Psychiatry & Psychotherapy Podcast - Long-Acting Injectables with Dr. Cummings

Episode Date: January 10, 2023

In today's episode of the podcast, Dr. Michael Cummings returns to discuss the use of long-acting injectable (LAI) antipsychotics. LAIs are administered in intervals ranging from every 2 weeks to every 6 months, eliminating the need for daily oral antipsychotics and thereby improving adherence. By listening to this episode, you can earn 1 Psychiatry CME Credits. Link to blog. Link to YouTube video.

Welcome back to the Psychiatry and Psychotherapy Podcast. My name is Trent Jones, and I'm the producer of this show. And what you just heard is a new intro that we're working on. Dr. Peter was really excited about it. He's got a friend who is a fabulous piano player that lent her talents to this bumper music. So I hope you like it. You'll be hearing different versions of it in the new year. All right, let's get to the show.

Welcome back to the podcast. I am joined today with Dr. Michael Cummings. And today we'll be talking about long-acting, injectable antipsychotics. We have no conflicts of interest, which is unusual. I'm surprised you have no conflicts of interest still, Dr. Cummings. Part of that is a result of the fact that I work for the common drug formulae for the state of California, which prohibits having any financial interests in the drug since I play a role in deciding what drugs the state contracts for yeah so today we will be talking about long acting injectable antipsychotics

and how to use them unique side effects we'll try to make this as practical as possible this is for providers but if you're listening in as someone who's either a therapist or someone who's considering antipsychotics for a loved one. Hopefully this gives you some information and knowledge to help inform that decision. So Dr. Cummings, why don't you start talking about when long-acting injectables are the most helpful? Essentially, long-acting injectable antipsychotics really should be the preferred form of antipsychotic administered. That is true, for example, in Europe. where 60% of the people suffering from a chronic psychotic illness, mostly schizophrenia,

are treated with long-acting injectable antipsychotic medications. Unfortunately, in the United States, that's only 10% of the treatment is provided with long-acting injectables. The reason I say, unfortunately, is that one of the major reasons for relapse and re-hospitalization is non-adherence. Most of the adherence studies out there show that for oral medications, the adherence rates are one-third or less, and that's even including a fudge factor of saying, well, if somebody takes 80% of their prescribed doses, will count that as good. That's what most of these studies have done. And even with that, the adherence rate is frankly fairly miserable, such that the most common reason for relapse in schizophrenia is non-adherence to antipsychotic treatment.

Yeah, I would say the most useful aspect of them for myself is in schizophrenia there is a very low insight into having the disease, and it's part of the disease to have a low insight. the parents often will be struggling with their 20-something-year-old, you know, trying to get medications in them every day, and it's just a constant battle. And the injection, although it does also require persuasion and boundaries and, you know, difficulty to try to get them the medication, it gets them a dose once a month or even less frequent. Yeah, there are now formulations that are every

three months and every six months for pellaparadone palomotate. So in some cases it can be as little as dosing twice a year. There are a number of studies out there that have essentially demonstrated that the long-acting injectable

antipsychotics, the LAIs, produce a lower rate of relapse, a lower rate of hospitalization, and probably the most impressive finding that I've read about was a Swedish study by Tepaley et al, in which they looked at 29,823 patients because they have birth to death records, and found that those people who were taking a long-acting injectable antipsychotic as opposed to the oral counterpart had a 30% lower rate of all-cause

mortality. That's just flatly an impressive number. If you are treated with a long-acting injectable antipsychotic, you're likely to live longer. Wow. That is, yeah, that is really significant. So what was the, like, what was the number again? All-cause mortality, decrease of how much? 30%. Wow. That's impressive. You know, I, they're, frankly, for a lot of treatments in medicine, that would be an impressive number. If you had a serious chronic illness and you went to your doctor, any kind of illness, and the doctor says, well, if I give you this medication,

as opposed to that medication, I can decrease your risk of mortality by almost a third. That would be a pretty good selling point for that drug, whatever it was. Was that over the course of a year, or how many years was that one-third reduction? over the course of the sample. They looked at the sample for a period of seven years. Okay.

And found that indeed for people taking the, and to be fair, they compared each long-acting injectable antipsychotic to the same medication given in oral form. And basically found that the rate of dying was 30% less with the long-acting injecting. antipsychotic. Yes, they're looking at like all-cause mortality. Yeah.

Comparing one to the other. Okay. Wow. That's again. Yeah. So that included death by suicide, death by accident, death by overdose of drugs, death via violence, because that's another, well, in the system I work in, the fact that the injectable medications are superior to the oral medications

and reducing violence is also a key finding. Yeah, I've had patients who spit out their meds afterwards. It's very common to cheek the meds, to put them under the tongue, and so it takes away that facet of noncompliance.

Yeah. Indeed, as far as I can tell, there is no way to cheat with the LIA antipsychotics, because once it's injected, there's no way to get it back out. Yeah. I actually give the injections in my office. I have a little red bin that I put the needles in afterwards.

I have some alcohol swabs. Patients bring them in from the pharmacy, or the family member brings them in. I inject it, inject it. and it's not too hard. I don't think there's a huge learning curve in learning how to inject it. Do you have any pro tips on how to inject it? Probably the pro tip I would have for many psychiatrists who don't normally do injections themselves.

Go talk with one of the nurses that you may have contact with and basically have them teach you how to give an. injection because every single nurse out there knows how to inject and they do it a whole lot more frequently than most physicians do. And, you know, it's for the saline-based long-acting injectables, the injection is very simple. It's just a straight, usually in the gluteal or deltoid muscle, you know, the needle goes in, you draw back slightly to be sure you're not in a blood vessel. you inject the medication, pull the needle out, and you're done, basically, except for putting a Band-Aid on the spot. The first-generation long-acting injectables, Halaparadol decanoate, and

flu-physine decanowate are a little tougher to learn because they're in an oil-based vehicle, and for them you have to use a method called Z-tracking, where you change the angle of the needle as you withdraw it so that the passageway, if you will, closes off and seals the oil-based medication in the muscle. It doesn't let it leak out. Even that's not too difficult to learn, though. Some of our physicians in the state hospital system have wanted to learn, and both methods take, you know, 20 minutes or so with a nurse who's a good instructor. and you're good to go. Yeah.

I found it's helpful to learn myself because the patients trust me because I've spent the time, you know, and so I'm not sending them to a third party that they don't trust. Yes. I also kind of like, I know if they're not taking it, you know, because I'm like, oh, this person missed their appointment and they missed their injection. Well, and you're hitting on one of my biases. I think that psychiatrists should always remember that they are first physicians, meaning that we should not be afraid to weigh our patients, examine our patients, give injections to our patients.

Yeah. You know, you're basically looking for a meaty part of the muscle. You're going into the muscle. You're leaving this crystal-type mass. material in there, which then slowly, well, let's talk about that a little bit. What are we actually injected in and how do they stay, you know, for a month at a time? Okay. Depending on which drug you're talking about, let's start with the oldest first. The decanoids are, the medication is bonded to a 10-carbon lipid chain. That is suspended in sesame oil. And essentially, you're injecting the oil into the belly of the muscle, the thick part. It forms a little sphere in there and gradually releases the medication over. In Flufenazine's case, the most common dose

interval is two weeks for haloperidol four weeks. With drugs like paloparidone palomotate, that is indeed a microcrystal that you're injecting into the muscle. It's in saline. So the crystals remain in the muscle and they slowly dissolve. The reason that they last a month is the tiny crystals dissolve more quickly and release the medication early. The bigger crystals dissolve more slowly and provide the later dosing of the drug. There's also a version of that microspheres for Depo-Resperadone, which is similar except that the Risperidone is bonded to essentially a polymer that dissolves, a very similar idea to the crystals. There are two formulations of Arapypiprozole,

Aripepresol monohydrate, which is again a crystal, and Arippiprozolyl, laroxyl, which is a different type of crystal, and has a longer variability in terms of

how slowly it dissolves. Essentially, the idea with all of these is that once they're in the muscle, they, by one mechanism or another, slowly release the medication into the bloodstream. There is also a long-acting injectable formulation of olanzapine.

That is olanzapine pamoate. Again, it's the medication joined to a salt crystal in this case. The salt crystal gradually dissolves, and it comes in both versions that are every two weeks and every four weeks. It does carry, unlike the others, there is a small but non-zero risk of 0.1% risk of rapid release of the olanzapine from the salt, which is why for it, the FDA mandates that the patient be watched for three hours post-injection to be sure they're not becoming

sedated by an increased release of the medication. Okay, so what do we do if someone does get very sedated on the injection of olanzapine? If they become very sedated, they need ongoing observation until they basically wake back up. They should have their vitals taken because what's happened to them is they're essentially receiving an overdose of the drug. There have been cases where that has required hospitalization until they recover from the overdose. and the FDA MedWatch has reported at least two post-injection deaths, one occurring three days and the other occurring five days post-injection. Of course, as you'd expect, there's a dispute about whether the medication was the cause or not,

but in both cases, the concentration of olanzapine recovered from the patient was quite high. For all of these reasons, frankly, the Department of State's... hospitals in California does not use the long-acting injectable formulation of olanzapine trade name relprev yeah I've never used it and I've never seen anyone no one's ever come to me on it whether I was doing inpatient work or outpatient so I don't think it's it's very commonly used have you well I think people are aware of this risk and consequently I don't want to use it yeah in Europe do they use it or is it more popular than other places? It is not, you will see it used in some settings,

but it has never become very widely used. I think because of that warning that there's a a 0.1% risk of rapid dissociation of the drug from its vehicle. That, you know, that risk does not exist for any of the other long acting injectables. Okay, so another broad question. When are they not helpful? Like, when would be, or what would be a situation where you would not think to use an injectable antipsychotic? They're not really contraindicated in any situation where an antipsychotic is appropriate to use. You might not want to start with a long-acting injectable until you're certain that the person responds to the medication that you're considering, because of course the caveat with all of them is that the elimination half-life is incredibly long.

So if you started with a long-acting injectable and said, well, this isn't working very well, the patient would then have to wait a very long time for the drug to wash out, you know, five half-lives of the drug, which, for example, in the longest, the in-vega-sostena, or in-vega half-yara, which is a cute name, which is paloparidone palmitate designed to last six months. Well, that would be 30 months for washout. That would be the extreme long end of the scale. The others have half-lives from 21 days to around 46.5 days.

So indeed, washout is still long. You do want to be sure the person is a responder to the medication you're considering. and if they are, then the long-acting injectable is appropriate for any situation in which the oral medication would be appropriate. One of the other nice things about the long-acting injectables is since they lack the sharp peak plasma concentrations of the oral medications, the side effect rate is about half for these drugs as opposed to the same drug given orally. and specifically like half of which side effects things like dystonia parkinsonism

acethegia some are even much less common a neurolyptic malignant syndrome for example is exceedingly rare with the long-acting injectables because there's not a there's not a sudden rise in dopamine blockade Do you think that any of that is from not having that first-pass liver effect of on the oral medications? Does that impact it?

It may be. It may. One of the curiosities about Halloperidol, when it was used frequently intravenously in ICU's, was that it was less likely to cause dystonia or Parkinsonism, given intravenously than it was given orally in comparable doses. So that indeed raised that question. Is there something different about giving the person this or other of these drugs and having it go through the liver versus bypass the liver for the first go-round?

I've never seen a completely satisfactory answer to that question, although it's clearly an observation that has been made. One of my thoughts on that observation is I heard a lecture by Montanado at Stanford who talked about how when someone's in a state of delirium, they don't get EPS with HALDAL. So I'm wondering if HALDA was given IV, maybe they were more sick, maybe they were more delirious than if it was given oral. Yeah, very frequently. I mean, it's very uncommon, of course, in the ICU setting for a drug to be given orally. And most commonly, haloperidol in the ICU setting has either been given IV push in Ebola or IV drip. Well, you will see some intramuscular use, but very little oral use in that kind of setting,

usually because the person is too ill to be taking oral medications. Okay, so when switching from, let's say, an oral medication to a similar intramuscular medication, long-acting intramuscular medication, do we need to continue the oral medications? And which ones do we need to continue it? Okay. Indeed, it depends on which one. for again we'll start with the old drugs Haloperidol de Canoate has such a slow

climb if you were just to start Halli-Paradol de Canoate and just give it every month it would take it three to five months to reach steady state so it would be a long, slow climb with haloparadal de Canoate that usually is overcome by loading the drug If you're, for example, switching from an oral dose, the person has done well on, say, 20 milligrams of haloperidol a day.

That would mean loading it at 200 milligrams a week for three weeks. That will produce roughly the same plasma concentration. You can stop the oral medication at the time the second loading dose is given. you would then start the maintenance haloperidol decano weight 14 days after the last loading dose at 20 times the original dose. So a dose of 20 milligrams a day would be equivalent to 400 milligrams of haloperidol decano weight per month. Because of volume issues, that usually winds up being given as 200 milligrams every two weeks. Flufenazine decanoid, very similar story, usually loaded at 24. to 50 milligrams a week for three weeks and then continued at a maintenance dose,

starting two weeks after the last loading dose. For flufenazine decano weight, 10 milligrams a day orally of flufenazine is roughly equivalent to somewhere between 12 and a half and 25 milligrams of flufenazine decanoid. for in Vega Sistina, and you're starting here with the monthly, because the every three months in Vega-Trenza and the every six months in Vega-Hafiara are intended for people who have responded and are stable on the monthly injection.

For it, it's very simple to start. You start with usually either 156 or 234 milligrams as the initial injection. One week later, depending on what you're aiming for and blood level, it's usually a second dose of 156 or 234, and then you simply continue every month after that. One of the limitations of in Vegas, Estenna, is that the 234 milligrams every month is roughly equivalent

to somewhere between four and a half. and five and a half milligrams of oral respiradone a day. So if you have somebody who has required more respiradone than that, you may have difficulty using the in Vegas Estenna because you can't within its recommended dose range achieve a higher level, if you will. You could simply increase the number of doses, but that gets, because it's still proprietary,

gets prohibitively expensive in some settings and insurance companies and so forth may bulk. To give you a cost comparison, halaparidal decanoid and flu-finazine decanowate are less than $500 a year. At its max dose, the wholesale acquisition cost for in Vegas is sent as about $25,000 a year. Whoa. There is also a subcutaneous, while there are two preparations of risperidone. Now, the paliparidone is simply the metabolite, the active metabolite of resperidone, and essentially is equivalent. I think of them as being essentially the same drug. There are two long-acting formulations of risperidone. There's a risperidone consta, which is in every two-week medication. You don't have to load it. You just start giving it. You do have to.

to continue oral crossover for three weeks because it doesn't start dissolving until you're out three weeks. And there is also proseris, which is a subcutaneous formulation of resperidone. It comes in a, I believe, in 90 and 120 milligram dose, which is equivalent to roughly 3 milligrams to 4 milligrams of oral Rospheridone-a-day does not require an oral crossover. And then you have the aeropipiprosols, of which there are two. There's aeropiprizole, monohydrate, maintaina. If you read the package, insert, what it says is given an initial injection of 300 or 400 milligrams, and then continue half the oral dose for two weeks. In a lot of countries outside the U.S., they've replaced that with you simply give a second injection after one week and then continue with maintenance treatment.

The company that manufactures Arapypiprizolyroxyl, Aristotta is the trade name. They have made Araprizole initio, which is essentially a more rapid released version of Arapypiprozo. So you give an initial dose of that and then start the maintenance medication. I believe a week later so you don't have an oral crossover with it either. The Olanzapine RELPrev also does not require an oral crossover. So it varies by drug as to the kinetics.

And in many ways, that's the secret to using these drugs well is to become familiar with the kinetics of each drug that you're considering using? Yeah, I was looking at the Invega Sistena and how, you know, like, imagine someone's hospitalized. So ideally they're given two doses of either Risperidol or Palo-parodone to kind of make sure that they're not going to have an allergic or hypersensitive response. And then on day three, they're given an injection of the palo-parodone. And then you can give the second dose on day three through 11.

Yes. So you don't have to wait a full seven days, so they don't have to be hospitalized, a full seven, or seven days after the injection, which should be nine days if they were starting. Yeah, no, you don't have to wait that long. I think most, in most settings, people think of a week simply because it's in the middle of that range.

And then they start in the shoulder with that one, the first two doses, because gluteal absorption is 28% less. And so you start in the shoulder and then you can move to the gluteal region after the first two doses if you want. Yeah, yeah. Although a lot of people are perfect, with once a month injection, they're perfectly happy with deltoid and, injection simply alternating sides. Because typically these medications do not cause a lot of problem with local reaction.

Like any injection, they will cause some degree of soreness in the deltoid muscle for a day or two. But there's not a large reaction to these. The older drugs, the haloperidol decanowate and the flufenazine decanivate, are more prone to cause a reaction if the person is sensitive to the vehicle, to the sesame oil. You'll find that out quickly, though, because the area becomes red and tender. Fortunately, allergy to sesame oil is relatively rare. Yeah. Yeah.

And, you know, I'm wondering kind of selection of Abilify apriiprizole. I've sent a couple of patients into the psychiatric hospital, and that seems to be what they put them on. Any thoughts on why they might choose that one over other ones? In part, it's been a marketing issue. The companies have been quite willing to give discounts on contracts. They've also done a good job of marketing the drugs. And I think for many patients in the community, aeropipyprazol is desirable also, because it tends to to have a fairly mild or modest side effect profile.

Like all medications, some people will develop acetheia. A few people will develop weight gain, but Araprizole is not horrendously provocative of side effects. In our own use of the drug, the partial agonists of which Arapyprizole is one appear to be very useful in treating people who have a predominance of negative and cognitive symptoms. They don't seem to do as well in people who have a predominance of positive symptoms, hallucinations, prominent delusions, psychomotor agitation.

Yeah. Less metabolic issues, less sedation, orthostasis, no risk of hyper-prolactinemia. No, in fact, aeropropysoil has actually been reported in the endocrine literature to have successfully treated a prolactanoma that has suppressed the drive toward hyperplasia to the point that the tumor shriveled up and went away. Yeah, I was looking at this 2020 study called a comparative effect. of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of

metabolic dysregulation and association, psychopathology, a systemic review and network meta-analysis. They looked at 100 randomized trials, 25,000 patients, and I'll put this in the notes and on psychiatrypodcast.com, but it's pretty amazing some of these graphs on how much you'll get weight change with the different ones, glucose change. Obviously things like olanzapine, clozapine, quitopine are some of the worst. Yes. Go ahead. The peens as a group, with the exception of acinopene, are very provocative of metabolic

syndrome. Araprizole, not as bad. Interestingly, the one that kind of won was Ziprazadone, was ricedone, was right, there with haloperidol. Suprazida not being something I often prescribe, but I'm trying it on a couple more patients who are very concerned about weight loss. Yes.

The limitation was a couple of limitations. It has. Of course, it's not available. It's a long-acting injectable. It's a very difficult drug for the GI tract to absorb. The person has to take it

proximate, meaning usually within 30 minutes of a 500 kilocalorie meal. Otherwise, the absorption is 50% of what it would be or less, which means it can be difficult to get enough of the drug into the person to be effective. It also, if you look at other meta-analyses like, I believe Luch did a comparison for efficacy of 32 antipsychotics. Resperidone, not resperidone, zeprazadone, tends to wind up at or near the bottom in terms of efficacy. Yeah, that's sad for all my patients that want to lose weight.

I'm hoping it. And I'll send you a copy of that luched article, as well as the article about the prolactinoma. Yeah, that'll be great. Yeah, the weight gain is just, it's like, it's like once you get a patient out of mania or out of psychosis it's like what do they care about they care about their weight they care about you know their metabolic health yeah one of the things we've been doing is we're actually developing a protocol related to uh metabolic syndrome and weight

gain because frankly psychiatrists that we star psychiatrists have not been nearly aggressive enough in terms of intervening to prevent metabolic syndrome or to treat it once it's present. Basically, our triggers for saying that somebody should be treated are a family history of obesity, a personal history of obesity, weight gain of 5% in the first month of antipsychotic treatment, 7.5% in the first two months or 10% in the first six months, or an increase. or an increase in BMI of one. All of that is enough to trigger a need to treat to prevent metabolic syndrome. Our most common preventive agent is metformin.

This is a drug that increases insulin sensitivity, not very prone to cause hypoglycemia, but does a very nice job of preventing antipsychotic associated weight gain and glucose intolerance. Now, if somebody has already gained weight and they're already glucose intolerance, frankly, the metformin ceases to be very effective. A new class of medication that we're encouraging people to use in that circumstance where it's not appropriate to switch the person's antipsychotic are the glucose. Gagon-Lip-like peptide 1, GLP 1 agonists.

The best studied in psychiatry so far has been lyraglutide. There are seven of them available on the U.S. market. Six of them are injections. One of them is available in an oral formulation. But basically, they not only in most studies, about two-thirds of people achieve a normal glucose tolerance, which is amazing. And the people also tend to lose about 10 to 30% of their baseline body weight. Those were in follow-up studies over of either one or two years. So I think

these are going to become a very popular medication and psychiatry because the metformin, while it's good at preventing metabolic syndrome, it's not very good at reversing it. Yeah, I did an episode with a, let's see, an endocrinologist who does weight management on, and we largely went over the GLP ones. And I became really, really interested in them sometime around January this year. When I saw this study on a 20% weight loss in a year, I was like, oh my gosh, can that, like, there's nothing out there that causes a 20% weight loss except for, like, maybe a surgery. Yes. So this is like really phenomenal to me.

20% weight loss. It's just unbelievable. I think we're going to see a lot more use of them. There are, like with all medication classes, there are a couple of caveats with them. They cause in animal studies increased hyperplasia of thyroid C cells, which would translate in human beings into a risk for medullary thyroid cancer.

So far, that hasn't actually been demonstrated in human beings. It has in animal studies, mostly mice and rats. It also does cause... Yeah, I haven't seen any of that in human studies. Time will tell. These have been used for over a decade, like some of the older ones. Yes. Yeah, they were introduced in 2002.

Yeah, I haven't seen that. I mean, nausea, gurd, vomiting, largely because the stomach, it delays gastric emptying, the stomach feels very full. And so I've given a number of patients these meds, and if they don't decrease the amount that they eat, especially at night, they end up waking up, wretching, or just feeling awful in the middle of the night. So you have to eat less because you're just not emptying.

Yeah, you have to warn them that they have to not eat as large a volume. Because most of these medications also are titrated from a lower dose to a higher dose, the nausea and GI side effects tend to mitigate over time. The other risk is rare pancreatitis and a theoretical possibility of pancreatic carcinoma, although that's again based on hyperplasia in animals, has not been seen in human beings. For the pancreatic issue, I mean, I've heard, and I would be curious if you've heard differently, but if you're not treating someone with diabetes, it's not impacting their pancreas that much. If it's preventative, it's weight loss.

Yeah, if the person has not developed type 2 diabetes malatis, their risk is much lower than somebody who has developed type 2 diabetes. The other listed contraindication is people with a family history of endocrine neoplasia syndrome type 2, which is a very rare genetic predisposition toward endocrine cancers. I think most psychiatrists are not likely to run across very many patients who have that history. A small pro tip if you do end up having a patient on one of these meds is to have them drink water because their drive to drink water will decrease just like their drive for food because it does. go into the brain. And the other pro tip I would say, and I want to hear your thoughts on these as well,

is this may be expensive because right now I'm having a hard time getting anyone on these who doesn't already have diabetes or some of them pre-diabetes. I can slip them through some insurances, but mostly they have to have diabetes already. So I'm wondering for patients who were just thinking about antipsychotic prevention, like if it's really even an operative for those people unless they're willing to pay a lot of money. It can be. Of course, pharmacies vary their pricing for retail of any drug. The wholesale acquisition cost for these drugs ranges from about $400 a month to about $1,000 a month.

I've been sending semi-glutide OZEmpic to Canada for like the 4 milligram semi-glutide. it's around $300 to $400. And the patient may be able to use that over the course of several months. So, you know, although it's labeled one milligram per injection, you know, realistically, you're not going to get to one milligram for quite a long time. And so 0.25 milligrams, which is around 18 clicks, you can cruise around that amount, for several months and get good weight loss at that level before you go up. So I would say pro tip number two or three is that you want to start lower and go slow

and kind of follow the weight and try to get them in a place where they're not having as many side effects early on because otherwise they'll just stop it. Yes. and the starting well as is often the case in medicine starting slow and going slow is a way to avoid side effects with these medications as with many other classes of medication it also gives you the opportunity to see what is optimal for the person there have been a few case reports where people went to higher doses and frankly excessive weight loss became a problem because for some individuals if they take too much of these drugs they have virtually

no drive toward either drinking water or eating food i think the quote that i heard one woman uh on the news she was saying well once she got up to a milligram a day of semi-glutide she would have a half glass of water in the morning and had no interest in food or water after that that. Yeah. I would also say that it seems to reduce alcohol cravings, and it's helped a couple of my patients, this is off-label, of course, with binge drinking. Like, I had a patient who would drink two bottles of wine, and once I got her on this, she was unable to drink half a bottle of wine. Yes. And so I'm really hoping, if you're listening to this and you're a researcher and you want a fun project, look at binge drinking or just drinking in general and how this impacts that.

It makes sense some of the downstream effects of stimulating the GOP-1 receptor includes a number of endocrine effects in the hypothalamic feeding center, which of course is linked to the nucleus accumbens, the human reward pathway, which is why food. and water and perhaps alcohol become a less rewarding and therefore less craved experience. I think the other issue we're having with this along with some other meds is just because of its very quick rise in popularity, it's hard. Some pharmacies are completely out. Yeah, there are shortages. As you may be aware, it's also become a vastly popular.

drug in the show business community in Hollywood. Because, of course, weight loss is always a consideration in that group. Yep, even Elon Musk has tweeted out something that inferred he was on it. Yes. It's kind of like, okay, you got Elon Musk, you got like this like, I think one of the Kardashians tweeted she was on it or something like that. Yes, we are, as a society, we are somewhat prone to. to medication fads. This could be it.

This is the medication fad of our time right now. Yes. I did want to touch on one other issue with long-acting injectable antipsychotics per se. There are also excellent studies out there, and I'll send a review of them, that have found that the LAIs are indeed safe in pregnancy. Sometimes people get nervous about giving an LAI during pregnancy and inappropriately stop it because, of course, during pregnancy, women with a psychotic disorder are more prone to relapse. So the last thing on earth you want to do is take away what is essentially their best antipsychotic treatment if it has worked for them and make them more likely to become psychotic during their pregnancy. Yeah, I would say, okay, another pearl. let's say someone is on a strong 2D6 inhibitor, how would that impact risperidol versus paliperidone?

In the case of risperidone, a resperidone is essentially the parent compound of 9 hydroxy respiradone, which is paliparidone. It will increase the risperidone more than the 9hydroxy Resperone. The Resperadone, when people take Resperadone, either in L-A-I or orally, Resperadone has a fairly short half-life so that roughly 80% of what is floating around in the bloodstream when somebody takes Resperadone is actually paloperidone, because most of it's converted. If you start with palaparadone, 2D6 inhibition has very little effect because by and large, paliparidone requires only conjugation, phase two liver metabolism. Yeah, so less of an, you're going to have more respiradone on a 2D6 inhibitor.

You're going to have a higher dose, possibly more side effects. Yeah, you may have to reduce the dose of respiradone, whereas it would be very unlikely that you'll need to adjust the dose of. of paloparidone. Yeah. Okay, let me see if there's any other big things jumping out. Oh, okay, yeah, I wanted to touch base on the aceshesia. What would you do if someone came in with restlessness who was on like, let's say, Abilify or Risperdal injection? For them, one, I would measure a plasma concentration to see if perhaps their plasma concentration is higher than is desiratory.

If so, dose reduction is always a good step to help mitigate the acathesia. Currently beyond that, provided they are not bipolar, the next best treatment for acetheia is mertazepine, 15 milligrams at night. in a head-to-head study with propranol and placebo, over five days, the mertazepine produced a response in a little over 42% of patients, the propranol, about 30%, and placebo about 7%. But indeed, I would start with measuring the plasma concentration of the drug to see if it is too high. So for acesia, first potential dose reduction, second, mertazapine, maybe third propanol or clonopin?

Where would clonipin kind of fit into this? Clonamine. Clonopin is kind of held until the dose reduction, the metazapine, the propranol fail, are not effective. Clonopin will also often be the preferred drug if somebody has unfortunately developed tardive acetheia, which usually means acetheia that has been consistently present for more than a month. Usually it's more like six months, and which fails to respond to either a reduction in medication or any other treatment. Unfortunately, like tardive dyskinesia, it's a more resistant, syndrome more likely to respond to the benzodiazepine, except for tardive syndromes and catatonia, frankly, I tried to avoid routine use of benzodiazepines because especially in the schizophrenic

population, they increased mortality significantly. The same group that did the study we referred to earlier about decreasing mortality with the LAIs found that benzodiazepine treatment had a hazard ratio for increasing all-caused mortality

in people with schizophrenia was almost hazard ratio was I think 3.93, almost 4, which is a huge increase in mortality risk. Yeah. And indeed the

the increased rate of suicide hazard ratio of 1.91, also not an insignificant increase in risk to the patient. So my listeners are always wondering how you pull these things out of your head. I read a lot and it sticks in there somewhere. Someone was like, Dr. Feuder, how do you do so much? How do you like have a full practice, run the podcast, have kids, a family? and I'm like, I think you'd be more impressed on how I'm able to keep up on my TV show series. I think that would be more impressive to you.

Okay, so let's go with like any closing thoughts to kind of wrap up our time here on this. Probably my closing remark would be that, you know, frankly, in the United States, we vastly under-trial. treat the seriously, mentally ill. One tool we need to be using a lot more of in this population are long-acting injectable antipsychotics to try to break that cycle of hospitalization, discharge, decompensation, and eventually becoming either homeless and on the street

or cycling through the jail system. Yeah. I would say my closing, remark is, you know, there are these 20-year-olds who have had a psychotic event who are living at home who are stuck. Their parents are having a really hard time getting them treatment. Once in a while, they're able to get them hospitalized because they're so, you know, psychotically disregulated that they finally just call the police. But a lot of times they're just living in their room without any treatment for a long time because the family just doesn't know what to do to help them.

And somehow in psychiatry, we need to bridge the gap to help these people and to educate the families. And I hope this episode can also be an education tool for your patients to educate them on just how helpful these actually are. These medications can make a huge difference, huge difference to get them on a stable dose of an antipsychotic out of the hospital, out of relapse. And that's really the goal, right? If you have a patient with schizophrenia, we do not want them to relapse because every time they relapse, their brain is like slightly a little bit more difficult to treat. There's more damage. And so the faster we can get them out of psychosis, the better, the faster, you know, the longer they're in the psychosis, the worse.

And Dr. Cummys, what do you think about, like, just the importance of getting someone on a stable dose of an antipsychotic, getting them out of psychosis? It's very important, especially early in the psychotic illness. The biggest predictor of relapse is non-adherence. people who have multiple relapses during the first five years of schizophrenia on average

lose about 2% of their brain mass per year that's a devastating loss of brain basically the long-acting injectable antipsychotic stand a much better chance of keeping the person stable

out of relapse and thereby avoiding, as you said, brain damage. Yeah. And we're going to be, we are working on an episode with a, I think a resident, on what happens to patients when they're not treated for decades, right? And we're looking at some historical, we'll be looking at some historical papers, looking at how Catatonia is kind of that final common pathway. And having worked

in Haiti a little bit, you see these patients who have chronically had schizophrenia that are untreated. And, well, I mean, we see that as well in the homeless population of the U.S. Yes, yes. And, you know, there's a very large proportion of homeless people who have severe psychotic illness.

And, you know, with true psychotic illness comes very low, insight into the psychotic illness. And it just makes it so hard to build the alliance to actually treat them. And so that this is like, it's like one thing to know about antipsychotics and injectable antipsychotics. It's another thing to be able to build the trust where they would actually allow you to put the injection in them. Well, on a broader issue, frankly, as a society, we have not made the commitment to care for our seriously, mentally ill. We frankly do not do nearly as good a job as a lot of other societies do in terms of there being support, supervised housing, treatment provided in that housing.

and I'm thinking of models that follow that plan, for example, in Italy, Austria, where people, if they're acutely hospitalized, they're not discharged to the street, they're discharged to a supervised apartment where they can live for up to a decade while they continue to receive treatment via house calls and ongoing care and social services, whereas we discharge people to the state. street, L.A. County, which I'm next to, has a homeless population of 69,000. The mayor of Los Angeles declared an emergency just last week over the homelessness issue. Not everyone who is homeless is mentally ill, but they account for somewhere between estimated 50 to 60 percent of the chronically homeless. Yep. Unfortunately, you know, when I looked at like every single predictor of worse mental health can be found in the homeless population. Going through the foster care system, like homelessness doesn't often start when people are homeless. It like starts like they've never had a home often.

You know, these kids are often going through the foster care system, having abuse, having trauma. it's not just schizophrenia, it's schizophrenia plus chronic trauma, plus attachment issues, plus, you know, et cetera. So it's very, very difficult population. Yeah. One movement that's out there now is, you know, in most places it's called something like Housing First, because a lot of people have discovered that all of the other social programs are ineffective if the person does not have. have a stable shelter. So there was this one guy I knew who was being given housing from some friends of mine.

They had been paying for his housing and then the friends could no longer pay for it. And he became homeless. And I would see him every week, you know, just around town. And he got so much worse within the first six months. And it was just very sad, very tragic. but it just made me realize like the chronic stress of not having a home, not having a safe place to sleep is like almost intersurmountable with medications. This is a guy who would go to the VA.

He would get meds there. It wasn't a med issue. It was the chronic stress of being homeless is very significant. Yes. Well, you know, sleeping out where it's cold, wet, miserable or hot, having unstable food supply. None of that is good for anyone's mental health, and certainly not if you're also struggling with

a severe mental disorder like schizophrenia or bipolar mood disorder. Yep. So, very good. Well, hopefully we inspire the next generation of mental health professionals to learn about this kind of stuff and see what they can do to help it. It's not something that is going to be helped right away. It needs brain power to think through all of the pieces

and put all the pieces together. Yes. And if someone is listening to this from Austria or Italy, who is a part of those very complex systems that are working, shoot me an email. I'd love to hear from you. And, yeah, we'll leave it there for today. Okay.

And I will send you articles later today. Okay. I will put in the summary all of the cited articles that we talked about for those who are curious and wanting to dig in more. And, yeah, I think this is an important topic to go through. So thank you for coming on. Okay. Great.