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

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. https://www.psychiatrypodcast.com/cme-program Link to blog https://www.psychiatrypodcast.com/psychiatry-psychotherapy-podcast/episode-271-rawlingsthompson-a-f-classification-low-slow-titration-amp-real-world-management-with-dr-michael-cummings-amp-dr-blaire-heath Link to YouTube video https://youtu.be/Eo--FJxEw1Y

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:14David Puder?

  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, 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?

• 0:46Speaker 01

  Well, I really appreciate Dr. Cummings' guidance over the years. And there's so many difficult areas of prescribing that having a psychopharmacology expert to help give us some awareness on how to approach new patients, prescribing situations, and side effects. So I thought we'd 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.

• 1:17David Puder?

  Great. Dr. Cummings, do you want to talk about your general approach to prescribing? And especially with the focus on adverse effects?

• 1:27Speaker 02

  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,

• 2:11Speaker 02

  at which at least 5% of the population will show a response.

• 2:17Speaker 02

  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.

• 2:55Speaker 02

  It can save a lot of confusion and not getting through 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, about that, Dr. Heath?

• 3:37Speaker 01

  That was kind of a lot of it. I think one of the things that, you know, we talked about like for antipsychotic, you know, I think we even 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.

• 3:56Speaker 02

  Yeah, there's 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.

• 4:13Speaker 02

  Is about eighty percent 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, you know, eventually you'll either get a response or you will 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.

• 4:58Speaker 02

  But at two weeks, the antidepressants and antipsychotics at least will produce about eighty percent of what they're going to.

• 5:07David Puder?

  Is that the case for OCD and anxiety?

• 5:11Speaker 02

  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 eighty percent of the response you're going to. I think the other, 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 three hundred to four hundred milligrams of sertraline, whereas for depression, the quoted dose range

• 5:55Speaker 02

  is fifty to two hundred milligrams per day.

• 5:58Speaker 01

  I really like how, what he was talking about just a few minutes ago, where we, 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, downregulating, and of course, the sensitivities based on, you know, metabolism. Can you talk a little bit about trying to address side effects and how we, those, you know, we, high doses?

• 6:26Speaker 02

  Yeah, the, um. 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 and 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.

• 7:12Speaker 02

  If the drug also has antihistaminic properties, you'll make them sleepy. And they'll, 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, 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

• 7:58Speaker 02

  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 increase in drug.

• 8:18Speaker 01

  You identify certain approach, like I, 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 they're a slow metabolizer, but I'll like go really low and slow to try to come establish that rapport. 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.

• 8:40Speaker 02

  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? Uh, that may help you not only with the rate of titration, but also with medication choice. Uh, 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, uh, a particularly bad actor in that area.

• 9:13Speaker 01

  And you talk about the uh bedtime dosing, not doing stuff more than twice a day. I saw this a lot as a pharmacist, people do give stuff three, you know, three times to four times a day. People always forget that middle dose, but.

• 9:26Speaker 02

  Yeah, most, 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, uh, adherence is a lot better if somebody's taking something once a day.

• 10:09Speaker 02

  Uh, most of us are pretty good at remembering to take something either when we get up or when we go to bed. Um, 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?

• 10:32Speaker 01

  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 going off theme, even IR and ER, even though the half-life of technically the IR is um 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.

• 11:00Speaker 02

  Yeah, for most of the drugs that have.

• 11:04Speaker 02

  Concentration-related side effects. If you can make the peak less steep, the drug becomes more tolerable. A good example of that is Valproacap. Divalprox, immediate release, produces the same side effects, but produces them about twice as often as the extended release formulation of Divalprox ER.

• 11:37Speaker 01

  Thank you. And one of the biggest things 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 there, this is, 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, you know, that situation?

• 12:14Speaker 02

  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

• 12:58Speaker 02

  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.

• 13:15David Puder?

  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 2 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 in 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.

• 13:55Speaker 01

  Now, if 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're gonna take them on? Is that responsible?

• 14:08Speaker 02

  It need not be acceptance of them as a patient at that first visit, but you need to be clear that 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.

• 14:27David Puder?

  I personally have that in my intake paperwork, that the first visit is a consultation. It's, 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 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 at this point, cash pay practice.

• 15:12David Puder?

  And that's just a reality, but yeah.

• 15:17Speaker 02

  Yeah. Dr. Peter makes a very good point. Having that in your intake paperwork. And having the patient acknowledge 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.

• 15:44David Puder?

  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, at that, you know, 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, I, they agreed. So I think, 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, what the story is, you know, especially if they come in,

• 16:28David Puder?

  you know, very demanding, very, you know, sure that this is the only medications that have ever helped.

• 16:37David Puder?

  So, yeah. What do you think? Is that reasonable, Michael Cummings?

• 16:41Speaker 02

  Yeah, I think that's very reasonable. You know, basically, the doctor-patient relationship is just that. It's a relationship. It's a 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.

• 17:05Speaker 02

  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.

• 17:15Speaker 02

  And I I'm very careful about educating patients about medications. That's an inherent part of prescribing. I I know a lot of, 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 upfront what to expect.

• 17:53Speaker 01

  Really know to come back to you. I know you 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.

• 18:03Speaker 02

  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 and 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? Uh, 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.

• 18:46Speaker 02

  That goes a long way toward making the medication more tolerable.

• 18:49Speaker 01

  Yeah, I had a patient that was, actually I found here in the hospital and I called him like, I'm like, oh, oh dear, you're in isolation room with TV. And I was going to get off, but the patient was really scary because their urine had turned red because of when the TB medications, I told him, oh, that's actually a side effect of that 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. And I was like, oh, okay, that's why I'm having red tears, red, you know? Uh, that expectation can make a really big difference.

• 19:22Speaker 03

  Yeah.

• 19:22Speaker 01

  On how people handle things. So is there any other things, Dr. Peter, that you wanted to add? Or do, are you okay if we move on to those different types of side effects?

• 19:31David Puder?

  There was, there was one thing coming, 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.

• 19:40Speaker 01

  And so we had to kind of like expand. So we just thought we'd go over the categories. This is based on, um, I don't know if you mentioned our findings, but the Merck manuals. There's the A through S. So we had.

• 19:53Speaker 02

  Yeah, these, these appear them work manual. They're actually, they're, they're called the Rawlings Thompson side effect classification. Uh, you know, like everything else, there's more than one classification out there. This one is particularly popular though. Uh, type A is an extension of what the drug does. Uh, either as 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 Merck manual, the example to give is if, if you were to give somebody too much warfarin, bleeding could become a side effect.

• 20:31Speaker 02

  But same thing, if you gave 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 antihistaminic. So they can make people orthostatic, make them dizzy. Or they can give them anticholinergic side effects, or they can make them sleepy. All of those are category A, uh, 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.

• 21:16Speaker 02

  But they 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. Uh, 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 a person's taken lithium for decades. That's a good example. Or osteoporosis if the person's been taking steroids for many years is a category C side effect.

• 22:01Speaker 02

  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. 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.

• 22:44Speaker 02

  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. Classic example of that is you give somebody an antibiotic for an infection and they have no benefit. The drug, the microbe has become resistant to that particular antibiotic, you didn't know that. Yeah. 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

• 23:29Speaker 02

  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 treatment 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.

• 24:08Speaker 02

  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, these, this isn't schizophrenia. This is something else. And they finally figured out, indeed, there was an antibody inflammatory encephalitis. You know, and they needed steroids. They didn't need an antipsychotic.

• 24:31David Puder?

  That's a great point. When, when there's a 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 reexamine, are there drugs or alcohol on board some? 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?

• 25:11Speaker 02

  So. And, uh, you know, it's always, if the treatment or response is not what we expect, we need to be very careful not to forget that our diagnostic impression may not be right or may not be complete. So we need to be willing to go back and exam- 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,

• 25:52Speaker 02

  now the patient, when they were hospitalized, when they were imprisoned, rather, uh, they malingered having psychotic symptoms. They got put on an antipsychotic and eventually developed tardive 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 cell. Unfortunately, to their own detriment eventually, but nobody ever questioned whether they actually had a psychotic illness, even though.

• 26:33Speaker 02

  People would write repeatedly that no psychotic symptoms were being observed. They were simply being rurally reported. You know, so we need to be careful about diagnosis.

• 26:46David Puder?

  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 flair to it. But she had developed real consequences of surgeries that were exploratory and, you know, she had got it, gotten addicted to trying to have another surgery to, for, for the benefit of having a relationship with a surgeon, you know, and this connectedness that she was getting from that. So, real consequences came from this, I think that's what you're describing here. Coming to your example, it's like, real consequences came from this side effect of the actual treatment.

• 27:30David Puder?

  And this is where it gets complicated as we were 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 gain that they were seeking for first?

• 27:45Speaker 01

  That goes back to what, you know, the education when you first start the medication. It's like being very real, you, you know, you have, you're reporting these symptoms. You might want this medication, but, you know, we have to determine whether or not it's 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 that true, those true symptoms because they be realized, oh, maybe it's not worth that secondary, that adverse effect because of the secondary, you know, the immediate gain.

• 28:18Speaker 02

  Mm-hmm. Yeah, you know, a lot of the treatments we prescribe, 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.

• 28:36Speaker 01

  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 warfarin or Coumadin. And you touched upon the orthostat hypotension. I wonder if you could go a little bit more into that. I know it's something you get with a lot of medications. You mentioned the slow titration, right? Can help decrease the amount of dizziness? Like, can you?

• 29:02Speaker 02

  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 blood 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.

• 29:47Speaker 02

  You know, 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, 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.

• 30:14Speaker 02

  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 vessels 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 midadren 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.

• 30:55Speaker 02

  Same thing is true of a lot of the other effects, like drugs that block histamine receptors.

• 31:03Speaker 02

  And make people sleepy. If the histamine receptors upregulate, that sleepiness tends to go away. You can also help that by the timing. Don't give personal major dose of antihistaminic drug first thing in the morning. You know, they might be better at night when it can maybe actually help them sleep. Anticholinergic 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.

• 31:46Speaker 02

  And if you're giving one that's anticholinergic, try to avoid others. In other words, avoid adding to the problem.

• 31:55Speaker 01

  Thank you. That's really helpful, but a lot of times people might be on, you know, olanzapine, anatrazidone, and you know, on several things that can cause that orthostatic or then have that.

• 32:07Speaker 02

  Yeah, a lot of these, because these are, 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 anticholinergic 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.

• 32:35David Puder?

  When, when I think about this specific issue of orthostatic hypotension, I think about trazodone, clozapine, serquel, risperdone. And probably the biggest issue I've had is in clozapine personally. Where it's like, we really have to add in a secondary medication to raise the blood pressure like midadren.

• 32:56Speaker 02

  Yes.

• 32:58David Puder?

  Yeah.

• 32:59Speaker 02

  Yeah, clozapine, despite being the gold standard for treatment of tremor resistant 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 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.

• 33:32David Puder?

  Here would be a good board question. Patient's on clozapine, but has some PTSD as well and is having nightmares, already having some orthostatic hypotension. Do you treat with Prozocin?

• 33:47Speaker 01

  I was gonna say, I would avoid an anti, I would avoid an antihypertensive, maybe use some Topamax that has some off-label PTSD and with the decreased appetite. I love them, the Prozocin, the Clonidine, the Guanfacine, 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.

• 34:17Speaker 02

  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 two agonists cause sedation and lower blood pressure. If you're giving the person clozapine, that may not make a great combination.

• 34:42Speaker 01

  Sometimes people put an alpha two agonist with an alpha one antagonist. Like I've seen the, that came to me on, two of them together, like a Prozocin 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?

• 35:01Speaker 02

  Yeah, well, and frankly, prazosin has taken a hit. I know the VA did a very large scale study of prazosin in combat PTSD and found that it had zero effect on nightmares.

• 35:16David Puder?

  So initial studies were more positive than more recent studies, is that what you're saying?

• 35:21Speaker 02

  The initial studies were positive. In fact, it, um, a lot of the literature started, uh, University of Washington and, uh, the VA in Washington state. The VA finally though, uh, did a large scale national study with literally thousands of veterans. Some of them, well randomized to either be on prazosin or not. And they found, uh, essentially the prazosin did not achieve a significant difference over placebo. Now, people have looked at that and said, well, maybe it's such a large study

• 36:02Speaker 02

  that it may have buried some subgroups that might be responders to prazosin. But it certainly suggests that prazosin was not nearly as effective in treating nightmares and PTSD as people had expected.

• 36:23Speaker 01

  Sometimes having a creative, you know, looking at that overall picture and, you know, seen as a really effective or that can become a tough one to approach. So thank you. Another one that we, 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 like SSRIs, especially SRIs. And I know that's been, um, do you want to talk a little bit about, you know, that, maybe how we can approach that?

• 36:51Speaker 02

  Yeah, well, you know, the SSRIs are block the reuptake transporter for serotonin, which of course means that they increase the amount of serotonin uh, available in synapses and our sweat glands uh, are modulated in part by, well, they're modulated by acetylcholine, serotonin and norepinephrine. Norepinephrine will tend to decrease sweating because it decreases blood flow.

• 37:26Speaker 02

  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 undevelop hyperhidrosis. And I've seen one or two patients who had such a severe reaction to increased serotonin that they literally were just dripping. You can, in milder cases, treat that with anticholinergic medication most often. But it can be a bit, ah, well, ineffective in really severe cases. You have to look for something that is not an SSRI to treat their depression.

• 38:11Speaker 01

  I'd say that glycopirolate's been really effective. I know that's what you talked about more, the peripheral, but not as centrally.

• 38:19Speaker 02

  Yeah. Yeah. Glycopirolate is an anticholinergic that does not effectively cross the blood-brain barrier. So it's, uh, it's often used when we're wanting to give somebody 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 code Benfia, which is zinolamine, uh, an acetylcholine agonist. And trospium, an antagonist, trospium is being used to block the zinolamine peripherally

• 39:03Speaker 02

  to try to make the drug more tolerable.

• 39:05Speaker 01

  So the serotonin, is it also the norepinephrine that plays a part in this sweating?

• 39:11Speaker 02

  Norepinephrine, um, it tends to decrease sweating because it decreases, it causes vasoconstriction.

• 39:20Speaker 01

  Oh, okay.

• 39:21Speaker 02

  You know, sweat is basically, um,

• 39:25Speaker 02

  When you sweat, that the liquid is being derived ultimately from blood plasma. So if you have a decreased blood flow to the sweat gland, you'll have decreased sweating.

• 39:36Speaker 01

  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 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.

• 39:59Speaker 02

  Yes. When you know, apocrine 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 on their sweat.

• 40:22David Puder?

  Sweet. Good. Tea tree. Essential oil is good in a, kills the bacteria and fungus a little bit. Soap. Blair, good questions. I really appreciate you pulling the good out of coming.

• 40:37Speaker 01

  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, it's 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.

• 41:05Speaker 02

  Yeah. You know, late, late luteal phase dysphoric disorder, also sometimes called premenstrual syndrome, is an actual deficit in serotonin neurotransmission.

• 41:24Speaker 02

  Uh, which is why if, if somebody has a very regular period, uh, that is, you know, you can predict when it's going to occur, they can actually treat their late libido phase dysphoria by taking an SSRI for only, well, usually for about 10 days before their menses. And then once the menses start, they can stop the drug and wait till 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 wind up having to take the SSRI on a more ongoing basis,

• 42:05Speaker 02

  even though you really only need it for about a week to 10 days before the menses.

• 42:12Speaker 01

  So if someone taking an SSRI, say, every day and, you know, female reports menstrual irregularities, there really is a level of 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?

• 42:33Speaker 02

  Uh, 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, 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.

• 43:18Speaker 01

  The oral contraceptives that concerns them, basically.

• 43:22Speaker 02

  Mm-hmm.

• 43:24Speaker 02

  Now, 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 before menstruation starts, or after menopause, the rates of major depression tend to be one to one between the sexes. The, the up and down cycle of the menstrual cycle is frankly, from the standpoint of the functioning of the brain, is kind of hard on, on brain function.

• 44:09David Puder?

  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.

• 44:27Speaker 02

  Yeah.

• 44:29David Puder?

  And

• 44:30Speaker 02

  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.

• 44:46David Puder?

  So anticholinergic medication, I'm thinking amitriptyline, oxybutynin, you know, benzapine, tricyclic antidepressants, clozapine, alenazepine, quetiapine.

• 45:00Speaker 02

  Yeah, anything with significant anticholinergic 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.

• 45:17David Puder?

  Also thinking about antipsychotics, 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?

• 45:44Speaker 02

  Basically, the very potent dopamine antagonists interfere with D2 receptors in the hypothalamus and can make people more hypothermic, that is, they they tend to then drift toward the environmental temperature, either hot or cold. There there have been cases where people living in cold climates who have taken a potent dopamine antagonist may become hypothermic more easily, or if they're living in a very hot climate, they may become hyperthermic.

• 46:22David Puder?

  Yep. So if you're getting into sauna like I am, and you're on an anticholinergic medication, tread carefully and maybe start slow and you monitor your internal temperature. Okay.

• 46:39Speaker 01

  You can't use one to offset the other, Dr. Cummings?

• 46:43Speaker 01

  You can't?

• 46:45Speaker 02

  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.

• 46:56Speaker 02

  Be sure you're not becoming

• 46:58David Puder?

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

• 47:27Speaker 01

  Yes. And one of the really good discussion we were just having recently was talking about some of the paradoxical effects we don't don't expect. And one of the things we're talking about were caffeine, cetacean, like stimulants causing people to get tired, which on the flip side, something like Benadryl, making people more active, hyperactive, and actually what you wouldn't expect. Can you expand on those, Dr. Cummings?

• 47:52Speaker 02

  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 receptors. Adenosine 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 gaparic response. The major inhibitory neurotransmitter will be activated,

• 48:34Speaker 02

  and it will shut down whatever increase in alertness you were having from lower levels of 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. It, 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 in most people, they'll get drowsy.

• 49:17Speaker 02

  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, their 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 kind of become, they look like they're on the sugar rush of all time. They've, you, you've created hyperactivity.

• 49:59Speaker 02

  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.

• 50:25Speaker 01

  Well, it's something we don't always expect. I know, especially as child psychiatrists who play, you know, the way that children respond to medications is not always what it's not as many adult with the same response.

• 50:37Speaker 02

  Yes, no, children are not just small adults.

• 50:42Speaker 01

  We see some more of that paradoxical agitation and things that we don't always expect as much. So, thank you. That's a interesting thing that I think a lot of times we don't think about what causes it.

• 50:52David Puder?

  But can I ask a question there? Because we're talking about type B bizarre idiosyncratic. I mean, but you, 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?

• 51:10Speaker 02

  It, it fits into the idiosyncratic in that it is not the expected response. You know, human beings have, you know, consumed coffee and tea, other caffeine containing beverages, mostly to produce an increase in alertness. So it's, 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

• 51:52Speaker 02

  that in the vast majority of people, if you give them an antihistamine, 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.

• 52:23David Puder?

  And what's your, what's your mechanism for the antihistamine in kids for why they would have that hyperactive response?

• 52:29Speaker 02

  Basically, kids' brains and elderly brains are not as well-integrated in terms of cortical and subcortical systems. And in the case of H1 histamine receptors, those are mostly distributed in the cortex. There, 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. In a more integrated brain, that results also in a decrease subcortically via other

• 53:13Speaker 02

  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.

• 53:33David Puder?

  Very good. And did you want to bring up alopecia?

• 53:37Speaker 01

  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 Anagen, Intelligen, the rest, that hair loss is a really disturbing to a lot of patients.

• 54:01Speaker 02

  Yes. You know, probably the most common drug that we use, again, not, it's not a bizarre response, but it was certainly unexpected, is valproic acid is great at causing alopecia.

• 54:20Speaker 02

  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 deacetylate inhibitor, a histamine deacetylate 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 deacetylate inhibitor like valproic acid, it prevents

• 55:01Speaker 02

  the histone from unwinding and therefore slows down mitosis. Turns out valproic 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 cells in your hair follicle can't undergo mitosis and produce adequate hair protein, you know, it, you're, you go bald.

• 55:31Speaker 01

  Some of the other ones I know talk about lithium. I think acutely with the weight loss, the gel.

• 55:36Speaker 02

  Lithium has some, has some similar effects in terms of decreasing the rate of protein synthesis in, in hair cells and the follicle and therefore can produce alopecia.

• 55:53Speaker 01

  How do you know 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?

• 56:07Speaker 02

  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. You know, it took, it took us decades to figure out that.

• 56:49Speaker 02

  Lithium can cause renal insufficiency.

• 56:53Speaker 02

  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'll, all you do is increase the risk to the person's kidney.

• 57:20Speaker 01

  How would you, um, 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 certain, certain, a certain pattern of it, like more like male pattern balding, for example?

• 57:36Speaker 02

  Um, most medications cause patchy hair loss.

• 57:40Speaker 01

  Okay. Okay. That's a helpful.

• 57:44Speaker 02

  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, uh, the more robustly chemotherapeutic agents.

• 57:57Speaker 01

  I.

• 57:57Speaker 02

  Used to treat cancer, most of those people go completely bald. Although if you watch their baldness unfold, it's initially patchy and then it becomes contiguous.

• 58:09Speaker 01

  Good point. How would you treat, uh, the hair loss? Would you decrease the agent, change it, or how could?

• 58:17Speaker 02

  Uh, there are a couple of things you can do. Uh, selenium tends to be protective, uh, in both valproic acid and lithium cases. So you can try supplementing the person with selenium. Uh, these days you also have, well, what was developed originally as nanti hypertensive, um, minoxidil uh, causes vasodilation. So it improves the blood flow to the hair follicles when applied topically.

• 58:49Speaker 02

  Um, some of the dermatologists are also now using laser stimulation of the scalp. Again, uh, the underlying mechanism is to increase, um, blood flow to the follicle. Uh, and that can, that can improve or reverse hair loss.

• 59:07Speaker 01

  The real concern for some patients, Dr. Peter, did you want to weigh in at all?

• 59:12David Puder?

  No, this is, this is great. Um, any other common medications outside of lithium? Papric acid, GLP agonists, cytotoxics, biologics?

• 59:25Speaker 02

  Hmm. Certainly, since they're a hot topic at the moment, the GLP-1 agonist, if the person has too much weight loss, too rapidly, uh, it can cause a number of things, hair loss, loss of bone and loss of muscle as well. You know, we've had, uh, a couple of cases where the person went from being obese to being underweight. And, you know, they were essentially too responsive to their GLP-1 agonist. And they needed, you know, they fortunately, in both cases, they needed and got their doses lowered

• 1:00:10Speaker 02

  so that they were not going to starve to death. Um, the last patient we had who had to be taken off the GLP-1 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 glass of water a day.

• 1:00:38Speaker 01

  Very important. Thank you. Um, 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.

• 1:00:50Speaker 02

  Mm-hmm. Yeah. Well, the lithium and renal insufficiency is a good example of a chronic effect.

• 1:00:57Speaker 01

  Can you expand a little bit more on that and how we can, you mentioned the once-a-day dosing?

• 1:01:02Speaker 02

  Once-a-day dosing, the, yeah, lithium traps itself fairly effectively in the distal principal cells of the nephron. The best

• 1:01:14Speaker 02

  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 twenty, twenty-eight to forty-eight hours.

• 1:01:58Speaker 02

  So, you know, you don't have to take lithium several times a day in order to maintain your brain level of lithium.

• 1:02:06Speaker 01

  Makes more sense for the loading, right? The loading doses that has longer in the brain?

• 1:02:11Speaker 02

  Yeah. Uh, yeah, the brain, uh, 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. Well, slowing that pump down means that it tends to get retained in cells. Longer than it will get retained, say, in plasma.

• 1:02:41Speaker 01

  Uh, one of the articles you sent me about this stratifying the risk of, of the lithium and it talked about even the point five. Like it was actually, I know we aim usually for point six, point eight with say bipolar, but that was kind of interesting. It was talking about the risk at like one point two versus, you know, one point O, like those long-term risks with the levels.

• 1:02:59Speaker 02

  Mm-hmm. Yeah. Uh, the higher the level. The bigger the risk and the more often it's dosed, 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 one point four millimoles per liter. The max recommendation now is one point two. And it's really encouraged that it really shouldn't be allowed to go over one. Or at least not stay there very long, under two weeks. Um. Because. Having lithium levels greater than one or giving lithium a divided dosing.

• 1:03:40Speaker 02

  Essentially worsens the prognosis for renal function in the long term.

• 1:03:48Speaker 01

  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 tardive dyskinesia, give me thoughts about the long-term use of antipsychotics? And?

• 1:04:02Speaker 02

  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% per year of exposure to 3.8. Not as much of a decline as people had hoped for.

• 1:04:30Speaker 02

  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

• 1:05:09Speaker 02

  like TD, tardive atherosia, yeah, all the things you really don't want to have.

• 1:05:17Speaker 01

  Thank you. It's really helpful. And moving on to the TID, delayed time release, appearing after long exposure, the tretogenic effects. And I, 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, we kind of buried on what that looks like. Do you want to expand on that?

• 1:05:42Speaker 02

  Yeah. Well, you know, 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. Valproic acid alters the methylation of DNA in sperm. So that if, if a man participates in fertilization, within three months after, from the last dose of valproic acid,

• 1:06:26Speaker 02

  there is a, an increased risk of neuro behavioral disorder in the offspring. It's not a huge increase, but it's there.

• 1:06:37Speaker 01

  Oh, good thing to educate about, you know, because we move more towards, I know we're picking on valproic acid today. I was going to say moving on to like the tremor is a really big one. I know here about Dr. Peter. I feel like I hear that from a lot of different antidepressants, Debcoate lithium, the dystonic tremor. You mentioned 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.

• 1:07:05Speaker 02

  Yeah, tremor, well, there are a number of types of tremor. The two most common types you see are from drugs like lithium or valproic 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,

• 1:07:26Speaker 02

  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. Dystonic tremor is exactly what it sounds like. It's a dystonia

• 1:07:50Speaker 02

  that produces a

• 1:07:54Speaker 02

  a rhythmic contraction of particularly the extensor muscles and produces a tremor in the hands.

• 1:08:03Speaker 01

  This is from antipsychotics, the dystonic tremor?

• 1:08:07Speaker 02

  Yeah, dystonic 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 basal ganglia.

• 1:08:24Speaker 01

  How do you distinguish? So would a dystonic tremor for antipsychopathy right away? Or would that be, would that become a sooner one or the Parkinsonian?

• 1:08:32Speaker 02

  The dystonic tremor tends to be immediate. The Parkinsonian tremor tends to be after a longer exposure.

• 1:08:43Speaker 01

  Okay, would you treat them with amantadine? Would that be?

• 1:08:47Speaker 02

  Yes, you could treat both of them with amantadine.

• 1:08:50Speaker 01

  I know we've talked about avoiding anticondor dix, especially long term. Even though

• 1:08:56Speaker 01

  would a beta blocker? I think when you think about a beta blocker for like essential tremor. But what about a tremor, say from? I know neurologists, I remember here neurologists didn't like valproic acid. I mean, they may use it for seizures, but like the lithium and the tremor from valproic acid.

• 1:09:12Speaker 02

  Lithium tremor, yeah, lithium tremor and valproic acid induced tremor resemble essential tremor in the underlying pathophysiology. And they, they will respond to a beta blocker.

• 1:09:28Speaker 02

  Not so much in terms of eliminating the tremor, but in reducing it. Now you can also get there by if, if the person's illness permits, if you lower the dose of valproic acid or lithium, that also will reduce the tremor.

• 1:09:46Speaker 01

  Now, and that's where we tremor this 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 might be delayed, but then it can be might be dosed.

• 1:09:59Speaker 02

  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 effect.

• 1:10:19Speaker 01

  And might exaggerate a physiological tremor potentially. I think that was the things that I was reading about.

• 1:10:27Speaker 02

  Yes.

• 1:10:28David Puder?

  So, 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, 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.

• 1:10:51Speaker 02

  It 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 coarse 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

• 1:11:32Speaker 02

  aggravated by the lithium, but maybe independent of the lithium in terms of it's it's coming from an evolving pathology.

• 1:11:43Speaker 02

  So you know, both of those things would be worth considering.

• 1:11:47Speaker 01

  When would it warrant a neurology referral? I mean, because with even antidepressants, I've seen tremor, tremor before, like, I mean, would you try the adjusted dose, try a beta blocker? When would you warrant a neurology referral for a tremor?

• 1:12:03Speaker 02

  Basically, when you can't figure out what the tremor is coming from.

• 1:12:08Speaker 02

  And, you know, this is when you ask for help. And in particular, you're looking for a neurologist who specializes in diagnosis of movement disorders.

• 1:12:21Speaker 01

  Okay.

• 1:12:22Speaker 02

  Uh, the reason for that being,

• 1:12:27Speaker 02

  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.

• 1:12:43David Puder?

  So let's say you had this patient and you were like, oh, okay, I increased the lithium from 900 milligrams at night to 1200 milligrams at night. Now they're having this tremor. Uh, you, you check the blood level, the blood level went from like a point six to a point nine. And, you know, they're on other medications, but those haven't really changed. So what would be your next step?

• 1:13:09Speaker 02

  Next step would probably be to lower the dose and see if it changes the tremor.

• 1:13:16David Puder?

  And then let's, 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.

• 1:13:25Speaker 02

  Um.

• 1:13:27David Puder?

  Or that you're treating the mania, they're recently manic.

• 1:13:30Speaker 02

  Is going to respond very quickly. So I, I would still probably lower the dose for at least one day.

• 1:13:38David Puder?

  Okay.

• 1:13:39Speaker 02

  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 uh, to treat the tremor.

• 1:13:56Speaker 02

  Um, 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, uh, then at least I know for sure that the lithium is the source of the trauma.

• 1:14:13Speaker 03

  Okay.

• 1:14:14Speaker 01

  Which beta blocker would you pick?

• 1:14:16Speaker 02

  Uh, propranolol.

• 1:14:18Speaker 01

  The press, the, the non crosses the blood brain barrier.

• 1:14:22Speaker 02

  Yes.

• 1:14:23Speaker 01

  Selective.

• 1:14:24Speaker 02

  There's a peripheral, a peripheral acting beta blocker is not going to address a problem that's coming from the person's basal ganglia.

• 1:14:33Speaker 01

  Would they have problems with asthma? Would there be a different like Primadon or?

• 1:14:38Speaker 02

  Uh, you could use metoprolol, uh, cause it also crosses the blood brain barrier.

• 1:14:46Speaker 01

  Okay.

• 1:14:47Speaker 02

  You just can't use a a beta blocker like a Tantalol that doesn't effectively get into the brain because the your target, if you will, is the basal ganglia and it's inside the blood brain barrier.

• 1:15:04David Puder?

  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.

• 1:15:15Speaker 03

  Mm hmm.

• 1:15:16David Puder?

  Anticholinergics.

• 1:15:17Speaker 02

  Anything that, you know, basically anything that, um, 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, um, you'll get the opposite response. For example, if it's a depressant, the person will have,

• 1:16:01Speaker 02

  you know, benzodiazepine withdrawal, alcohol withdrawal, opioid withdrawal, you know, activation symptoms, basically.

• 1:16:11Speaker 02

  On the other hand, if you suddenly take somebody off of a stimulant, uh, 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, 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 alcohol's mixer

• 1:16:53Speaker 02

  would be very hard to work with unless you had an IV alcohol drip. Now, you know, the major mistake I've seen made in with people who were serious drinkers and were going to develop delirium treatments was 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, Q 12 hours PRN alcohol withdrawal.

• 1:17:27Speaker 01

  My God.

• 1:17:28Speaker 02

  You know, 25 milligrams of Librium or a milligram of lorazepam is equivalent to about

• 1:17:38Speaker 02

  one shot of whiskey. Well, I've, at the, when I worked at the VA, I had patients who would tell me, oh, I drank two fifths of whiskey a day, every day.

• 1:17:49Speaker 02

  So, you know, giving this person a tiny dose of benzo and expecting it to treat their alcohol withdrawal was nonsense.

• 1:17:57Speaker 01

  But one of the really good things you were talking about recently was the anticholinergic uh, medication and like someone on like cogentin uh, programs, or you talk about changing the clozapine to like maybe benzobrane cogentin to slowly taper.

• 1:18:12Speaker 02

  The major thing uh, that I've where the acetylcholine system's been involved is if somebody has, for example, severe neutropenia with clozapine and some, and their clozapine is then necessarily abruptly stopped, they're at real risk of cholinergic rebound.

• 1:18:33Speaker 02

  Clozapine, 50, 50 milligrams of clozapine is roughly equivalent to a milligram of Benstruc. So if you've got somebody on

• 1:18:43Speaker 02

  500 milligrams of clozapine, they're taking the 10 milligrams of benzopyrene. If you suddenly stop that, you can put the person into cholinergic rebound, which can include irium, nausea, vomiting, diarrhea, cramping, sweating. So if you're, if you have to stop the clozapine like that, or any other really anticholinergic drug, you need to put them on an anticholinergic like benzopyrene and then taper it.

• 1:19:15Speaker 01

  You say like a half, you said a half milligram every, every?

• 1:19:19Speaker 02

  Probably a half milligram per week.

• 1:19:21Speaker 01

  And I know before we've talked about the benzodiazepines, like I know we worry about any dose for the withdrawal procedures, but I think you've kind of mentioned for lower doses. I think you, you know, if they're only on maybe a couple, one milligram of clonazepam, or maybe if they're only on the benzopyrene, one milligram or something, or two milligrams would be, be less concerned about those.

• 1:19:42Speaker 02

  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, 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

• 1:20:07Speaker 02

  to compensate for the presence of the drug. And then suddenly the drug is gone and there's nothing opposing those systems.

• 1:20:17Speaker 01

  How slowly would you taper off a benzodiazepine? Like, do you have a certain?

• 1:20:22Speaker 02

  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.

• 1:20:32Speaker 01

  And I think you recommend going with the longer acting, like the longer.

• 1:20:36Speaker 02

  Yes.

• 1:20:36Speaker 01

  Clonazepam.

• 1:20:37Speaker 02

  It's easier, it's easier to taper a longer acting drug like clonazepam or previously dazepam.

• 1:20:47Speaker 02

  You know, we went through a period, fortunately, it's not as prevalent anymore, where people would come in and I've had patients who came in taking 40 milligrams of dazepam valium a day. And in their history, ask, well, how long have you been taking it at this dose? Oh, three decades.

• 1:21:07Speaker 01

  Yes. Oh, my God.

• 1:21:09Speaker 02

  That person was going to take, 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.

• 1:21:31Speaker 02

  They eventually got off though and did much better in terms of cognitive and memory performance.

• 1:21:39David Puder?

  What about like serotonin, you know, serotonin reuptake inhibitors? There's been a lot of talk in the, some new articles on the withdrawal of that. What's your thoughts on?

• 1:21:52Speaker 02

  Yeah, the, the antidepressants, including the SSRIs, do have a withdrawal syndrome.

• 1:21:59Speaker 02

  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. You know, so it's it's not quite as dramatic as some of, you know, certainly not as dramatic as say benzodiazepine withdrawal or opioid withdrawal, but it but the antidepressants do come with withdrawal syndrome. And truth is, we should, if we're going to stop an

• 1:22:42Speaker 02

  antidepressant, we should be tapering it. There is also data suggesting that abruptly stopping antidepressants may encourage a relapse of the depression. So we should be tapering people off of the off of them. Unless there's some urgent medical need to take them off of the antidepressant.

• 1:23:04Speaker 01

  Dopamine antagonist, the hyperkinetic and the slow taper, just seeing how they tolerate it perhaps.

• 1:23:13Speaker 02

  Yeah, it's 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, a series of papers actually pointing out that we've probably been titrating clozapine too rapidly until very recently, particularly in some populations that don't metabolize the drug very well.

• 1:23:46Speaker 01

  Which I also think that kind of leads us into the type F failure and unexpected. I liked, I know we're closing, you know, losing time really fast, only a few more minutes, but I wanted to, you could briefly at least go over pharmacodynamic versus pharmacokinetic failures, because I know we talked a little bit earlier about metabolizers.

• 1:24:04Speaker 02

  Yep. Pharmacodynamic failure means that the activity of the drug, the, you know, whether you're talking about inhibition of serotonin reuptake 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. Good example of that is in, you know, there have been some recent magnetic resonance spectroscopy studies where they found that in treatment-resistant schizophrenia, those people actually have normal or decreased

• 1:24:48Speaker 02

  dopamine turnover in the ventral tegmentum.

• 1:24:52Speaker 02

  So it's not surprising that if you give them a dopamine antagonist, it doesn't treat their psychosis.

• 1:25:02Speaker 02

  You're basically giving them something that they don't need. You're off target in terms of your treatment.

• 1:25:10Speaker 02

  So that's a good example of pharmacodynamic failure. Your, your, your drugs mechanism of action isn't what the person's illness needs.

• 1:25:22Speaker 02

  Pharmacokinetic failure means basically that the drug is not present in a sufficient amount

• 1:25:31Speaker 02

  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, their it can be because they don't absorb the drug. Some drugs require active transport in the GI tract and they don't get absorbed very well. Uh, and there are also ultra rapid metabolizers for drugs. And if the person, basically their liver chews up the drug and eliminates it before it can reach its target organ, those are all examples of pharmacokinetic failure.

• 1:26:14Speaker 01

  Maybe, maybe unusual, but you mentioned a patient on a dose of halol 80 and their level is only two.

• 1:26:21Speaker 02

  Yeah, uh, we had, we had that patient, uh, younger African American male. And

• 1:26:29Speaker 02

  people were very puzzled for him because he was titrated up to eight zero milligrams of haloperidol in the mornings and he took it.

• 1:26:42Speaker 02

  But his plasma level got to a grand total of two nanograms per milliliter. Trick in his case was to switch him to an antipsychotic that didn't principally go through, uh, side from V450 to D6.

• 1:26:58Speaker 01

  Thank you.

• 1:27:00David Puder?

  Great. Well, this is a

• 1:27:03David Puder?

  an important discussion, maybe not the most entertaining of, you know, of late. Delusions is, I don't know, much more fascinating to me, but I think, 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

• 1:27:44David Puder?

  think that our medications can cause side effects and getting them off of medications can cause other side effects. So.

• 1:27:52Speaker 01

  That's good.

• 1:27:54David Puder?

  Yeah, this is a great discussion. Thank you so much, guys.

• 1:27:58Speaker 01

  Thank you.

• 1:27:58David Puder?

  Okay. Thanks.