Psychiatry & Psychotherapy Podcast - Side Effect Mastery in Psychopharmacology: Rawlings–Thompson A-F Classification, Low Slow Titration & Real-World Management with Dr. Michael Cummings & Dr. Blaire Heath

Episode Date: June 19, 2026

Dr. David Puder sits down with psychopharmacology expert Dr. Michael Cummings and Dr. Blaire Heath to discuss Side Effect Mastery in Psychopharmacology. This episode dives deep into the Rawlings–Thompson A-F Classification system for understanding and managing medication side effects, emphasizing low and slow titration strategies to improve tolerability and patient outcomes. They discuss practical, real-world approaches to common challenges, including orthostatic hypotension, excessive sweating (hyperhidrosis from SSRIs/SNRIs), tremor management, alopecia from valproic acid and lithium, anticholinergic burden, and much more. Dr. Cummings shares his insights on receptor dynamics, metabolizer status, bedtime dosing, and when to reconsider diagnosis after treatment failures.  By listening to this episode, you can earn 1.25 Psychiatry CME Credits. Link to blog Link to YouTube video

All right, welcome back to the podcast. I am joined with Dr. Blair Heath. She is a pharmacist, now child psychiatrist, working in the forensic setting. Also with me is Michael Cummings, psychiatrist, a psychopharmacologist, and a true expert that I've had on multiple times. We will be discussing some psychopharmacology. We will be discussing different approaches to side effects. Blair, Do you want to introduce this topic before we kind of jump into it? Well, I really appreciate Dr. Cummings, you know, guidance over the years. And there's so many difficult areas of prescribing that having a psychopromancology expert

to help give us some awareness on how to approach new patients, prescribing situations, and side effects. So I thought we kind of start with a little bit of ways that we focus on prescribing and then going into some of the major side effect categories to help us kind of break that down. Great. Dr. Cummings, do you want to talk about your general approach to prescribing and especially with the focus on adverse effects? Yeah, I'm, first off, pleased to be back. In terms of prescribing, I think it's important for clinicians to conceptualize. Each prescription as essentially a medication trial. The first goal, of course, is to educate the patient about why you're recommending the medication you are,

what its potential benefits and liabilities are, and then to initiate the prescription and reach what is called minimum response threshold, that is the level of drug, either dose or preferably plasma concentration, at which at least 5% of the population will show a response. Then continuing titration to one of three endpoints, either the person gets better, which is, of course, what we desire, or the person develops intolerable side effects that can't be managed, or you reach the point of futility for that particular medication, which is formally defined as the point at which a further increase in the medication

has a less than 5% chance of producing the desired result. I think if people have that structure in mind, it can save a lot of confusion and not. not getting through a medication trial and doing consults, I come across a lot of cases where the trial just sort of stalled and the person never got an adequate trial of medication, or they were started on a number of things that, all of which were sub-therapeutic, and one of the things I'm fond of telling people is that, you know, multiple sub-therapeutic treatments don't add up to a therapeutic treatment.

Did you have further thoughts about Dr. Heath? That was kind of a lot of it. I think one of the things that we talked about like for antipsychotic, you know, I think we've talked about that the first two weeks you should see some response, but then usually a clarified full trials, say before clozapine would be like six to eight weeks, right? Getting to more than levels. Yeah, there's a, it's not a.

It's not a formal rule per se, but there have been a number of studies that have observed that if you give a medication at a given dose, whatever response you have is about 80% of what you're going to get at the end of two weeks. So typically if someone's on a medication, say an antipsychotic or antidepressant, it's being titrated upward. you have an initial dose, there's not much change after two weeks. You don't need to wait further. You can titrate the dose further and eventually you'll either get a response or you'll reach the point of futility for the drug. I think sometimes people wait either not long enough and titrate too quickly and produce a lot of side effects or they wait too long recalling that the drug won't in many cases reach its full effect for four to six weeks but at two weeks the antidepressants and antipsychotics at least will produce about 80% of what they're going to

is that the case for oCD and anxiety like um uh ocd has a longer response curve so that you could roughly double that and say at the end of four weeks at a given dose you've got about 80% of the response are going to. I think the other issue with OCD is people sometimes mistakenly use the dose ranges for major depressive disorder, whereas the required dose ranges for OCD are typically higher. For example, I've treated a number of OCD patients where they required 300 to 400 milligrams, of cerchraline, whereas for depressionally, quoted dose range as 50 to 200 milligrams per day.

I really like what he was talking about just a few minutes ago, where I think one of the biggest things that have been helpful is kind of not being afraid to do a low and slow approach. Dr. Cummings, you're saying people go up too quickly, so especially as the receptors, we talked about them, upregulating, down-regulating, and, of course, the sensitivities based on metabolism. Can you talk a little bit about trying to address side effects and how we, those, you know,

high dose? Yeah, the, we're touching on the Rawlings-Thompson classification of side effects. It's, well, currently it's A through F types. It started out as just A&B, expected and idiosyncratic. The A-type is related to the known, receptor activities or other activities of the drug. And these are the most common side effects that we see. For example, if you're giving somebody a drug that is a good alpha adrenergic antagonist,

if you go too quickly, you'll make the person hypotensive. They'll be dizzy when they stand up. If the drug also has antihistaminic properties, you'll make them sleepy. and they may complain of fatigue and lethargy. And if the drug has anticholinergic properties, of course, they can get everything from blurred memory, blurred vision, rather, memory impairment, GI problems, urinary retention.

All of those can be mitigated by titrating the drug more slowly. And indeed, one of the points of getting plasma concentrations for things like the antidepressants and the antipsychotics is if you have a slow metabolizer, you need to titrate the drug in smaller steps because a smaller change in dose produces a bigger change in plasma concentration. The opposite is true if you have a rapid metabolizer, you may need to make bigger steps in order to get the same amount of increased in drug.

Do you identify certain approach? Like, this is just for me. Like, if someone seems like they've had a lot of side effects from a lot of things to me that identifies, I don't know for sure there's a slow metabolizer, but I'll, like, go really low and slow to try to kind of establish that rapport. And, hey, you know, we can, it may seem even, I don't want to say, ridiculously slow, but for, you know, a person, you know, and someone took a year to cross titrate from one else.

Yeah. Yeah, it's always fair to ask people, you know, when you've taken medications in the past, Are you the sort of person who generally tolerates medicines pretty well? Or do they cause you a lot of problems? And if so, what kind of problems? That may help you not only with the rate of titration, but also with medication choice. Because in many cases, the person can tell you what kind of side effects they're sensitive to. And you can pick something that is not a particularly bad actor in that area.

And you talk about the bedtime dosing, not doing stuff more than twice a day. I saw this a lot as a pharmacist. People give stuff three times, four times a day. People always forget that middle dose. Yeah, most of the medications that we use in psychiatry, there are some that during the titration of the drug, you need to give it in divided dosing essentially so that you don't have very high peak levels and produce side effects that way.

But once you get the person adapted to the drug, most of the drugs we use can then be consolidated to bedtime. So that two things happen. One, the peak occurs during sleep when it's not likely to bother the person, not likely to produce side effects. And frankly, as you point out, adherence is a lot better if somebody's taking something once a day. Most of us are pretty good at remembering to take something either when we get up or when we go to bed. I have, frankly, yet to see anybody manage to take all of the doses in a five-time-per-day regimen of antibiotics, for example. Invariably, in the middle of the day, it's all, did I take it or didn't I take it? So I think that's a really good thing, but I like how you pointed out that we don't always think about the concentration.

of the medication correlating the side effects. And so I know that's something we talked about with guanofthine, even IR and ER, even though the half-life of technically the IR is 17 hours and the ER is 18 hours. You talked about how it was, I think, coded and how the side effects could be based on the peak times that we don't always. Yeah, for most of the drugs that have concentration-related side effects, if you can make the peak less steep, the drug becomes more tolerable. A good example of that is Valproicath.

DiValprox, immediate release produces the same side effects, but produces them about twice as often as the extended release formulation of DiVal Prox ER. Thank you. And one of the biggest thing I know you get a lot of questions about that's really helpful is a lot of us will get a really difficult patient that they'll come to us on multiple controls. They might be on one or even two benzodiazepines and a, you know, stimulant. And then this is my last dose and you're worried about withdrawal seizures or, you know, you don't want to take on this patient. But then you feel some degree of, I want to say, responsibility or even liability.

if you don't prescribe or continue the regimen, how do you approach that situation? Well, you know, if you're treating somebody, if you've accepted them as a patient, you do have a legal obligation to them. There is a legal concept called abandonment, meaning that you're not allowed simply to say, well, I'm out of here, I'm not going to see you any.

Now, that doesn't mean that you can be forced to prescribe things in the long term that you don't want to. If somebody is demanding a drug that you don't think is appropriate for them or they are misusing the drug, you can certainly tell them, you know, unless you use the medication reasonably, I won't be able to continue to treat you. Your obligation in that sense, if the person simply won't agree, is to say, well, I will manage you in the short term

and I will provide you with referrals to other clinicians. One of my thoughts right off the bat with that one, Dr. Heath, is sometimes they'll come in saying that they're taking meds that they haven't really been prescribed lately. So say I am prescribed and I'm running out of Xanax to four times a day. and nowadays we can look up on cures or various different things what they've actually been given recently and so sometimes there's strong inconsistencies and what they say they've been on consistently and what's been documented that they've been prescribed or how frequently they've been

prescribed now are you it's your first visit with a patient do you feel like you've officially taken them on or is that first visit the evaluation whether or not, you know, you're going to take them on? Is that responsible? It need not be acceptance of them as a patient at that first visit, but you need to be clear that you're, if that's the case, that your first meeting is an evaluation and you will decide whether you will take them on as a patient. I personally have that in my intake paperwork, that the first visit is a consultation. It's just, you know, we're trying to find mutually agreed upon goals and directives and that it's not establishing a patient doctor relationship.

And often the people who come in with a lot of meds, when you tell them that your plan would be to, to decrease them over time or that this is not, you know, appropriate, they will not want to continue to see you again. And maybe not even pay you since I'm at this point, cash pay practice. And that's just a reality, but yeah. Yeah. Dr. Peter makes a very good point.

Having that in your intake paperwork and having the patient acknowledged that, in some cases by signing said paperwork, it makes it clear that the treatment relationship has not yet begun, and you're seeking to come to an agreement about working together. I had a patient the other day that they almost wanted me to agree in the first meeting that I was going to completely not change any meds, and they also were very guarded to give a release for me to talk to their previous psychiatrist. And they wouldn't.

And I sent them a nice email and I said, hey, I don't think this is going to be a good fit for us. And they said, yes, they agreed. So I think that there needs to be like, you know, for me, I want to know why they were put on this cocktail of medications, what was the thought process. Were they actually on this? what the story is, you know, especially if they come in, you know, very demanding, very, you know,

sure that this is the only medications that have ever helped. So, yeah. What do you think? Is that reasonable, Michael Cummings? Yeah, I think that's very reasonable. You know, basically the doctor-patient relationship is just that. It's a relationship. It's essentially a business relationship in which,

the patient or their insurance pays you for services, and you provide services that you've been licensed to provide by the state. But you have to, in order to have a productive working relationship, you and the patient have to have an agreement about what the goals and methods are going to be. And I'm very careful about educating patients about medications. and that's an inherent part of prescribing. I know a lot of, well, I know from doing consults, a lot of physicians don't spend enough time talking about

why a particular medication would be desirable or why another medication might be undesirable in this particular patient's case. And frankly, also, with respect to side effects, a lot of side effects are much more manageable if you tell the patient up front what to expect. I know to come back to you. I know you've mentioned that before, like trying to have that open channel of someone being able to come back

and be able to adjust things with this. You know, and I think sometimes because as physicians, we tend to be familiar with the potential side effects of a given drug. Sometimes we forget the patient may have no idea what to expect, and it can be very frightening if, you know, you take a drug in the first, next time you stand up, you feel dizzy or you feel unusually sleepy the next morning after

you take a medication at night. You know, am I going to die of this? Is this bad? What's happening? But if you, if they've been educated and say, well, you know, when you start taking this drug, these things may happen, but they will typically get better. They're not dangerous. That goes a long way toward making the medication more tolerable.

Yeah. I had a patient that was actually I found here in the hospital and I called him like, oh, oh dear, you're in an isolation room with TV and I was going to get off. But the patient was really scary because their urine had turned red because it was one of the TB medications. I told him, oh, that's actually a side effect of medication and no one had told him. And so it was just kind of, you know, this person in the hospital already. But it was like a really scary side effect. It was like, oh, okay, that's why I'm having red tears, red, you know. that expectation can make a really big difference on how people handle things. So is there any other things, Dr. Peter, that you wanted to add? Are you okay if we move on to those different types of side effects? There was one thing coming and said earlier that there were different, yeah, different types of side effects. Okay, so we're going to go through each one, one by one. And Seattle had to kind of expand. So we just thought we'd go over the six categories.

This is based on, I don't know if you want mentioned our account. but the Merck Manuals, there's the A through Fet. So we had- Yeah, these appear in the Merck Manual. They're actually, they're called the Rawlings-Thompson side effect classification. You know, like everything else, there's more than one classification out there. This one is particularly popular, though.

Type A is an extension of what the drug does, either is its primary effect or from other interactions. In other words, it's part of the known pharmacology of the drug, for example. I think in the work manual, the example they give is if you were to give somebody too much warfarin, bleeding could become a side effect. Same thing, if you give somebody too much anti-hypertensive, you might make them hypotensive. We mentioned briefly drugs.

A lot of the drugs we give are alpha-adrenergic antagonists, or they're anticholinergic, or they're anticholinergic, or they're antips. dominic so they can make people orthostatic make them dizzy or they can give them antich side effects or they can make them sleepy all of those are category a side effects category b are idiosyncratic unexpected side effects classic example of that is allergy you know the person takes the drug and no one expected but they are are allergic to it and they break out in a rash and, you know, they're itchy, all of the classic signs and symptoms of allergy.

That's a category B. Category C, are chronic exposure side effects. If you take the drug over many, many years, probably for us, a chronic side effect is development of renal insufficiency when the person's taken. Lithium for decades, as a good example. Or osteoporosis, if the person's been taking steroids for many years, is a C-side effect. Category D are delayed effects.

These are things like you've been exposed to the drug. You're not necessarily taking the drug now, but the drug did something that causes a later adverse effect. A good example of that are teratogenic risks. with some medications. And then E is ending treatment. These are the drugs that can produce withdrawal syndromes, as we were alluding to,

if somebody's been taking benzodiazepines for years, or they're taking an opioid over a long period of time and the drug is stopped abruptly, they will, of course, have withdrawal signs and symptoms. That's category E, most easily avoided by tapering the drug. And then finally, there's category F, which is an unexpected failure of the drug. The classic example of that is you give somebody an antibiotic for an infection,

and they have no benefit. The microbe has become resistant to that particular antibiotic. You didn't know that. For the psych meds, I think an important issue with failure, is it's a good signal for us that we need to go back and reconsider the diagnosis. If we give somebody, you know, trials of several medications that should be effective for what we think the person has, and they get nothing, you know, no benefit,

it should cause us to go back and say, well, is there something in the diagnosis I'm missing here? Do they have something else? that I missed and I may need to take a completely different training approach. We've discovered some things like that. That's how anti-NMDA antibody psychosis was discovered is those, they were mostly young women initially. They were diagnosed incorrectly as having schizophrenia, but they didn't particularly benefit from the antipsychotics. It just got worse, and then they started developing cognitive problems.

And eventually people started saying, you know, this isn't schizophrenia, this is something else. And they finally figured out if indeed there, it was an antibody inflammatory encephalitis. And they needed steroids. They didn't need an antipsychotic. That's a great point. When there's one or two med failures,

you should think, am I getting the full picture? Is there something I'm missing? Am I missing personality disorder or style that may be influencing things or secondary gains in the illness role? Or, yeah, we kind of re-examine other drugs or alcohol on board. You know, I've had therapy patients where it's like years into treatment and then finally it comes out. They've been drinking.

So it's like we do not know within one session if a person is using how much they're using. Often shame keeps the truth from us, right? And, you know, it's always, if the treatment response is not what we expect, we need to be very careful not to forget that our diagnostic compression may not be right or may not be complete. So we need to be willing to go back and examine that. I've seen way too many cases where, because somebody way back when wrote down the diagnosis in the chart, everyone after that just sort of automatically believed that that was the diagnosis. Sometimes to the patient's detriment, one consult I did for the Department of Corrections,

now the patient, when they were imprisoned, when they were imprisoned rather, they malingered having psychotic symptoms. They got put on an antipsychotic and eventually developed tartaract. I had dyskinesia. You know, that patient unfortunately never had psychotic illness. They were malingering in order to get better housing because they were trying for a single cell, single person's cell.

Unfortunately, to their own detriment eventually, but nobody ever questioned whether they actually had a psychotic illness, even though people would write repeatedly that no psychotic symptoms were being observed. they were simply being really reported you know so we need to be careful about diagnosis

I remember a patient who had about 20 abdominal surgeries by the time I saw her and in getting a close history it was there was a psychosomatic flare to it but she had developed real consequences of surgeries that were exploratory

and you know she had gotten addicted to trying to have another surgery for the benefit of having a relationship with a surgeon and this connectedness that she was getting from that. So real consequences came from this, I think that's what you're describing here.

Cummington, your example, it's like real consequences came from the side effect of the actual treatment. And this is where it gets complicated as we're trying to pull the threads of the diagnosis and what happened first, right? did the, was there malingering first or was there factitious disorder or some sort of secondary game that they were seeking for first?

Yeah, that thing does back to what, you know, the education when you first start the medication, it's like being very real. You, you know, you're reporting these symptoms. You might want this medication, which, you know, we have to determine whether or not is appropriate, but realizing this is what you may be taking on as a side effect, you know, and I think sometimes people may backtrack a bit going, oh, okay, you know, trying to find those true symptoms because they'd be realized, oh, maybe it's not worth that secondary, that adverse effect because of the secondary, you know, the immediate gain.

Yeah, you know, a lot of the treatments we've prescribed, they're beneficial in the right context, but if they're overused or if they're used in somebody for whom that isn't the right medication, almost all medical treatments come with a risk. Stimulants, if they don't really have ADHD, have real risk and consequences. So kind of go a little bit more in depth in each category. The type A augmented, you mentioned the bleeding with Werfer and Arkhamidin, and it touched upon the orthostack hypotension. I wonder if you could go a little bit more into that.

I know something that would get with a lot of medications. You mentioned the slow titration, right, can help increase the amount of dizziness. Like, can you explain? Yes. Yeah. A lot of the drugs that we use in psychiatry, a lot of the antidepressants, the antipsychotics, in addition to the thing we're wanting them to do, their alpha adrenergic antagonists. So when you take them and they block alpha receptors, it makes the bullet vessels expand.

Well, you know, pressure is how much fluid you've got and how small the vessel. If the vessel gets bigger, the pressure goes down. And, of course, if you're standing upright, you have to have enough pressure to get the blood from your heart up to your head. Otherwise, you'll faint. The way to mitigate that in most cases is to titrate more slowly. Don't give the person more than they can handle until their alpha receptors upregulate and can resist the effect, that particular effect of the medication. And people who you really need to give them the medication,

but they're incredibly sensitive. There are the things you can do. You can use fluid or cortisone to make the person retain more fluid. That's essentially adding to the volume of their blood and filling up the blood vessel so their pressure stays up. There are some people who are very prone to orthostasis with or without medication. Some of those people get treated with an alpha agonist like middrine to constrict their blood vessels. But in the vast majority of people, the trick to not causing dizziness is simply to slow down the titration

and give the receptors time to catch up. Sammy is true of a lot of the other effects like drugs that block histamine receptors and make people sleepy. If the histinid receptors upregulate, that sleepiness tends to go away. You can also help that by the timing. Don't give personal a major dose of anti-estaminic drug first thing in the morning. You know, they might be better at night when it can make. maybe actually help them sleep.

Antich cholinergic effects, most often the issue there is be cautious about not adding multiple anticholinergic medications. Sometimes people forget that a lot of the medications we use are anticholinergic, and if you're giving one that's anticholinergic, try to avoid others. In other words, avoid adding to the problem. Thank you. That's really helpful, but a lot of times people might be on, you know, an olanzapine, an atrazadone, you know, on several things that can cause that orthostatic or then have that in. Yeah, a lot of these, because these are off-target receptors, it's important

to think about, well, if I'm giving this drug and it's a good alpha blocker or it's a good antihistamine or it's an anti-cholineersic drug, maybe if I need to add a second drug, I need to be looking at things that don't share those properties so I don't just add to that particular side effect burden. When I think about this specific issue of orthostatic hypotension, I think about trazodone, chlozapine, serriquil, risperone, and probably the biggest issue I've had is in chlospin,

chlozapine personally where it's like we really have to add in a secondary medication to raise the blood pressure like midadrine yes yeah yeah close a colozapine despite being the gold standard for treatment of treatment of treatment resistance psychosis unfortunately it comes with a whole host of side effects it's an excellent alpha blocker it's very anticholinergic and it's also a very potent antihistamine. So if you go too quickly, you've got somebody who has no blood pressure, they're lethargic, and they have all of the panoply of anticholinergic side effects. Here would be a good board question. Patients on clozapine, but has some PTSD as well and is having nightmares, already having some orthostatic hypotension. Do you treat with prozocin?

I was going to say I would avoid an anti-hypertensive that I maybe use some topomax that has some off-label PTSD and with the decreased appetite I allow them the prosocin the clonidine, the gonfizine, all our blood pressure ones. So I'd probably go a little bit off the beaten track for maybe considering something like that, which I've had that benefit in some of my patients actually without the they can't do the antihypertensives. Yeah, that's a good point. You want to, if you can, avoid drugs that will add to the problem. For example, you know, drugs that are alpha antagonists or that are alpha-2 agonists cause sedation and lower blood pressure. If you're giving the person a clozepine, that may not make a great combination. Sometimes people put an alpha-2 agnist with an alpha-one antagonist.

Like, I've seen the, that came to me on, two of them together, like a prososin and, like, a clonidine or something. It's like, well, you're kind of, you know, it's really one or the other. All right, Dr. Cummings? Yeah. Well, and frankly, Prozacin has taken a hit. You know, the VA did a very large-scale study of Prozacin and combat PTSD and found that it had zero effect on nightmares. So initial studies were more positive than more recent studies? Is that what you're saying? The initial studies were positive. In fact, a lot of the literature started University of Washington

and the VA in Washington State. The VA finally, though, did a large-scale national study with literally thousands of veterans, some of them, well, randomized to either be on praisesin or not, and they found essentially the praisesin did not achieve a significant difference over placebo. Now, people have looked at that and said, well, maybe it's such a large study that it may have buried some subgroups

that might be responders to praisesin, but it certainly suggests that Prazacin was not nearly as effective in beating nightmares and PTSD as people had expected. Sometimes having a creative, you know, looking at that overall picture and, you know, seeing as a really effective or, it's been kind of a tough one to approach. So thank you. Another one that I know we've gotten a lot of questions about is a common side effect. that would go under that type A category is sweating. I know I've heard a lot with SSRI, especially SRIs,

and I know that's been, do you want to talk a little bit about, you know, that, maybe how we can approach that? Well, as you know, the SSRIs are blocked the re-uptake transporter for serotonin, which, of course, means that they increase the amount of serotonin available in synapses. And our sweat glands are, modulated in part by, well, they're modulated by acetylcholine, serotonin, and noropenephrine. Noroponephyran will tend to decrease sweating because it decreases blood flow.

Serotonin opposes that and actually increases blood flow to the sweat gland, and in some people that will produce a huge amount of sweating. People develop hyperhydrosis, I've seen one or two patients who had such a severe reaction to increase serotonin that they literally were just dripping. You can, in milder cases, treat that with an anticholinergic medication most often, but it can be a bit, well, ineffective in really severe cases. and you have to look for something that is not an SSRI to treat their depression. I'd say the glycopyrolate's been really effective. I know that's when you talk about more of the peripheral, but not essentially.

Yeah. Lecopyrylate is an anticholinergic that does not effectively cross the blood-brain barrier. So it's often used when we're wanting to give something that's anticholinergic. that doesn't affect the acetylcholine in their brain. Another one that's currently in use is trospium, as you know, currently being used in the combination medication, covenphy, which is xenolamine, an acetylcholine agonist,

and trospium, an antagonist, trospine, trospine is being used to block the xenomaline peripherally to try to make the drug more tolerable. So the serotonin, is it also the norpenaphrin that plays a part in the sweating? Norophenephrin, it tends to decrease sweating because it decreases, it causes vasoconstriction. Oh, okay. You know, sweat is basically when you sweat that the liquid is being derived ultimately from blood plasma.

So if you have decreased blood flow to the sweat gland, you'll have decreased sweating. I think one of the most interesting points that I had never thought about is you talked about the location of the glands and that the sweat might even be, it was so funny, I had a patient that actually said that it was stinky sweat versus maybe night sweats and that actually the location, and the type of sweating may even vary. I thought that was an interesting point you made before. Yes. When you know, apicum sweat glands produce not only essentially order amounts to saline, they also produce lipids as well.

And it's, frankly, bacterial action on the lipids that causes people to smell bad when they sweat. It's very good. Tea tree. Essential oil is good because the bacterian fungus, a little. but so Blair, good questions. I really appreciate you pulling the good out of Cummings. These are ones that have come over over time with just different providers. And these are really common side effects that are really hard.

And I think one, the other one, that was a really good discussion that we've had. I mean, there's so many. I mean, so helpful. But a really interesting one that I don't know if you've come across this also, Dr. Peter, the menstrual irregularities with the SSRIs, Dr. Cummings. I know we've talked about that before. like having the hormonal fluctuations being impacted by that? Yeah, you know, late-lidial phase dysphoric disorder,

also sometimes called premenstrual syndrome, is an actual deficit in serotonin neurotransmission, which is why if somebody has a very regular period, that is, you know, you can predict when it's going to occur, they can actually treat their late-leof-phase dysphoria by taking an SSRI for only, well, usually for about 10 days before their mincees, and then once the ones you start, they can stop the drug and wait until the next month and do it again.

Of course, the problem for people who are not very regular, is if you can't predict, then you end up having to take the SSRI on a more ongoing basis, even though you really only need it for about a week to 10 days before the minces. So if someone taking an SSRI, say, every day, and female reports menstrual irregularities, there really is a level of the SSR impacting the hormones and not just their mood. So taking on a regular basis, would you be concerned about that? or just say that can be part of the medication acting on that level? Basically, the SSRIs, well, the hormone, it's a two-way street.

The hormones alter receptor sensitivity in the brain for both dopamine and serotonin. And in turn, the neuromodulators, the monoamines, alter the secretion of some of the hormones. So that you can, in some cases, if the modulation is not maintaining homeostasis, you can then help regulate it by using drugs that give the person a more consistent level of serotonin. Like rural contraceptives, it concerns them, basically. Now, well, there is a, you can see this more broadly. there's a reason that women during their reproductive years are four to five times more vulnerable to episodes of depression than our age-matched men. Interestingly, either the four menstruation starts or after menopause, the rates of major depression tend to be one-to-one

between the sexes. The up and down cycle of the mental cycle is, frankly, from the standpoint of the functioning of the brain, it's kind of hard on brain function. I actually wanted to go back to sweating because I did an episode on sauna, and one of the things that I found was that some people actually are on medications

that decrease the ability to sweat and they become more heat intolerant. Yes. And if they're taking an anticholinergic medication, they can become dangerously overheated either in sauna or certainly here in Southern California where I am, just summertime can be dangerous to them. So anticholinergic medication,

I'm thinking amotryptylene, oxybutin, you know, Benstrapine, tricyclic antidepressants, clozapine, olanzapine, quatypine. Yeah, anything with significant anticholinergy properties will decrease the person's ability

to sweat and therefore to lose heat. And if they're in a very hot environment, that can lead to either heat exhaustion or heat stroke. Also thinking about anti-psychotics, especially first-generation ones with their high affinity to the D2 receptors can cause hyperthermia through neuroleptic malignant syndrome and potentially through non-NMS

mechanisms by affecting the hypothalamus. Any thoughts on that? Basically, the very potent dopamine antagonists interfere with D2 receptors and the hypothalamus and can make people more pokeyothermic. That is, they tend to then drift toward the environmental temperature, either hot or cold. There have been cases where people living in cold climates who take a potent docketal. immune antagonist may become hypothermic more easily, or if they're living in a very hot climate, they may become hyperthermic. Yep.

So if you're getting into sauna like I am, then you're on an anticholinergic medication, tread carefully, and maybe start slow and you monitor your internal temperature. Okay. You can't use one to offset the other Dr. Cummings? I don't think that would be a very safe approach. It would be far better to be sure that you're well hydrated and as Dr. Peter suggests, monitor your internal temperature. Be sure you're not becoming hypothermic.

Put it like an anal thermometer in there, you know, like have some doctor oversight. Okay. So this was all talking about type A, which is augmented, dose-related, kind of like, along with the drugs, known pharmacology. And now let's talk about type B, which is bizarre idiosyncratic.

Yes. And one of the really good discussion we were just having recently was talking about some of the paradoxical effects we don't expect. And one of the things we were talking about were caffeine, dephedrine, like stimulants causing people get, tired, which on the flip side, something like Benadryl, making people more hyperactive and actually what you wouldn't expect. Can you expand on those, Dr. Cummings? Yeah. You probably everyone has observed that if somebody drinks too much coffee too quickly,

they may complain of feeling tired, sleepy, lethargic afterward, which is not what you would expect from caffeine, which blocks adenosine receptions. Adonacine is a minor inhibitory pathway in the brain for decreasing arousal. If however you kind of poke that system a little too hard, you'll cause a gap aurgic response. The major inhibitory neurotransmitter will be activated and it will shut down whatever increase in alertness you were having from lower levels of caffeine. caffeine. So you can, you can, essentially it's an example of poking the bear and the bear

fights back. Same thing is true with other stimulant drugs. There tends to be a counter response by GABA, and GABA is very effective at turning off brain activity. You can also see this with antihistamines though particularly in children and the elderly where if you block histamine receptors and most people they'll get drowsy but in children and the elderly in particular if you block histamine receptors you may turn off their cortex because that's where histamine receptors reside in the brain for the most part and their subcortical systems they're basal ganglia and the more inferior, posterior parts of their limbic system are now free of any regulation by the cortex that you've put to sleep. And the person becomes idiosyncratically excited. And in the

case of kids, they look like they're on the sugar rush of all time. You've created hyperactivity. Fortunately, as it wears off, they will calm down. Same thing in the elderly. You'll see somebody become very agitated. The children are usually easier to contain just because they're physically smaller. Occasionally, in the elderly, it can become dangerous because they may have become agitated to the point where they're at risk of harming either someone else or themselves. Well, it's something we don't always expect. I know especially as a child psychiatrist who, like, the way that children respond to medications is not always what, it's not many adults. let the same response.

Yes. No, children are not just small adults. We see some more of that paradoxical agitation and things that we don't always expect as much. So thank you. That's an interesting thing that I think a lot of times we don't think about what causes it. But can I ask a question there? Because we're talking about type B, bizarre, idiosyncratic. I mean, but Dr. Cummings is talking about a mechanism for how to make sense of it.

is that bizarre and idiosyncratic then or is that like just it it fits into the idiosyncratic in that it is not the expected response you know human beings of you know consumed coffee and tea other caffeine containing beverages mostly to produce an increase in alertness so it's idiosyncratic in that if you push too hard, you can produce a countervailing response in the brain. The histamine response is also, it's not bizarre, but it is unexpected in the sense that in the vast majority of people, if you give them an anahistamine, they'll get sleepy, but in a few cases they'll become very hyper alert, very agitated.

And that tends to show up mostly in children and the elderly. I don't think I've ever actually seen a case in an adult, although I've read that there have been adults who've had a similar response to antihistamines. And what's your mechanism for the antihistamine and kids for why they would have that hyperactamines? The anti-safety-sme, basically kids' brains and elderly brains are not as well integrated in terms of cortical and sub-cortical systems. And in the case of H-1 histamine receptors, those are mostly distributed in the cortex. You don't really find a lot of histamine receptors in subcortical systems. So if you give somebody an antihistamine, you're basically decreasing neuronal activity in the cortex.

And a more integrated brain that results also in a decrease subcortically via other communication systems. But if those subcortical systems are not all that well connected to the cortex yet, or they've lost some degree of connectedness, the subcortical systems may sort of run amok because they're no longer being modulated by the cortical systems. Very good. And did you want to bring up alopecia?

Yeah, this is, I think, something I've definitely heard from different medications and we've talked about Dr. Cummings is how medication can disrupt you know, normal hair growth during the growth phase, I think it was antigen, intelligent, the resting thing, that hair loss is a really disturbing to a lot of patients. Yes. You know, probably the most common drug that we use, again, not, it's not a bizarre response,

but it's certainly unexpected, is valproic acid is great at causing alopecia. And in the case of this drug, it's because, well, frankly, we didn't realize for many, many, many years that valproic acid aside from being an anti-epileptic and a mood stabilizer, it's also a deacetylase inhibitor, a histamine deacetalase inhibitor, which histone is the protein that wraps around your DNA and you have to, get it to unfold in order for the DNA to be replicated, if you give a deacetylase inhibitor like viparic acid, it prevents the histone from unwinding and therefore slows down mitosis. Turns out, voporic acid essentially is a chemotherapy agent, and like many of the chemotherapy agents, can cause alopecia. Because, you know, if you, if you're, if the The cells in your hair follicle can't undergo mitosis and produce adequate hair protein. You go bald.

Some of the other ones I know talk about lithium. I think acutely with weight loss, the joke. The brain has some similar effects in terms of decreasing the rate of protein synthesis in and hair cells in the follicle and therefore can produce alopecia. How do you know if hair loss is from a medication

and this may be too broad of a question versus from a different cause or from more pattern, you know, it's more because of the pattern balding or thing? For a lot of adverse side effects, at least the category A and category

B, essentially there's a fairly clear temporal association between the presence of the drug and the adverse effect. When you get into some of the more chronic adverse effects or the delayed effects, that basically depends a lot on knowing that that's a property of those drugs. It took us decades to figure out that lithium can cause renal insufficiency. And it took even longer for us to figure out that the best way to prevent that was to be sure that we never prescribed lithium in a divided manner. In fact, to this day, if you go back and read the package insert for lithium, it says to give lithium in a divided dosing schedule. which is exactly wrong because all you do is increase the risk to the person's kidney.

How would you, so it sounds like a lot of time looking when the agent was started, and I think we also talked about the pattern, like would it be more of an overall hair loss versus maybe a certain pattern of it, like more like male pattern balding, for example? Most medications cause patchy hair loss. Okay. Okay. That's a helpful. Of course, if it goes on long enough and it's severe enough, then it becomes, the person becomes completely bald.

As in the actual, the more robustly chemotherapy agents. Right. Use to tree cancer. Most of those people go completely bald. Although if you watch their baldness unfold, it's initially patchy and then it becomes contiguous. Good point. How would you treat the hair loss? Would you decrease the agent, change it, or how could...

There are a couple of things you can do. Selenium tends to be protective in both valproic acid and lithium cases. So you can try supplementing the person with selenium. These days you also have, well, what was developed originally is an anti-hypertensive monoxidil causes vasodilation so it improves the blood flow to the hair follicles when applied topically some of the dermatologists are also now using laser stimulation of the scalp again the underlying mechanism is to increase blood flow to the follicle and that can that can improve a reverse hair loss.

The real concern for some patients. Dr. Peter, did you want to weigh in it all? No, this is great. Any other common medications outside of lithium, bupric acid, gupis, agonists, cytotoxics? Biologics. Certainly, since they're a hot topic at the moment, the GLP1, agonists, if the person has too much weight loss,

too rapidly, it can cause a number of things, hair loss, loss of bone, and loss of muscle as well. You know, we've had a couple of cases where the person went from being obese to being underweight. And, you know, they were essentially too responsive to their GOP-1 agonist, and they needed, you know, They fortunately in both cases they needed and got their doses lowered so that they were not going to starve to death. The last patient we had who had to be taken off the GOP1 agonist for a while, basically she had no appetite. She would get up in the morning. She had one piece of toast and a glass of water and felt full for the whole day. Of course, you can't live long term on one piece of bread.

and a glass of water a day. Very important. Thank you. And moving on to the chronic and dose-related and time-related, you mentioned the osteoporosis and steroids, which is kind of a pretty well-known long-term effect. Yeah, the lithium and renal insufficiency is a good example of a chronic effect. You expand a little bit more on that and how we can,

you mentioned the once-a-day dosing, limit. Once a day dosing, yeah, lithium traps itself fairly effectively in the distal principal cells of the nephron. The best help for that is to give the kidney time to clear the lithium out of those cells. Lithium gets into them very easily, but doesn't get out very easily. So it takes much longer for the lithium to clear than it does for it to enter. So the longer the trough time you can give the person between lithium doses, the better. The good news is lithium also traps itself in the brain. So the brain half-life of lithium is substantially longer than the plasma half-life.

So we don't really need divided dosing. The brain half-life of lithium is 28 to 48 hours. so you know you don't have to take lithium several times a day in order to maintain your brain level of lithium makes more sense for the loading right the loading doses that it has longer in the brain yeah yeah the brain basically lithium even at non-toxic concentrations slows down the sodium potassium uh pump at the cell membrane, and that's the principal way it exits cells, while slowing that pump down means that it tends to get retained in cells longer than it will get retained, say, in plasma. One of the articles you sent me about the stratifying the risk of the lithium, and it talked about

even the 0.5, like it was actually, I know we aim usually for 0.6.8 with say bipolar, but that was kind of interesting. It was talking about the risk at like 1.2 versus, you know, 1.0, like, those long-term risks with the levels. Yeah. The higher the level, the bigger the risk, the more often it's dose, the bigger the risk. The recommendation, you know, it used to be that it was recommended that lithium could be

pushed up to as much as 1.4 millimoles per liter. The max recommendation now is 1.2, and it's really encouraged that it really shouldn't be allowed to go over 1. or at least not stay there very long under two weeks. Because having lithium levels greater than one or giving lithium a divided dosing essentially worsens the prognosis for renal function in the long term. So the doses, the long-term exposure,

some of it can be mediated, some of it's just, you know, a long-term risk. Also, Tardad dyskinesia, do you have any thoughts? about the long-term use of antipsychotics and yeah tardive dyskinesia i think people had hoped that when we moved from first generation to second generation antipsychotics that that risk would be greatly reduced well it was reduced it went from about an incident rate of 5.5 percent per year of exposure to 3.8 not as much of a decline as people have had hoped for.

I think the key is we need to monitor carefully for emergence of involuntary movements. We do need to, well, we need to use antipsychotics at effective doses. We need to be careful not to push the dose beyond the point of futility for the drug, because oversaturating the receptors is one of the, setups for causing upregulation of the receptor numbers, which seems to be a real risk factor for developing tardive syndromes like TD, tardivacetheia, yeah, all the things you really don't want to have. Thank you.

It was really helpful. And moving on to the tight-de delayed time release appearing after long exposure, the teratogenic effects. And I know we've kind of touched about this before, but there's the ones, of course, in pregnancy, but also for men, like you've been talking about the registries and sperm even for a few months, so that long-term exposure will be kind of buried on what that looks like. Do you want to expand on that? Yeah. Well, again, we're back to valproic acid.

People have been aware for quite a while that valproic acid does very bad things during pregnancy in terms of risk of neural tube defects, also risk of loss of intelligence in the offspring. Turns out men don't escape unscathed. Valkeric acid alters the methylation of DNA in sperm, so that if a man participates in fertilization within three months, months after the from the last dose of valproic acid there is an increased risk of neural behavioral disorder in the offspring it's not a huge increase but it's there well good thing to educate about

you know because we move more towards i know we're picking on valproc acid today i was going to say moving on to like the tremor is a really big one i know i hear a lot about i dr peter i feel like i hear that from a lot of different antidepressants, Deb coat lithium, the dystonic tremor, you mentioned am antipsychotics. Do you want to talk a little bit about that there's a lot of different types,

tremor from a lot of different things, plus the central tremor. Yeah, tremor, well, there are a number of types of tremor. The two most common types you see are from drugs like lithium of balkyric acid, where you're interfering with the firing of neurons.

And in order to you know, have your hand at a particular point in space, you have to be able to process the sensory input of where is your hand versus where you want it to be. And if the motor and sensory systems are a little bit out of phase with each other, the system overcorrects in both directions. So you get an intention tremor. Dastonic tremor is exactly what it sounds like. It's a dystonia that produces a rhythmic contraction of particularly the extensor muscles

and produces a tremor in the hands. This is from antipsychotics, the dystonic tremor? Yeah, distonic tremor comes from dopamine antagonist antipsychotics. Of course, you can also get a Parkinsonian tremor for the same mechanism except in this case, a direct effect on the LeBazil ganglia. How do you distinguish? So would a dystonic tremor for antipsychopi right away, or would that become a sooner one or the Parkinsonian?

The dystonic tremor tends to be immediate. The Parkinsonian tremor tends to be after a longer exposure. Okay. Would you treat them with amantadine? Would that be? Yes, she could treat both of them with amantadine. I know we've talked of avoiding anti-conergic, especially long-term. Would a beta blocker, I think when you think about a beta block more for like essential tremor,

but what about a tremor, save from, I know neurologist, I remember her neurologist didn't like valproic acid. I mean, they may use it for seizures, but like the lithium and the tremor from baroque acid. Yeah, lithium tremor and valproic acid, indeed. tremor resemble essential tremor in the underlying pathophysiology and they will respond to a beta blocker not so much in terms of eliminating the tremor but in reducing it now you can also get there by if the person's illness permits if you lower the dose of oproic acid or lithium that also will

reduce the tremor Now, and that's where we, tremor, the tremor actually was kind of a tricky one because it actually, a medication can have different categories. It like overlaps, right? Not just the one category. It might be delayed, but then it can be, might be dose related. Yeah, this classification system, you know, it's intended to talk about having essentially classes to put side effects in, but different patients can fall into different categories depending on the, timing and development of their side of it. And might exaggerate a physiological tremor, potentially. I think that was one of the things that I was reading about. Yes.

So one thing about the lithium is that usually it happens early on, but what if someone on lithium gets one later? Like what would you think? Like let's say all of a sudden their right hand has been shaking and they can get it to stop by moving, but it starts without them even noticing it. It's certainly, well, I would be suspicious of a couple of things.

I would want to know if their lithium level has changed because if it's dose-related or concentration-related, if you give any of us enough lithium, we'll have a tremor. In fact, that's one of the development of course tremors, one of the signs of lithium toxicity. So either the lithium has changed or the person may be developing an underlying tremor that's being aggravated by the lithium,

but may be independent of the lithium in terms of it's coming from an evolving pathology. So, you know, both of those things would be worth considering. When would it warn a neurology referral? I mean, because with even antidepressants, I've seen tremor before, like, I mean, would you try the adjusted pills, try a bit of blocker? When would you warrant a neurology referral for a trauma? Basically, when you can't figure out what the tremor is coming from,

from. And, you know, this is when you ask for help. In particular, you're looking for a neurologist who specializes in diagnosis of movement disorders. Okay. The reason for that being you can get pure movement disorders, but you can also get some interesting syndromes that are that are compilations of more than one type of movement disorder. And those can be incredibly complex and difficult to unravel. So let's say you had this patient and you were like, okay, I increased the lithium from 900 milligrams at night to 1,200 milligrams at night. Now they're having this tremor.

You check the blood level, the blood level went from like a 0.6 to 0.9. and, you know, they're on other medications, but those haven't really changed. So what would be your next step? Next step would probably be to lower the dose and see if it changes the tremor. Okay. And then let's say you really need them on the dose, though,

because, like, they're currently manic and you don't want them to go back into... Um... Or that you're treating the mania that recently manic. is going to respond very quickly. So I would still probably lower the dose for at least one day. Okay. And see what the tremor does.

If it changes, it tells me, yes, it's definitely the lithium. If I have to keep the lithium, that means I'm going to have to give them a beta blocker to treat the tremor. unless, you know, depending on what other factors, whether there are other mood stabilizers that they respond to or not. But if I'm going to keep the lithium, then at least I know for sure that the lithium is the source of the tumor. Which beta blocker would you pick?

Procriminal. The cross the blood-brain-barrier. Yes. Selective. A peripherally acting beta blocker is not going to address a problem that's coming from the person's basal ganglia. What if they have problems with asthma? Would there be a different, like primadone? You could use metoprolol because it also crosses the blood-brain barrier.

Okay. You just can't use a beta blocker like a tel-lol that doesn't effectively. get into the brain because your target, if you will, is the basal ganglary, and it's inside the blood-brain barrier. Let's move on to type E, types of side effects, which are end-of-use withdrawal, occur with stopping the medication, like benzodiazepine withdrawal, anticholonex.

Anything that, you know, basically anything that causes, chronic arousal, or anything that is a CNS depressant, if you give either category to somebody long-term, their brain systems will adapt so that the countervailing systems upregulate, and then if you suddenly take away, you know, either the stimulant or the brain depressant, you'll get the opposite response. For example, if it's a depressant,

the person will have benzodiazepine withdrawal, alcohol withdrawal, opioid withdrawal, activation symptoms, basically. On the other hand, if you suddenly take somebody off of a stimulant, they are going to be incredibly lethargic until their system comes back to homeostasis, which is why it's not good to if somebody's on either category the only way you can really avoid withdrawal is to taper the agent or put them on a cross-tolerant agent and then taper that i mean that you know for alcohol withdrawal that's basically what we do when we put the person on a benzodiazepine and then taper it uh you could stair step them down using alcohol itself but alcohols makes her it would be very hard to work with unless you had an IV alcohol drip. Now, you know, the major mistake I've seen made

with people who were serious drinkers and were going to develop delirium treatments while people overestimate how effective the benzodiazepines are going to be. I've seen orders like, well, way back in the day, 25 milligrams of Librium Q12 hours, PRN and alcohol withdrawal. Like that.

You know, 25 milligrams of librium or a milligram of lorazepam is equivalent to about one shot of whiskey. Well, when I worked at the VA, I had patients who would tell me I drink two-fifths of whiskey a day, every day. So, you know, giving this person a tiny dose of benzo and expecting it to treat their alcohol withdrawal was nonsense.

One of the really good things you were talking about recently was the anti-colonergic medication and someone on like cogenton programs, or you talk about changing the chlozapine to like maybe Benstroving cogentin to slowly tape people. The major thing that I've, where the acetylcholine systems have been involved is if somebody has for example, severe nutropine with chlozapine and their clozapine is then necessarily abruptly stopped. They're at real risk of colonergic rebound. Closopine, 50 milligrams of closopine is roughly equivalent to a milligram of vinstrel. So if you've got somebody on 500 milligrams of chlozapine, they're taking the equivalent of 10 milligrams of vinstapine.

If you suddenly stop that, you can put the person into colonergic rebound, which can include learium, nausea, vomiting, diarrhea, cramping, sweating. So if you have to stop the clothes of being like that, or any other really anticholinergic drug, you need to put them on an anticholinergic like then strepene and then tape with it. You say like a half milligram every...

You can only a half milligram per week. And I know before we've talked about the benzodiazepines, like I know we worry about any dose for the withdrawal seizures. But I think you've kind of mentioned for lower doses. I think if they're only on maybe a couple, one milligram of clenazepam, or maybe if they're only on the benzophanotropine, one milligram or something or two milligrams would be less concerned about those.

The lower the dose and the less time the person's been on the medication, the less likely withdrawal symptoms are. Now, the higher the dose than the longer they've been taking it, the more likely it is that they will have significant withdrawal because, again, the underlying mechanism is the countervailing systems have upregulated to concensate for the presence of the drug, and then suddenly the drug is gone, and there's nothing opposing those systems.

How slowly would you taper off a benzodiazepine? Like do you have a certain? Depends on how long the person's been on it and how high the dose. I think the longest it's taken me to get a person off of benzodiazepine was 18 months. And I think you recommend going with the longer acting, like the longer act. Yes. It's easier to taper a longer acting drug like clonazepam or previously daisapine. You know, we went through a period, fortunately it's not as prevalent anymore, where people

would come in and have had patients who came in taking 40 milligrams of dazepam, Valium a day, and in their history, asked, well, how long we've been taking it at this dose? Oh, three decades. Yes. Oh, my gosh. That person is going to take a, it's going to take them a while to get off of the benzodiazepine. you know that was that was the case actually that took me a year and a half because the person couldn't tolerate going down by more than about two and a half milligrams every couple of months they eventually got off though and did much better in terms of cognitive and memory performance what about um like seroton you know serotonin re-uptic inhibitors know there's been a lot of talk in the some new articles on the withdrawal of that.

What's your thoughts on? Yeah, the antidepressants, including the SSRIs, do have a withdrawal syndrome. I think until recently, psychiatry largely ignored it because the vast majority of such cases are relatively mild. and the person in the sense that the person doesn't feel well, kind of flu like malaise symptoms for a few days to two or three weeks, and then it gradually gets better and goes away. So it's not quite as dramatic as some of, you know,

certainly not as dramatic as, say, benzodiazepine withdrawal or opioid withdrawal. But the Afidepressants do come with a withdrawal syndrome, and truth is we should, if we're going to stop an antidepressant, we should be tapering. There is also data suggesting that abruptly stopping antidepressants may encourage a relapse of the depression. So we should be tapering people off of them. Unless there's some urgent medical need to take them off of the antidepressant. Dopamine antagonist. the hyperkinetic and the slow taper,

just seeing how they tolerate it, perhaps. Yeah, it's a bit like the titration and taper. I think historically we've tended to go a little too fast in both directions. And in fact, we've been talking quite a bit about clozapine. Jose de Leon just published a number of a series of papers, actually pointing out that we've probably been titrating, Lusapine too rapidly until very recent, particularly in some populations that don't metabolize the drug very well.

Which I also think that kind of leads us into the type F failure and unexpected. I know we're losing time really fast, we're only a few more minutes, but I wanted to, if you could briefly at least go over pharmacodynamic versus pharmacokinetic failures, because I know we talked a little bit earlier about metabolizers check. Yeah, pharmacodynamic failure, means that the activity of the drug, whether you're talking about inhibition of serotoninary uptake or antagonizing dopamine receptors, a pharmacodynamic failure means that the person's illness does not respond to what that drug does as its intended mechanism of action. A good example of

that is in, you know, there have been some recent magnetism Magnetic Resonant Spectroscopy, studies where they found that in treatment-resistant schizophrenia, those people actually have normal or decreased dopamine turnover in the ventral tegmentum. So it's not surprising that if you give them a dopamine antagonist, it doesn't treat their psychosis. You're basically giving them something that they don't need. you're off target in terms of your treatment. So that's a good example of pharmacodynamic failure. Your drugs mechanism of action isn't what the person's illness needs.

Pharmacokinetic failure means basically that the drug is not present in a sufficient amount to get above the minimum response threshold and to achieve. the threshold that this person needs. That can be for a number of reasons, can be because they don't take the drug, they're non-interrent. It can be because they don't absorb the drug. Some drugs require active transport in the GI Triactin. They don't get absorbed very well.

And there are also ultra-rapid metabolizers for drugs. And if the person basically their liver should, choose up the drugging and eliminates it before it can reach its target organ. Those are all examples of pharmacokinetic failure. Maybe unusual, but you mentioned a patient on a dose of halal 80, and their level is only two. Yeah, we had that patient, younger African-American male. And people were very puzzled for him because he was titrated up to 8 zero milligrams of haloperidol in the mornings. And he took it.

But his plasma level got to a grand toll of two nanograms per millimetri. Trick in his case was to switching to an antipsychotic that didn't principally go through, aside from few 450 to D6. Thank you. Great. Well, this is an important discussion, maybe not the most entertaining of late. Delusions is, I don't know, much more fascinating to me, but I think this is the practical stuff of sometimes

a lot of what we do in outpatient psychiatry is manage side effects of medication, patients get better on absurd medication, and then have some side effect. And it's like, what do we do next, right? And it's like a lot of what we do is think about how we minimize side effects. And a lot of our decision making is around, do we decrease the med? Do we try to treat the side effect another way?

And I think it's important as providers to think that our medications can cause side effects and getting them off of medications can cause other side effects. So, yeah, this is a great discussion. Thank you so much, guys. Thank you, guys. Okay. Thanks.