Psychiatry & Psychotherapy Podcast - Using Antipsychotic Plasma Levels-Therapeutic Threshold

Episode Date: October 5, 2021

On this episode, we are joined by psychiatrist, psychopharmacologist, and author, Dr. Jonathan Meyer, to talk about using antipsychotic plasma levels to assess treatment response, safety, and oral medication adherence. He is a clinical professor of psychiatry at the University of California, San Diego. He recently published a book with Dr. Stephen Stahl for clinicians to utilize called, The Clinical Use of Antipsychotic Plasma Levels: Stahl's Handbooks. 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, I wanted to take a moment before we start the episode to introduce my guest. Jonathan Meyer. He is an assistant clinical professor of psychiatry at the University of California San Diego and a psychopharmacology consultant at the world's largest forensic psychiatric hospital,

the California Department of State Hospitals. Dr. Meyer is a graduate of Stanford University and Harvard Medical School and finished his adult psychiatric residency at Los Angeles County USC Medical Center. at the LA County USC, he subsequently completed his fellowship in consult and liaison psychiatry and psychopharmacology research. In addition to teaching duties at UC San Diego, Dr. Myers has performed extensive research on the metabolic effects of antipsychotics and the impact of antipsychotic medication on glucose, insulin, homeostasis. Dr. Myers has published numerous articles and book chapters on various aspects of antipsychotic pharmacology,

including the pharmaconetics of oral and injection antipsychotics, metabolic effects of atypical antipsychotics, as well as healthcare outcomes in patients with severe mental illness. Dr. Myers is a national speaker on the subject of side effects and metabolic issues surrounding antipsychotic therapy. He is the chief editor of medical illness and schizophrenia, now in its second edition, and is the sole author of a chapter in Goodman and Gilman.

You may remember that for medical school on the pharmacotherapy of psychosis and mania. Dr. Myers on this episode will dive into a new book that he wrote on the clinical use of antipsychotic plasma levels. This is something that he co-wrote with Dr. Steven Stahl. And I think that you will gain a lot of clinical pearls on how to treat very complex and treatment-resistant skin. schizophrenia and also just good management of patients with psychosis. So welcome Dr. Meyer to my podcast. Of note, I have to report the Conflicts of Interest because we do CME for these episodes. Dr. Myers reports having advising fees in the past 12 months with Acadia pharmaceuticals, alkymes, intra-cellular therapies, crannua and neurocrin and sonovan pharmaceuticals.

Based on our assessment, Dr. Myers did not unduly mention or promote the associated medications associated with those companies. And myself and Joshua Salzman, who wrote up this summary, have no conflicts of interest to report. The summary is on my website, Psychiatryp. podcast.com in the research library. In that summary, we will put the table, the updated table, on the minimum response for the different antipsychotic medications and the point of futility. So you could take a quick look at that and a summary of the episode. If you want to find

further information on this, you can check out his new book. All right, now let's welcome our guest. Welcome back to the podcast. I am joined today with Dr. Jonathan Meyer. He is a psychiatrist, a professor at UCSD in beautiful San Diego. And in his background here, I see some camel cigarettes and a bike. And we are going to do an... The camel cigarettes is a poster. That'll be interesting. You have to tell me about that. and we are going to do an episode regarding a recent book that he has published, which you can get through the publisher. I will put a link in the show notes and on my website. It is on antipsychotic blood levels and why we should be measuring blood levels of antipsychotics. And we have talked about that several times with Dr. Cummings. And you will probably remember that Dr. Cummings is a fan of that. and this is just a deep dive in this. This is just going to be really nice because this is a topic I'm passionate about

and passionate about treatment resistant schizophrenia, which I can't see not measuring plasma levels if you're having difficult to treat schizophrenia clients. Dr. Myers, I think from what I've heard from Dr. Cummings is probably one of the top 10 psychopharmacologists in the world, or at least the ones that I know their names of. So it's a pleasure to have you on. Thanks for coming. Thanks so much, and it's a pleasure to talk to your broader audience about what may seem like a niche topic, but I think it really falls under the large umbrella of measurement-based

care. That it's really no longer acceptable just to assume anything when you prescribe medications, and part of it has to do with the fact that occasionally when we prescribe oral medications, People don't actually take them as prescribed. I know it's shocking, shocking to hear that, that my patient might not be taking her medications, but it's been known to happen. And also, there's just large variations in drug metabolism. And as we'll get into it, it's just one of many reasons why measuring levels can be really helpful when you're dealing with people who have severe mental illness. Nice.

So tell me what's behind the posters. People are going to be curious. So I made that comment. I've had a long-standing interest in schizophrenia, and one of the comorbidities in schizophrenia is smoking. And I actually used to do research in schizophrenia. One of the NIH grants I put in, although this one wasn't funded, was looking at smoking and smoking cessation. And because of that large comorbidity, I just sort of developed an interest in that. So I collected some of these old tin signs on camel cigarettes.

There's nothing else behind that, really. But just that overlap between schizophrenia and really substance use of all types, but the most common one, of course, is cigarette smoking. Yeah, it seems like there's just an increased drive to smoke and the patient's taking antipsychotics. Is it taking the antipsychotics or is it having schizophrenia that increases the drive to smoking? We would think generally it relates to the mental illness itself. Nicotine being one of those substances, which is readily available, if I want to stimulate, my nucleus accumbens, my reward pathway. There's lots of substances available, but nicotine is one,

which is generally socially acceptable as opposed to methamphetamine. It's also legal and relatively inexpensive, although in California not so much so anymore. And I think that's a big part of it. There's a lot of research also into any transient effects that nicotinic agonism may have on cognition. Whatever effects they do have are relatively transient. If that's the case, case than every schizophrenia patient who smoke would be a whole lot smarter, and it doesn't seem to improve them a lot. So I think that's really probably the major biological drive is just we feel like a lot of these people have deficits in the reward pathway, and they're looking for ways to stimulate it. It could be food. It could be substances, and whichever substance they choose

often has to do with availability and just personal preference. Yeah. Okay. So, okay, the case for therapeutic drug monitoring, give me the basic case to my audience and maybe some of the things that you hear as like the counter arguments and then what would be your counters to those counters? Sure. So there's one basic case and it's when people are not getting better, especially on a dose where you think they should have some type of response. Even if you're wondering, why is this person not getting better?

and she has no adverse effects. Well, if it's an oral medication, it could be there's simply not taking it. It's very common. Non-adherence, no matter how you identify it, it's roughly around 50% in any chronic illness. So if you go to the hypertension clinic, non-adherence with oral therapy is 50%,

the same is true for schizophrenia. One reason people don't get better, they don't take their meds. How would you know? You have to measure it. There could also be kinetic reasons. People metabolize medications differently. maybe your patient is very adherent with her medication, but biologically, she just choose it up,

and she's not getting the expected level. So that's one basic reason. People actually did a pharmacoeconomic analysis. There's a psychiatrist up in Boston. Her name is Marcella Horvitz-Lennon. She's in community practice, but she also does some work for Rand Corporation, and she did an economic analysis. And given the fact that people don't take their medicines, and that's a big cause of relapse, she found that obtaining plasma antipsychotic levels could save a large health care system, like maybe the VA, $1,560 per patient per year. So there's a cost associated with getting levels, but the system recoups that several times over. And as we found, people don't take medicines, and sometimes it's wrongly assumed that they must be treatment resistant,

and that we stood different types of decisions. So before assuming anything, in general, we would say, well, we're not measure it. And I think it's the same logic if you had a bipolar one patient who wasn't getting better on lithium. First question is, are they taking it? And then the second question is, if they are taking it, how much is in their system? So that's one basic argument. The second basic argument is even when you get somebody who is stabilized, adherence with oral therapy is dynamic. It is not static.

And what does that mean? I may have a patient who's been taking his respiradone orally for the last decade and everything seems fine, as far as we can tell, but perhaps something changes in his life for whatever reason, and he now no longer takes it. Well, we know this to be true, and it's important on an ongoing basis to periodically check levels for oral therapy, just to see if people are sticking with the program. There is a reason we do this every six month for patients on lithium and valproa. Sometimes there's a safety issue.

Want to make sure it stays within the therapeutic range. But also just the basic question is, has my patient been taking her lithium or depicode recently? And if not, then we can have a discussion about what to do about the adherence issues. And acknowledging, again, that non-adherent to the oral therapy is common. And it's important to normalize that when you talk to patients. If you see the level was low and you think you have an understanding of why because it used to be much higher in the past, then you can just say, look, I know people sometimes miss medicines. It's very common. What is going on?

How can I help you? And then you can open the discussion in a non-judgmental way. One of the big downsides, of course, is many people just don't know how to interpret the levels. It's one reason why I wrote the book. A common question we will get in a state hospital is, I have this patient on some whopping dose of olanthapine. He's not getting better. And the first question we always ask, being somewhat naive and stupid, is, I don't know he's taking it. I know. We're troublemakers that way. The doctor comes back and says, okay, I'm going to order a level and this person's on 40 milligrams QHS of olantapine.

What level do I expect? It's an important question. A good rule of thumb when you're practicing medicine is that if you're going to order a test, you should know how to interpret it. I'm just suggesting it. And one reason I put that information in the book is people would say, okay, I'm going to get a level in this lady on six of Risperidone. What level should I expect? I have a whole section in there just about what are the correlations between oral doses and 12-hour trough plasma level? And that's sort of the standard. We usually try to give antipsychotics at night because they're much better tolerated. It's best not to split them up because you can incur more tolerability problems as people have higher persistent trough levels throughout the day. And we usually get levels as a 12-hour trough.

And that's just by convention. We just figured out this was the easiest and most convenient way to do levels. So you don't get the levels back right away, though. And that is, I think, something you were alluding to in addition to the expense. Is that right? Well, to sort of go into one of the details in your book that you talk about, with what you were saying that once a day dosing is so important. You talk about Latuta at 40 milligrams,

had 2.3% aceshesia when given at night with a meal, where it was 7.1% when it was given in the morning. That was pretty interesting to me, that little piece. It's something we had, I think, known clinically, but we did not have the data to back it up. And for those of you who are interested, to download the PDF of the Latuta package insert, go to the table on what we call extra-paraminal side effects.

It's a terrible term, but that's what we use. It's kind of outdated. An even better example in that same table is that 120, which was given in the morning and most studies, had an ekeithosure rate of 22%. And they have a study with 160, which they gave with an evening meal. Now you're thinking, my God, they had a 22% acathia rate on 120. Who could tolerate 160? The rate of acethesia on 160 with an evening meal was 7%.

Wow. Two-thirds lower, even though you're taking 33% higher of a dose. So I really do want to drive home the point that antipsychotics in your brain generally have, for the most part, biological durations of action which exceed 24 hours. There is really no good reason to dose these agents multiple times per day with rare exceptions. Closopin sometimes if you give too much at night as a single dose, people have trouble tolerating it, so maybe you'll have to split it up a little bit, but try to minimize the morning dose as much as possible, mostly for sedation.

Zeprazadone was always studied as a B-I-D drug. You can't give it once a day. There's a once-a-day study out there. Most people just don't know how to prescribe it that way. I would say if you're going to prescribe zeprazadone for its metabolic profile, I'd just go to Lurazodone because at least people only have to get it right once a day and they can take it with an evening meal. But that's a concept that many folks don't understand.

and I think, oh, this person's really sick, I'll give their halaparadol four times a day. You're not maximizing efficacy that way. You're just maximizing adverse effects. Yeah, one of the, and I want to mention another thing you mentioned in the book is that most psychiatrists base their optimum dose on past experience with similar patients, not drug levels. And in one study of 99 patients with schizophrenia, it showed that 35% had sub-therapeutic plasma antipsychotic levels. And so we may think that we're in the right range, but we don't really know until we check. You really don't know. And that one study you cite, I think, is so important because those 99 people were going to be placed on chlozapine. The clinicians thought, oh, these folks are non-responders.

It turns out a big chunk of them, a third had subtherapeutic levels. And among that 35%, a third of those had zero, zero level whatsoever. However, we often mislead ourselves because as we become more seasoned clinicians, we think, oh, I have good rapport. My patient must be taking their medications. It has nothing to do with it, nothing to do with it. You have to measure. I don't want to say trust no one.

It's just the nature of chronic illnesses. Don't take it personally. It's just business. It's a chronic illness. People have trouble with adherence. They have a cognitive disorder. And even if they're taking it, maybe they have a variation in drug metabolism, which will just render it.

them sub-therapeutic levels for any dose. So some people are going to say, well, why not just check the P450 genetic profile of your patient? So what's your argument for why that would not be the best choice and drug levels would be a better choice? For one thing, the genetics panels that are done by the commercial companies were often fixed based on polymorphisms identified more than a decade ago. And while they may have been cutting edge and up to date a decade ago, they haven't been updated.

And we're continuing to identify new alleles within the genes of these P450 enzymes, which cause functional differences. So the report might say, oh, your patient is an extensive metabolizer 2D6. It can, in fact, be wrong. And so that's why, rather than getting information which is wrong, what I'm interested mostly in is the net result. Also, people can have multiple polymorphisms, and sometimes they're also taking medications which may alter drug metabolism. It can be a very complicated situation for an individual person. As long as everything remains fixed, the levels will give you the net result.

If you said, well, this person's an ultraab metabolizer 3A4, but they smoke and there are poor metabolizer at 2D6, what's the clozepine level? I have no idea, and that's why I say, don't sweat it, just go ahead and measure the level because I can interpret that directly, whereas the P450 info, even if it's correct, which I think it's actually mostly not anymore for the commercial panels, you're still going to have to infer from that what the level should be. And I think it can be very difficult sometimes to make that inference. Yeah, I think my other critique on those genetic panels is like some medications that are antidepressants, they'll give a definitive like this isn't the best medication, whereas this medication might have

so many P450s that are breaking it down that the P450s might not matter that much, you know, on blood level. I don't know if you've thought about that yourself. Yeah, I mean, medicine like Lozapine is very complicated. It goes through a number of P450s. We think 1A2 is one of the big contributors, but not always. And I think the way they present the information that genetic panels is, I'm going to say a tad misleading.

Let's say you have a drug which goes through 2D6, like Arapyproprozole. and the person's a poor metabolizer. So they'll give you like a big red X or a stop sign or a color code saying this may not be the best medicine. There's nothing wrong with that. All you have to do is just adjust the dose. You know, it's not like it's poison. We know if you're 2D6 poor metabolizer, your Aripepazol exposure will be about doubled. It doesn't mean you can't give it to them.

You just cut the dose in half. And that type of information is what clinicians need, not some overly simplistic system, which says don't use it. I think there's fine to use it. You just have to make the appropriate corrections. Yeah. Yeah. Okay. So let's talk about pet scans.

Pet and spec scans have given us some information about D2 and how much occupancy is going on. And I think this is a good discussion on, like, how you kind of think about blood levels or how you think about effectiveness. Like, what is the correct sort of D2 blockade? Obviously, we're not going to run a pet or a spec scan. on N-check D2 levels. But tell me a little bit about the history there, and then what you've learned about that and how that's useful to understanding this.

So I'm going to confine this discussion, just for the sake of the audience, to those antipsychotics, which work as D2 antagonists, and that's their primary mechanism of action. So in this sense, at least for now, I'm going to set aside Closepine, which, as most of you know,

is a very weak D2 antagonist, and whatever its magic properties are has nothing to do with D2 blockade. I'm also going to set aside the partial agonist antipsychotics, which work at the D2 receptor, but the levels of occupancy are different. And those three agents are Araprizole, which is Abilify, Brexeprizole, which is Rixalti, and chryprazine, which is Ralear. We're going to talk about those, perhaps next. Let's take all the other antipsychotics, Rospiridone, Atlantipine, first generation, whatever. what we've learned over time is that efficacy seems to correlate with having a D2 occupancy in the striatum

of around 65%. That's sort of the threshold. And people debate about the number. Could it be 60%, but 65% is generally agreed upon as the threshold of D2 occupancy to get adequate response in schizophrenia if the person will respond, meaning they're not treatment resistant. As you start to get beyond 80% occupancy, you do start to incur higher rates of neurological adverse effects. It does not mean that everybody who has 85 or 90% d2 occupancy with an antagonist is going to have Parkinsonism or acathia or dystonia. In fact, there are some people out there who literally will never get those neurological adverse effects no matter how much you give them. And we'll get into that in a bit when I talk about concepts about how to use the levels, meaning the threshold

level and what I call the upper end, which is going to be the point of futility. But that information, knowing that the sweet spot for DTO occupancy for antagonists is between 65 and 80 percent, can help us provide information about the target levels, which will be supplemented by the clinical trials data. In the end, the clinical trials data gives us our best source of human information about what plasma level seems to be associated with adequate response and what point seems to be kind of the end of the road, meaning even if the person could tolerate it going beyond there, you may not get, you may only pick up perhaps another 5% of responders. So when I go through the book, I try to primarily rely on the clinical trials data, but where there is,

pet data, which is the modern way of doing D2 occupancy spec was the original way decades ago, has very poor spatial resolution and is not used for that purpose anymore. It helps us say, hmm, the clinical trials data indicates that we think for respiradone, and we'll add up the respiratoryome metabolite levels, that a level of around 21 nanograms looks to be from the clinical trials where the threshold of response is. And then we can go look at the pet occupancy, and lo and behold, it corresponds roughly to something in the mid-60s. It's helpful because it makes a nice, consistent story in terms of how we understand the mechanism of action for D2 antagonists. In some instances, the clinical trials data is not so great, and we maybe will rely a bit more on the imaging data.

In some cases, the imaging data isn't good. And then I would say the clinical trials data is always the best source of info. But it helps build a consistent story for the D2 antagonists about how those molecules work and where we think the sweet spot is for treatment. Okay. So since we're talking about spec and pet scans, are there any indications that psychiatry patients should get spec and pet scans if they can afford it? So pet scans are for research purposes only. In order to do a pet scan, you have to create with a cyclotron. a radioactive compound until oxygen 18, for example. I don't have a cyclotron in my home office. I don't think so.

And most people don't either. So those are only for research purposes. Extremely expensive to do. Speck scan in psychiatry, I think, is only reserved because the technology is so old, has such poor spatial resolution. They'll look at it for gross information on perfusion. like they may use it in looking at certain dementia syndromes and trying to get a sense of kind of where the brain is missing. You can get structural information from an MRI and that's often sufficient.

Sometimes the spec scan may supplement that and it's relatively easy to do. But there is no appropriate use for spec scan to diagnose mental disorders. I know there are people out there who sell them and they've become very wealthy on selling spec scans to the unwary and really to the unhappy. The hardest part in psychiatry is making a diagnosis. We don't have blood tests, although we wish we did. We don't have other assays to say, you're unipolar depressed as opposed to you might be bipolar depressed, and therefore I can give you an antidepressant or I can't. We wish we did. People are difficult to diagnose, and that's why sometimes patients become frustrated.

Well, this guy said I'm bipolar one with psychotic features, and this person said I had schizophrenia, and, and this person said I had schizophrenia, And this other person said, I'm schizoaffected bipolar type, and I'm not doing well, and I don't know what's going on. Well, sadly, there are opportunists who take advantage of these people and saying, I can diagnose every mental disorder using this 40-year-old technology with poor resolution. I mean, on the face of it, it doesn't even make sense. And certainly there's no published data which backs it up. The people at NIMH who have the cunning edge state-of-the-art technology cannot diagnose schizophrenia based upon a pet scan. But what happens is they prey on people's uncertainty. They want a definite answer.

Well, they'll get a definite answer, and there'll be $3,000 poorer for it. It'll be definitely wrong, but they'll get something which is definite. And it's just very sad. I will see in the form of second opinion consultations, people come with these reports. which say they have something, I'll review the clinical data and say it's wrong. And sometimes these reports will try to predict which medications they should be on also. It's just really sad. Often these were families who did not have means, who really could not afford that $3,000. It's just very, very sad that we have our colleagues who are doing these types of things.

But if you look at actually the peer review published data, there's no data to support that this is a way we should be treating people or diagnosing psychiatric disorders. Yeah, I had a patient recently who came to me who was like, I was diagnosed with a TBI from a spec scan, but I've never had a TBI, but maybe when I was really young, maybe when I was like a week or two old, I fell and hit my head. And now I know that it's because of that one incident that this happened and because I had lower frontal low function or something like that. And I was, yeah. But, you know, it's people, people love, you know, ritual. They love miracle mystery and authority, according to Dolsafsky. They want that sort of, they want that bling and shine, and it seems that way, right? And if you have $3,000, go spend it on some therapy, go spend it on a good psychiatric consult. You know, and yeah, okay.

Yeah, I would agree, take that money and try to find the best person. The hard part is many people are not very sophisticated consumers in this space. And it doesn't mean they're uneducated. It just may be they've not been in the world of mental health. So the question is, how do I find, you know, the person like Steve Stahl in my community? And that can be challenging. And maybe in some instances there isn't anybody like that. And that's the unfortunate aspect that sometimes there simply isn't a person in your community.

Sadly, I just got to call this past week and spent a lot of time on the phone with a family who is in a major city in Nevada and they're having trouble. finding somebody who's competent to continue managing their son's Closopine. They move from another state. And it's just very unfortunate that they're having this difficulty, you know, in a developed country in a major metropolitan area. Yeah. Yeah. So if you're listening to this, this is a good reason to get this book to keep kind of studying this higher level of stuff.

I actually have a lot of respect for people who spend the extra. time and energy to learn this. And I have a lot of, I have a lot of listeners who reach out and they're very, very willing to spend the time of all sorts of backgrounds. And I, I appreciate their diligence. So there will be people who listen to this and, and prescribe the right things and, you know, are more motivated to get levels and figure out what that means and become an expert on it, you know? It doesn't, it would take you one book and maybe 10 pages a day. It would take you a month or so to get through this, and you would know a ton. So there's my sale for your book. How's that? That's great. And actually, the first five chapters, I think more than anything,

give people the conceptual aspects about why to use levels and how to use them. There's some basic practical aspects, and I've already alluded to one. If you're on oral medicine, give it all at bedtime, or I guess if it's lorazodone, with an evening meal, and get it as a 12-hour trial. And get it as a 12-hour trough. So you're getting numbers which are interpretable within the world of this. If you have people on long-acting injectables, wait until just before their next injection and get the level maybe one to three days before. So it's at the lowest point in the injection cycle. So just some basic things such as that, try to get the level when people are at steady state. You know, if you say, well, I started the medicine yesterday. Should I get a level tomorrow? No. Maybe, you know, five-half

lives to steady state. So that's just some basic aspects. And one thing with the five half-lives, which I think is really important that you talk about, is think about the importance of the breakdown products of this drug when you're thinking about the five half-lifes. Can you speak to that a little bit? We recognize that metabolites may be part of the picture. It doesn't mean that the lab is going to give you those levels, but they can be very important for that particular compound. I'll give you one example. I'll give you one example is risperidone. Spiridone has been around since 1993, very useful antipsychotic. If I give you respiradone in your body, and assuming you have a liver, you will convert that

to nine hydroxy resperidone, which is also known as palperidone. So for people on oral or even long-actinjectable respiradone, in their system at steady state, it's about 20% respiradone and about 80% palaparidone. If I order respiradone level, all labs in the U.S. will actually give you both the respiradone level and its metabolite level, because the metabolite has so much of what we call the active moiety of what's going on in your system. That's one of the best examples of where the metabolite is important, and the lab gives it to you. Closopine also has an active metabolite nor Clozapine.

We think the efficacy best correlates with just the Closepine level, but we can look at that ratio to see how people are metabolizing the drug. And that can be important. A big inducer of clozapine's metabolism is actually cigarette smoke. And this is very critical. It's not the nicotine. It's the smoke. Not the nicotine. I made that mistake once. Yeah. Well, people don't know, and that's why I write about this. It's the smoke itself. You have to be burning the leaf. And I guess you can be burning other leaves, too, as you know. You can you can buy other stuff in Florida and California and burn that as well. But you've got to be burning the leaf to generate the aerohydricarbon to induce that P4501A2 enzyme. And if I'm inducing that, what will happen is I'll

metabolize Clozapine more quickly and the ratio of Closopin to its metabolite will change. The metabolite level will go up and the Cholopin level will go down. Well, why is this important? In hospitals, people can't smoke. What's the first thing they often do once they leave the hospital? they'll smoke and they'll actually smoke a cigarette, they'll burn the leaf, and that could drive their closopine levels down by 50%. If all you do is look at the level of closopine, you say, oh, this bad patient, he's not taking his closepine, we should have kept him in the hospital. He actually may be taking it, but he started smoking. If you look at the ratio, though, of closepine to nor clozapine, then you'd say, aha, I know why his level dropped.

He started smoking, and I can see that in what we call that metabolic ratio. and we're fortunate that you actually do get both of those from the lab. Some compounds have active metabolized the lab just doesn't give them to you. We think you can make adequate efficacy decisions based upon the parent compound, like Irapypiprosol, for example. One frustrating aspect, and I know you alluded to some negative things, is that if I order lithium level or depocote level, I'll get that result back, maybe the same day if they got it drawn in the morning,

certainly within 24 hours. But I don't know if you've ever ordered a Closapine level on your patients or a Halaparadol level, but it may take a week to get back, maybe two weeks, depending on how it's processed. Often, sometimes it'll sit at a local lab who will batch them and then send them off to the other lab, which will run the levels and you don't get the results back. It's not a reason to avoid getting the information, but it does mean in the short run you'll have to make decisions, the way people have been making decisions for the last 60 years. So you're seeing a lady, she has schizophrenia, she's new to you, you're starting her on a

medication for the first time. Let's say you've picked respiradone for whatever reason. Doesn't matter. You keep titrating the dose. She's now taking six, or you're prescribing six, I should say. She's not getting better, and she has no side effects. And you're wondering, well, what the heck's going on? Well, I think at that point you'd say, you know, this doesn't all add up.

I would say get a level. That's fine. So the patient goes in the morning, gets a 12-hour trough, sees you later that day. Now, you're not going to have that result back for one or two weeks. In the meantime, if she's not having adverse effects and she still has positive symptoms, the reasonable thing to do would be in the short run, give her more. You know, let's just keep going up. It's the way you have made a decision for the last 60 years on any antipsychotic.

Well, he's tolerating it and he still has a lot of positive symptoms. We'll give him more. But then you can get the level back and you can put two and two together. I can tell you if you're on resperidone and you're on six milligrams, your active moiety level should be 42. Let's say hers comes back as zero. Well, I think you'll know what's going on there. Or maybe it's extremely low.

And then you have to wonder, was she actually taking it? It could be she's an ultra-rapin metabolizer. And in that instance, I would say, ask the patient about her adherence, ask about it, non-judgmentally. My usual way of phrasing it is, many people miss doses. It's very common. How many do you think you've missed, let's say, in the last two weeks? And try to get an answer that way. The worst question to ask is, did you take your medicine? That's just a waste of error. That's just a waste of time. Who's going to say no? Oh, I'd never take it out. It's just a terrible way to ask about adherence. So normalize not adherence because it is normal. Make it non-judgmental.

I'll indicate, you know, your level is a little lower than I'd expect for that dose. And the appropriate response I usually give back to them is, how about if we just check it again? And then you'll have a sense. And I try to give you some guidance on that in the book. Even when people are adherent, you may see their trough levels fluctuate as much as 30%. It just happened. You know, it's not always exactly 12 hours. They took a little early.

They went to the lab a little late. Who knows, maybe you had to do with what they ate. You never know. you have to expect a bit of noise in the system. But if you see levels jumping by 50% or more for a given dose, then you're saying this is non-adherent. And at that point, you can have a different discussion with your patient about their difficulties with adherence.

Yeah, that's good. Let's see, jumping to some of the nuance of chlozapine. Now, you wrote a book on chlospine. I'd like to have you come back, talk about that. but when we when we look at levels you talk about 350 kind of being where the response begins 600 you can have a little bit increase 700 a little bit increase 1,000 being kind of beyond what is helpful so with that level how do you use that in your clinical practice to kind of like help yourself make clinical decisions yeah I think most people would agree that we would call

the response threshold for Closopine as 350 nanogram per ML. And what that means is just to give you a definition of response threshold, if you look at the bulk of the data, there are very few responders with plasma levels below 350. If you came to me and said, my patient's responding beautifully and her levels 200 nanogram per amount, what should I do? I'd say, nothing. She's a responder. You got very lucky. But the way to use those threshold appropriately is if the is not responding and you're below that response threshold. You need to kind of get into the ballgame. Let's get it above there. It's not a guarantee they'll respond. As you know, half the people, even on Closopin, don't respond to it, but it maximizes the chance of responding.

A good rule of thumb for oral antipsychotics is that if they will start to respond to a given dose or level, you'll see it within the first couple of weeks. Don't want to. leave people on a given dose for months on end, hoping there'll be late response. It does not happen. People have done these studies. The bulk of all antipsychotic response happens very early. What you're looking for is just a signal of response. So you say, okay, this lady's level was below 350. I bumped up her dose, now her level is 450. How long do I let her sit there? I would say, give her two or three weeks. I'm not looking for her to be cured. I'm just looking for her to say, you know, I'm seeing something better.

You're just looking for some minimal response. If you see at least minimal response within the first couple of weeks after a dose change or increase, that bodes well for them getting even further approval, further on down the road at week six and beyond. But if you see less than minimal response after a few weeks, it's probably not going to work out for that given level, and it's probably time to move along and manage their adverse effects if there's adverse effects related to it. The upper end has been a source of debate for all antipsychotics, and it wasn't often well-defined. I tried to give people an easily retainable clinical definition for the upper end. I call it the point of futility.

So already you have a sense of what I'm talking about. What that means is even if they tolerate that molecule, once you get to that certain point, and you alluded to that being a thousand nanogram per mel for close apit, even if they tolerate 1,000, which some people won't. But there's many who do. You managed all their side effects and you got them to 1,000. Your chances of converting them to a responder with significantly higher levels is less than 5%. And I tell people, you know, if you have whatever the antipsychotic is and you've reached that point of utility, it's time to find something else.

Now, for clozapine, you don't have many other choices. But certainly if they're on resperidone or lantapine or halapar at all, if you've reached that point of, utility, even if the person tolerates it, going beyond that is generally going to be a waste of time. Your chances of making that non-responder a responder are less than 5%. And the point is, I don't want to see patients suffer unnecessarily because the clinician thinks, oh, well, she's tolerating. Why don't we just give her more? Well, you could, and she'll probably tolerate that, but you're unlikely to make this person a whole lot better. Yeah. Sometimes I see people in the inpatient setting. It seems like they'll put on one antipsychotic. They don't get the

result they want, so they add a second. Oh, I can see your face. You don't like that idea. So you would probably prefer to push that one up to a better range and to keep checking the levels and then switch them from that one to a second one and then take them off the first one. Is that how you would, how you normally practice? Well, a couple of things. It depends on what agent you started with initially. As many of you probably have learned in practice, week D2, D2 antagonists like patyapine, not very effective, probably not the drug to ever start with. And there are some people who really need an antagonist and may not respond to a partial agonist like Eripeperazole.

But let's say you had somebody on a D2 antagonist. Again, I'll just use halaparodic, just an example. We think, and once the person is treatment resistant, overall, the response to antipsychotics are more alike than they are different. The idea that respiratone is dramatically more effective or different than halaparidol is not true. It may be more tolerable. It may have less neurological adverse effects. But if you're just trying to treat the positive symptoms of schizophrenia, the idea of combining

to antipsychotics really doesn't make a whole lot of sense. And I would rather people find the agent with the most overall benign adverse effect profile and then try to maximize that. The advantage of that, of course, is if the person responds, then they are on a single agent with what you thought was the most benign, adverse effect profile that would seem appropriate for their situation. If they don't respond to that, then really the question you have to ask is why? Why are they not responding?

Maybe their levels are too low if they're not taking it or they're an ultra-rapin metabolizer. you know, maybe they actually just need more. And the only way you would know is by looking at their levels. Now, the problem, of course, is you don't get the levels back right away. And in an inpatient unit, you may have to make decisions more quickly. But I would still prefer people to do serial monotherapy. You know, the one exception, of course, is chlizapine. If you get a partial response to chlizapine, you've maxed out what that person can tolerate

in terms of a plasma level, it seems not unreasonable to say, well, I may want to augment it because I've given them all they can handle. What does Closopin not do? It does a lot of special things, but it's not a strong D2 antagonist. It does make perfect pharmacological sense to say, maybe I'll add back a little bit of D2 antagonism. They may not have done really well with rsperidone or Arapyrol or haloperidol, but it gave them something. You know, it wasn't nothing. If they got nothing from it, I'd say, well, what's the point? If they got something from it, maybe you'd say, let's add it back.

Let's see if we can make that closopine just a little bit better by giving it something in a form of d2 blockade, which plosepine itself has a molecule, doesn't. But the idea is we're going to combine respiradone and olanzapine. That's just doesn't make sense at all. Yeah, I appreciate that. I've had a couple of patients where you get the closepine, they can't tolerate it for a number of reasons. And then a little bit of, like, Risperdol, a little bit of How'd All makes a huge difference and makes them be able to kind of rejoin life.

Yeah, you're just looking to just to increase the response, just a little bit more, reduce their symptoms a bit more than they achieve with the Closipede. Sometimes people tell me, well, the reason they're wrong Closapin is because I failed to Sparerdown. And I'm not stupid. I appreciate that. But my rejoinder is usually, did they get zero from the respiradone? Or was it just not sufficient? And often the case was they got something from it, but it wasn't sufficient.

And then I'd say, okay, well, let's see if that little bit they got can help out the close. Sometimes not. You know, the effect size is not huge when you look at these meta-analysis. It's 0.24. It's not zero, though. And at this point, you're sort of at the end of the algorithm anyhow, and you'll do what you can. As long as it seems reasonable and safe to try to make this person a bit better. Yeah. Do different labs report varying plasma level ranges?

Yeah, so this is a big problem, and I'm glad you brought that up. If I were a lithium level at most hospitals, it would usually give me a range, which is fairly consistent from hospital to hospital. Typically, they'll say the range for lithium starts at 0.6, and it goes up to, let's say, 1.2, something like that. you'll never have a lab which says, oh, yeah, you can go up to four. I mean, obviously lithium is not all tolerated, but you'll never see those huge variations. But one thing I've learned in studying this area is that what you get from labs for antipsychotic plasma levels is not evidence-based at all. It's really the one exception, I would say, among the world of psychotropic drug levels. Well, what you get from the lab is among the least reliable sources of information. And I have

have a little graphic in the book. I give you some level ranges for some common antipsychotic. So I have Alaparidol-Flufenazine, Alanzepine, and Closopin. Okay, those are lab. Those are lab levels, which most commercial labs will do without any big issue. Flufthensine, one person has the upper limit of the range of 2.0. The next guy, it's 10.0. 10.0. I don't even understand how they got this information. So I called them and you know what their response was? We don't know either. Like, you didn't even know how you came up with that range. Like, well, one guy, look at the literature, you know, however many years ago, and this is what we've stuck with. It's terrible. And it's unfortunate because it really is confusing to clinicians, number one. I think it can cause some

adverse events for patients. And it may deprive people of adequate drug trials. The biggest issue more than anything I have, among the issues I have, is that many of them will report an upper limit of the range for Clozapine of 600 or 700. Well, there are a number of papers which show that, if tolerated, philosophy levels up to 1,000 nanogram per ml should be explored. And that was actually fortunate last Friday. I spent an hour with a very famous pharmacist. His name is David Taylor. So he's a farm d. He's been affiliated with Modley. He is a is the one which helps publish the Maudsley guide for psychiatry. I mean, this is the guy.

Very smart guy, very nice guy. And I asked him about that, because we were talking about the Closabin Handbook, which came out two years ago, and he had some questions. And I said, David, what do you think is the upper limit? Do you agree with 1,000? He said, absolutely. I think 1,000 is very reasonable as the point of futility. The problem we see sometimes when people get labs at the state hospital is that, say, oh my

God, this patient's level is 725 and the lab says the upper limit is 600, what should I do? And we have to spend a lot of time trying to talk them off the edge of the roof. Say it's fine. There's a lot of evidence. What you're getting from the lab in this instance is not evidence-based. And we really try to educate them that the literature says otherwise. It's hard, though, because most people wouldn't sit there and argue with the lab about the serum sodium range or anything else. it's just a unique problem with plasma antipsychotic levels.

And I hope over time, by having more standardized sources of information, we'll get some more consistency among the lab reports, so we don't get into these issues where either the ranges are giving you are way too high or they're not high enough and it's just really confusing for clinicians. Yeah, one of the things that I noticed in our psychiatric hospital at Lomelinda when I was there, I think the max dose of olanzapine you can give with something like 40 or 60. whereas if you're going to a level of 200 nanograms per ML, and you're estimating that by two times the oral dose milligrams per day,

that's essentially like 100 milligrams a day that you could go up to. Any thoughts on the dosing of olanzapine and kind of maybe where it's underdosed or overdosed? Well, for one thing, you may be limited just by the system you're at about what you can prescribe. I, for many years, was affiliated with the VA here in La Jolla, which is a UCSD hospital, they would not allow you to prescribe more than 40. When I wrote this book, I looked at the literature. I think the point of futility for Lanzapine, I would argue maybe it should be 150. I think I used to think it was 200, but I'm going to lower it a little bit to 150.

I don't think it changes anything that you just said, though. If you're a non-smoker on a Lanzapine, generally your trough level is two times your oral dose, as you said. But there are some people who do metabolize things a bit more slowly, and you may see a range of levels for somebody, even on 40, where you could get levels above 100. By the time you may just be limited, you say, well, this guy's taking it. His level on 40 QHS is 80, exactly what I expect. It's exactly according to the book, his liver has read Myers' book. I would like to give it more. You just may not be able to, and that's just a reality, depending on the situation you're at.

It is what it is. Many countries outside the U.S., you're actually limited to what's called the registrational dose. I don't know if you recall. Do you know what the maximum approved dose is for Lantapine in the package insert? Is it 10? It's 20, yeah. 20.

So other countries, you actually can't go above 20. If you do, there's all sorts of liability things or whatever. We are fortunate in the U.S. that we're actually often practicing in places where they have a little bit of flexibility, but sometimes not. And you can only do what you can do. You max out what you're allowed to prescribe if they're a non-responder. Then more likely than not, your only options, if they were on a Lampedepine is you'd either hypothesize, well, I like to give this person more D2 blockade, which case I'll probably go to a high potency typical, just so I can say, I've checked that box off. I've given them as much D2 blockade as they could handle, and that didn't work out. And then

you're probably going to end up on closopine. But that's a reason to get the level, though. I mean, I think that's where it comes down to you. Just before you write off a molecule, you just like to say, look, I know what they were exposed to. So I won't erroneously assume that they were treatment resistant. Maybe they were a kinetic failure. Maybe I just couldn't get the levels up because I'm limited in what I can prescribe. Certainly if you're prescribing a newer drug, which is still on patent like Latuda, which is Lerazidone,

I may want to give somebody 320, but no one's going to approve. that dose, you know, it's just not going to happen. You know, the max approved dose for schizophrenia is 160. No one's going to approve higher doses because it becomes more expensive. It is what it is. You just have to work within the constraints of what's allowable within your system. Okay. Well, I want to clarify. So it wasn't from your book that I got the 200 level. It was from the DSH, Dr. Cummings, the group he's affiliated with Guide. Do you have any other differences between that guide because I have given that out to my audience in the past. It's in my resource library. Yeah, I was one who wrote that guide and that particular section on plasma levels. And early on,

when I look at the literature, I did peg the point of futility of a way it's being at 200. And so you can blame me. It's my fault. I did it. I confess. And what happened was as I spent more time with the literature, I lowered it a bit to 150. To be honest, when you look at the literature, they've done high-doseal antivine studies. There's a group of people who were walking around with levels in the mid-200, like 265, assuming they did not get acetheas or Parkinsonism on the way. The only big side effect they got at that high level is constipation, actually. So it's tolerated, and I don't feel like if you push somebody's level of 200,

you'd be causing them grievous harm. I feel like now, having spent a bit more time from the literature, I would lower that number maybe a bit to 150. That's all. And I would say most of the other ones are probably fairly consistent. But that's one thing is having spent a bit more time, some of those things are modified. Maybe you can check with Dr. Cumman because we may have updated that table just in this past year as I wrote my book. And so you may see some changes.

For example, for Halaparadol, I think I had the point of futility, maybe as high as 30 at one point. And I think now I'd probably put it more like an 18 nanogram peramel as the point. Yeah. where I'd say, you know, I think you're probably kind of reached whatever, you know, 95% of the people who respond will have responded to that. Okay. So go ahead and ask Dr. Cummings and you can put that out. I'll get an update on that in my website.

Yeah, exactly. Thanks for recommending that, yeah. And I believe one of the handouts I sent you, the handout five actually has a table, which has that information on there. And that'll be probably the latest and greatest source of information, at least from my perspective, how the world should work. Great. Well, as we kind of come to a conclusion here of our time, are there any other pearls that kind of like are sticking in your head that you just want to get out there about plasma levels, about medications, antipsychotics? Admittedly, there aren't some levels available for certain agents. If you came to me and said, well, what do I do? I have somebody on kriperzine. You may not find a lab running that in the United States. And because measurement-based care is so important to making good to see.

decisions, just like you do with lithium or valproate, I think it does maybe raise in your mind the idea that perhaps I should try to get people to respond to drugs, always give them a crack at drugs for which levels are readily available. I like Rexpeperzole. I think it's a useful molecule. I don't know that you can get a level on anywhere in the United States. There may be reasons to try it, but it's important to also know what's going on when people aren't getting better. And if you feel like using some of those agents may get you into a bind with certain patients, not all, that you're just unsure of the situation. I feel like having that extra bit of information, again, like lithium.

You know, let's say there's some new mood stabilizer out there and you say, oh, it works as well, but you can't get levels. Somebody doesn't get better. What are you going to do? You're really in a dark area, and you're just kind of flying blind. And I think that's why I do encourage people to find the molecules, which I feel like are the most benign. So if you want to use a partial agonist, why not try aeropepipersol first? Levels are readily available.

We know how to interpret them. We like aeropeprezole as a molecule because of his adverse effect profile. There's two long-acting ejectable forms for those who are non-adherent. And then if they don't respond, that's fine. but at least you can measure it. If you want to use a first generation, you know, pick one that's readily available, haloperidol, among some of the other atypicals.

I don't think there's anybody out there doing alloparodon levels. I wouldn't know what to do with it if you ordered one. So, yes, there's reasons maybe to use it, but if you can't measure it, it does make it harder for you to practice. Very good. Very good. Well, this has been a good discussion.

I think a lot of the people who are really, into psychopharmacology are going to love this episode. I think there's some therapists who have made it all the way through who are now going to, you know, think when they have a schizophrenic patient, like, okay, which provider in this community knows about this stuff? And I think that's, that'll be helpful. So really glad you were able to come on. I think that the theme of, you know, what was the Katie study? Katie's study said the compliance rate was, what, 30, somewhere on 30 percent? Yeah. That was the biggest schizophrenia trial that's ever been done. And imagine, 30% compliance somewhere on there.

Yep. If you have the exact percent. Do you have the exact percentage? I don't, but I think if you even want to decide a number of 50%, people would accept that. If you go to longer time frames, it becomes lower and lower. And I think that's the point. Oral non-adherence is common. We say, oh, our patients are so ill, blah, blah, blah.

Go to the diabetes clinic. It's no better, you know. It's just the nature of the beast when you're dealing with chronic illnesses on oral. therapy. And that's why measurement-based care is so important, especially considering the consequences. If I don't take my anti-hypertensive for a month, I'm not going to die. I'm not going to have in the hospital. I can not take it for years before I'll suffer consequences. But if our patients don't take the oral antipsychotics, you know, it's a whole different ballgame. And it's important to really understand. And that's why I say, even for people on stable therapy, oral therapy,

check it once in a while. There's reasons to get it. And certainly as patients are not getting better and you're trying to optimize response, the levels are really the best tool you have to augment your clinical judgment. Very good. Very good. Well, I appreciate your time, and I would recommend if you do get his book, put in a nice Amazon review for him and mention your appreciation of this interview so we can know where you came from. And that will also help me pull in bigger authors in the future, you know, or big authors. I don't know if there's a bigger author. I haven't had stall on here, I guess. I guess he would be considered a big fish. The biggest, the biggest, the biggest, the biggest, the biggest, publisher of psychopharmacology,

no demand. Yeah. Yeah, so we will have you back to do clozapine once I have a couple weeks to read the book. Appreciate your time. Yeah, absolutely. Thank you for having me. I look forward to doing this again sometime in the future. All right, well, I do hope that you enjoyed that episode with Dr. Jonathan Meyer. If you have any questions, let me know. You can always reach out to me on my website, Psychiatrypodcast.com. I hope you check out his book, and I hope that you consider leaving him a review on Amazon. And we will leave it there for today.

If you would like to get to see me for this, you can sign up on the website, Psychiatrypodcast.com. and if you want more content like this, let me go. If you have other thoughts on what content I should have in the future, other authors, let me know as well. Thank you.