Pod Insights Psychiatry & Psychotherapy Podcast Clozapine & Schizophrenia with Michael Cummings, MD About this episode Join Dr. David Puder and expert psychopharmacologist Dr. Michael Cummings in a detailed discussion on Clozapine, the gold standard medication for treatment-resistant schizophrenia. They explore recent significant updates, including the removal of the Clozapine REMS program, which simplifies patient care and medication management.
This episode covers optimal dosing practices, managing side effects, crucial drug interactions, and approaches to related conditions such as catatonia. An essential resource for psychiatrists and mental health professionals seeking updated clinical insights.
By listening to this episode, you can earn 1.75 Psychiatry CME Credits. https://www.psychiatrypodcast.com/cme-program
Link to blog. https://www.psychiatrypodcast.com/psychiatry-psychotherapy-podcast/episode-236-clozapine-schizophrenia-treatment-michael-cummings
Link to YouTube video. https://youtu.be/3nv3XLluQ1Q
Transcript 13,505 words · 2 speakers
Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.
0:14 David Puder? Hello and welcome back to the Psychiatry and Psychotherapy Podcast. I am joined today with Michael Cummings, expert psychopharmacologist, was the head consultant in Patton State Hospital for a number of years now, semi-retired. How's retirement going?
0:31 Speaker 01 Pretty well, pretty well, actually. I came back as I retired and knew it, and so I'm still working part-time, but the important feature there is part-time. So.
0:41 David Puder? Yeah, that's good. That's good. Well, okay, so I wanted to jump in. We're gonna, we're gonna get through a lot of questions hopefully today, but I wanted to start with clozapine. And there's a new law that the clozapine REMS is scrapped.
0:55 Speaker 01 Yes.
0:56 David Puder? And it happened two days ago, so that's February 25, 2025.
1:03 Speaker 01 Yes.
1:03 David Puder? And so we no longer need to report clozapine REMS, which was something I did on a weekly basis for some of my clients. So walk me through what happened and what this means for us.
1:15 Speaker 01 Basically, a number of us have been lobbying the FDA for a number of years now to do away with the REMS program, in large part because it's become clear, based on research data, that the primary risk for severe neutropenia occurs fairly early in clozapine treatment, and then declines to a level of about somewhere between 1 and 6 per 10,000 after a year of treatment, which are levels comparable to other drugs that can affect the bone marrow.
1:55 Speaker 01 And we don't have REMS programs for those. So the FDA finally reconsidered the issue and two days ago, they basically abolished the REMS program for clozapine and simply noted that people should um exercise good judgment and follow the recommendations in the package insert. In part, what prompted this was the Europeans dropped all requirements for monitoring after one year. Um, I think more than a decade and a half ago now. Their rates of morbidity and mortality due to severe neutropenia related to clozapine
2:37 Speaker 01 are no larger than ours, uh, which argued that the monitoring beyond a year does not actually serve any purpose. My guess is what most individual clinicians and very likely systems like the California Department of State hospitals are likely to elect to continue monitoring weekly for the for the first six months. And then may or may not elect to monitor every two weeks for the following six months and then may stop routine monitoring altogether. Um, and simply as the Europeans do, they advise and educate their patients and families that if someone develops a persisting infection or if they develop a sore throat that is
3:22 Speaker 01 not getting better, not going away, they should go and have a CBC done to look at their absolute neutrophil count.
3:30 David Puder? Okay. So this is, this is like revolutionary to the, to the world of treatment resistant schizophrenia.
3:37 Speaker 01 Yes.
3:37 David Puder? We uh, we spoke about treatment resistance schizophrenia way back in episode 49. So it may be worth repeating some of the key points that we, we brought forth. The thing that I'm thinking about is there's a number of patients who due to an anastomia and just resistance, like maybe they'll take a pill, but to get them to draw a lab once a week is, has just been absolutely difficult in my, in my practice. But these are like the people that need it the most, you know? And so I'm like thinking to myself, do I, is, is there a case for this type of patient due to the risk of them being psychotic for the rest of their life, for them not to take the blood test every week?
4:22 Speaker 01 Well, certainly it's arguable that after the first six months,
4:28 Speaker 01 weekly monitoring is no longer necessary because the primary principle area of risk is during the first 18 weeks of treatment.
4:39 David Puder? Okay.
4:39 Speaker 01 And then it begins to decline fairly steadily. It peaks at about 1.3% and then declines thereafter fairly steeply. You know, it's an autoimmune process. So during the first month of treatment, there is very little risk because the person has not had time to develop an immune response to clozapine or actually its metabolites. And then it peaks and then it gradually declines in terms of risk in the population. I think the the chief benefit, well, there are several here. One will be it's much easier to talk somebody into doing lab monitoring if it can be made clear it will not last forever.
5:21 Speaker 01 It will decline in frequency and then at some point it will go away.
5:27 Speaker 01 The other valuable point is you can now do ANC monitoring via finger stick rather than venipuncture. So that is a benefit. Other benefits related to RIMS going away is there will no longer be a need to send things to a pharmacy for their review before they can dispense the clozapine. Instead, like all medications, they will be relying on the judgment of the prescribing physician to have judged that it is safe to dispense this medication.
6:03 David Puder? Wonderful. Good. Okay, so let's let's back up a little bit because I feel like we need to prescribe clozapine more in America. I feel like this is an underutilized medication and I think this is a good time to advocate for it.
6:16 Speaker 01 We do, because certainly in the context of treatment resistance schizophrenia, and we went over this way back when we talked about treatment resistance schizophrenia, if somebody has failed to adequate trials of two different antipsychotics from different classes given adequate dose and duration, their odds of responding to anything other than clozapine is less than 7%.
6:46 David Puder? Yeah. So if, if you think about that, like, like if, if a patient's coming in and they've, they're on an antipsychotic and they've been on another antipsychotic and they're not responding, clozapine is like the first medication you should think of.
7:04 Speaker 01 Yeah.
7:04 David Puder? Because you're going to get 40 to 60% of those people responding.
7:09 Speaker 01 Yeah. Well, many of our, many of our patients who are treatment resistant, it's clear clozapine is essentially their only real option. We don't have any other tools that are as good as clozapine. You know, aside from decreasing violence and suicide risk, it's also the only thing that's effective for treating treatment resistant schizophrenia. The other element of that is if you let somebody remain treatment resistant without clozapine treatment, the Yashimura study found that, you know, after 2.8 years of treatment resistance, even clozapine's effectiveness begins to decline. Fortunately, it doesn't decline to zero. It goes
7:52 Speaker 01 from somewhere between 40 and 60% down to hovering around 30%, at least for the period of time that they studied. But, you know, there, there are now a number of articles that have been published that point out the benefits of switching earlier to clozapine.
8:13 David Puder? Yeah. We talked about a number of things, including the dose. So let's talk about the dose briefly. What do you normally start a patient on? How quickly do you escalate the dose? How high do you go?
8:26 Speaker 01 For, and on DSH, we, we differed slightly from the package insert, although the package insert's fairly close to this. First dose is 12 and a half to 25 mg at bedtime.
8:40 Speaker 01 Not that we expect that to do anything to the psychosis. That's mostly because Clozapine is a very good alpha antagonist, very anti cholinergic and a very good histamine antagonist. So you can make somebody hypotensive and over sedated fairly easily. If they tolerate that well, the next day they can go to 12 and a half to 25 milligrams BID. And then we titrate aiming to be at around 100 milligrams by the end of the first week. And by and to about 200 milligrams by the end of the second week, we rarely titrate faster than in 50
9:20 Speaker 01 milligram increments. And that usually is at a rate of once or twice per week. We're aiming for an initial plasma concentration range of 350 to 600 nanograms per milliliter. If the person responds to that fine. If they are still suffering from significant positive psychotic symptoms, we then will titrate the dose further until we get up to around 1,000 nanograms per milliliter. We do also use what's called a two week rule in terms of titration. This actually applies to all of the antipsychotics. If you increase the
10:04 Speaker 01 dose of an antipsychotic, what you have after about two weeks is 80% of what you're going to get at that dose slash concentration. So there's no reason to wait for prolonged periods before you titrate further, you know, and you for a trial, you you come to one of several endpoints. One, the one you're hoping for is the patient gets better.
10:31 Speaker 01 Two, the person develops intolerable side effects. So you've gone as far with that drug as you can, and you may have to back down and come to a balance between benefit and risk, or you reach the point of futility for the drug, meaning the odds of producing a positive response are less than 5% if you push higher. Now, for clozapine, that occurs at about 1,000 nanograms per milliliter. Although I will tell you, we do have rare patients who require clozapine plasma concentrations of 1,200 to 1,400 nanograms per milliliter, and actually tolerate those concentrations. There aren't very many of those. Those are
11:16 Speaker 01 the people out in the tail of the bell curve, out in the, you know, three standard deviations from the mean. But we have one or two of them in the state hospitals.
11:29 David Puder? Okay, so just to, you know, I have this DSH psychotropic medication guide that you gave me. It talks about for a male, the average expected level is about 1.08 times the oral dose. It's about one to one. So it's like if you gave 350 to 600 milligrams, you're going to get close to that level, which is the target range. For females, it's the multiplier is 1.32. And I'll put this hand out in the guide and my website, psychotropicodcast.com. And so the expected level is going to be a little bit higher. So you might need a little
12:10 David Puder? bit less than the 350 to 600 milligram dose. It might be more like 250 to, I don't know, 400. What do you say?
12:22 Speaker 01 Yeah, I think that would be about right. We, as a caveat, we always encourage people to get a plasma concentration. Because indeed, the numbers you're reading are based on the average metabolizer. Uh, but like most things, rates of metabolism vary from person to person. And actually describe a, you know, the typical bell curve or Gaussian curve. Uh, so you'll have people who are slower, poor metabolizers who will have much higher levels than you'd expect. And people who are rapid metabolizers who eliminate the drug more rapidly than some people. The other caveat in this is if you have a patient who smokes.
13:03 Speaker 01 On average, smoking will roughly double the rate of metabolism or cut the expected plasma concentration in half.
13:13 David Puder? Great. Okay. So another thing that comes up often is patients who get put on clozapine have a higher rate of developing OCD. Can you talk about that?
13:25 Speaker 01 Uh, yeah. Uh, like many of the second generation antipsychotics. Clozapine is an antagonist at serotonin 5-HT2A receptors. And in some people antagonism of that receptor will induce obsessive compulsive symptoms, obsessional thoughts, compulsive behaviors. It is dose dependent. So in some cases, lowering the dose, if that's feasible, given the person's psychosis, will get rid of the obsessive compulsive symptoms. Uh, in other cases, you may need to add an SSRI.
14:06 Speaker 01 Our usual go-to medication is sertraline because it has very few strong interactions with other drugs via the cytochrome P450 system. And then we treat them with that to increase serotonin and hopefully get rid of that particular adverse effect of clozapine. Where we get stuck frequently is if we have somebody who is not purely schizophrenic, but who is schizoaffective disorder bipolar type.
14:38 Speaker 01 Then it becomes very risky to give them an antidepressant. Although clozapine itself is a fairly good mood stabilizer. So we have, in some cases, crossed our fingers, held our breath, and titrated the SSRI very gingerly to see if we could strike a balance between their mood stability and their OCD symptoms.
15:04 David Puder? Okay, so number one, check their blood level. Try to get their, try to get it down to like the effective range. Number two, sertraline, what do you think about fluoxetine? Is that a decent option?
15:16 Speaker 01 Uh, no, for two reasons. Uh, one, fluoxetine is a potent inhibitor of cytochrome P450 2D6 and will raise clozapine levels about 30%.
15:31 David Puder? Okay.
15:32 Speaker 01 The other problem I have with fluoxetine is its half-life. If the person is not tolerant of fluoxetine, or say, for example, this person actually is vulnerable to a bipolar diathesis and you didn't know that, but you unfortunately discovered it when you started the fluoxetine. Half-life is nine to 14 days, which means washout is 10 weeks, two and a half months.
16:03 David Puder? Okay, very good. Okay, so quiz question for my audience. You should know this if you listen to the podcast. Quiz question would be, what is the most common reason why people die on clozapine?
16:15 Speaker 01 Uh, the most common reason for death due to clozapine is bowel obstruction.
16:20 David Puder? So what is, uh, constipation, right? Bowel obstruction?
16:23 Speaker 01 Yep, yep. Oh, it's constipation that has progressed to bowel impaction, meaning there's a very hard lump of stool stuck in the bowel, uh, followed by usually ischemia of the bowel wall, uh, obstruction of the bowel, and that can have catastrophic.
16:45 Speaker 01 Produce a catastrophic outcome. That's actually has always been the most common cause of death with clozapine. It statistically, it far outstrips the severe neutropenia.
16:58 David Puder? Okay, another, another question would be potential board question. So let's say you have a patient who is with Parkinson's disease where standard treatment has failed. Is there a case for clozapine?
17:15 Speaker 01 Yes, there is. Clozapine does not tend to engender adverse motor effects and that's primarily because it's frankly, a very poor antagonist at D2 receptors. At therapeutic concentrations, the occupancy in D2 receptors is around 25 to 40%. You know, typical antipsychotic D2 blockade is in the 60, 65, 60, 65 to 80% range. So clozapine
17:55 Speaker 01 is well below that. So it doesn't tend to cause motor symptoms. In fact, people, they looked at, for example, clozapine as a potential treatment for tardive dyskinesia because it does seem to benefit TD and many patients. The American Neurological Society did not include it as a proven treatment, basically because it had two large positive studies and one large negative study, which no one has yet figured out why the negative study was negative.
18:34 David Puder? Okay, here's a, here's another. Clinical case scenario you should be aware of as a provider. Patient comes in with fluvoxamine and recently had started clozapine.
18:49 David Puder? He is heavily sedated and hypotensive. What do you imagine is going on?
18:56 Speaker 01 His clozapine has gone through the roof. Clozapine is metabolized principally by cytochrome P451A2, for which fluvoxamine is a potent inhibitor. It basically will turn 1A2 off. And now clozapine does have a couple of other metabolic pathways in the cytochrome system. It's also metabolized by 2D6 and by 3A4, but those are relatively minor pathways compared to 1A2. So if somebody gives fluvoxamine at antidepressant or anti-obsessional doses,
19:41 Speaker 01 they have essentially removed the ability to metabolize clozapine.
19:47 David Puder? Yeah, so, so yeah, be, be very careful with, I mean, that's a very potent inhibitor, which leads to very large amounts of clozapine.
19:56 Speaker 01 Yeah, I and a couple of my colleagues reported on
20:01 Speaker 01 a case in which
20:05 Speaker 01 patient was given fluvoxamine, a woman who had been on 100mg of clozapine twice a day for two years, had a fairly responsive psychosis, was doing well, developed obsessive compulsive symptoms, as we've talked about. Unfortunately, the clinician who next saw her was not aware of the 1A2 inhibition by fluvoxamine and promptly put her on 100mg of fluvoxamine. She died two days later.
20:40 David Puder? Be careful, guys, be careful. This is why, like, you know, you need to, you need to pay attention to this stuff. Absolutely important. Okay, here's, um, here's another question for you. Patient comes in, recently started Clozapine, now at 400mg per night. They complain that they wake up in the middle of the night and they feel like they're choking. And they feel like they're having some panic or something. Okay, so what do you imagine might be going on?
21:13 Speaker 01 As you know, the metabolite of Clozapine, nor Clozapine, unfortunately stimulates the salivary glands rather strenuously and increases saliva production, produces scialeria, drooling, in many patients. That actually increases the risk of aspiration and of aspiration pneumonia. It's one of the dangerous side effects of Clozapine, not as dangerous as bowel obstruction, but it's not inconsiderable either, which is why we should pay attention if our patient's
21:52 Speaker 01 developing scialeria and attempt to reduce the scialeria. We start typically with topical anticholinergic agents that can be given orally. 1% atropine drops sublingually.
22:09 David Puder? Eye drops.
22:10 Speaker 01 Eye drops, well, yeah, they are eye drops, but, you know, they work in the mouth. They work in the mouth as well. You put it under the tongue, have the person kind of swish it around, then after they've held it in there for 30 seconds to a minute, you give them about a teaspoon of water, have them swish and then spit the excess so they don't swallow it. Because in this case, we're trying to avoid, trying to avoid them having systemic anticholinergic effects. Because that, if you give somebody who's on Clozapine a systemic anticholinergic, it will roughly double their risk of developing ileus and bowel obstruction.
22:52 Speaker 01 If that doesn't work and we're stuck, in some settings, we will give glycopirolate. It still has the bowel risk, but does not cross into the brain, so it will not add to the person's central anticholinergic burden, meaning we won't make them dumber and have a poorer memory while we're trying to treat their psychosis. If that doesn't work, or it's inadvisable, because this is a person who's had bowel difficulties, we, in the state hospitals, we are using botulinum toxin, botulinum A
23:30 Speaker 01 specifically, to inject the parotid and submandibular glands on a three to six month interval, which works very nicely, and 90% of cases, it resolves the scolluria. We actually stole that from the neurologists, because of course, people with things like Parkinson's disease and Huntington's disease also have a difficult time with scolluria. And they started injecting botulinum toxin to control the scolluria, then psychiatrists in research settings started using it in clozapine patients and found out it works just as well there.
24:14 David Puder? Okay, let's go through some things that psychiatrists may not know about this. I would say, one of them is that clozapine may reduce, or can reduce, mortality in schizophrenia patients.
24:27 Speaker 01 Yes. The original study in this area came out of the Maudslay Hospital in London, where they looked at their clozapine patients versus their non-clozapine patients, and found that those who were taking clozapine, despite all of its risks and side effects, those patients lived longer. And it was not a small, I've forgotten now what the increment was, but it was not a small percent increase in survival. Later, in the Scandinavian countries, Johan and Nadal did a very similar, similar population-based study and found that the best overall survival
25:12 Speaker 01 amongst schizophrenic patients occurred in those who were taking clozapine. Second best were long-acting injectable antipsychotics, and worse were the oral antipsychotics.
25:25 David Puder? Okay, number two. So I'll ask this as a question. So kind of like, if you're listening, just try to answer before Cummings does. You have a patient who started on 50 milligrams a day of clozapine at night. He comes in, having fallen at night while trying to go to the urinal. He also feels very, very groggy. What's, what's the, the reason for this? And what is the thing that you would do next? So try to answer that in your mind?
26:02 Speaker 01 Yep.
26:03 David Puder? And then Cummings, what do you think?
26:05 Speaker 01 Well, um, we already noted clozapine is a very, very potent antihistamine.
26:13 Speaker 01 This person has two things going on, antihistamine blockade, which will make them groggy. Having started at 50 milligrams at night, that's too high a starting dose for most people.
26:27 Speaker 01 This would be like taking a whopping dose of 75 to 125 milligrams of Benadryl when you went to bed. There are people who can tolerate that much antihistamine, but not a lot of them. The other element that may add to this is that clozapine also is a good alpha one antagonist and causes blood vessels to dilate. So that when the person stands up, especially if they stand up rapidly, they may have some degree of orthostasis on top of being over sedated. Well, those are a wonderful recipe for falling. So basically the, the treatment for this is to go back, reduce the dose to a more tolerable level,
27:11 Speaker 01 and then titrate more slowly, as we outlined previously.
27:16 David Puder? Okay, case number two. Patient comes in to the ER having been on clozapine for three months, having a new onset seizure. Clozapine level is drawn and is at 1,200 nanograms per ml. Patient is only on 600 milligrams of clozapine a night. What do you imagine is the next course of action for this patient?
27:44 Speaker 01 Well, next step is to figure out if they've been taking the drug as directed or if they are on any 1A2 inhibitors. In other words, you're looking for things that might have increased the clozapine level more than expected. If none of those things turn out to be true, this may just be a slow metabolizer of clozapine, in which case the next step is to lower the dose of clozapine and try to get it back down around 1,000. The risk of seizure with clozapine is related to two factors. One is the rate of titration. If you go too fast, the person may seize.
28:28 Speaker 01 If you get beyond 1,000 nanograms per milliliter, you may start to see myoclonic jerks, which are a harbinger of either myoclonic or tonic clonic seizure. Now, if somebody has a seizure on clozapine, even at, you know, an at a therapeutic dose that you want to keep, seizure per se is not a reason to stop clozapine. It's a reason to add an anti-epileptic to prevent the seizures. Because remember, these are people for whom clozapine is likely their only viable treatment option. Most common agents are valproic acid or levodaracetam, Kepra.
29:12 Speaker 01 Valproic acid is undergoing some reconsideration, certainly in Europe and in the UK, and is likely to undergo some degree of reconsideration here in that it has reproductive risks, certainly in women. But it also appears to have reproductive risks in men as well in that it causes methylation of the sperm. So that if a man gives rise to a pregnancy within three months of taking valproic acid, the rate of neurobehavioral syndromes in that child are increased significantly.
29:53 David Puder? On further interview, you find the patient was recently put on ciprofloxacin
29:59 David Puder? for a UTI. What, what, or you could, you know?
30:06 Speaker 01 Yeah, well, ciprofloxacin is one of the medications, and indeed, but it's the only one of this group of antibiotics that is a potent 1A2 inhibitor. So essentially the same thing has happened as with the fluvoxamine. The person got put on the antibiotic and essentially their metabolism of clozapine came to a stop. And consequently, their plasma concentration began to climb rapidly, in this case inducing a seizure.
30:39 David Puder? Okay, let's say another scenario. You have a patient in the first three weeks of starting clozapine who develops a fever. You fear the worst that this patient has NMS, but all they have is a fever. What is actually going on?
31:04 Speaker 01 Fever is a fairly common adverse effect with clozapine affecting up to 20% of those who start clozapine. It does deserve attention. Now, in most cases, it's a benign fever.
31:20 Speaker 01 Where the person will have an elevation of temperature for the first several weeks, two months of clozapine treatment, and then the fever will just gradually fade away. The main thing that you want to be cautious of if somebody develops fever is to be sure to ask them if they have any additional associated symptoms, particularly symptoms related to the heart, that is shortness of breath, chest pressure or discomfort, feelings of orthostasis. If those things are occurring, you want to be sure to rule out
32:02 Speaker 01 clozapine-induced myocarditis, which is relatively rare, but very important because of course if people develop myocarditis, they can progress into a dilated cardiomyopathy with decreasing ejection fraction over time. The way you make the diagnosis other than looking at the symptoms is to get a troponin. If troponin is more than up two times the upper limit of normal, that's essentially diagnostic of myocyte damage. You may also want to get a C-reactive protein because there are some cases in which the troponin does not rise
32:47 Speaker 01 as much as people would expect, but C-reactive protein does in those cases. Fortunately, the risk period for myocarditis is fairly short. Eighty percent of cases occur within the first four weeks of clozapine treatment, and essentially 100% occur within the first six weeks of treatment. This is, this is not a problem that you will see in people who've been taking clozapine for months or years.
33:20 David Puder? Yeah, well, that was one of the things that I was going to put on my list of things to ask you. Myocarditis is rare, but a serious early side effect.
33:30 Speaker 01 Yes.
33:30 David Puder? In summary, troponin, get a troponin level, and it's usually in the first month of use, right?
33:37 Speaker 01 Yes, yeah, 80% in the first four weeks.
33:40 David Puder? Tachycardia, flu-like illness, prompt investigation needed. So what are the differentiation types of things are you looking at for that? So tachycardia, flu-like symptoms, that's, that's the go-ahead to kind of?
33:55 Speaker 01 Yeah, and particularly if those are associated with additional things such as, you know, my chest feels tight, my chest feels heavy, I feel short of breath when I walk upstairs. All of those should be sounding alarm bells that we need to check this person carefully to be sure they're not developing myocarditis. After, you know, if the troponin and C-reactive protein come back positive, the next steps, of course, are to discontinue the clozapine and sign the person up for an echocardiogram to see what effect has already occurred with respect to their ejection fraction.
34:34 Speaker 01 Now, the vast majority of people, if you identify them, if you hold off on the clozapine, their myocarditis recovers, and just with supportive care. Can you re-challenge them with clozapine? Yes, in fact, there are a couple of published re-challenge protocols. The key element of the re-challenge is the titration is incredibly slow, meaning on the order of five to six and a half milligrams per week until you get to therapeutic levels. In other words, you don't ever accelerate the clozapine titration until you're past the risk period.
35:20 David Puder? Okay, so what's the, uh, what's the main takeaway? If, if someone had, let's say, the need to be on this medication,
35:30 David Puder? or they were going to remain psychotic for the rest of their life?
35:33 Speaker 01 Well, the need is, even though this is very dangerous, yes, you can go back and re-challenge them once they've recovered. The key to a successful re-challenge, and it's successful, if done correctly, in 70 to 80% of cases,
35:52 Speaker 01 is to go very slowly, you know, starting at 5mg at night, and, you know, week one, 5mg at night, week two, 10mg at night, week three, 15mg at night, until you're out well past the six weeks, and only then increasing the rate of titration. That seems to be the key to avoiding the myocarditis.
36:15 David Puder? Okay.
36:17 David Puder? Okay, so the increased titration does increase the risk of this, right? Greater than 50mg a day if, if people are rapidly titrated?
36:30 Speaker 01 Yes. Uh, another, yet another reason not to engage in rapid titration. You know, and in fact, I think a lot of people are not adequately aware that if Clozapine is interrupted, you have only a very brief period before you have to go back and start all over as if the person had never been exposed to Clozapine.
36:54 Speaker 01 Under 48 hours of interruption, two days, uh, you can start back at half what their Clozapine dose was and titrate from there. If you're out beyond four days, you're starting over from the beginning. Because all of the adaptive responses in terms of their alpha receptors, their histamine receptors, their immune risks, all of those adaptations go away fairly quickly.
37:25 David Puder? Okay, let's talk about what can happen with abrupt discontinuation. So if someone abruptly discontinues, what is the chance that they may re-enter into psychosis?
37:38 Speaker 01 Very high for a couple of reasons, and in fact, it may be more than psychotic relapse. It may also be a cholinergic delirium. You know, these are people with a severe psychotic illness that's largely unresponsive to anything other than clozapine. So if the clozapine goes away suddenly, their psychosis tends to come roaring back. On top of that, because clozapine is so highly anticholinergic, I think a lot of people don't realize this either, 50mg of clozapine is as anticholinergic as 1mg of benzoprene, trade name cogentin.
38:23 Speaker 01 So if you have somebody who's taking 500mg of clozapine a day, that's the equivalent of taking 10mg of benzoprene. If you stop that suddenly, this person now has a flood of acetylcholine, looking at a lot of uncovered acetylcholine receptors, and they may develop cholinergic delirium as well as the GI side effects of excessive acetylcholine activity, nausea, vomiting, diarrhea, cramping, sweating, all of those things.
39:04 Speaker 01 So if you have to discontinue clozapine abruptly, it's prudent to put the person on benzoprene and then gradually taper the benzoprene. We typically don't start the benzoprene at an equivalent dose. We'll shave that by half, start the benzoprene, and then gradually taper it at a half-milligram a week, so that the person doesn't have a cholinergic rebound.
39:38 David Puder? Yeah, so cholinergic rebound, you also things see things like nausea, vomiting, sweating, diarrhea, restlessness, headache, insomnia.
39:48 Speaker 01 Yeah.
39:48 David Puder? And it's gonna happen within 12 to 48 hours of stopping.
39:52 Speaker 01 Mm hmm. Yeah, and it's often it's often fairly dramatic and the delirium can be quite severe as well.
40:00 David Puder? Do you see this as well when you're stopping someone on like olanzapine, which is fairly anticholinergic?
40:05 Speaker 01 Uh, you can. It is less common than with clozapine, but you can. You could also see it, for example, if you did that with chlorpromazine of the antipsychotics. If you put them in a rank order in terms of how anticholinergic they are, clozapine's at the top. Number two is chlorpromazine, thorazine. Number three is olanzapine. So you can see it with the other two. Clozapine, though, is is really prone to causing cholinergic rebound if it's stopped abruptly.
40:40 David Puder? Yep. So, okay, I was thinking about like how much anticholinergic that capacity to that is like 10 milligrams of cogentin. Oh, my gosh. And then
40:50 Speaker 01 Yeah, and you know, and we have patients, you know, say you have somebody on not 500, but 900. You're not, you know, you're now getting up into astronomical levels of bin strapien because normally bin strapien, when it's being given as a principal treating agent, the max dose for it is six milligrams a day.
41:12 David Puder? Okay, let's say you have a patient who starts clozapine and then two months into it, he starts complaining that he's not being productive. He no longer hears demons in his head anymore. But for the first time, and you're seeing him weekly, he's complaining of not being productive with his life. He's just sitting around the house all day. What do you imagine? Why do you imagine he's starting to talk about that?
41:43 Speaker 01 Part of it may be, it may be the first time he's realizing that his life is not being productive. People on clozapine do not uncommonly have kind of an awakening. In fact, in the early literature of clozapine, they often described people as having awakenings where they sort of woke up and said, "Oh, my life isn't what it should be," which can be an exceedingly distressing mental state to find yourself in. You know, one, realize that you have a severe mental illness, and two, realize that your your productivity, your ability to form relationships, your ability to work are all seriously impaired.
42:26 Speaker 01 You know, this calls on the clinician to do a good evaluation, not just focusing on the positive symptoms, also taking into account what cognitive deficits and negative symptoms the person may have. Unfortunately, we don't at this point have
42:48 Speaker 01 great treatments for negative symptoms or cognitive deficits. But there are some things that have been tried and have shown at least modest benefit. Antidepressants may help in some cases. In a few cases, they've tried things like mementine and cholinesterase inhibitors with some benefit, not huge, but some. And of course, a psychotherapeutic orientation to look at, well, what does the person want to do that would be productive? Because often people who've been sidelined by a severe psychotic illness, their life plan was going along and then it got severely derailed.
43:31 Speaker 01 I mean, after all, if you're dealing with a head full of demons, it's sort of hard to focus on your life goals. Those go away, and now all of a sudden you're saying, "Oh, wait, what?" You know, and that can be a very rich field. For psychotherapy to begin looking at, well, what can I do? That's one of the sub focuses of CBT for schizophrenia, which I think is is very useful. Now, unfortunately, since schizophrenia, you know, starts in utero and we don't treat it until after it's well progressed. Our results aren't very good, only about six percent of people with schizophrenia maintain stable employment.
44:13 Speaker 01 Uh, sufficient to live independently and even a smaller percentage uh, maintain stable. Interpersonal relationships such as being married and having kids.
44:26 David Puder? With with the percentage on that for people on clozapine or not on clozapine?
44:30 Speaker 01 Uh, for schizophrenia as a whole, six percent.
44:34 David Puder? But, I mean, in my, well, that that seems pretty abysmal, but even on medications?
44:41 Speaker 01 Yes, uh, it is, and part of it is, you know, it's because. Frankly, we don't treat these people until the underlying pathology has. Progressed hugely, uh, Krepelin was right when he termed this dementia pre-cocks or early dementia. It's really a developmental dimension, which the brain has been abnormal. From the second trimester of pregnancy onward, we start usually treating these people. When they're in their teen, late teens, early twenties. Well, with most severe illnesses, if you let the illness run rampant for two decades. It diminishes your prognosis.
45:27 David Puder? Yeah. No, absolutely. I think, um, yeah, okay. So here's, here's another, um, patient says he's, let's say this patient ongoing three months in. You have, he, he came in initially on risperdal, four milligrams. You've reduced it to two, he's on clozapine as well. Four hundred and subsequently you decide to stop the risperdal.
45:57 David Puder? The week after you stopped the risperdal, he says, I'm no longer pacing around all day. I'm more just sitting around doing nothing. How do you interpret this statement?
46:08 Speaker 01 If he was pacing around all day, I would wonder if the risperdal was causing him some degree of akathisia, which was originally actually named can't sit down syndrome, which was a very descriptive name. It was named in what is now the Czech Republic.
46:27 David Puder? Which, I know you're laughing, but I know there's someone who probably has had that, who's going to hear you laughing and be like, this is not funny. This is the worst, literally the worst thing in my life, which I think you would agree is the worst thing.
46:38 Speaker 01 No, it's a horrible syndrome. I'm laughing because of the unusual naming.
46:42 David Puder? Okay, good.
46:44 Speaker 01 In the Czech Republic. No, no, it's not a, the syndrome itself is not funny. The, the medical history of its naming, it was originally named in Parkinson's patients who literally could not sit down. So the neurologist who was treating them just named it by, you know, in descriptive terms.
47:07 David Puder? Okay, so when we think about, there's, there's an intense restlessness that's quite often occurring with antipsychotics, especially at high doses. Typical than atypical clozapine, does that cause this, this restlessness of akathisia?
47:27 Speaker 01 No, it doesn't. In fact, as far as anyone can find, clozapine is not prone to cause any of the antipsychotic related movement disorders. I mean, you will see case reports of, oh, maybe clozapine caused an atypical form of this or that. But there's not really been any convincing data that, that clozapine causes Parkinsonism or akathisia or dystonia. And in fact, in most cases, it's actually something of a treatment for all three conditions. And that's because, again, the dopamine D2 receptor blockade appears to be the source of these movement disorders.
48:09 Speaker 01 In the case of akathisia, there's also dysregulation of noradrenalergic and serotonin receptors, which is why akathisia is harder to treat.
48:19 Speaker 01 Acathesia is the only one of the movement disorders that has been clearly identified to cause an increased rate of suicide. And that's because, as you point out, it is truly a miserable condition in which the person feels restless. I think one of my most articulate schizophrenic patients once described it as, he said, it felt like there were ants crawling up and down the bones in his legs, which I can understand why somebody would, you know, if that kind of feeling is going on, it's a truly miserable condition.
48:58 David Puder? Yeah, absolutely miserable. Every psychiatrist should know about this. It should be on the forefront of their mind when they're treating patients because it can be, it can happen from a number of different psychiatric medications and it should be-
49:12 Speaker 01 Yes, anything that particularly interferes with dopamine transmission and the nigrostridal pathway, you know, if you, particularly in somebody who is a younger patient in whom the dose has been increased relatively rapidly, you know, somebody comes in, they're agitated and they get, you know, a lot of haloperidol or a lot of risperidone over a fairly short period. So they go from zero exposure and blockade to a lot of exposure and blockade. If that person's exhibiting restlessness and they're pacing, odds are they're taking
49:49 Speaker 01 too much antipsychotic. Again, that's another point for measuring blood levels. Measuring a blood level can tell you if you're beyond the point of futility of the drug because once you've reached the point of futility, increasing the dose for most of these drugs is not providing the patient with any benefit. It's just increasing the intensity and severity of adverse effects from the drugs.
50:20 David Puder? I've had a couple people reach out to me of chronic akathisia. And I'm curious, you know, like, what are the treatments that are known? Do you just stop the agent? I had one person develop it after decreasing their SSRI or being on the SSRI for a long time. Any thoughts around that?
50:50 Speaker 01 When people develop tardive akathisia, it is one of the most difficult of all the movement disorders to treat successfully. Acute akathisia is fairly responsive to either beta blocker, buprenolol, or to mirtazapine. Tardive akathisia is miserably less responsive. Drugs that have been used include things like clonazepam, often at relatively robust doses. Vitamin B6 has been used with mixed results. Lowering the dose or switching to an alternative drug may be beneficial.
51:32 Speaker 01 People have also tried other gabagergic agents like gabapentin or pregabalin. Bottom line with all of these is, yes, they produce some effects, but none of them have emerged as a wonderfully robust treatment for tardive akathisia.
51:51 David Puder? So this is, the time course is usually different than acute akathisia?
51:59 Speaker 01 Yes. Yeah, acute akathisia usually occurs beginning within, well, anywhere from hours to days after exposure to a dopamine antagonist. Tardive akathisia often emerges after the person's been on a stable dose of something that is a dopamine antagonist or a drug like an SSRI that decreases dopamine release, often for months or years. And the person, even though they've been at a stable dose for a long period of time, they will begin to develop signs and symptoms of achytheia, usually starting with the internal sense of restlessness and then eventually spilling into overt movement.
52:44 David Puder? So would the, would there ever be a role for increasing the antipsychotic in this type of issue? Or is it always decreasing?
52:53 Speaker 01 It's always decreasing. If you increase the amount of D2 blockade, it will tend to worsen the achytheia. Now, you can get away with that in tardive dyskinesia. If you increase the amount of D2 blockade in TD, it will temporarily mask the movements. Now, the unfortunate part is the temporary word.
53:25 Speaker 01 The receptors will adapt and the dyskinetic movements will reemerge and, you know, you can wind up chasing that so that each time you increase the dose, it gets worse.
53:36 Speaker 01 Now, one thing with TD, you have to watch out for is if you decrease the dose or you stop the offending agent, the dyskinesia may get much worse for a while because you're adding a withdrawal dyskinesia on top of the tardive dyskinesia.
53:52 Speaker 01 With all of the movement disorders, I think the key element is to be aware of them in your patients and be sure that you routinely check to see if your patients have any evidence of dystonia or achytheia or tardive dyskinesia because all of these syndromes are more treatable the earlier they're caught.
54:16 David Puder? Awesome. Okay. As you're thinking about clozapine, I'm glad we covered this again. What are the common issues that you find psychiatrists have regarding this medication that you continually are telling people over and over again?
54:30 David Puder? That we haven't covered. Let's restrict it to what we haven't covered.
54:33 Speaker 01 Okay, um, I think the most common thing I see or the most common question I get regarding clozapine is can I combine it with other antipsychotics? And the answer is yes. Like most polypharmacy, you're looking to combine different mechanisms of action, hoping for additive benefits across drugs. You know, it makes no sense to combine two things that essentially do exactly the same thing because that's inherently no different than giving somebody more of, you know, one or the other. The nice thing with clozapine is it blends
55:15 Speaker 01 well with both the dopamine antagonists and the partial agonists because its mechanisms of action don't appear to have anything to do with blockative dopamine receptors. We think it acts, one, by increasing glutamate signal transduction and particularly in the frontal lobes, and also by decreasing dopamine release by stimulating muscarinic four receptors in the ventral tegmentum. So it's, it's not hitting the same sites as the dopamine antagonists or the partial agonists. So it combines well with both of those groups. The only antipsychotic
55:59 Speaker 01 you cannot combine clozapine with is the very newest one, zanolamine slash trospium. And that's because of clozapine's anticholinergic effects. It will essentially wipe out zanolamine's mechanism of action, which is dopamine muscarinic agonism at M1 and M4 receptors.
56:26 David Puder? You probably would want to avoid any CYP 1A2 inhibitor.
56:32 Speaker 01 Yes.
56:33 David Puder? To combine it with like cloprazidine.
56:36 Speaker 01 Uh, yes, yeah, I with clozapine, you do not want to give the person a 1A2 inhibitor because as we've talked about, you may well
56:48 Speaker 01 do the patient in if it's a potent inhibitor. If you give a more modest inhibitor, you need to be sure that you are adjusting the clozapine appropriately to maintain the person at the right level. Similar issues arise in people who develop severe infections. I mean, people are, given our recent history, people are well aware that close that COVID-19 could increase clozapine levels. Frankly, any infection that causes a severe enough immune response can do that. And it's because it's not the drug that directly increases the clozapine level, it's the fact that interleukin six and interleukin eight, two of the cytokines
57:33 Speaker 01 produced by more severe infections inhibit the cytochrome enzymes.
57:40 David Puder? What, what, what's the second most common question that we haven't covered that gets asked?
57:45 Speaker 01 Probably people often ask, well, what should I absolutely stay away from if I'm treating somebody with clozapine? And although we've touched on this, basically anything that is a very potent 1A2 inhibitor, some of which are well known, like fluvoxamine, and some of which are relatively unknown, like ciprofloxacin. I, I always encourage people, if you're going to combine a drug that you're not very familiar with, with something like clozapine, you know, look up its effect on the cytochrome system. These days with the internet, that information is readily available
58:29 Speaker 01 from a number of sources, including Wikipedia, if you enter a drug name, one of the things that you'll commonly find there, although they're stealing it from PubChem is, you know, what are the effects on the cytochrome system?
58:45 David Puder? Anoxacin is another antibiotic. Anoxacin is a potent CYP 1A2 inhibitor. Caffeine is a weak inhibitor.
58:58 Speaker 01 Yeah, caffeine's a weak inhibitor.
59:00 David Puder? What if they're drinking eight cups a day?
59:02 Speaker 01 They can, they may get a five to 15% increase in their clozapine blood level. And you have to watch out the other way, too. If somebody starts taking or doing something that is a, an inducer at 1A2, they can lower their clozapine levels and may have a psychotic relapse because they've become sub therapeutic. Probably one of the most common that we've run into in the state hospital system has been the proton pump inhibitor, omeprazol. It is a weak to moderate 1A2 inducer.
59:44 Speaker 01 Now, in most people, it's weak enough that you don't see a huge change in clozapine or olanzapine levels, but in a few people, you'll get a 30% drop in their plasma concentration, which in some people, that may be enough to trip them into having a psychotic relapse. So it's good to pay attention to what may induce or inhibit the cytochrome system and thereby alter the, you know, the concentration of your, of your clozapine or other drugs, for that matter.
1:00:21 David Puder? Let's say, let's say you had someone on suprazidone. Would you be concerned about TTC prolongation?
1:00:29 Speaker 01 Uh, no. We do get that question as well quite a bit. Clozapine is a very weak inhibitor of the potassium rectifier channel, also known as the HERG potassium channel. This is the channel that lets. Potassium out of myocytes, thereby allowing them to repolarize and be ready for the next cardiac cycle. If you inhibit that, the heart can't repolarize and you may have first prolongation of the
1:01:10 Speaker 01 QT interval and eventually a risk of torsades de point. Clozapine only very weakly inhibits that channel. Concentrations of clozapine that are clinically significant for doing that are above 1,500 nanograms per mill. By that point, the vast majority of people couldn't tolerate clozapine anyway. But in overdose or in cases of where the metabolism has been inhibited, that is the likely cause of death, sudden cardiac arrhythmia, like the cyprophloxins in case we talked about where the person's level suddenly went sky high.
1:01:46 David Puder? Okay, next question. Would you fear putting someone on a tricyclic antidepressant if they're on clozapine due to risk of lowering the seizure threshold?
1:01:57 Speaker 01 I would do it cautiously. The tricyclics, I would consider carefully the anticholinergic characteristics of the tricyclic, because of course that's additive with clozapine. Again, I would also look at the tricyclic's alpha adrenergic antagonism, because that's also additive. And it's anti-staminic effect, so there's a rich possibility of additive adverse effects. Frankly, my major concern and the reason I don't use tricyclics very much as an antidepressant treatment has nothing to do with clozapine, it has to do with the fact that they can inhibit
1:02:41 Speaker 01 the cardiac conduction system. You know, the LD-50 for tricyclics ranges from around 6 to 8, meaning that 6 to 8 times the therapeutic concentration is enough to kill 50% of people.
1:02:59 David Puder? Let's say the patient is a heavy tobacco smoker. Smoke actual cigarettes.
1:03:07 David Puder? How much would that change the clozapine level?
1:03:11 Speaker 01 If you have somebody who comes along and they're not a smoker, or they've not been smoking, say they've been someplace where they couldn't have access to tobacco, and then they resume smoking, on average, that will roughly cut their clozapine plasma concentration in half. It will take them about
1:03:31 Speaker 01 two to four weeks for their clozapine level to drop that much. Because what's happening is the, several of the polycyclic compounds in cigarette smoke are very important inducers of cytochrome P450 system. So you're ramping up their enzymes and the enzyme is chewing up the clozapine, the 1A2 in particular, as well as the 2D6 and 3A4. The other thing you have to worry about is if you have somebody who's a consistent smoker, they're a pack a day person, and they finally listen to health messages and say, you know, I'm going to stop.
1:04:08 Speaker 01 And they do. Same thing, their clozapine level is going to double over a little longer period. It takes a little longer to go the other way. It's about four to six weeks. But you can wind up with either the person becoming subtherapeutic, or the person becoming toxic. It's an important discussion to have with people who may be smokers, so that they're aware that if they change their smoking habits, it will change their clozapine level. And they need to, if they decide to start smoking, or they decide to stop smoking, they need to let you, their clinician, know that so that you can monitor what's happening and adjust the clozapine appropriately.
1:04:49 David Puder? Okay, so let's see if people are listening. A patient is a heavy tobacco smoker, smokes one pack per day, switches to vaping the exact same amount of nicotine per day. How much do we expect the clozapine level to increase or decrease?
1:05:06 David Puder? And the answer is?
1:05:08 Speaker 01 It will roughly double.
1:05:10 David Puder? So this is something that I I've I've thought about because I had a patient who was smoking cigarettes and then would stop and start vaping. And I had to like, you know, chase the the dose.
1:05:25 Speaker 01 Yes, you're chasing you're chasing that plasma concentration because indeed cigarette smoke induces the liver vaping of nicotine does not.
1:05:35 David Puder? Okay, let's say you had a patient who was smoking marijuana. How might that impact their psychosis while you're trying to treat them with Clozapine?
1:05:47 Speaker 01 Well, marijuana, particularly in younger people, is psychogenic in some. Estimated that among marijuana smokers, delta nine THC, the active ingredient to get high produces some degree of psychosis in somewhere between eight and 12% of those individuals. Now, if somebody has already has a psychotic illness, marijuana may make it worse. We don't have really great numbers on that.
1:06:24 Speaker 01 In terms of inducing the liver marijuana cigarettes, joints tend not to be as bad an offender as tobacco, largely because people don't tend to drink, you know, don't tend to smoke 20 to 40 joints a day. Even a heavy marijuana user will typically not smoke more than around six to eight joints in a day's time. So it's it's purely an effect of how much. The same polycyclic compounds occur when you burn marijuana leaves as occur when you to burn tobacco leaves. But in in the case of tobacco, people are often smoking a lot more.
1:07:08 Speaker 01 But then you have the issue of delta nine THC itself is psychogenic for some people.
1:07:16 David Puder? What does clozapine do to brain-derived neurotrophic factor?
1:07:22 Speaker 01 Increases it. Also increases glial-derived neurotrophic factor as well as epithelial-derived neurotrophic factor. Increases all three. Now, we are presuming that is a good thing, and you do see cortical thickening in people who are treated with clozapine largely due to increased dendrite arborization. You know, those are the short projections from neurons that tend to receive signals. And for all the world, if you're looking at them under a microscope, they look like small bushes. Well, if your bushes have kind of lost their
1:08:03 Speaker 01 leaves, if you will, you have cortical thinning as a result. If they get bushier, you get thickening. We presume that's good, and it seems to correlate with improved cognitive and attention and processing performance in people treated with clozapine. We don't know all of the details of the responses to brain-derived neurotrophic factors well enough to know in detail what the clozapine does downstream, but we're assuming at this point that it's good.
1:08:42 David Puder? There was a 2018 study that showed clozapine decreased IL6 and TNF-alpha patients, which may be another potential mechanism, anti-inflammatory properties.
1:08:59 Speaker 01 Yes. Yes, which may be a benefit because one of the things we've discovered is that abnormal inflammation appears to play a role in the pathophysiology of schizophrenia.
1:09:13 Speaker 01 And indeed, the increased inflammatory response over time may be one of the mechanisms by which people with evolving, well, I should say, people evolving towards schizophrenia are losing synaptic connections and neurons via abnormal inflammatory responses.
1:09:35 David Puder? What do you think about the genetic studies showing polymorphisms in genes like DR D3, dopamine receptor D3, and COMT, catecholomethyltransferase, which is associated with treatment outcomes?
1:09:52 Speaker 01 Basically, I think we're discovering, we're gradually beginning to understand some of the genetics and epigenetics of schizophrenia. I just wrote a review paper for CNS Spectrums entitled, "What is the Neurobiology of Schizophrenia?" One of the early parts of that paper noted that, you know, we've discovered that there are 240 gene loci associated with risk for schizophrenia, and those include not only 108 single nucleotide polymorphisms, but also things like DNA transpositions, DNA deletions,
1:10:37 Speaker 01 DNA recursions, where there's more than one copy of a DNA strand. Interesting, when you look at them kind of en masse, it suggests that signal process, the genes that are involved or that seem to crop up over and over again are genes involved in modulation of signal processing, genes involved in migration of neurons, orientation of neurons, growth of axons, cell adhesion, which is why I think, again, Krepelin was
1:11:15 Speaker 01 right in calling this a developmental dimension, which the gene abnormalities give rise to both an anatomy and a physiochemistry that aren't
1:11:33 Speaker 01 What they should be that aren't truly healthy, which is how these people get into having a progressive, an illness that is largely genetically determined. Schizophrenia is about 80% determined by genes, about 20% by environment. There are things you can do to people that will make it more likely if they're genetically loaded that they will become overtly ill, and those include things like childhood adversity, infection of the mother during the second trimester. Interestingly, growing up in an urban as opposed to rural environment.
1:12:10 Speaker 01 And exposure to things like cannabis during adolescence or other drugs that are, tend to be neurotoxic like methamphetamine during adolescence can worsen the risk that the person will develop an overt psychotic illness.
1:12:28 David Puder? Very good. What, um, let's say the patient has schizophrenia and catatonia. Would you treat them and they're currently, let's say they've had a history of responding well to clozapine in the past, but they've been off medications for a while. What would you treat first and why?
1:12:47 Speaker 01 I would probably start with the catatonia. One, the clozapine treatment is going to take longer to get in place. I would start frankly in somebody who I suspected of having catatonia with doing a Bush Francis rating scale and get a good sense of, you know, what catatonic signs and symptoms they were exhibiting. I would then give them a lorazepam challenge, which is two milligrams via the intramuscular route. And then I would reevaluate the patient after 45 to 60 minutes to see if their catatonia had ameliorated or gone away.
1:13:29 Speaker 01 An important caveat with that is it should not be by the oral route because the peak will not be high enough and the onset will be too slow. If the lorazepam challenge is positive, they're then going to get put on standing either lorazepam or clonazepam to control their acute catatonia while at the same time instituting anti-psychotic treatment, not excessive D2 blockade, but either.
1:14:00 Speaker 01 Moderate D2 blockade or initiation and titration of clozapine, or perhaps both, depending on the person's history. An important caveat with catatonia is catatonia is always a secondary syndrome. It's always catatonia due to something. Now, the something can be a whole list of things, ranging from schizophrenia to neurologic conditions, to medical conditions, to mood disorders. So you ultimately have to treat the underlying condition if you hope to control the catatonia. But you can control the catatonia relatively quickly.
1:14:41 Speaker 01 Now, if the person is not a responder to a lorazepam challenge, that doesn't mean that they don't have catatonia. It just means that they're not a benzodiazepine responder. And that person is going to get moved along to ECT fairly quickly.
1:14:57 David Puder? So some of the most common things on the Bush Francis scale that we would see are mutism, not speaking, immobility stupor, which is being abnormally still or unresponsive, staring with this kind of fixed gaze, and negativism, resisting instruction. Those are some of the most common. So if you were to see someone with that, I'm curious what so you're saying, one, inject them with two milligrams Ativan, see them back 40 minutes later?
1:15:38 Speaker 01 Yeah, that can, when that's a positive test, it's often exceedingly dramatic. Last person we did that with, this guy, man, mid 30s, nursing found him basically standing naked in his room staring at a light bulb. And his roommates reported he had been standing in that same position staring at that light bulb for about two and a half hours. Mute, non-responsive. Occasionally would switch into excited catatonia where he would kind of run around the room and touch all the walls, and then go back, stand in the same spot and start staring at the light bulb again.
1:16:19 Speaker 01 He got two milligrams of lorazepam and 45 minutes later, he was dressed, conversant, and asking what he could have for lunch.
1:16:30 David Puder? It's truly fantastic. I once injected someone on a unit and it was right before lunchtime. So his family came and I came out to talk to him while his family was there and his family was like, "Doctor, thank you so much. We have our husband back. We've made this is, he's so much different." And I was like, "Oh, tell me, like, what's different?" He's like, "He's talking. He hasn't talked to us." Oh, and it was just, you feel so good as a psychiatrist.
1:17:00 Speaker 01 Yes, and it's an amazing difference. Now, the other caveat that goes with this is a very important take-home lesson for people is if you have somebody who has catatonia and they're a benzodiazepine responder, do not be in a hurry to take them off the benzodiazepine because benzodiazepine withdrawal is one of the causes of catatonia. You often wind up titrating them to relatively high doses in a six to 12 to 18 milligrams of lorazepam
1:17:36 Speaker 01 a day is not uncommon. Now, if you switch them to clonazepam, the dose is half. But you should then plan to be keeping this person on the benzodiazepine for a period of usually months with a very slow taper, not faster than a milligram of lorazepam a month or a half milligram of clonazepam a month because you want to be sure the underlying conditions in control and the catatonia is in control. Now, the vast majority of people, you can eventually taper them off and they're done. You will find a very small number, probably
1:18:18 Speaker 01 somewhere between 5 and 10% of the catatonic population who you will get down to a very minimum dose of ativan or clonazepam and you will find you can't go any lower.
1:18:33 David Puder? And can I just reiterate, like, guys, if you take one thing from this, do not pull your patients who have catatonia off of lorazepam too quickly. One milligram a month, one milligram a month. It is like... That is such a pearl because so often people are like, well, I know they responded to Ativan. Now I need to prepare them for ECT. So I'm going to take them off the Ativan and wait two weeks for them to get to ECT. It's like, no, don't do that.
1:19:04 Speaker 01 No, because you'll have a severely catatonic patient again. Because again, abrupt discontinuation will induce the catatonia.
1:19:15 David Puder? Yeah, and I would say like, when I would go on the unit and I would see maybe 50 people when I would cover on the unit, which sounds crazy, but that used to be how I would do call. You know, you see everyone for like five or 10 minutes. I would inevitably catch one of them with catatonia who had not been diagnosed. And because I was always looking, it's like, it's the one thing you need to catch. You need to catch every catatonic patient. Sometimes they repeat the same thing. So you ask a question, they answer it, and then you ask another question and they repeat the same thing that they said again for the prior question.
1:19:56 Speaker 01 Yes, they will perseverate or they will echo what you said. You know, they'll repeat the last part of your question.
1:20:03 David Puder? Yeah, there you go like, so how do you feel today? And they'll go, how do you feel today?
1:20:08 Speaker 01 Yeah.
1:20:09 David Puder? How do you feel today? How do you feel today?
1:20:13 Speaker 01 Yeah, echolalia.
1:20:16 Speaker 01 You'll also see the the praxis version of that where if you move a certain way, they will do a mirror movement.
1:20:24 David Puder? Or or stopping drinking. If they stop, if you have a patient that ever stops drinking water. Okay, who's not on a GLP one, maybe catatonia.
1:20:35 Speaker 01 Yeah. Well, it's estimated that probably about 10% of schizophrenic patients at some point in their course will exhibit catatonic symptoms.
1:20:47 David Puder? And autism spectrum disorder has a higher rate, too.
1:20:51 Speaker 01 Yeah, as do, of course, all of the mood disorders, particularly the depressive disorders. And as well as a variety of neurologic conditions and inflammatory diseases, all of them can exhibit catatonia. So I really encourage people to read through the Bush Francis scale and kind of commit those signs to memory. And then every patient you see, just look them over and see if you see any of those. And if you do, take a closer look.
1:21:22 David Puder? There is a significant neglect of their basic needs. They stop eating, they stop drinking, maybe they've lost 20 pounds in the last couple of months.
1:21:34 Speaker 01 I have seen more than one catatonic patient actually
1:21:40 Speaker 01 misdiagnosed as, oh, he's got adult failure to thrive. Well, no, he's not got adult failure to thrive, he's got catatonia.
1:21:52 David Puder? Or if you're treating enough patients, you'll have the spouse bring in the patient. They say, I don't know what's going on. He doesn't talk. He just sits there. And I'm like, well, when he's sitting there, is he watching TV? No, he sits there and does nothing. I'm like, well, is he on like his phone scrolling? No, he's just sitting there. And it's like, oh, okay.
1:22:16 Speaker 01 Yeah, it's, yeah.
1:22:20 David Puder? Okay. Wow, we've covered a lot today. This is good. I feel like, I feel like this is AI pharmacology, Dr. Cummings, you know, it's like.
1:22:30 Speaker 01 I, um. Yeah, I think you told me you got a lot of the questions from, was it Chat GPT?
1:22:36 David Puder? Well, this, in this case, today, we were gonna go through the 50 most common questions asked on, on X, but we didn't get to that. We, I instead, because of the clozapine
1:22:50 Speaker 01 change.
1:22:50 David Puder? Rems being dissolved, which, which is so nice. This is like such a big. It's like one barrier for treatment, right? We shouldn't increase the barriers for treatment. So it's been dissolved and so now we can work directly with the patient and not have to log on to a cumbersome website, which was, it was cumbersome. I always say we'd have to log on twice for some reason.
1:23:19 Speaker 01 Yeah, I'm not, frankly, I'm not sure where the FDA got the programmers for that, but they were not the cream of the crop in terms of software creation.
1:23:30 David Puder? Yeah. So, okay, I think we're wrapping it up. I think this is a good, a good amount. And I always, I always, whenever I see like antipsychiatry people on X and they're like, you know, psychiatry is not a brain disorder. I'm like, do you want me to send you some catatonic patients? Because like, honestly, you will not be able to. Would you like a catatonic patient to move in with you for one month? We should have a program that we can like lease a catatonic patient to these, to these antipsychiatry people.
1:24:01 Speaker 01 Yes.
1:24:02 David Puder? But then, but then when you say that, they'll say like something like, well, this is not what you really do. Don't lie. You're being deceitful. And it's like, no, I really do treat catatonic patients.
1:24:13 Speaker 01 Yes.
1:24:15 Speaker 01 Well, not just catatonic, but you know, people with severe mental illness that is brain, you know, and these are brain diseases. You can take a picture of the changes. You can do the genetics and all of it points to this person has a brain that is not put together right and is not working correctly. And we're trying to coax it into working the best we can manage.
1:24:38 David Puder? Or, you know, depression. It's like, if you have frontal temporal dementia, your risk of dementia is like, or depression is like 40%. So it goes way up. If you have uncontrolled diabetes, your risk of depression goes up fourfold, you know, or something like that. It's like, there are real biological impacts on our bodies. And, and in the same way, we like exercise, diet, all of that stuff improves the risk of depression and mental illness. How do you think it does that? It does that by changing the brain and making the brain healthier.
1:25:11 Speaker 01 Yeah, I'm not sure where this idea came from that somehow the brain is not. Part of the rest of our biology. It seems it's, I mean inherently, it's just an absurd idea.
1:25:24 David Puder? Well, but, but, but you know, like in defense of people who are, who are therapists who want to, who are focused on talking to patients, you know, it, it does make sense that they're focused on, on that lane and I'm all for it. Like do psychotherapy as well. Like that changes the brain.
1:25:44 Speaker 01 Yeah, it changes the brain. But there, I mean, that's the whole thing. It was psychotherapies. You're either engaging in an exchange of behaviors or an exchange of ideas, but you're exchanging them with a brain. It's not like the brain is off somewhere doing something else.
1:26:02 David Puder? Yep. A couple of things I've been thinking about is creatine. There's some new studies on creatine and there's one for creatine added with CBT for depression. The group that was on creatine had like a five point better change than the group on the placebo. So I'm like, you know, I've been watching these studies for years, but that one seems to have pushed me over the edge to recommend it to most people.
1:26:29 Speaker 01 Well, I think the, I think the area where, in this scenario, we've been kind of, some people have been doing research and poking around in for a long time is are there things we can get people to do that would enhance neuroplasticity? Because when we apply a treatment, whether it's medication or psychotherapy, the more plastic, the more changeable the brain is, the more bang we get for our buck out of the treatment. And certainly some things like creatine, some things like, as we've talked about frequently, sleep, exercise, all of those influence how plastic the brain is.
1:27:16 David Puder? And, and you know, neurotrophic factors are a, are some way of measuring neuroplasticity. So creatine, I've also been thinking about microplastics. I wrote, wrote a paper with a colleague, two colleagues on this. The recent study showing a spoonful of plastics found in the brain, four times more in people with dementia.
1:27:38 Speaker 01 Yes.
1:27:40 David Puder? It's concerning?
1:27:41 Speaker 01 Yeah, unfortunately, we have polluted the world with microplastics. And that's not a good thing because these are molecules that do not degrade easily.
1:27:54 David Puder? So, so here's, here's, uh, here's my hot take. Okay. So zebrafish, when subjected to a high microplastics environment, it took them 70 days to get out of their brain 70%.
1:28:13 David Puder? So it took them, oh, wait, 70 days to get out 75%. Okay. So there is an elimination that goes on. And if you looked at the histology of the, the recent study that came out on, um, microplastics in the brain, the, the microplastics are in the white blood cells in the brain.
1:28:33 Speaker 01 Yes.
1:28:34 David Puder? So my hot take is, uh, number one, we have to figure out how to reduce it from our intake. And when I looked at everything that possibly can be, probably the biggest bang for the buck is to not microwave plastic ever, when you cook, when you heat up your food, like, and to never do anything hot with plastics, right? So tea bags, um, microwaving baby bottles that are plastic, awful, just awful. Secondly, things that are produced with plastics, like, uh, highly processed foods, uh, chicken nuggets have 30 times more microplastics in them than chicken breast. So those are some easy wins. Uh, the, the next one is traffic. When you're
1:29:19 David Puder? stuck in traffic, recycle the air in your own car and make sure you have a good filter. And then at home, you could get a HEPA filter. I've gotten some since I started looking at this. And that can be an easy win to reduce the consumption while you're sleeping. Speculation, you know, there's a lot of speculation here. And I think that this field is going to, is going to explode in the next decade with lots of studies because it's, it's like, it's environmental psychiatry that is just completely unexplored.
1:29:51 Speaker 01 Yes.
1:29:51 David Puder? And so I'm writing a paper with some colleagues. We're looking at the, I'm creating a microplastic index, which, which will have kind of an estimation of like, okay, if you do these types of things, you may have this much microplastic. So then we can compare that to, to trials that are already out there and see if that correlates at all to mental health issues. Cause it's kind of like, it's, you know, we don't know how much this is impacting us.
1:30:18 Speaker 01 Right. Right. Because we don't understand that much about the effects of microplastics in the brain, which is an area that we need to study much more since the microplastics are ubiquitous. And unfortunately, despite all the talk about plastics and about global warming, frankly, we produce more plastic and more greenhouse gases each and every year. Last year was the largest amount in history and this year is looking already to outpace that. So.
1:30:55 David Puder? You know, it's interesting, like, I feel like, you know, despite the executive order to, to bring back plastic straws, I think that when both sides of the aisle can, can definitely get behind, like, we should probably not keep putting plastics in the ocean.
1:31:14 Speaker 01 No.
1:31:15 David Puder? We should, we should get these plastics and like out of our water supply. We should, you know, like, please, like, have, like, both sides should be like a hundred percent on board with this, you know, like this is not going to disrupt the oil cartels. It's not going to disrupt, you know.
1:31:33 Speaker 01 Wow.
1:31:33 David Puder? We need, we need to do something about this.
1:31:35 Speaker 01 It should be. Unfortunately, there are people in positions of power who just deny that this is a problem.
1:31:43 David Puder? You know, I think, yeah, and how, how we execute our distribution of the, the literature and the science, I think, hopefully we'll engage that more. But I'm, I'm, I think that's one thing that I've been thinking about. Anything that you've been like really into in the last couple, couple of months, just that's kind of on the forefront?
1:32:08 Speaker 01 Uh, basically been looking a lot at, uh, looking for really data that might suggest how, uh, in particular, we might be able to prevent schizophrenia.
1:32:25 Speaker 01 And I think it comes, well, two, the two elements in that are we need to be much better at being able to identify who's truly at risk, which I think is going to come down to understanding the genetics much better than we do.
1:32:41 Speaker 01 Uh, and two, then designing socially acceptable strategies for preventing some of the excessive neurotransmitter excursions and inflammation that appear to give rise to the progression from genetics to overt illness. I think we will get there. It's a very slow process and it's, I think, the only way that we're going to truly make a, a dent beyond what clozapine offers in, in improving schizophrenia, both with respect to decreasing the incident rate and also hopefully ameliorating the severity of the illness.
1:33:26 David Puder? So what would be like the biggest wins that you could say, like to prevent schizophrenia?
1:33:31 Speaker 01 Well, if we knew who, if we knew who was at risk, that is, we could do a, you know, a gene association study at birth, basically, and say, okay, this infant's got, you know, not any risk, this other infant's got a huge risk. Well, maybe this one that's got a huge risk, they ought to be on a dopamine modulator from birth onward.
1:34:00 Speaker 01 Or an anti-inflammatory from birth onward. We don't quite know what those choices should be yet. Uh, they're, you know, the PACE clinic in Australia has done some preliminary studies. Where they looked at the children of schizophrenic parents who have a forty to fifty percent risk of developing schizophrenia. And they put their sample on either placebo or very low dose. Antipsychotic dopamine antagonist, I think it was two and a half milligrams of alandapine. Or a half milligram of risperidone. Um, they got a five-fold reduction. In conversion to overt illness in late adolescence. That needs to be replicated.
1:34:46 Speaker 01 But the reason we can't apply that more broadly is. Most people with schizophrenia are not descended from two parents with schizophrenia. They're spontaneous cases. And we can't. Prospectively tell who those people are.
1:35:05 David Puder? Yeah, this is gonna be tough. I mean, trying to sell parents to take. Put their kid on a low dose of an antipsychotic is like pretty. Well, I don't know. I would, my hesitancy towards that's pretty high also.
1:35:18 Speaker 01 Well, if you, if you think about it, though, the risk from that sort of dosage slash concentration. Of a dopamine antagonist is. Exceedingly minimal. That compared to the impact of schizophrenia. Might make it worthwhile.
1:35:39 David Puder? I, I think the, um, what about other things like, you know. Recognizing that they really need to stay away from marijuana, recognizing that they.
1:35:51 Speaker 01 Those things.
1:35:52 David Puder? Exercise.
1:35:53 Speaker 01 Those things would all.
1:35:55 David Puder? Try to reduce adverse childhood experiences at all, if at all possible.
1:35:59 Speaker 01 Those would be, those would be beneficial, but remember, this is an illness which is. Eighty percent genetically determined, twenty percent environmentally determined.
1:36:10 David Puder? Right.
1:36:10 Speaker 01 So, so if you improve all of the environmental. Things, you can reduce risk by twenty percent. If you can find some way to alter the. Phenotypic expression of the genes in a way that produces pathology, you could potentially reduce the risk 80%.
1:36:34 David Puder? Hmm. Well, interesting. Well, I think that the, if not anything else, if you had a genetic type that you kind of had labeled like, hey, parents, this is an increased risk of schizophrenia. This is how it looks. This is how it presents. If, you know, in the adolescence, this kid starts to have these issues, like come and see a specialist and let's really plan ahead on strategies for early treatment, early intervention, because it's going to be a long journey.
1:37:05 Speaker 01 Yeah.
1:37:06 David Puder? That, that seems like a viable option for me as well. I don't know if you've thought about that, just like.
1:37:13 Speaker 01 Yeah, well, certainly. Again, if we got better at predicting who's at risk, we could then monitor them much more carefully.
1:37:19 David Puder? Any idea on how, because we have the genes that are abnormal. I mean, do we have a risk calculator? Has that been developed?
1:37:28 Speaker 01 Uh, no, we don't. It should be. Part of it is the genetics of the illness are so complicated altogether. If you just count number of gene sites that appear to be related to schizophrenia or the risk for developing schizophrenia, there are 240.
1:37:49 David Puder? I think.
1:37:50 Speaker 01 Now, now in those, you have 108 of those are single nucleotide polymorphisms. Now, if you do the gene wide association studies, so that you identified all of these, the next step is indeed then the data we're missing at this point is we don't know clearly how many or which of these abnormalities have to be present to essentially form the critical burden for developing a psychotic illness.
1:38:21 David Puder? What, what we really need is we need like one of these countries, the US would be game or some European country to do genome mapping on all of their whole population.
1:38:32 Speaker 01 Yeah. And that, that I think will be the next step because I, gene, you know, gene analysis is going to become much more common because it's become cheaper and easier. And I would imagine in some countries, they're likely to do. You know, A to Z gene mapping of the individual at birth.
1:38:52 David Puder? And I, and I think that's, that to me is not overly intrusive and it's not like a bad idea. It makes sense. Like in your medical record should be your gene map, which should have a list of things that doctors could look at that are potential linked to various diseases. Like if, I think with AI and the way it is, if you had a gene map for everyone in the population and you had like, you, you could tag them all with like what diseases they had, the AI could quickly tell you what is the best algorithm for predicting future schizophrenia.
1:39:24 Speaker 01 Yes. And not only schizophrenia, this will be useful more broadly for, you know, it could be very useful for a new infant to know, well, over this person's lifetime, their risk is elevated for the following illnesses.
1:39:38 David Puder? The, the problem with that is the psychological weight that that puts on a parent. And so I feel like you almost like need to increase the, the education level of the average person before you release something like that. Because if a parent hears, oh, my kid has a 20% risk of this thing, it could feel like a doomsday to them. Like psychologically, they may not do well with that information.
1:40:01 Speaker 01 Yeah, no, it's very difficult because you know, the few autosomal dominant illnesses we do have where you know what the risk level is, those obviously are devastating for families.
1:40:13 David Puder? Yeah. So I think that's my other thought is like, okay, this, this can feel really weighty to, to a population. So it's like, how do you, how do you allow this to be something that's a positive and not like a detriment?
1:40:28 Speaker 01 Yeah, we're going to have to get a lot better at genetic counseling.
1:40:31 David Puder? What are the, the, the, the intellectual knowledge of the, um, the average person is going to have to increase. What I, you know, when sometimes they can't name the. You know, very basic facts about DNA or RNA is like, it's hard, it's hard for, for very complex topics like this to be widely adopted. So.
1:40:55 Speaker 01 Yes.
1:40:56 David Puder? All right, guys.
1:40:57 Speaker 01 Hopefully, we will get there.
1:41:00 David Puder? Well, we will leave it there today. Hopefully, you enjoy this conversation with Dr. Cummings. If you did, let me know. I'm on X. You can tweet this, this, this out with your thoughts. I really love hearing that. I can see that. Or on Blue Sky, or on Instagram, or just shoot me an email message. And Dr. Cummings, thank you so much.
1:41:22 Speaker 01 Okay, thank you.
1:41:23 David Puder? For your continued wisdom. I really appreciate you. And we'll leave it there for today.
1:41:28 Speaker 01 Okay, thanks.
Previous The Serotonin Hypothesis: Controversies and Nuance with Awais Aftab, MD Next Ketogenic Diet Review and Update with Dr. Matt Bernstein Page updated November 3, 2026 · transcript and summary are machine-generated