Welcome to another episode of the NEI Podcast.

Sabrina Siegel with the Neuroscience Education Institute.

In today's episode, we are coming to you from the 2023 NEI Synapse in Nashville, Tennessee.

Today we sit down with 1 of our incredible speakers in this special extended Q&A episode to give you a chance to get your unanswered questions addressed from selected presentations.

Welcome to an exclusive extended Q&A podcast episode.

We are coming to you from Nashville and this is the 2023 NEI Synapse and Dr.

Jonathan Meyer just finished his exceptional presentation titled Dopamine Partial Agonists, How They Work and Why They Don't Always Play Nice with Other Antipsychotics.

So this is a chance for our audience to get some of their unanswered questions addressed and we had so many great questions.

I'm so grateful you were able to answer some of these, but we have just a few more.

So my first question for you is What do you recommend for an inpatient unit that is trying to control an aggressive psychotic patient coming in on long-acting aripiprazole?

Yes, this is the scenario we talked about in the lecture and you really are stuck for a while because it's very difficult to override the erythropozole at the D2 receptor even with heroic doses of a potent D2 antagonist like haloperidol.

And sadly, you may have to resort to sedating strategies.

Sometimes if the patient will take a sedating molecule like chlorpromazine, again, we're only exploiting it for sedating properties.

The D2 blockade of chlorpromazine really won't have any impact and you're just going to have to wait it out.

The only thing I will say is that if the person has a history of mania, if you can get them to take a mood stabilizer that may help a great deal.

Now often these people are so difficult they won't take anything orally, but sometimes we occasionally can do inducements like if you take the lithium, we're not going to give you another shot of something, But that's important because people who are schizoaffective disorder by poor type typically will not look stable until they are mood stabilized and the 1 thing you can do is introduce a mood stabilizer like lithium or Divel Pro-X to control the mania component with their disorder until you can switch them from the aripiprazole or more appropriately wash out the aripiprazole and let a D2 antagonist work.

Okay, the next question is how about giving a D2-6 inducing medication to speed up the watch out of aripiprazole?

Well aripiprazole does go through 2 pathways, cytochrome P450, 2D6, and 3A4.

Sadly, 2D6 is not inducible, but all is not lost.

3A4 is strongly inducible and the strong inducer which we most commonly use is a drug like Tegretol.

The question of course is could I get the person to take the Teguatol, that's 1 thing, and also be mindful that Teguatol will lower the drug levels of the second antipsychotic too.

So if you had somebody on long-acting injectable erypiprazole, you could start the carbamazepine, it will lower the levels.

The impact on the levels does depend to some extent on the LAI preparation.

The impact of carbamazepine is much greater on LAI monohydrate than it is on LAI erypiprazole lauroxal and that's reflected in the fact that you actually are not supposed to use erypiprazole monohydrate with carbamazepine but you can use lauroxal.

If you want to give it a try, that's fine.

I would do serial erythropozole levels maybe every few weeks to see where you're getting and the same rule of thumb is the antagonist will also be affected by the carbamazepine and at some point if you want that antagonist to work, the second drug, you're probably going to have to get rid of the carbamazepine.

The next question is, when starting a D2 partial agonist and stopping an antagonist, is there any risk of withdrawal symptoms when stopping abruptly, for example, risperidone to cariprazine?

Well, the point I was trying to make is that let's say you wanted to go from risperidone, I'll say 4, to cariprazine and maybe they're having a tolerability issue on the risperidone or maybe they're on a long-acting injectable form.

But if they're on the oral in particular, which is you're more worried about the withdrawal effect, what happens is once you've added that caribouzine, you've effectively displaced the risperidone from the D2 receptor.

Usually we don't see a lot of withdrawal effects there.

There is a phenomenon called super sensitivity psychosis, which is most commonly a phenomenon we'll see in a patient who's on a potent first-generation antipsychotic where it's withdrawn or the dose is reduced very drastically.

But for those individuals who are on normal human doses of a second generation like risperidone, what you would see If their brain does not like the partial agonist, meaning they need full antagonist, is that after you've added the coryprazine or the eryproprazol, their positive symptoms will get worse and their brain has told you, it's voted.

It says, look, I need a full antagonist, the partial agonist would not work.

But this is not a withdrawal effect per se, but it's just you're seeing whether this brain can do just as well on the G2 antagonist.

The only withdrawal effect you might experience would be if you had somebody who was on a sedating antipsychotic like olanzapine.

You say, boy, I'd like to take this person off of olanzapine 20 and put them on cariprazine or piperazole for metabolic reasons.

Because olanzapine is sedating, If you stopped it abruptly, you'd have a rebound insomnia.

That's not a D2 issue, that just relates to sedating properties of the molecule itself.

Any issues combining stimulants for ADHD and atypical antipsychotic for depression.

What are the pharmacological interactions?

So here's an example, you have somebody who's on let's say a long-acting stimulants, doesn't matter what it is, we'll call it an amphetamine, doesn't matter to me, methylphenidate, and maybe they're on an SSRI, fair enough, they're depressed, people with ADHD are depressed, you've tried antidepressant combinations, it doesn't work out and you want to add adjunctive, let's say, aripiprazole.

The way a stimulant typically works is by 1 of 2 mechanisms.

Either it's inhibiting dopamine uptake at the dopamine transporter, so it's a DAD inhibitor, that's how methylphenidate works, that's how stimulants work, which are amphetamines, but also the amphetamines also inhibit the NET transporter, the norepinephrine transporter.

But the D2 receptor partial agonist is not going to interfere with any of those mechanisms and all you'll see is simply the antidepressant effect of adding the D2, D3 partial agonist because the antidepressant property of aripeprazole and chiroprasine we think relate to D3 and the D2 is not going to interfere because how stimulants work and what they're doing is not highly dependent on D2 stimulation overall, but more broader effects of dopamine in various areas of the prefrontal cortex and reward pathway.

But the point being is if you did push the partial agonist to higher and higher levels, eventually it might start to interfere at the D2 receptor at higher doses.

But we typically use aripiprazole at very low doses and we should be unlikely to interfere with the overall mechanism of action of stimulants.

The next question is, what are case situations where you would add another antipsychotic to a partial agonist or would you basically never do that?

The only instance where it makes perfect pharmacological sense for schizophrenia, and I'll be very specific here, for schizophrenia is the combination of clozapine and a partial agonist.

So let's say somebody had failed a couple of antipsychotics, the last 1 they're on is eripeprazole or coryprazine, but you're like, okay, they've already failed a couple of drugs, I'm going to go to clozapine.

That's an instance where I have no problem adding clozapine to the eripeprazole or coryprazine because whatever clozapine's magic properties are do not require D2 binding, Clozapine has other properties.

In the future, if we have agents that don't rely on D2 blockade, let's say a Tarwan agonist or these muscarinic agonist strategies or PAM strategies, that would be a circumstance where you could combine them with a partial agonist.

Now let me give you a different scenario which I talked about in the lecture.

Let's say you had somebody who was bipolar

or schizoaffective disorder bipolar type who for example was on an LAI form of aripiprazole, but now they're depressed.

Well what are the things that work for bipolar 1 depression or schizoaffective disorder type depression.

Well, it's going to be a drug like limeteperone or lorazodone or criprazine.

Well, whatever I'm going to get from specifically limeteperone or lorazodone has nothing to do with the D2 receptor.

I mean, I don't care if erypiprazole wins that battle, the D2 receptor.

What I want from lumataparone is a constellation of activities, but none of which are dependent on D2 binding to achieve its antidepressant properties.

You could add those and I wouldn't worry about it because all you want is the other non-D2 property of those molecules to treat the bipolar 1 depression.

The weird scenario would be if you say, well, I really want to add cariprazine to the erypiprazole for their bipolar depression.

Because they're both partial agonists with very high affinity, you may have some fight going on there at the D2 receptor which may have some implications for the stability of their schizophrenia.

It's a very interesting scenario to reason through.

It might be a wash and in that case I might say well maybe switch the schizoaffective or bipolar 1 person to cariprazine as their maintenance antipsychotic.

The next question we have is, says, is there any situation in which you would augment a partial agonist?

So if we're talking specifically schizophrenia and the partial agonist isn't working, the problem is when you add an antagonist, it's not going to do anything.

And I think that was the whole point of the lecture.

Like, wow, this lady doesn't look good on 30 of oral-air prepazole for her schizophrenia.

I'm going to add haloperidol to it to make it better.

Well, it's not, and I think that's really what the point was I was trying to drive home.

Her brain has voted, her brain has said a partial agonist for me is not sufficient.

Partial agonists do work for schizophrenia, I do wanna say that.

They do work for schizophrenia and many people respond quite well, but some people don't and they need a full antagonist.

And if the person's brain says, look, this erypiprazole or the creperzine or the brexipiprazole is insufficient, I think what the brain is telling you is I need a full antagonist.

Adding the antagonist to the partial agonist is not going to accomplish anything as I discussed using several scenarios simply because the partial agonists work between 80 and 100% receptor occupancy and they have higher affinity than most antagonists.

The antagonist that you're adding really isn't doing anything and so it really isn't augmenting anything and it's only just prolonging the patient's suffering to some extent.

In those situations, I usually say, look, it's time to go to a full antagonist because the partial agonist is just insufficient to control their positive symptoms of schizophrenia.

How would you manage acute delirium agitation in a hospital setting for a patient on a partial agonist?

Well, my hope is that partial agonist is not in an LAI form.

But if they already have the partial agonist on board, really, you're kind of stuck.

We don't think benzodiazepines are very effective for delirium.

You're really in a bind there because you can inject them with haloperidol, but you're not really doing them any good whatsoever.

If they were on oral aripiprazole, I would stop it abruptly and then maybe over time, if you needed an antipsychotic, a D2 antagonist would work, but it's not going to work right away.

As we know, the hallmark of treating delirium is to treat the underlying cause, whether it's an infection, an electrolyte disturbance, alcohol withdrawal, that's where most of your mileage is.

I hate to say it, if somebody's really agitated and they were on LAI or a piperazole, you probably will not be able to use a D2 blocker to control their behavior and until such time as you can rectify the underlying metabolic or infectious disturbance or remove something which is causing the delirium like an anticholinergic or an opiate, there are instances where you may simply have to restrain the patient until such time as you can correct the underlying cause of the delirium.

The next question is, how long do you give a patient aripiprazole and on what dose before you determine they won't respond?

Well, typically the rule for oral antipsychotics is that if you see a less than minimal response by week 2 for a given dose, they are unlikely to be a responder at week 6.

What that means is not that the molecule has failed, but that dose has failed.

For aripiprazole specifically, I do like to get people as high as 20 before I consider that maybe it won't work out simply because 20 is the maximum dose I can provide in the form of a long-acting injectable either monohydrate or loroxyl form.

You know, if the person responds to 45 of aripiprazole orally, that's fine, but I really want to convert most of my patients to a lung hacking injectable simply because oral non-adherence is so common for chronic illnesses like schizophrenia that we now appreciate the costs of non-adherence in terms of not only relapse, but the impact that relapse has on their brain itself.

So 20 typically is my goal for the result.

If you put somebody on 10 and after a couple of weeks and say, look, she already looks a bit better, I would say just leave her on the 10 and see what you get over the next month.

If the person didn't have a response and all we're looking for is minimal response, I mean clinically detectable benefit where you as a clinician say, I think the patient's a bit better or the patient herself or himself says, I feel like I'm a bit better.

Then we'll give you another month on that dose and see what we get out of it.

But if he's literally seen nothing after 2 weeks and the person's taking it, which is sometimes an if, it's time to go up on the dose and then the clock starts over again for the next two-week trial of the next dosage increment.

Well, That takes me to our final question which is, can you recommend a resource such as a chart that would summarize D2 occupancy and affinity rates for all of the antipsychotics for comparison?

Yeah, so there are review articles out there.

The hard part is they often rely on dose.

And 1 of the issues is that people metabolize drugs differently.

And a big point of emphasis for me, especially as you're dealing with sicker patients is the dose you prescribe often bears a poor relationship to what's actually in their system.

If they're on oral, it's because they either don't take it, they take it erratically, or they could have variations in drug metabolism.

But even for something on a long-acting injectable, the dose that you administer often does not correlate well with their systemic levels.

I covered in a book I wrote a couple of years ago on how to use antipsychotic plasma levels, all this information.

I think to be honest, I think it's the best resource which is comprehensive, which allows you to make conversions between antipsychotics not based on dose, but based on plasma level because plasma level is the best correlate for D2 occupancy.

And I think that's the way to look at it is not dosing D2 occupancy, but it's level in D2 occupancy.

And separately, you have to look at partial agonists differently than antagonist antipsychotics.

Antagonist antipsychotics generally we feel like have a similar mechanism of action and we're looking for a sweet spot between 65 and 80%.

But based on the level, you can find out for that paliperidone, that risperidone, that olanzapine, what their level of D2 occupancy is for the patient's given level.

A couple of exceptions are drugs like lumateparone which is a very low level of D2 occupancy and quetiapine.

The partial agonists though work roughly between 80 and 100% D2 occupancy and you can't infer their antipsychotic activity just from D2 occupancy because they're partial agonists And that's why I say it becomes a little more complicated to rely on that.

But you can interconvert between antagonist antipsychotics based on D2 occupancy, knowing that level is the best correlate of D2 occupancy.

From that information, that also can give you some sense of whether a partial agonist will work.

Again, the point I was trying to make is that let's say you have a partial agonist which has 25% intrinsic activity.

of the D2 receptors, I would have reduced that postsynaptic activity, that signal down to essentially 25% of what you get from dopamine.

But maybe based upon the D2 antagonist, that patient needed 80% reduction, meaning 80% occupancy or more.

Well, knowing that information is very helpful because you could say, wow, this person needed like 83% D2 occupancy based on their level, which means I've reduced things by

I don't know if I can get that from a partial agonist and that's where that information can be very helpful if you're considering going from a full antagonist to a partial agonist.

Meyer for being on our show and for sharing such amazing information with us.

This is such an incredible topic and I really thank you for joining us today.

Thank you all of you for joining us at the 2023 NEI Synapse.

Thank you so much for joining us for another episode of the NEI Podcast.

Please let us know what you'd like to hear more about by leaving a review.


Speaker 0: Welcome to another episode of the NEI Podcast. I'm Dr. Sabrina Siegel with the Neuroscience Education Institute. In today's episode, we are coming to you from the 2023 NEI Synapse in Nashville, Tennessee. Today we sit down with 1 of our incredible speakers in this special extended Q&A episode to give you a chance to get your unanswered questions addressed from selected presentations.

Speaker 1: Welcome to an exclusive extended Q&A podcast episode. We are coming to you from Nashville and this is the 2023 NEI Synapse and Dr. Jonathan Meyer just finished his exceptional presentation titled Dopamine Partial Agonists, How They Work and Why They Don't Always Play Nice with Other Antipsychotics. Welcome Dr. Meyer.

Speaker 2: Thank you so much Sabrina. It's wonderful to be here.

Speaker 1: So this is a chance for our audience to get some of their unanswered questions addressed and we had so many great questions. I'm so grateful you were able to answer some of these, but we have just a few more. So my first question for you is What do you recommend for an inpatient unit that is trying to control an aggressive psychotic patient coming in on long-acting aripiprazole? Would a benzodiazepine be appropriate?

Speaker 2: Yes, this is the scenario we talked about in the lecture and you really are stuck for a while because it's very difficult to override the erythropozole at the D2 receptor even with heroic doses of a potent D2 antagonist like haloperidol. And sadly, you may have to resort to sedating strategies. A benzodiazepine seems reasonable. Sometimes if the patient will take a sedating molecule like chlorpromazine, again, we're only exploiting it for sedating properties. The D2 blockade of chlorpromazine really won't have any impact and you're just going to have to wait it out.

The only thing I will say is that if the person has a history of mania, if you can get them to take a mood stabilizer that may help a great deal. Now often these people are so difficult they won't take anything orally, but sometimes we occasionally can do inducements like if you take the lithium, we're not going to give you another shot of something, But that's important because people who are schizoaffective disorder by poor type typically will not look stable until they are mood stabilized and the 1 thing you can do is introduce a mood stabilizer like lithium or Divel Pro-X to control the mania component with their disorder until you can switch them from the aripiprazole or more appropriately wash out the aripiprazole and let a D2 antagonist work.

Speaker 1: Okay, the next question is how about giving a D2-6 inducing medication to speed up the watch out of aripiprazole?

Speaker 2: Well aripiprazole does go through 2 pathways, cytochrome P450, 2D6, and 3A4. Sadly, 2D6 is not inducible, but all is not lost. 3A4 is strongly inducible and the strong inducer which we most commonly use is a drug like Tegretol. The question of course is could I get the person to take the Teguatol, that's 1 thing, and also be mindful that Teguatol will lower the drug levels of the second antipsychotic too. It is something that could be tried.

I think theoretically it makes sense. So if you had somebody on long-acting injectable erypiprazole, you could start the carbamazepine, it will lower the levels. The impact on the levels does depend to some extent on the LAI preparation. The impact of carbamazepine is much greater on LAI monohydrate than it is on LAI erypiprazole lauroxal and that's reflected in the fact that you actually are not supposed to use erypiprazole monohydrate with carbamazepine but you can use lauroxal. If you want to give it a try, that's fine.

I would do serial erythropozole levels maybe every few weeks to see where you're getting and the same rule of thumb is the antagonist will also be affected by the carbamazepine and at some point if you want that antagonist to work, the second drug, you're probably going to have to get rid of the carbamazepine.

Speaker 1: The next question is, when starting a D2 partial agonist and stopping an antagonist, is there any risk of withdrawal symptoms when stopping abruptly, for example, risperidone to cariprazine?

Speaker 2: Well, the point I was trying to make is that let's say you wanted to go from risperidone, I'll say 4, to cariprazine and maybe they're having a tolerability issue on the risperidone or maybe they're on a long-acting injectable form. But if they're on the oral in particular, which is you're more worried about the withdrawal effect, what happens is once you've added that caribouzine, you've effectively displaced the risperidone from the D2 receptor. Usually we don't see a lot of withdrawal effects there. There is a phenomenon called super sensitivity psychosis, which is most commonly a phenomenon we'll see in a patient who's on a potent first-generation antipsychotic where it's withdrawn or the dose is reduced very drastically. But for those individuals who are on normal human doses of a second generation like risperidone, what you would see If their brain does not like the partial agonist, meaning they need full antagonist, is that after you've added the coryprazine or the eryproprazol, their positive symptoms will get worse and their brain has told you, it's voted.

It says, look, I need a full antagonist, the partial agonist would not work. But this is not a withdrawal effect per se, but it's just you're seeing whether this brain can do just as well on the G2 antagonist. The only withdrawal effect you might experience would be if you had somebody who was on a sedating antipsychotic like olanzapine. You say, boy, I'd like to take this person off of olanzapine 20 and put them on cariprazine or piperazole for metabolic reasons. Fine, I fully appreciate that.

Because olanzapine is sedating, If you stopped it abruptly, you'd have a rebound insomnia. That's not a D2 issue, that just relates to sedating properties of the molecule itself.

Speaker 1: Okay. Any issues combining stimulants for ADHD and atypical antipsychotic for depression. What are the pharmacological interactions?

Speaker 2: Dr. Kahneman So there really aren't. So here's an example, you have somebody who's on let's say a long-acting stimulants, doesn't matter what it is, we'll call it an amphetamine, doesn't matter to me, methylphenidate, and maybe they're on an SSRI, fair enough, they're depressed, people with ADHD are depressed, you've tried antidepressant combinations, it doesn't work out and you want to add adjunctive, let's say, aripiprazole. There really is no interaction. The way a stimulant typically works is by 1 of 2 mechanisms.

Either it's inhibiting dopamine uptake at the dopamine transporter, so it's a DAD inhibitor, that's how methylphenidate works, that's how stimulants work, which are amphetamines, but also the amphetamines also inhibit the NET transporter, the norepinephrine transporter. But the D2 receptor partial agonist is not going to interfere with any of those mechanisms and all you'll see is simply the antidepressant effect of adding the D2, D3 partial agonist because the antidepressant property of aripeprazole and chiroprasine we think relate to D3 and the D2 is not going to interfere because how stimulants work and what they're doing is not highly dependent on D2 stimulation overall, but more broader effects of dopamine in various areas of the prefrontal cortex and reward pathway. But the point being is if you did push the partial agonist to higher and higher levels, eventually it might start to interfere at the D2 receptor at higher doses. But we typically use aripiprazole at very low doses and we should be unlikely to interfere with the overall mechanism of action of stimulants.

Speaker 1: The next question is, what are case situations where you would add another antipsychotic to a partial agonist or would you basically never do that?

Speaker 2: The only instance where it makes perfect pharmacological sense for schizophrenia, and I'll be very specific here, for schizophrenia is the combination of clozapine and a partial agonist. So let's say somebody had failed a couple of antipsychotics, the last 1 they're on is eripeprazole or coryprazine, but you're like, okay, they've already failed a couple of drugs, I'm going to go to clozapine. That's an instance where I have no problem adding clozapine to the eripeprazole or coryprazine because whatever clozapine's magic properties are do not require D2 binding, Clozapine has other properties. That would make sense. In the future, if we have agents that don't rely on D2 blockade, let's say a Tarwan agonist or these muscarinic agonist strategies or PAM strategies, that would be a circumstance where you could combine them with a partial agonist.

Now let me give you a different scenario which I talked about in the lecture. Let's say you had somebody who was bipolar

Speaker 0: 1

Speaker 2: or schizoaffective disorder bipolar type who for example was on an LAI form of aripiprazole, but now they're depressed. Well what are the things that work for bipolar 1 depression or schizoaffective disorder type depression. Well, it's going to be a drug like limeteperone or lorazodone or criprazine. Well, whatever I'm going to get from specifically limeteperone or lorazodone has nothing to do with the D2 receptor. I mean, I don't care if erypiprazole wins that battle, the D2 receptor.

What I want from lorazadone is serotonin

Speaker 0: 7.

Speaker 2: What I want from lumataparone is a constellation of activities, but none of which are dependent on D2 binding to achieve its antidepressant properties. You could add those and I wouldn't worry about it because all you want is the other non-D2 property of those molecules to treat the bipolar 1 depression. The weird scenario would be if you say, well, I really want to add cariprazine to the erypiprazole for their bipolar depression. Because they're both partial agonists with very high affinity, you may have some fight going on there at the D2 receptor which may have some implications for the stability of their schizophrenia. It might not.

It's a very interesting scenario to reason through. It might be a wash and in that case I might say well maybe switch the schizoaffective or bipolar 1 person to cariprazine as their maintenance antipsychotic.

Speaker 1: Okay. The next question we have is, says, is there any situation in which you would augment a partial agonist? How and why?

Speaker 2: Yeah, really not. So if we're talking specifically schizophrenia and the partial agonist isn't working, the problem is when you add an antagonist, it's not going to do anything. And I think that was the whole point of the lecture. Like, wow, this lady doesn't look good on 30 of oral-air prepazole for her schizophrenia. I'm going to add haloperidol to it to make it better.

Well, it's not, and I think that's really what the point was I was trying to drive home. Her brain has voted, her brain has said a partial agonist for me is not sufficient. Partial agonists do work for schizophrenia, I do wanna say that. They do work for schizophrenia and many people respond quite well, but some people don't and they need a full antagonist. And if the person's brain says, look, this erypiprazole or the creperzine or the brexipiprazole is insufficient, I think what the brain is telling you is I need a full antagonist.

Adding the antagonist to the partial agonist is not going to accomplish anything as I discussed using several scenarios simply because the partial agonists work between 80 and 100% receptor occupancy and they have higher affinity than most antagonists. The antagonist that you're adding really isn't doing anything and so it really isn't augmenting anything and it's only just prolonging the patient's suffering to some extent. In those situations, I usually say, look, it's time to go to a full antagonist because the partial agonist is just insufficient to control their positive symptoms of schizophrenia.

Speaker 1: How would you manage acute delirium agitation in a hospital setting for a patient on a partial agonist?

Speaker 2: Well, my hope is that partial agonist is not in an LAI form. But if they already have the partial agonist on board, really, you're kind of stuck. We don't think benzodiazepines are very effective for delirium. They tend to make it worse. Other sedative molecules do not.

You're really in a bind there because you can inject them with haloperidol, but you're not really doing them any good whatsoever. If they were on oral aripiprazole, I would stop it abruptly and then maybe over time, if you needed an antipsychotic, a D2 antagonist would work, but it's not going to work right away. As we know, the hallmark of treating delirium is to treat the underlying cause, whether it's an infection, an electrolyte disturbance, alcohol withdrawal, that's where most of your mileage is. I hate to say it, if somebody's really agitated and they were on LAI or a piperazole, you probably will not be able to use a D2 blocker to control their behavior and until such time as you can rectify the underlying metabolic or infectious disturbance or remove something which is causing the delirium like an anticholinergic or an opiate, there are instances where you may simply have to restrain the patient until such time as you can correct the underlying cause of the delirium.

Speaker 1: The next question is, how long do you give a patient aripiprazole and on what dose before you determine they won't respond?

Speaker 2: Well, typically the rule for oral antipsychotics is that if you see a less than minimal response by week 2 for a given dose, they are unlikely to be a responder at week 6. What that means is not that the molecule has failed, but that dose has failed. For aripiprazole specifically, I do like to get people as high as 20 before I consider that maybe it won't work out simply because 20 is the maximum dose I can provide in the form of a long-acting injectable either monohydrate or loroxyl form. You know, if the person responds to 45 of aripiprazole orally, that's fine, but I really want to convert most of my patients to a lung hacking injectable simply because oral non-adherence is so common for chronic illnesses like schizophrenia that we now appreciate the costs of non-adherence in terms of not only relapse, but the impact that relapse has on their brain itself. So 20 typically is my goal for the result.

They respond lower, that's fine. If you put somebody on 10 and after a couple of weeks and say, look, she already looks a bit better, I would say just leave her on the 10 and see what you get over the next month. If the person didn't have a response and all we're looking for is minimal response, I mean clinically detectable benefit where you as a clinician say, I think the patient's a bit better or the patient herself or himself says, I feel like I'm a bit better. It's all I want to know. Then we'll give you another month on that dose and see what we get out of it.

But if he's literally seen nothing after 2 weeks and the person's taking it, which is sometimes an if, it's time to go up on the dose and then the clock starts over again for the next two-week trial of the next dosage increment.

Speaker 1: Okay, okay. Well, That takes me to our final question which is, can you recommend a resource such as a chart that would summarize D2 occupancy and affinity rates for all of the antipsychotics for comparison?

Speaker 2: Yeah, so there are review articles out there. The hard part is they often rely on dose. And 1 of the issues is that people metabolize drugs differently. And a big point of emphasis for me, especially as you're dealing with sicker patients is the dose you prescribe often bears a poor relationship to what's actually in their system. If they're on oral, it's because they either don't take it, they take it erratically, or they could have variations in drug metabolism.

But even for something on a long-acting injectable, the dose that you administer often does not correlate well with their systemic levels. I covered in a book I wrote a couple of years ago on how to use antipsychotic plasma levels, all this information. I think to be honest, I think it's the best resource which is comprehensive, which allows you to make conversions between antipsychotics not based on dose, but based on plasma level because plasma level is the best correlate for D2 occupancy. And I think that's the way to look at it is not dosing D2 occupancy, but it's level in D2 occupancy. And separately, you have to look at partial agonists differently than antagonist antipsychotics.

Antagonist antipsychotics generally we feel like have a similar mechanism of action and we're looking for a sweet spot between 65 and 80%. But based on the level, you can find out for that paliperidone, that risperidone, that olanzapine, what their level of D2 occupancy is for the patient's given level. A couple of exceptions are drugs like lumateparone which is a very low level of D2 occupancy and quetiapine. The partial agonists though work roughly between 80 and 100% D2 occupancy and you can't infer their antipsychotic activity just from D2 occupancy because they're partial agonists And that's why I say it becomes a little more complicated to rely on that. But you can interconvert between antagonist antipsychotics based on D2 occupancy, knowing that level is the best correlate of D2 occupancy.

From that information, that also can give you some sense of whether a partial agonist will work. Again, the point I was trying to make is that let's say you have a partial agonist which has 25% intrinsic activity. Even if I maxed it out, If I covered

Speaker 0: 100%

Speaker 2: of the D2 receptors, I would have reduced that postsynaptic activity, that signal down to essentially 25% of what you get from dopamine. So I've reduced things by roughly 75%. But maybe based upon the D2 antagonist, that patient needed 80% reduction, meaning 80% occupancy or more. Well, knowing that information is very helpful because you could say, wow, this person needed like 83% D2 occupancy based on their level, which means I've reduced things by

Speaker 0: 83%

Speaker 2: in terms of post-synaptic activity. I don't know if I can get that from a partial agonist and that's where that information can be very helpful if you're considering going from a full antagonist to a partial agonist.

Speaker 1: Thank you, Dr. Meyer for being on our show and for sharing such amazing information with us. This is such an incredible topic and I really thank you for joining us today. Thank you all of you for joining us at the 2023 NEI Synapse.

Speaker 0: Thank you so much for joining us for another episode of the NEI Podcast. Please let us know what you'd like to hear more about by leaving a review. Don't miss another episode. Subscribe today.

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NEI Podcast - E182 - 2023 NEI Synapse Extended Q&A: Dopamine Partial Agonists with Dr. Jonathan Meyer