly on neuropsychological testing. And so they essentially made the hypothesis that people who can think are less likely to become violent.

Yeah. Yeah. So, Closopin uniquely impacts, would you say the negative symptoms of schizophrenia? Yes. Would you also say the cognitive symptoms of schizophrenia? schizophrenia or would you put that in a different category? No, since the executive functions are indeed part of cognitive performance, it has benefits for cognition as well, which is a typical of the antipsychotics as a whole.

The first generation pure dopamine antagonists are very good at suppressing positive symptoms, things like hallucinations, delusional ideation, they are much less effective in benefiting either cognitive symptoms or negative symptoms. And in fact, they may actually worsen negative symptoms if the plasma concentrations are too high. Had this patient kind of right in line with a lot of stuff we're talking about, aggression was put on howl-dall-closapine before they saw me had some obsessiveness put on fluvoxamine and when i saw the person i felt like the person was like lethargic the person was also on cogentin 50 at night took them off the cogenton checked a blood level of the clozapine

came back at um like 1400 haldall came back at blood level of three And I decided to lower their clozapine. It was only 300. Good. I lowered it. Well, yeah, what you were looking at, of course, is fluvoxamine. Fluoxamine is a very potent cytocrone P450, 1A2 inhibitor. And frankly, it's very dangerous to give fluvoxamine with clozepine unless you're incredibly

careful with it, because you can very easily push somebody into potentially lethal clozapine concentrations by the other drug I want to mention for psychiatrists

to be on the lookout for in that regard as Cyproflux I mean the antibiotic superfluoxic because

it also is a potent 1A2 inhibitor and can kill people if somebody inadvertently

puts a clozapine patient on it yeah so yeah we're working on that. Actually, I lowered it to 250, and it was still above a thousand, so I lowered it again

to 200, which, you know, Clozapine at 200, it seems like a lower dose, but the fluvoxamine can double the dose or triple the dose. Actually, it's worse than that. At therapeutic fluoxamine doses, it can increase the closopine concentration tenfold. Okay. A thousand Wow. Wow. Okay. Maybe I should just stop the fluvoxamine and have a little bit more accuracy. Well, the other thing is, the other thing that's important for people to know is that the other SSRIs are just as effective in treating obsessive-compulsive symptoms as fluvoxamine. The fact that it was marketed for OCD was entirely a marketing decision. It was the fourth S-Svacemines. It was the fourth S-Fluvoxamine. It was the fourth S-Voxamine. SSRI introduced to the market, and the company, frankly, did not want to be another antidepressant. It had nothing to do with the activity profile of the drug. All of the SSRIs are equally effective if you give them at equivalent amounts for OCD. Good. Good. I'm looking at this Stop a Phase 1 diagram. I think this is from your book.

Yes, it is. And so it's kind of like taking you through like what you could do with someone with schizophrenia bipolar spectrum, borderline personality disorder, with overt verbal, physical aggression, verbalized persecutory delusions or severe behavioral discontrol. Yes. The first thing is olanzapine. And like started at 10, we go to 20 per day. Why start with olanzapine?

Essentially because the olanzapine is moderately anticholinergic, but not overwhelmingly. So it's a good dopamine antagonist. And as you get to a higher doses, you do get at least a weak reinforcement of glutamate signal transduction. So for a lot of patients, it is a good choice for reducing. the underlying causes of their psychomotor agitation or aggression, in part because it exerts both antipsychotic and mood stabilizing properties. Okay, so let's say you have them on the 20, they're not improving, your next step is to consider valproc acid.

And if valproc acid is contraindicated for some reason, you consider lithium. Yes. And why would you start with valpric acid and then move to lithroch acid and then move to lithium, why not start with lithium and then move to valve prog acid? You could start with lithium in particular if the person is a bipolar patient. For a lot of clinicians, frankly, that was a choice based not only on patient characteristic, but physician characteristic. Frankly, there are a lot more psychiatrists who are comfortable in loading valproic acid as

opposed to loading lithium and also a lot more comfortable with valproic acid because it has a much wider therapeutic index than does lithium. So that was the order of choice there was based on current familiarity. Frankly, for treating patients who are vulnerable to a bipolar diathesis, my own preference is for lithium. It is neurotrophic. It does very robustly well in terms of controlling. bipolar illness having both anti-manic and antidepressant properties. But I will recognize that in

the broader context of psychotic disorders without mood or for schizoaffective disorder bipolar type, there are a lot of clinicians who in the acute setting are a lot more comfortable with valproic acid. Yeah. I'm happy to say if you want to learn more about the loading, we did an episode both on voproch acid and lithium, you can go to check those out. If those are not working and they're not improved, then you're considering hydroxazine or clonazepam. Yeah. Essentially at this point, because you have ongoing psychomotor agitation, you're now looking at means to essentially directly sedate the individual somewhat. And both hydroxazine by blocking cortical H-1 receptors, or clonezepam by, of course, increasing gab aurgic signal transduction may help calm the person acutely.

I would comment for both of them, neither one of those is intended to be an ongoing treatment. This algorithm is set up in three phases. Essentially, phase one is focused entirely on control of the acute agitation. phase two moves toward beginning to consolidate and normalize the medication regimen, and then phase three is transitioning to maintenance treatment once the agitation has been dealt with. Okay, and yeah, I think this is a good episode to focus in on this phase one. So let's say they're not improving by the hydroxazine and the, clenazepam, then you're considering, is this a bipolar diethesis? If it is, you say to augment

with a stronger dopamine antagonist, and if it is not, you're considering an SSRI trial. Yes. And indeed, at this point, one of the overriding principles in applying this algorithm is to always be open to reconsidering your initial diagnostic formulation. As we talked about, you've started often from no information at all to at least being able to form an initial hypothesis about what you think the underlying problem is. And if you're going down this treatment algorithm and it's not working, it's important to go back and reconsider. well, is my hypothesis about the diagnosis?

It's incorrect. Am I missing something? For people, particularly those who are prone to impulsive violence, there is evidence to suggest that a central deficit in serotonin may help drive impulsive violence. And that's certainly the reason for the inclusion of the SSRIs here, although the important caveat with this or any other antidepressant is, if the person is bipolar, don't give them an antidepressant. It's like throwing gasoline on a fire.

Right. Yeah. And if they're still not improved, there's one last consideration, which is to add Zopidem or S. Zopaclone. And I imagine that's for sleep. Yes. To make sure they're getting good sleep. That's because one of the things that will disrupt

control of agitation in many contexts, whether it be schizophrenia or bipolar illness, is disrupted sleep. I think most everyone has had the experience of just how horrible they felt and how irritable and out of sorts they were, if they didn't sleep well for two or three nights. Many of our patients who suffer from major mental disorders, their sleep records are horrible looking. They have disrupted inefficient sleep, and if you can improve that, particularly in the case of the bipolar patients, you'll

find it goes a long way toward helping to stabilize them. Good. I think, and we'll include this in our notes. Our notes are always on psychiatrypodcast.com, so you can look at this figure. It's also in your book Treatment-resistant schizophrenia, which I highly recommend.

Is that what it's called? I want to get the name right. Oh, yeah. It's Management of complex treatment-resistant psychotic disorders published in 2021, and you can find it on either Amazon or directly from Cambridge University Press. Please go get that to support Dr. Cummings and his effort there. I think it's a monumental book. Very good. We should all be educated on how to treat this population at the highest levels.

Okay, I'm thinking that I'm going to bring it to a close here. I think we've covered a lot of stuff, and I imagine there's more, but there's always more time to do more episodes. Oh, yes. And yeah, so I hope this has inspired some of you to keep digging a little bit more. I will include the citations that we spoke about on the website, psychiatrypodcast.com. Do you have any final remarks, final things that kind of you'd like to get out there? No, I think we've done a pretty good job of covering acute psychomotor agitation. Of course, this is a, as you say, a topic that has many aspects that we could spend many, many episodes covering. But I'm sure we will talk further about this in different contexts.

Yeah, so as you're signing up for the resource library, if you have any desires for future episodes by Dr. Cummings, you could just jot a little note. I read those. I'm a little bit behind. I'm a 300 emails behind right now, but I will get to it eventually. They seem to be coming faster than I can handle right now with everything going on in life. So yeah, Dr. Cummings, it is a true pleasure to have you on, and I know people are grateful. Pretty much, I would say, yeah, it's like every day I'll get an email that's like I really appreciate Dr. Cummings. I really, I don't forward them all to Dr. Cummings, but there are people all around the Australia, there's a big following of the podcast and Dr. Cummings in Australia. So have you heard from anyone who's heard you on the podcast at this point?

I have. I've actually communicated with a couple of people, one in Australia, one in person in Vienna, and a couple of people in the UK. That's fun. That's fun. So making an impact all around the world. Appreciate you, Dr. Cummings. All right.

We'll leave it there for today. Okay. Thank you.