Psychiatry & Psychotherapy Podcast - Psychosis: Management of Complex Treatment-Resistant Psychotic Disorders

Episode Date: October 21, 2021

In this episode we discuss, with Dr. Michael Cummings, a new book he co-authored with Steven M. Stahl on the management of treatment-resistant psychosis. An increasing number of individuals with psychotic illnesses deal with homelessness, repeated incarceration, and associated trauma. There is limited access to care for these individuals, leading to poor prognosis. This book provides prescribers with information regarding treatment of the most challenging, treatment-resistant, severely psychotic patients. By listening to this episode, you can earn 1 Psychiatry CME Credits. Link to blog. Link to YouTube video.

Hello and welcome to the Psychiatry and Psychotherapy Podcast. I'm here to talk about getting rid of burnout, increasing job satisfaction, and feeling like an expert in what you do. One thing that created a lot of burnout and angst for me was trying to get continued medical education right at the last minute. So why not join the CME membership and do CMEE while listening to this podcast. Go to Psychiatrypodcast.com, sign up, sign in, take the test, and the certification is email to you in seconds. All right, welcome back to the podcast. I am joined today with Kat Wu, who is a second-year resident, and Michael Cummings, who is a psychopharmacologist who has been on the podcast many times. Today we will be talking about a book he released recently called Management of Complex Treatment

Resistance Psychotic Disorders. This was with Michael Cummings being the first author, Stephen Stahl being the second author, you can get this at Amazon. And I would say if you get this as a fan of the podcast, if you are a fan of the podcast, interested in psychopharmacology, I would say, please get this book and give Dr. Cummings a nice review, maybe mention that you appreciate him from the podcast, and I'm sure he would appreciate that. So Dr. Cummings, welcome to the podcast. Well, thank you very much. I'm happy to be back. I should say a little bit about the origins of this book.

As you know, I'm a member of a network of Psychopharmacology, consultants who work for the California Department of State hospitals where a system of five forensic psychiatric hospitals with approximately 7,000 beds. A number of years ago, we realized that that was sort of a great naturalistic laboratory, if you will, for people who have fairly severe, complex, very often treatment-resistant psychosis, most often a schizophrenia spectrum disorder. We also realized a number of years ago that most of the research literature that is out there

does not directly address this population because, well, these are not the patients who make it into most randomized clinical trials. With that in mind, we set about gathering data and ultimately that resulted in our writing a book, this book and to help address the treatment approaches for this type of patient who may indeed have both the primary psychosis, but how is likely to have other issues such as traumatic brain injury, substance use disorder, personality disorder as comorbid conditions. So indeed,

this book goes through strategies for dealing with a number of issues in addition to the psychosis, provides a review of the 85 most commonly used medications in this group, and then also offer some appendices at the end of the book that are, frankly, the frequently recurring questions that we get for consultation questions, a way to easily find that information. Yeah, I found it very helpful. There's a lot of clinical pearls. It's interesting because I know we've discussed, like, you'll have one sentence in the book, and I know we've discussed it probably for like 15 minutes or so, but it's just like so succinctly put in the book as like just a singular sentence. So I appreciate just how succinct it is and readable, and there's tons of tables.

It's a 500-page book, but it's very readable because of the tables. Oh, indeed, Cambridge University Press gave us limits and said, no, you can't write the the tome of all time. We want this to be a book that people can actually pick up without risking hernia. And consequently, we worked a lot toward putting as many things as we could into graphs and tables for ease and speed of access. Well, I'm going to have Kat Wu ask you some questions. She read the book with me, and I will interject sub-questions. Okay.

and some of the pearls that I pulled out. So go ahead, Kat. Okay. Well, nice to meet you, Dr. Cummings. Nice to meet you, too. So I had a chance to read this book, and I agree with you. It was very simple to read, and the chapters weren't, like, really long. It didn't make it difficult for me to kind of read and get the important information I needed. So I guess to start, can you remind, I guess, us and just the listeners what the hypothesis for positive symptoms of schizophrenia is and kind of like the proposed treatments there are right now.

Okay. Basically for positive symptoms, and the book actually starts with a chapter entitled approach to positive psychotic symptoms. There have been a number of studies in the community suggesting that in the community, the reason people with schizophrenia spectrum disorders have difficulty working, maintaining relationships has more to do with cognitive and negative symptoms related to their schizophrenia. However, for forensic settings, it is the positive symptoms that get people in trouble. That's what leads them to do things that attract the attention of the legal authorities. And indeed, the positive symptoms,

of schizophrenia appear to derive from overactivity of dopamine and the mesolimbic system, in particular the dominant temporal lobe appears to be the source of a lot of symptoms such as auditory hallucinations. And elaborated from that to forebrain areas, you also get delusional ideation. And it's most often those things such as delusions associated with anger that lead to behaviors that are problematic with respect to the law. And so the cornerstone of approaching positive psychotic symptoms remains dopamine antagonism, that is drugs that decrease dopamine signal transduction in the mesolimbic system. Okay, and so you talked about like PRN and stat medications as well.

and assessing for severity and correct recommendations, I'm sure that will be an interesting thing to discuss for our audience. So what do your recommendations on how to assess for mild versus moderate, severe agitation of positive symptoms? And then what are your treatment recommendations? Yes. Severity is often very much based on observation of the actual physical level of activity, the person. Can they sit still? Are they hyperverbal? Are they making aggressive threats or attempting to actually destroy physical objects or attack people? And of course, the more of those things that are

positive, the greater the degree of psychomotor agitation. Psychomotor agitation itself, if people want an example. If anyone has ever tried to put a cat into a cat carrier and the cat doesn't want to go, you're looking at psychomotor agitation. The cat's sympathetically aroused. The fur stands up. The back is arched. The eyes are dilated. In many ways, people are very similar and have the same type of underlying mechanisms. Psychomotor agitation is a product of the amic amygdala being overactive and essentially initiating a sympathetic fight-flight response. The treatment for that is largely to inhibit those systems and the sympathetic arousal. We're not treating the psychosis per se at that point.

We're simply trying to decrease the acute psychomotor agitation that most commonly involves administration of o dopamine antagonist, haloperidol, flutinazine, suprasidone, olanzapine, in combination with a sedating medication such as lorazepam, and in many cases, an antihistamine such as hydroxazine or diphtromine. Clinically, we suggest that people titrate against the degree of psychomotor agitation. One of the most common errors we see people make is to spread the PRN medications too far apart in time so that the psychomotor agitation rekindles between available doses. Instead, it makes more sense to use smaller doses, but to basically give the medications

more frequently as needed, essentially to titrate the person down to a more calm state without hopefully over-sedating them. Yeah, that's good. You talk about how oral zyprexa may not be the best option in more moderate cesvir because the plasma concentration takes six to nine hours. I think that's a good reminder. Yeah, yeah, indeed. Intramuscular olanzapine works just fine, albeit there is a risk of inducing hypotension because it's a pretty good alpha adrenergic antagonist. But given orally, the olanzapine gradually climbs up to a peak over about six to nine hours. And frankly, that makes it orally not a very good medication for acute treatment of psychomotor agitation.

Okay. So Dr. Cummings, so let's kind of talk about treatment-resistant schizophrenia now. So what's the criteria you use to diagnose someone with treatment-resistant schizophrenia? And how do you go about assessing that? Okay. Well, the very first definition of treatment-resistant schizophrenia came from John Kane in 1989. Now, he was conducting a research study involving chlizepine versus other antipsychotics. So he required failure of at least two antipsychotics from different classes, given at 1,000 chlorpromazine equivalents for a period of at least six weeks. no good functioning in the last five years, and a prospective failure of heloperidol titrated

to as much as 60 milligrams a day. Frankly, that's a very difficult set of criteria to replicate outside of a research setting. Howes et al currently have published a set of alternate criteria for defining treatment resistance, which involves, again, trial and failure of at least two antipsychotics from different classes. The dosing is a little lower. Must be at least 600 milligrams chlorpomazine equivalents for a period of six weeks without significant improvement. If it's a long-acting injectable antipsychotic, the trial period is at least four months. And it should all also involve measurement of plasma concentrations without prior notification of the patient so that you can actually tell if the person's taking the medication. Frankly, if the person is treatment

resistant, that is, they have two such failures, there are odds of responding to any of the antipsychotics, and this is a very important point, any of the antipsychotics, other than chlopin, is less than 7%. we've looked at that at the state hospitals, and on average, the patients we get have had 7.3 antipsychotic trials before they get here. One of the things psychiatrists tend to do at times is to continue to pursue more and more antipsychotic trials, even though the probability of success is vanishingly small. That's especially important because the likelihood of response to clozapine, once somebody is treatment resistant, begins to decline after about 2.8

years of treatment resistance. That comes from a study by Yamashira at Al in Japan. Closopine and treatment resistant patients has a response rate of 40 to 60% versus less than 7% for everything else. Okay. So I guess we kind of I've jumped the gun a little bit. So I know in the book you talked about measuring in order to assess whether or not a patient has had fair trials of antipsychotics. To meet the criteria for treatment-resistant schizophrenia, you measure the plasma levels or the serum levels of these antipsychotics. Can you tell us a little bit more about that? Yes.

One of the things that's true is that, you know, psychiatry has relied on doses. for a long time because, frankly, until recent years, plasma concentrations of drugs were not readily available. That has changed. We can now measure the plasma concentration of any of the antipsychotics. And frankly, dosing is a poor guide because things such as absorption, metabolic rate, very hugely across the population. And without measuring the plasma concentration, of the drug, you can't know for certain that the person is actually taking the medication. You also can't know whether they're an extensive metabolizer of the drug, and they may not be responding simply because you're giving them a sub-therapeutic treatment.

Okay, so we talk about, you know, drug equivalents, getting it to 600 or 1,000. would you prefer to do the first trials of the non-closopine with blood levels and get it to kind of like the upper limit of the blood level without? Yes. Yeah, if the person has, you know, I realize that having said that plasma levels are available, that is true. But not every psychiatrist in every setting may have easy access to plasma concentrations. If plasma concentrations are readily available, they are very much preferred to dose as a guide to adequacy of treatment. Because it actually tells you what's in the person's bloodstream and therefore what is essentially in their brain. Whereas dose just tells you that's what you wrote on the prescription pad.

Yeah, I think people are more used to doing levels of, of tepicoat and lithium. And I wonder if you can talk about some of the nuance with dosing those and what you found with what the blood levels mean and if there's any nuance there that you can give us. Yes, there is. In particular for valproic acid, it's important to have an adequate plasma concentration

to achieve a free fraction that is big enough, large enough to enter the brain and be active. Valproic acid is very highly protein bound, primarily to albumin in the bloodstream. And for example, at a concentration of around 50 micrograms per milliliter, 95% of the drug is bound to albumin. Only 5% is floating around as free drug, and it's only the free drug that enters the brain. So you don't have very much. by the time you titrate to the point where you have a plasma concentration of 120

micrograms per milliliter, you have about 25 to 30 percent of the dose is available as free drug because you've filled up the binding sites on the plasma albumin. In most patients, if you're talking about treating impulsivity or trying to provide mood stabilization, you really start to see an improvement in the size of the free fraction, starting at about 80 micrograms per milliliter and increasing thereafter. In this book, we essentially recommended an optimal range for psychiatric purposes of 80 to 120 micrograms per milliliter. you have to have enough of the drug available to enter the brain and actually be active. Yeah.

This is something we've talked about in prior episodes, and I think it's worth repeating because there's such a big jump from that level 80 to level 120. So you're getting this, by the way, 12 hours after you give the last dose, so the nighttime dose, and then you check a blood level. That's the way all blood levels are done, 12 hours after. and then going from 80 to 120, at around 80, you have 90% of the valproic acid protein bound. But when you get up to 120, it's like so much more. So there's such a huge difference between that 80 dose and a 120 dose.

And I think that's just really worth repeating that if you're at 80 and you're not getting the full effectiveness of what you're looking for, treating with this, then going to the 120 might be worthwhile. Yeah, indeed very much so. Neurology does push even higher in cases of refractory seizure disorder. We picked 120 as our recommended upper limit simply because tolerability for valproic acid becomes an increasingly difficult problem at higher plasma concentrations. I have a question about that. So what if a patient, let's say you put them on Depico and their levels are subthreshold? So lower than 80, but their symptoms seem to be well managed. Would you still recommend going up until they're at that range?

No, you may have somebody who is unusually sensitive to the drug. Like all things, the ranges that we're recommending are based, of course, on study of groups. You will find individuals who respond to lower concentrations than those cited as the the optimal concentration range. You'll also find people who both tolerate and require levels that are higher than the optimal range that we've cited in this book. These are based on studies that, like everything in medicine, looks pretty much at Gaussian distributions so that you're looking at what will provide benefit for most people,

but you have by definition, 2.5% of the population will fall below that and 2.5% above. And so what about carbamazepine or oxcarbazepine? Carbamazepine is an effective mood stabilizer. It is not, however, very desirable, primarily because of its own side effect profile, it can be a very difficult medication for people to tolerate in terms of risk of blood disgracies. It also is a problem unless the person is on carbamazepine monotherapy, because it's a great hepatic inducer, induces the cytochrome P450 system,

and will reduce the plasma concentration of other drugs, such as antidepressants or antipsychotics, by anywhere from around 30% to 80%. So you may essentially lose the efficacy of your other drugs unless you're very careful about adjusting. Oxycarpezepine was originally looked at by a lot of people, and it was hoped it would be as effective a mood stabilizer as carbamazapine. However, it turns out oxycarpazepine is not really a mood stabilizer.

It's the epoxide metabolite of the carbamazepid. carbamazapine that appears to provide the mood stabilization, and unfortunately, oxygirbinopine does not provide that. Okay, in appendix 3.11, you talk about kind of where the mood stabilizers fall in to the treatment of psychomotor agitation, and you talk about how, you know, if after the antipsychotic, if they're adherent to PO medications, and there's still agitated, you may need to move on to foproic acid, and then if that's not indicated, maybe lithium. So can you tell me a little bit just to kind of clue our audience into the bigger picture of where mood stabilizers fit in treating this disease?

Yeah. In this case, and in this context, we're talking primarily about people with schizophrenia spectrum disorder, albeit some of those will be schizoaffective disorder by polar type. Beyond mood stabilization, that is, decreasing mood cycling, lithium and valproic acid do also have efficacy in decreasing psychomotor agitation. These drugs essentially inhibit the activity of the limbic system, and as you may recall, the psychomotor agitations being driven by positive psychotic symptoms that arise in the mesolimbic circuit. So if dopamine blockade by itself is not adequate, the next step is to add a drug that will further suppress the activity of the limbic system and the activation of the sympathetic nervous system. And valproic acid likely via modulation of second messengers and by blockade of voltage dependent sodium channels and lithium likely by causing. a loss of the second messenger,

trifoshoinocytol, both will go a long way toward dampening limbic responses and thereby decreasing psychomotor agitation. Voproic acid can be very useful at the outset of treating a psychotic disorder with exacerbation because its onset of action is pretty rapid. It only takes about three days to reach steady state when it's started. And usual dosing is 20.

20 milligrams to 30 milligrams per kilogram. These days, usually given as dival proex and a BID schedule, although the ER formulation also can be used once a day. A lot of people aren't aware that lithium too can be loaded. There was a great study by Cook et al a number of years ago now that found that if you start with lithium, again, 30 milligrams per kilo. and you give the person on day one, lithium extended release, divide whatever that number was into three doses, give it at 4 p.m., 6 p.m., 8 p.m. and then measure a plasma level the next morning. If it's less than one, then the person gets 1,500 milligrams of immediate release as their initial dose the following night. If it's over 1, they get 1,200, so a little lower dose. Then after 5 days,

you measure the lithium level, and you can then fine-tune the dosing. Interesting, in their study, they had no toxic responses at all, and people actually tolerated that lithium loading quite well. And for the persons who were acutely manic or acutely agitated, getting a medication on board rapidly, of course, is important in terms of decreasing the degree of risk, both to the patient and to others. Okay, Kat, so when I get psychotic, you'll give me 1,000, 1,000, 1,000, 1,000 live there. Okay, all right, got it.

No, when I go maddo. That seems like a lot, 3,000 in the first night, but I think... Well, no, 30 milligrams per kilogram, so... I'm about 100 kilograms, so... Okay. Pretty easy. Yeah, so it's a thousand, thousand, thousand. which sounds like a lot, but isn't.

A lot of people aren't aware that in John Cade's original study in 1949, his dosing of lithium initially was 1,300 milligrams TID. Okay. Which I have to say, though, made a number of his patients fairly toxic, and he had to back down from that. Okay, yeah, that's good to know. All righty, so for, so that was the mood stabilizers. what are the advantages of long-acting injectables or any opinions?

Oh, very much opinion. And indeed, there's an entire chapter on this, indeed entitled, Advantage of Long-Acting Injectable Antisicotics. Frankly, the crux of the issue is that adherence to antipsychotic medication is terrible. When they've done studies where they use electronic, bottles to monitor how often the person opens the bottle and they presumably take an oral medication and they even give people a fudge factor and say, well, if you order, you know, if you open the bottle 80% of the time that you're supposed to, we'll count that as good.

You get full credit. The adherence rate for the antipsychotics in those studies is between 30% and 40%. Not very good. Under half. you know frankly and most psychiatrists are aware of those studies but invariably the psychiatrists that I've talked to will say yeah I'm aware of the studies and I know adherence is terrible but not my patients well I'm sorry to tell you but your patients cheat on you too that's what I said that's what I think Dr. Cummys I think to myself no my patients are really good

And, you know, and frankly, this is borne out when people have looked at things like re-hospitalization rates, even longevity rates. Some of the Scandinavian countries have provided data because they have access to population databases. People who take long-acting injectable antipsychotic medications live 30% longer than people who take the same oral antipsychotic. They also were hospitalized at a far lower rate than the people who take. oral antipsychotics. So, you know, frankly, one of the problems we have in the U.S. is that we don't use long-acting injectables nearly enough. If you're in Europe and you're a schizophrenic patient, the odds that you'll be on a long-acting injectable is about 60%. In the U.S., it's under 10%. Whoa. Well, let's go Europe. Europe's got it down then. What do you think about, like,

let's say you're an outpatient provider and you have no experience with long-assioned. injectables. What's the easiest way to get started? Do you have someone in your clinic give the injectable? Do you find a pharmacy that can give the injectable? Like what's actually available and the best way to get started? If you have a clinic that has nursing staff, nurses are very well practiced at giving injections. And so if you have a clinic that has nurses, it's good to talk with the clinic administration, maybe develop a position for, you know, an L-A-I injection nurse, or at least people who can fill that role. If you're in a practice by yourself, it's not that difficult to learn to give along-acting injectable medication. Most physicians have

given injections during their training, but a lot of them aren't very good at it because they don't do it very often. This may be a case where you may want to ask nurse trainers or nurses in your area. If basically they can give you lessons as to how to give injections. I mean, the injection itself is not difficult. It's just a number of psychiatrists don't do it very often. And like everything else, if you don't do it very often, you're not very good at it. So are you imagining the patient picks it up from the pharmacy, brings it to you, and you inject it if you're like, a solo practitioner? Yes, you can do that.

Some clinics actually, if you're a solo practitioner, you also have the option. With the right storage, you can actually store medications. A lot of psychiatrists aren't aware that physicians are allowed to both store and dispense medications.

Let's talk a little bit about clozapine and where that falls into you know, treatment resistance, schizophrenia. You mentioned before, you know, you get that 40 to 60 percent response rate instead of the really low, you know, like 5 percent response rate. Are there any other benefits for closopine, such as decreasing suicidality or aggression? Yes. Yes to both of those questions. There have been a number of studies. Best one was done by Krakowski et al in New York. they looked at a sample comprised of these were not treatment-resistant patients.

They, however, were male patients who had a rich history of violent behavior, and they randomly assigned them to haloperidol, olanzapine, or clozapine. After 12 weeks, they looked at their rates of violence on the modified aggression scale, and found that the psychosis had declined about the same in all three groups. Their pan scores went down about the same degree, but the violence had dropped almost twice as much in the Clozapine-treated patients as in the Olanspin and Heliparidol treated patients, suggesting that the Clozapine was exerting an anti-violence effect

that was over and above its antipsychotic effect, efficacy. And indeed, they had done neuropsychological testing during the study. They did a post-talk analysis of that data and found that what had changed was people's executive functioning had improved on chlozapine, but it had not changed on olanzapine and haloperidol. What we're likely seeing is clozapine does not provide its antipsychotic or any other benefit, as far as we can tell, from modulating dopamine directly. Instead, it appears to be a glutamate modulator, the brain's primary stimulatory neurotransmitter, and in particular, it improves glutamate signal in the frontal lobe, so people actually can think and have better executive functioning, and that appears to be associated

with a decline in violence. In terms of suicide, there may be a very parallel effect. A number of studies have found that clozapine compared to other antipsychotics and schizophrenic and schizoaffective patients decreases the rate of both suicide attempt and completed suicide by about fivefold. That's pretty cool. I think it's a great medication and I actually have a couple of patients on it still. you know when I was looking with Dr. Myers talking about antipsychotic levels, we were talking about how

in the spec and pet scans there's a saturation of the D2 receptor and you can kind of look at that and that clozapine is unique in that you're not looking at the same level of saturation do you have anything to say about that

kind of remind the audience of what that means yes if you look at Chlosepine, even at fairly robust plasma concentrations, its D2 dopamine receptor occupancy is pretty low, typically down in the 30% to 40% occupancy range, whereas we think for antipsychotic effects, dopamine antagonism requires typically occupancy of between 60 and 80% to exhibit an antipsychotic benefit. So it's fairly clear that Clozapine is not providing its benefits by blocking dopamine. Just a side question here. Is there any indication that a psychiatric patient should get a spec or a

pet scan? Certainly in terms of somebody who is presenting newly with schizophrenia or what is suspected to be schizophrenia, if they have not had any imaging done in their lifetime, and often they haven't, because these are very often teens or early 20s, if there are any unusual or atypical features to their psychosis, then certainly getting at least one image of their brain, preferably be a MRI initially, can be useful as a screening mechanism. Frankly, the yield is going to be low, but occasionally you find things you weren't expecting. A lot of patients are feeling the necessity to do these sort of expensive imaging tests for cash. Do you find any helpfulness from those?

Typically no, unless the person has specific neurologic complaints and positive findings on neurologic examination. Yeah, so if they have like unilateral neurological findings, decrease sensation, decrease, you know, strength, that would be a great indicator of a MRI. Yes, or if there is something atypical about their presentation, for example, we had a patient present who had been diagnosed in the community as suffering from schizophrenia, but most of the time this person did not exhibit psychotic symptoms, but then intermittently, they would. They would appear to be confused, disoriented, we're making nonsensical statements, talking to people who weren't there, and then that after a while would pass and they would go back to normal.

Turns out when we did an MRI, they had a hamartoma and their left temporal lobe. They were having intermittent complex partial seizures. They didn't have schizophrenia. Okay, but just to be clear, can you diagnose mental illness from imaging? No. There is no imaging study that will directly tell you that a person has a psychiatric disorder. That's up to and including the neurocognitive disorders. You may find features that are suggestive. For example, somebody with marked atrophy, very likely may be demented, but again, it's not, a diagnostic test. Okay.

So Dr. Cummings, what are your opinions on motivational interviewing for these kind of patients to kind of promote adherence to chlizapine? Because I know you have to adhere to strict REM's guidelines and stuff like that for these kind of patients. Frankly, for psychotic patients, motivational interviewing has been found. to be of limited benefit. In many ways, the overall care of the patient and an environment that provides external structure for what the person may lack internally appears to be more effective than motivational

interviewing. Yeah. So I had a patient actually on an inpatient unit, and I would say he definitely meets criteria for treatment-resistant schizophrenia. and we started him on clausapine. And I feel like he just became more distant and definitely not responsive to motivational interviewing or anything. Have you seen sort of like a side effect of clausapine as like emotional blunting? I know it's difficult to tell between like negative symptoms of schizophrenia versus the side effect of the clausapine.

But I felt like it's just gotten worse after we put him on clausopine. it's certainly difficult to tell one of the one of the adverse effects of clozapine is indeed sedation you know it's a very robust antihistamine or actually inverse histamine agonist and consequently it will sedate people essentially turn off their cortex in some in some folks so that they are not very attentive fortunately that's not an effect in most people for most people the glutamate increase overrides that and they actually become more alert and more interactive, but you do see exceptions to that. The other problem we deal with with all of the antipsychotics is, with the exception of chlospine and those who respond to the increase in glutamate signal, the antipsychotics

as a group tend to improve positive symptoms but may actually worsen negative symptoms. That is, make the person more apathetic, more withdrawn. That's especially true of the first generation antipsychotics if the concentration is really higher than the person can tolerate. Okay. If it is a sedation, would that decrease over time? How long do you think it would take? It will, and some people, most people for the acute sedation, they may get from clozapine that will tend to go away over anywhere from four to 12 weeks. In part, it depends entirely. on how sensitive the person is to histamine blockade. And if you ask among your friends,

you'll find people who can take a first-generation anihistamine like diphenhydramine, and they'll go, oh, it has no effect at all. Other people take 25 or 50 milligrams of diphenhydride, and they'll sleep for 24 hours. So there's a huge range of difference in sensitivity to histamine blockade, and my guess is those people who are at the very most sensitive end may not accommodate entirely. Whereas people who are more in the middle to less sensitive end of the spectrum, their sedation will improve at a fixed dose over a few weeks.

So now that we're talking about kind of like the negative symptoms and the sedation, what are your treatment recommendations for patients who are endorsing? mostly negative symptoms or cognitive kind of deficits? Well, in terms of the antipsychotics themselves, one thing that people sometimes learn in residency that is just flatly wrong is to give antipsychotics in divided dosing. There is essentially no reason to give any of the antipsychotics in divided doses. They can all be dosed at bedtime.

That has a couple of advantages. It lets the person be more awake during the daytime because they're not having a morning peak in terms of histamine blockade. It also tends to mitigate against other adverse effects because the peak plasma concentration of the drug occurs during sleep and people don't have extraperaminal symptoms while they're asleep because our basal ganglia are in essence a part of our reticular activating system. Now, in terms of cognitive deficits, there's a great deal of work going on in terms of cognitive rehab programs, and those have shown positive results. There have also been positive results with the partial dopamine agonist antipsychotics, which, you know, frankly, combining a partial agonist and an antagonist doesn't make much sense because the partial agonist will win because all of them areapriols.

Brexpiprosol and carriperzine all have higher binding affinities than the antagonists. But one of the things that came out of an interesting study by Corral adal in 2017 was that combining chlozapine and a partial agonist aeropiprizole in their study provided quite a bit of benefit for both cognition and negative symptoms. Hmm. What about... Okay. There have also been some studies looking at Mementine and acetyl-colon esterase inhibitors, and although the data is awfully slim. There is some evidence to suggest that Mementine and colonesterase inhibitors may improve cognition and schizophrenia. Yeah, I've also read a study about Pramapixel.

Have you heard about it? Yes. That's helped with mood and other negative symptoms in these patients. Yes, with negative symptoms, also, Pramapixel is on the fairly short list of medications that may be helpful in bipolar depression. What do you think about like concerta during the day with a person on, let's say they're on clozapine? where we have observed benefit for concerta and we have used it in the state hospitals albeit very very carefully because of course the dopamine stimulants can be psychotogenic in people whose psychosis is not well controlled

but provided their psychosis is under good control we've observed benefits with respect to both impulsivity not unlike what you see in ADHD where the person becomes less impulsive because their prefrontal cortex is functioning, as well as cognitive deficits, I suspect for the same reason because the functioning of their prefrontal cortex has been improved by the stimulant. Being frankly, that we're a forensic facility, we're very picky and careful about what we use. we avoid things that can be easily diverted and abused, which pretty much limits us to the extended release or extended, yeah, methylfinidate, concerto would be the trade name, although there's a generic of that,

and Lists Xanphetamine, which of course is a pro-drug until the lysine is cleaved from the amphetamine molecule. Would you ever consider antidepressants? Yes. Antidepressants are indicated for people with schizophrenia spectrum disorder provided you're not talking about schizoaffective disorder bipolar type. For bipolar illness or for those people who have a bipolar component to their schizophrenia, the antidepressants are essentially contraindicated because they don't provide much benefit for depressive symptoms, but they're a wonderful way to increase the rate of cycling of the mood

or to drive the person into hypomania or mania. For people who don't have that liability, then indeed the antidepressants may help improve the dysphoria that's common in schizophrenia as well as apathy and negative symptoms. Let's jump into persistent aggression and violence in schizophrenic patients. Now we know that, you know, you know, first episode, schizophrenia, they have increased aggression, treated schizophrenia, probably pretty close to the average of the population, would you say, but with some patients, they have continued issues. Would you add any nuance to what I just said? Yeah, you know, until the environmental catchment area studies done in the 1980s and then analyzed

in the early 1990s, it was unclear whether people with schizophrenia had increased. rates of violence. Those studies supported that, yes, they do. In particular, those who are suffering from psychosis that includes persecutory delusions associated with anger. And indeed, the first step is to try to treat the person's psychosis, often with dopamine antagonists, and indeed, if they respond to that, their risk of violence declines dramatically and approaches that of the general population. In the state hospital system, we've had the opportunity to observe people, of course, who were, in many cases, selectively sent to us because of violent behavior. After they're stabilized on dopamine antagonists, we have about 2 to 3 percent of our patient

population who then are responsible for about 30 to 40 percent of subsequent violent episodes. Those are the people with persistent problems with violence and aggression. Often they require ongoing mood stabilizer, the valprocaster, or lithium that we've talked about, if it's being driven by essentially limbic overactivity, overly affective responsiveness. There's also a good deal of benefit to be had from putting them into cognitive rehab. rehabilitation. And of course, we ultimately come back to clozapine, which has a very direct effect on improving executive functioning and decreasing violence risk. Essentially for those people who suffer from schizophrenia, but who remain violent, despite control of their positive symptoms,

it appears to be related to cognitive deficits. The person has a limited repertoire of responses if they're upset and consequently they may revert to aggressive behavior as a protective maneuver. Again, an impulsive violence, and that seems to improve mostly in response to giving the person better prefrontal cortical functioning, the ability to think through a situation and to think about consequences before they act. So you probably want to minimize in that group anticholone or something. medications. Yes. Yeah. In fact, for a whole variety of reasons, you know, one of the things, and this is pointed out in the book as well, the anticholinergics like trihexifidil,

bin, strepene are excellent rescue medication. Somebody has acute dystonia. They've essentially become a pretzel, giving them oral or intramuscular anticholinergic medication. We'll reverse that within minutes, and frankly, you want to because it's a distressing and painful condition. However, ongoing anticholinergic medication should be avoided, if at all possible. They come with the price of decreased cognitive in memory performance, blurred near vision, increased dental cavities, risk of bowel obstruction, and in males, urinary retention. and frankly, one of the bad things I've seen happen to patients is they had an episode of dystonia when they were young and put on antipsychotics for the first time, and 30 years later, they're still taking Benztropine, even though they've had no EPS since.

Data would suggest that about 70% of people who have an acute episode of EPS can be taken off of the anticholinergic after three months without any recurrence of EPS because they've adapted to the presence of the antipsychotic. Frankly, a mantadine antiviral agent initially, although it's become ineffective for that purpose, is a much better long-term solution to risk of Parkinsonism or dystonia. Typical dosing starts at 100 milligrams a day, up to as much as either 100 milligrams TID or 200 BID. for those people who develop post-dose nausea, there are two extended release formulations

that can mitigate against motor side effects. Yeah, I see that all the time. You get these patients, new patients, you know, schizophrenia treated for years on cogentin, on daphnein. I like to cut it in a quarter and see them back in a week. I mean, so if, let's say they're on like,

I cut it down 25%. And then I have them come back and we cut it, cut it again 25%. Cut it again 25%. And get them off. So I can kind of watch them and watch the change. And sometimes the change is like, it's just they come more alive during the day. The family gets excited about, you know, wow, you know what you're doing. The patient gets excited.

So I highly recommend doing that on patients that have been on these things for a long time and been fine. So I really appreciate your emphasis on that. One of the things that I actually had a nurse practitioner reach out to me by email and caught a discrepancy in two episodes, one in which I said that hydroxazine was anticholinergic. And then the recent one with you for sleep, you said that it wasn't anticholinergic.

And we had an email exchange back and forth on this. I looked back at the papers. that I was getting that it was anticholinergic. And they did say that it was anticholinergic. So there are papers out there that say it's anticholinergic. But then you shared some really good studies looking at it. And you want to talk about this and why it's not anticholinergic for my audience? Yes.

Yes. And I can tell you where the original misinformation came from. As you know, diphonhydromine was the first antihistamine released in the U.S. 1946. Hydroxazine was developed in the 1950s, and people assumed at the time that because it was also an antihistamine, it was anticholinergic. That made its way into the original package insert and several iterations thereafter, and consequently, hydroxazine had the reputation of being anticholinergic. It turns out, though, that as people began to get the capability to actually do binding studies for acetylcholine receptors,

the K-I values for hydroxazine at the acetylcholine receptor range from the upper hundreds, around 800 in human beings, up to greater than 10,000 in some animal species. affinity for a receptor is one over the KI value. Most of the drugs that are effective at a receptor have a KI value of 10 or less for that receptor, or at least certainly less than 100. So based on those binding studies, essentially hydroxazine is not anticholinergic. you'd have to take multiple gram amounts of the drug in order to have any significant effect on acetylcholine signal transduction. Yeah.

At the hospital that I work at, I think we get a lot of consults by the medicine team saying that, you know, the hydroxenein is on the beers list for the older patients. But we do get, we do learn that, you know, like hydroxasine is not anticholinergic and we give a lot of hydroxenium. scene. Yes. You know, it's it's it's it's one of those pieces of misinformation that has a somewhat vampireish or zombie like quality. It keeps re-rising even though it has long since been disproven. Yeah, so I will be correcting the Excel sheet that I was giving out, talking about antichalergic activity. And I think I think the astuteness of my audience for seeing discrepancies. I do update documents. Maybe like once a month

I'll get something small, but if you notice anything and you want to let me know, let me know, because I appreciate keeping my audience informed of the newest information. And I did want to say, too, in the book that we're discussing, there is a section in part two of the book that deals specifically with the anti-Parkinsonian drugs. All of the chapters in part two are entirely made up of tables that quickly go through things like basic information, mechanisms of action, including where it does and doesn't have effects, what you need to do to get the drug started, how you titrate the drug, what effects you're looking for, both positive and negative, what warnings and interactions are there.

And then finally, the very final table in each of those chapters are clinical pearls. What can you really do that will be, that will make you essentially look brilliant in using the drug? Okay, I'm going to do some rapid questions to kind of wrap this up. You know, we did this prior episode on insomnia. Any specific recommendations for insomnia in schizophrenic patients? schizophrenia patients have often very fragmented sleep and in particular for those who are schizoaffective bipolar type sleep is a very vital issue the drug we used most often among the selective sedatives is ssopaclone because of its longer half-life xaloplan and xolpidim often are too short acting

for people with difficult sleep issues. So indeed, those as Zopaclone is the common drug that we use in difficult sleep cases. Yeah, and in the book you also talk about, you know, sleep hygiene and going through, you know, if it is a sleep wake cycle issue, considering other things like melatonin or the melatonin agonists. Yeah, anything on that you want to mention? Yeah, we do talk about both the direct treatment for insomnia and frankly the fact that the benzodiazepines are not a good choice because people become 100% tolerant to their sedative effects, as well as having issues with diversion and abuse. Again, hearkening back to the fact that I work in a forensic setting. We do talk about melatonin as well as romeltyon and tasimeltion for people who may have.

sleep phase problems. These are the patients who are up all night, but they sleep perfectly fine during the daytime. You may have to work on getting them back to sleeping at night and, you know, being awake during the daytime when everyone else is. And a circadian rhythm modulator can be helpful with that. You also talk about early onset, childhood onset schizophrenia, which is less than 12 or early onset schizophrenia 13 to 18. One of the things I noticed in that chapter is you make a big emphasis of substance use

and medical issues. Any nuance you want to throw out there quickly on that to kind of in some ways the core point of that chapter is that if you have someone with what looks like childhood onset schizophrenia

this is prior to the typical age of onset for the disease and consequently it deserves a very careful workup in terms of looking for medical and developmental issues that may be mimicking psychosis or for particularly in adolescence substance exposure that parents and others may not be initially aware of that may mimic psychotic illness so that people don't essentially miss things that are not schizophrenia, spectrum disorders. Specifically from that, one of my questions for you is what substances could make a kid look psychotic but not be found in a UDS? Some of the designer drugs, if they've come

across, for example, things like bath salts, the keto amphetamines, or things like that, I mean, there's an entire industry out there devoted to developing synthetic cannabinoids and synthetic amphetamines for the purpose that they're not easily detectable using standard tests. Urine drug screens are based on antibody affinity for a molecule. And if you tweak molecules, you can get around that so you'll end up with the false negative. So certainly in this day and age, there are a lot of drugs out there, and there's an entire industry devoted to trying to stay ahead of detectability. So that's one issue. The other thing is kids are sometimes creative. It was a while before people realized that dextramothorfen from cough syrup is a halocinogen, if you take enough of it.

And now, unfortunately, it becomes a halocinogen at about the same concentration that it becomes cardiotoxic. But, you know, that's why if you go in a drugstore these days, you'll see all the dextramothorfan products back behind the counter as opposed to out on the shelves and readily available. Yeah, kind of jumping to a comorbid substance use disorder that can often be present with someone with schizophrenia. What are some of the things that you look for that are kind of really important to know about this comorbidity? Essentially, it's an area that sometimes is under-recognized. The prevalence of comorbid substance use in schizophrenia spectrum disorders has been cited

as running anywhere from 50% to 80%. So it's very common. And it appears that a number of the drugs of abuse promote the deterioration of the brain into a schizophrenia spectrum disorder or may actually cause damage that is parallel and essentially wind up in a disorder that looks like schizophrenia. And that includes the stimulants like methamphetamine. There's also now evidence that. that cannabis in adolescence does very much worse things to adolescent brains than to adult brains

and people particularly who are predisposed to a psychotic disorder may push them in that direction. So the first take-home lesson is always, always, always in somebody with new onset schizophrenia to take a very careful drug abuse history not only from the patient, but from any collateral sources of information, you can get your hands on, family, friends, et cetera. Because if you treat the psychosis, but you fail to treat the substance use disorder, basically the person's prognosis is going to be terrible.

Yeah. Yeah, I think we see a lot of amphetamines in this day and age. Yeah, well, yeah, I'm in Southern California. We are in many ways the amphetamine capital of the world, I think. Yep. So remember, on the UDS, you're only going to see it for 48 hours. And if they're on buproprion, nasal decongestions, they can have a false positive. That was a nice pearl that you added in your book that I think is worth mentioning.

Yes. And indeed, if you get a positive, and this is something you'll have to work out with whatever lab you use, When you send them samples, have them reserve part of the sample, because if they get a positive, they can always then run a gas or liquid chromatography, mass spectrometry analysis of the, quote, positive sample, and that will clearly identify for you whether the drug is actually present or not. So in summation, you know, Dr. Cummings has been just giving tons of information and knowledge for the beneficial of the public for free for this podcast. I highly recommend you check out his book. I think that a good way to read it is to try to read five pages a day. And then before you read

your new five pages, go back and look at your underlined notes and the things that you scribble on the side of the pages. And spend some time also looking at the appendix and appendices. there's a lot of good things on how to treat constipation and, you know, sort of clinical pathways on treating agitation that I think are very helpful. So I think it's a great, a great book for a book, you know, part of your sort of basic books that you need to know to treat this disorder, schizophrenia. And Dr. Cummings, thank you so much for coming on and talking about it. Okay, thank you. Yeah, any other, Dr. Cummys, any final words?

Kowu, any final words? The only other thing I would say about the book is it is available both in paperback for those who prefer a physical book as well as in electronic form. The advantage of the electronic form is, for example, if you put it on a Kindle, it is then searchable. Yeah, it's a very good format, so it's not wonky. like sell me e-books, so I really liked it. But thank you for having me here, too, Dr. Cummings and Dr. Peter. Yeah, Kat, I'd be curious as the weeks progress, if this creates any good discussions and the treatment of your patients, I know you're in the thick of it in the patient setting mostly. Yeah, for sure. So, well, good. I'm glad to put this information out

there for people. We will have a little summary of our episode in the show notes. You should see a link to the book. And if you have any kind words for Dr. Cummings, go ahead and just put them on an Amazon review. Those do help get the information out. And if it's helpful for you, then it validates the helpfulness for people who will come in the future and read those things. So just like I appreciate iTunes reviews, I will be asking my audience to give you some nice Amazon reviews. Oh, well, thank you. I appreciate that. Very good. All right. We'll leave it there for today. Okay, thanks.