Psychiatry & Psychotherapy Podcast - Clozapine & Schizophrenia with Michael Cummings, MD

Episode Date: March 28, 2025

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. Link to blog. Link to YouTube video.

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? Pretty well, actually. I came back as they retired and knew it,

so I'm still working part-time, but the important feature there is part-time, so... Yeah, that's good. That's good. So I wanted to jump in. We're going to get through a lot of questions, hopefully today. But I wanted to start with Closopine. And there's a new law that the Closepine REMs is scrapped.

Yes. And it happened two days ago. So that's February 25th, 2025. Yes. And so we no longer need to report to 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 is. means for us? Basically, a number of us have been lobbying the FDA for a number of years now to do away

with the RIMS program in large far because it's become clear based on research data that the primary risk for severe neutropenia occurs fairly early in chlozapine treatment and then declines to a level of about somewhere between one and six per 10,000 after a year of treatment, which are levels comparable to other drugs that can affect the bone marrow. And we don't have REMS programs for those. So the FDA finally reconsidered the issue, and two days ago they basically abolished the REM's program for Closopine and simply noted that people should 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, I think more than a decade and a half ago now. Their rates of morbidity and mortality due to severe neutropinia related to chlospine are no larger than ours, 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 a following six months and then may stop routine monitoring altogether.

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 not getting better, not going away, they should go and have a CBC done to look at their absolute. neutrophocale. Okay. So this is like revolutionary to the world of treatment-resistant schizophrenia. Yes. We spoke about treatment-resistance schizophrenia way back in episode 49.

So it may be worth repeating some of the key points that we brought forth. The thing that I'm thinking about is there's a number of patients who, due to anisinomia and just resistance, like maybe they'll take a pill, but to get them to draw a lab once a week has just been absolutely difficult in my practice. But these are like the people that need it the most, you know? And so I'm like thinking to myself, 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? Well, certainly it's arguable that after the first six months, weekly monitoring is no longer necessary because the primary principal area of risk is during the first 18 weeks of treatment. Okay. And then it begins to decline fairly steadily. It peaks at about 1.3 percent and then declines thereafter fairly steeply.

It's an autoimmune process. So during the first month of treatment, there's 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 chief benefit, well, there's 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. It will decline in frequency, and then at some point it will go away.

The other valuable point is you can now do ANC monitoring via fingerstick 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. Wonderful. Good. Okay, so 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. We do, because certainly in the context of treatment resistance, schizophrenia, we went over this way back when we talked about treatment resistance. in schizophrenia, if somebody has failed two adequate trials of

two different antipsychotics from different classes given at adequate dose and duration, their odds of responding to anything other than chlozapine is less than 7%. Yeah. So if

you think about that, like if a patient's coming in and 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. Yeah. Because you're going to get 40 to 60% of those people responding.

Yeah. Well, many of our patients who are treatment are resistant, it's clear. Cloosapine is essentially their only real option. We don't have any other tools that are as good as Cloosepine. 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 Yashomura study found that, you know, after 2.8 years of treatment

resistance, even close-a-pean's effectiveness begins to decline. Fortunately, it doesn't decline to zero. It goes from somewhere between 40 and 60 percent down to, hovering around 30%, at least for the period of time that they studied. But there are now a number of articles that have been published that point out the benefits of switching earlier to chlozapine. 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? For an on DSH, we differed slightly from the package insert, although the package insert's fairly close to this. First dose is 12.5 to 25 milligrams at bedtime. Not that we expect that to do anything to the psychosis. That's mostly because clozapina is a very good alpha antagonist, very anticholinergic, and a very good histamine antagonist.

So you can make somebody hypotensive and over-sadated fairly. easily. If they tolerate that well, the next day they can go to 12.5 to 25 milligrams BID, and then we titrate aiming to be at around 100 milligrams by the end of the first week, and to about 200 milligrams by the end of the second week, we rarely titrate faster than in 50 milligram increments, and that usually is at a rate of once or twice per. a 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

a thousand 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 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 tightens. trade further. You know, and for a trial, you come to one of several inpoints. One, the one you're

hoping for is the patient gets better. 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 chlozapine 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 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. Okay, so just to, 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. Yes. It's about one to one. So it's like if you gave 350 to 600, 600 milligrams, you're going to get close to that level, which is the target range. For females, the multiplier is 1.32, and I'll put this handout in the guide and my website, Psychiatrypodcast.com. And so the expected level is going to be a little bit higher, so you might need a little 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?

Yeah, I think that would be about right. 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. But like most things, rates of metabolism vary from person to person and actually describe the typical bell curve or Gaussian curve. so you'll have people who are slow or 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, on average smoking will roughly double the rate of metabolism

or cut the expected plasma concentration in half. Great. Okay. So another thing that comes up often is patients who get put on chlizapine have a higher rate of developing OCD. Can you talk about that? Yeah. Like many of the second generation antipsychotics, Clozapine is an antagonist at serotonin 5HT2A 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. In other cases, you may need to add an SSRI. Our usual go-to medication is certraline because it has very few strong interactions with other drugs via the cytochrome P-450 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, then it becomes very risky to give them an antidepressant, although chlozapine 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 okay so number one check their blood level try to get it down to like the effective range number two searcherline what do you think about fluoxetine is that a decent option uh no for two reasons uh one fluoxetine is a potent inhibitor of cytochrome p450 2d6 and will raise clozapine levels about 30% okay 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 9 to 14 days, which means washout is 10 weeks, 2 and a half months. Okay, very good. Okay, so quiz question for my audience. You should know this if you listen to the podcast. The quiz question would be, what is the most common reason? why people die on clothespe. The most common reason for death due to clozapine is bowel obstruction.

So what is constipation, right? bowel obstruction. Yep. Oh, it's constipation that has progressed to bowel impaction, meaning there's a very hard lump of stool stuck in the bowel, followed by usually ischemia of the bowel wall, obstruction of the bowel, and that can have catastrophic

produce a catastrophic outcome. That's actually, has always been the most common cause of death with clozapine. Statistically, it far outstrips the severe neutropenia. Okay, 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 chlizapine? 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 to 80% range. So Clozapine is well below that, so it doesn't tend to cause motor symptoms.

In fact, people, they looked at, for example, Cloosepine is a potential treatment for tardative 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. Okay, here's another

clinical case scenario, you should be aware of as a provider. Patient comes in with fluvoxamine and recently had started chlozapine. He is heavily sedated and hypotensive. What do you imagine is going on? His clozapine has gone through the roof. Closopine is metabolized principally by cytochrome P-450-1-A-2. for which fluvoxamine is a potent inhibitor. It basically will turn 1A2 off.

Now, Clospen 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, they have essentially removed the ability to metabolize closopine. Yeah. So, yeah, be very careful with, I mean, that's a very potent inhibitor, which leads to very large amounts of clospen. Yeah, I and a couple of my colleagues reported on a case,

in which a patient was given fluvoxamine, a woman who had been on 100 milligrams of chlozapine 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 100 milligrams of fluvoxamine. She died two days later.

Be careful, guys. Be careful. This is why, like, you know, you need to pay attention to this stuff. Absolutely important. Okay, here's another question for you. The patient comes in, recently started Clozapine now at 400 milligrams per night. They complain that.

They wake up in the middle of 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? As you know, the metabolite of chlozapine, nor chlozapine,

unfortunately stimulates the salivary glands rather strenuously and increases saliva production, produces scyalluria drooling. In many patients, that actually increases the risk of aspiration and of aspiration pneumonia. It's one of the dangerous side effects of clospein, not as dangerous as bowel obstruction, but it's not inconsiderable either, which is why we should pay attention if our patients

developing scyalleria and attempt to reduce the scyallaria. we start typically with topical anticholinergic agents that can be given orally, 1% atropine drops sublingually. Eye drops. Well, yeah, they are eye drops, but 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 10. teaspoon of water and 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 if you give somebody who's on clozapine, a systemic anticholinergic, it will roughly double their risk of developing ilias and bowel obstruction. If that doesn't work and we're stuck, in some settings, we will give. glycopyrolate. 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 specifically, to inject the parodid and submandibular glands on a three to six-month interval, which works very nicely. In 90% of cases, it resolves the salariah. We actually stole that from the neurologists because, of course, people with things like Parkinson's disease and Huntington's Cary also have a difficult time with Cialore. and they started injecting botulinum toxin to control the scyalleria, then psychiatrists in research settings started using it in clozapine patients and found out it works just as well there.

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. Yes. The original study in this area came out of the Maudsley 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, Tohananadal did a very similar population-based study and found that the best overall survival among schizophrenic patients

occurred in those who were taking chlozapine. Second best were long-acting injectable antipsychotic, and worse were the oral antipsychotics. Okay, number two, so I'll ask this as a question. So kind of like, if you're listening, you try to answer before Cummings does. You have a patient who started on 50 milligrams a day of clozapine in night.

He comes in, having fallen at night, while trying to go to the journal. he also feels very, very groggy. What's the reason for this, and what is the thing that you would do next? So try to answer that in your mind? Yep. And then Cummings, what do you think?

Well, we already noted Chlozapine is a very, very potent antihistamine. 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. 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 Closepine also is a good,

alpha-1 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-sidated. Well, those are a wonderful recipe for falling. So basically, the treatment for this is to go back, reduce the dose to a more tolerable level, and then titrate more slowly, as we outlined previously. Okay, case number two. The patient comes in to the ER,

having been on chlozapine for three months, having a new onset seizure. Closepine level is drawn and is at 1,200 nanograms for ML. The patient is only on 600 milligrams of chlopine at night. What do you imagine is the next course of action for this patient? Well, the 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 closepine, in which case the next step is to lower the dose of closepine and try to get it back down around 1,000, thousand. 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. If you get beyond a thousand nanograms per milliliter, you may start to see myoclonic jerks, which are a harbinger of either myoclonic or tonic chronic seizure. Now, if somebody has a seizure on clozapine, even at, you know, and 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 Chlozapine is likely their only viable treatment option. Most common agents are valproic acid, are levitor acetam, Kepra. 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, and 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.

On further interview, you find the patient was recently put on Cyberophore. for a uti what what what um or you could you know yeah well yeah well you the syprophloxicin is uh one of the medications and in indeed but it's the only one of this group of antibiotics that is a potent one a two inhibitor so essentially the same thing has happened as with the fluvoxamine the person got put on the antibiotic and essentially their metabolism of chlozapine came to a stop and consequently their plasma concentration began to climb rapidly in this case inducing a seizure okay let's say another scenario you have a patient in the first three weeks of starting chlozapine who develops a fever you fear the worst that this patient has an amic a

mess, but all they have is a fever. What is actually going on? Fever is a fairly common adverse effect with chlozapine affecting up to 20% of those who start chlozapine. It does deserve attention. Now, in most cases, it's a benign fever where the person will have an elevation of temperature for the first several weeks, two months. of chlozapine 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 um

If those things are occurring, you want to be sure to rule out chlozapine-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 as much as people would expect, but the C-reactive protein does in those cases. Fortunately, the risk

period for myocarditis is fairly short. 80% of cases occur within the first four weeks of closamine treatment and essentially 100% occur within the first six weeks of treatment. This is not a problem that you will see in people who have been taking clozapine for months or years. Yeah, well that was one of the things that I was going to put on my list of things to ask you. Mycarditis is rare but a serious early side effect. Yes. In summary. Traponin, get a troponin level. And it's usually in the first month of use, right?

Yes. Yeah. 80% in the first four weeks. 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 the go-ahead to kind of...

Yeah, and particularly if those are associated with additional things such as, you know, my chest feels tight, my chest feels heavy, I feel shorter 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-reactor protein come back positive, the next steps, of course, are to discontinue the clozapine and sign the person up for an echocardiogram to see if what effect has already occurred with respect to their ejection fraction. Now, the vast majority of people, if you identify them, if you hold off on the closepine, their myocarditis recovers and just with supportive care. can you rechallenge them with chlozapine? Yes.

In fact, there are a couple of published rechallenge protocols. The key element of the rechallenge 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 closeap. being titration until you're past the risk period. Okay. So what's the main takeaway?

If someone had, let's say, the need to be on this medication, or they were going to remain psychotic for the rest of their life, everything else tried. Even though this is very dangerous, yes, you can go back and rechallenge them once they've recovered. The key to a successful rechallenge. And it's successful, if done correctly in 70 to 80% of cases, is to go very slowly. Starting at 5 milligrams at night and, you know, week one, 5 milligrams at night, week 2, 10 milligrams

a night, week 3, 15 milligrams 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. Okay. Okay, so the increased titration does increase the risk of this, right? Greater than 50 milligrams a day if people are rapidly titrated. Yes. 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 leucine 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.

Under 48 hours of interruption, two days, you can start back at half what their closepine 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. Okay, let's talk about what can happen with abrupt discontinuation. So if someone abruptly discontinues, what is the chance that they may reenter into psychosis? 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 closopine 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. 50 milligrams of chlizene is as anticholinergic as 1 milligram of Benstropine, a trade name

cogentin. So if you have somebody who's taking 500 milligrams of chlopine a day, that's the equivalent of 10 milligrams of Benstrapine. 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 a cholinergic delirium as well as the GI side effects of excessive acetylcholine activity, nausea, vomiting, diarrhea, cramping, sweating, all of those things. So if you have to discontinue clozapine abruptly, it's prudent to put the person on benz-tropine

and then gradually taper the benz-tropine. We typically don't start the benzoprine an equivalent dose. We'll shave that by half, start the binstropine,

and then gradually taper it at a half-mill a week so that the person doesn't have a colonergic rebound. Yeah, so a colonergic rebound, you also see things like nausea, vomiting, sweating, diarrhea, restlessness, headache, insomnia. Yeah. And it's going to happen within 12 to 48 hours of stopping. Mm-hmm. Yeah, and it's often fairly dramatic and the delirium can be quite severe as well.

Do you see this as well when you're stopping someone on like olanzapine, which is fairly anti-cholinergic? You can. It is less common than with chlospine, but you can. You could also see it, for example, if you did that with chlorpromazine of the antipsychotics,

if you put them in rank order in terms of how anticholenduric they are, closepine's at the top. Number two is chlorpromazine, thorazine. Number three is olanzapine. So you can see it with the other two closopine, though,

is really prone to causing colonergic rebound if it's stopped abruptly. Yep. So, okay, I was thinking about like how much anticholinergic, that capacity to that is like 10 milligrams of cogenton, oh my gosh. And then- Yeah, and we have patients, you know, say you have somebody on not 500,

but 900? You're now getting up into astronomical levels of Benstropine, because normally Benstropine, when it's being given as a principal treating agent, the max dose for it is 6 milligrams a day. 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. Why do you imagine he's starting to talk about that? Part of it may be the first time he's realizing that his life is not being productive. People on Closopine do not uncommonly have kind of an awakening. In fact, in the early literature of Closopin, 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. One, realize that you have a severe mental illness, and two, realize that your productivity, your ability to form relationships, your ability to work, are all seriously impaired. You know, this calls on the clinician to do a good evaluation. not just focusing on the positive symptoms, but also taking into account what cognitive deficits and negative symptoms the person may have. Unfortunately, we don't at this point have 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 colon estraceous 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. 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 of a sudden you're saying, oh, wait, what? 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 very useful. Now, unfortunately, since schizophrenia starts in utero and we don't treat it until after it's well-progressed, our results aren't very good. Only about 6% of people with schizophrenia maintain stable employment sufficient to live independently, and even a smaller percentage, maintain stable interpersonal relationships such as being married and having kids.

With the percentage on that? For people on closopine or not on clospein? For schizophrenia as a whole, 6%. But, I mean, in my... Well, that seems pretty abysmal. But even on medications? Yes. 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. Creppelin was right when he termed this dementia precox 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 20s. Well, with most severe illnesses, if you let the illness run rampant for two decades, it diminishes

is your prognosis. Yeah. No, absolutely. I think, yeah. Okay. So here's another patient says he's, let's say this patient ongoing,

three months in. You have, he came in initially on respiroral four milligrams. You've reduced it to two. He's on close of penis well, 400. And subsequently,

you decide to stop the risk. The week after you stop the risperol, he says, I'm no longer pacing around all day. I'm more just sitting around doing nothing. How do you interpret this statement? If he was pacing around all day, I would wonder if the risperidone was causing him some degree of acathesia, which was originally actually named Can't Sit Down syndrome, which was a very descriptive name.

in what is now the Czech Republic. Which you're, 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. It's the worst thing. No, it's a horrible syndrome. I'm laughing because of the unusual naming. Okay, good. We've got to clarify. In the Czech Republic. No, no, it's not a, the syndrome itself is not funny. 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. Okay. So when we think about there's an intense restlessness that's quite often occurring with antipsychotics, especially at high doses, typical than a typical clozapine. Does that cause this restlessness? of aceshesia? 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 Closepine caused in atypical form of this or that, but there's not really been any convincing data that that Closepine causes Parkinsonism or Acethesia or dystonia, or dystonia. or dystonia. 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. In the case of acetygia, there's also dysregulation of noreadrenergic and serotonin receptors,

which is why eucathias harder to treat. 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 schizphrineic 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, if that kind of feeling is going on,

it's a truly miserable condition. 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 happen from a number of different psychiatric medications, and it should be...

Yes, anything that particularly interferes with dopamine transmission in the Niagara Astridal 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 and they're agitated and they get, you know, a lot of haloperidol or a lot of respiradone 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 their pacing, odds are there. they're taking 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. I've had a couple people reach out to me of chronic acetheia. 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? When people develop tardive acetheisha, it is one of the most difficult of all the movement disorders to treat successfully. Acute acethehesia is fairly responsive to either beta blocker, propranol, or to mertazapine. Tartavacet cathesia 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. People have also tried other GABA urgic agents like GABepentin 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 acethecia. So the time course is usually different than acute acesia. Yes. Yeah, acute acethesia usually occurs beginning within, well, anywhere from hours to days after exposure to a dopamine antagonist. Tartavecathia 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 a catheteria, usually starting with the internal sense of restlessness and then eventually spilling into overt movement.

So would there ever be a role for increasing the antipsychotic in this type of issue? Or is it always decreasing? It's always decreasing. If you increase the amount of d2 blockade, it will tend to worsen the acetheasia. Now you can get away with that in Tardiv 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.

The receptors will adapt, and the disconnect movements will reemerge, and you can wind up chasing that so that each time you increase the dose, it gets worse. Now, one thing with TD, you have to watch out for, 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. 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 acuthesia or tardive discontia, or tardive dyskinesia, because all of these syndromes are more treatable the earlier they're caught.

Awesome. Okay. As you're thinking about Closopine, 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?

That we haven't covered. Let's restrict it to what we haven't covered. Okay. I think the most common thing I see are the most common question I get regarding clozapine is can I combine it with other antipsychotics? The answer is yes.

Like most polypharmacy, you're looking to combine different mechanisms of action, hoping for additive benefits across drugs. 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 one or the other. The nice thing with chlozapine is

it blends well with both the dopamine antagonists and the partial agonists because its mechanisms of action don't appear to have anything to do with blockade of dopamine receptors. We think it acts, one by increasing glutamate signal transduction, and particularly the frontal lobes,

and also by decreasing dopamine release by stimulating muscarinic four receptors in the ventral tegmentum. So it's not hitting the same sights as the dopamine antagonists or the partial acinists. So it combines well with both of those groups. The only antipsychotic you cannot combine chlozapine with is the very newest one,

xenolamine slash trospium. And that's because of colizapine's anticholinergic effects, it will essentially wipe out xenolamine's mechanism of action, which is dopamine, muscarinic agonism, at M1 and M4 receptors. You probably would want to avoid any CYP-182 inhibitor Yes. To combine it with cloparmazine.

Yes. With chlozapine, you do not want to give the person a 1A2 inhibitor because, as we've talked about, you may well 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 chlozapine appropriately to maintain the person at the right level. similar issues arise and people who develop severe infections. I mean, given our recent history, people are well aware that COVID-19 could increase chlozapine 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-6 and interleukin-6. and interleukin 8, two of the cytokines produced by more severe infections inhibit the cytochrome enzymes. What's the second most common question that we haven't covered that gets asked? Probably people often ask,

well, what should I absolutely stay away from if I'm treating somebody with chlozapine? And although we've touched on this, basically anything that is a very, and 1A2 inhibitor, some of which are well-known like fluboxamine, and some of which are relatively unknown, like syprophyxacin.

I always encourage people, if you're going to combine a drug that you're not very familiar with with something like chlopine, look up its effect on the cytochrome system. These days, with the Internet, that information is readily available 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 Pub Kim, is, you know, what are the effects on the cytochrome system? Anoxysin is another antibiotic anoxysin. Yes. That is a potent CYP-182 inhibitor. Caffeine is a weak inhibitor.

Yeah, caffeine's a weak inhibitor. What if they're drinking eight cups a day? They may get a 5 to 15% increase in their closopine blood level. And you have to watch out the other way, too, if somebody starts taking or doing something that is an inducer at 1A2, they can lower their closopine levels and may have a psychotic relapse because they've become subtherapeutic. probably one of the most common that we've run into in the state hospital system has been the proton pump inhibitor omeprosol. It is a weak to moderate 1A2 inducer. 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 concentration of your, of your chlizapine or other drugs for that matter. Let's say you had someone on suprasidone. Would you be concerned? Would you be concerned? concerned about QTC prolongation? No. We do get that question as well quite a bit. Closopene 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 QT interval and eventually a risk of Torsad to point. Clozapine only very weakly inhibits that channel. Concentrations of clozapine that are clinically significant for doing that or above 1,500 nanograms per mil. By that point, the vast majority of people couldn't tolerate

chlozapine 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 cypherloxin case we talked about where the person's level suddenly went sky high. Okay, next question. Would you fear putting someone on a tricycic antidepressant if they're on Closopine, due to risk of lowering the seizure threshold? 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 tricyclics alpha adrenergic antagonism, because that's also additive, and it's antihistaminic 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 close bean.

It has to do with the fact that they can inhibit the cardiac conduction system. The LD50 for tricyclics ranges from around 6 to 8, meaning that 6. to eight times the therapeutic concentration is enough to kill 50% of people. Let's say the patient is a heavy tobacco smoker, smoke actual cigarettes. How much would that change the closine level? 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 two to four weeks for their closopine level to drop that much, because what's happening is several of the polycyclic compounds in cigarette smoke are very important deucers of the cytochrome P450 system. So you're ramping up their enzymes and the enzyme is chewing up the chlizepine. 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.

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 sub-therapeutic 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 closepine appropriately. 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? And the answer is? It will roughly double.

So this is something that 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 dose. Yes, you're chasing that plasma concentration because, indeed, cigarette smoke induces the liver, vaping of nicotine does not. 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 close bean? Well, marijuana, particularly in younger people, is psychotogenic and some. It's estimated that among marijuana smokers, Delta 9 THC, the active ingredient, to get high, produces some degree of psychosis in somewhere between 8% and 12% of those individuals. Now, if somebody already has a psychotic illness, marijuana may make it worse. We don't have really great numbers on that.

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-day joints in a day's time. So it's purely an effect of how much. The same polycyclic compounds occur when you burn marijuana leaves as occur when you get to burn tobacco leaves. But in the case of tobacco, people are often smoking a lot more. But then you have the issue of Delta 9 THC itself is psychotogenic for some people. What does clozabine do to brain-derived neurotrophic factor?

Increases it. Also increases glial-derive 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 chlozapine largely due to

increased dendrite arborization. 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 leaves, if you will, you have cortical thinning as a result. If they get bushyer, you get thickening. We presume that's good. and it seems to correlate with improved cognitive and attention and processing performance and people treated with chlozapine.

We don't know all of the details of the responses to brain-derived neurotrophic factors well enough to know in detail what the chlozapine does downstream, but we're assuming at this point that it's good. There was a 2018 study that it showed clozapine decreased IL-6 and TNF alpha patients, which may be another potential mechanism, anti-inflammatory properties. 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. 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. What do you think about the genetic studies showing polymorphisms

in genes like DRD3, dopamine receptor D3 and COMT, Cacol O-Methyl-transferase, which is associated with treatment outcomes. 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 and titled, 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, 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 the genes that are involved are 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, Kreplen was right in calling this a developmental dimension in which the gene abnormalities give rise to both an anatomy

and a physiochemistry that aren't 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, and exposure to things like cannabis during adolescence or other drugs that tend to be neurotoxic like methamphetamine during adolescence can worsen the risk that the person will develop an overt psychotic illness.

Very good. Let's say the patient has schizophrenia and catatonia, would you try? treat them and they're currently, let's say they've had a history of responding well to Chlozapine in the past, but they've been off medications for a while. What would you treat first and why? I would probably start with the catatonia. One, the Chlozapine treatment is going to take longer to get in place. I would start, frankly, in somebody who I suspected of having catatone 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 laresopam challenge, which is two milligrams via the intramuscular root, and then I would reevaluate the patient after 45 to 60 minutes to see if their catatonia had ameliorated or gone away. An important caveat with that is it should not be by the oral root because the patient 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 antipsychotic treatment, not excessive

d2 blockade, but either moderate d2 blockade or, uh, 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 that 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. Now, if the person is not a responder to a loresapam challenge, that doesn't mean that they don't have catatonia. It just means they're not a benzodiazepine responder,

and that person is going to get moved along to ECT fairly quickly. 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 out of van seizing back 40 minutes later

yeah that can when that's a positive test it's often exceedingly dramatic last person we did that with you this guy man mid 30s nursing found him basically standing naked in his

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. He got two milligrams of lorazepam, and 45 minutes later, he was dressed, conversant, and asking what he could have for lunch. 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

I mean, 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, you feel so good as a psychiatrist. Yeah, 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 are 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 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 laryzepam a month or a half milligram of chloroanazepam a month,

because you want to be sure the underlying conditions in control and the catatone 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 somewhere between five and 10% of the catatonic population, who you will get down to a very minimum dose of Aivan or Klonazepam, and you will find you can't go any lower.

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. No, because you have a severely catatonic patient again. Because, again, abrupt discontinuation will induce the catatonia. 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 ten 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. Yes, they will perseverate, or they will echo what you said. They'll repeat the last part of your question. Yeah, they go like, so how do you feel today? And they'll go, how do you feel today?

Yeah. How do you feel today? How do you feel today? Yeah, echolalia. And you'll also see the praxis version of that where if you move a certain way, they will do a mirror movement. Or stopping drinking. If you have a patient that ever stops drinking water, okay, who's not on a gLP one, maybe catatonia. Yeah.

Well, it's estimated that probably about 10% of schizophrenic patients at some point in their course will exhibit catatonic symptoms. And autism spectrum disorder has a heart rate too. 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. 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 months. I have seen more than one catatonic patient actually misdiagnosed as, oh, he's got adult failure to thrive. well no he's not got adult failure to thrive he's got catatonia or um 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. Yeah, it's, yeah. Okay. Wow, we've covered a lot today. This is good.

I feel like this is AI pharmacology, Dr. Cummings, you know? It's like, I, um. Yeah, I think you told me you got a lot of the questions from, uh, was it chat GPT? Well, this, in this case today, um, we were going to go through the 50 most common, questions asked on on x but we didn't get to that we instead because of the klozapine um change rims being dissolved which um which is so nice um this is like such a big it's it's like one barrier for treatment right we 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 would have to log on twice for some reason. 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. Yeah. So, okay, I think we're wrapping it up. I think this was a good, a good amount. And I always, I always, whenever I see, like, anti-psychiatry 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 anti-psychiatry people.

Yes. 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. Yes. Well, not just catatonic, but 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. 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 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 it? does that. It does that by changing the brain and making the brain healthier.

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. Well, 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 that lane and I'm all for it. Like, do psychotherapy as well. Like, that changed the brain.

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. Yeah. A couple things I've been thinking about is creatine.

There's some new stuff. 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. Well, I think the area we're, in a 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. And, you know, neurotrophic factors are some way of measuring neuroplasticity. So creatine, I've also been thinking about microplastics. I 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.

Yes. It's concerning? 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. So here's my hot take, okay? So zebrafish, when subjected to, to a high microplastics environment,

it took them 70 days to get out of their brain 70%. So it took them, 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 recent study that came out on microplastics in the brain,

the microplastics are in the white blood cells in the brain. So my hot take is, 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 heat up your food. And to never do anything hot with plastics. So tea bags,

microwaving baby bottles that are plastic, awful, just awful. Secondly, things that are produced with plastics, like highly processed foods, chicken nuggets have 30 times more microplastics in them than chicken breast. So those are some easy wins. The next one is traffic. When you're 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 explode in the next decade with lots of studies because it's like it's environmental psychiatry that is just completely unexplored. Yes. And so I'm writing a paper with some colleagues.

We're looking at the creating a microplastic index. which will have kind of an estimation of like, okay, if you do these types of things, you may have this much microplastics, so then we can compare that to trials that are already out there and see if that correlates it all to mental health issues. Because it's kind of like, we don't know how much this is impacting us. Right.

Right, because we don't understand that much about the effects of microplastics in the brain, which is an area that we don't know, 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, you know, It's interesting, like, I feel like, you know, despite the executive order to bring back plastic straws,

I think that both sides of the aisle can definitely get behind, like, we should probably not keep putting plastics in the ocean. No. Like, 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, 100% on. word with this. You know, like this is not going to disrupt the oil cartels. It's not going to disrupt, you know, we need to do something about this. It should be. Unfortunately, there are people in positions of power who just deny that this is a problem. You know, I think, yeah, and how we execute our distribution of the literature and the science, I think hopefully we'll engage that more.

I think that's one thing that I've been thinking about. Anything that you've been like really into in the last couple months that's kind of on the forefront? Basically been looking a lot at looking for really data that might suggest how, in particular, we might be able to prevent schizophrenia. And I think it's, comes to, well, 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.

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. I think the only way that we're going to truly make a dent beyond what chlozapine offers in improving schizophrenia both with respect to decreasing the incident rate and also hopefully ameliorating the severity of the illness. So what would be like the biggest wins that you could say like to prevent schizophrenia?

Well, if we knew who was at risk, that is we could do 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 or an anti-inflammatory from birth onward we don't quite know what those choices should be yet the Pace Clinic in Australia has done some preliminary studies

where they looked at the children of schizophrenic parents who have a 40 to 50% 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 alanzapine or a half milligram of respiradone. They got a five-fold reduction in conversion to overt illness in late adolescence. That needs to be replicated. But the reason we can't apply that more broad, as 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. Yeah, this is going to be tough. I mean, trying to sell parents to put their kid on a low dose of an antipsychotic is like pretty, I don't know. My hesitancy towards that is pretty high also. Well, 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. I think what about other things like, you know, recognizing that they really need to.

stay away for marijuana, recognizing that they exercise, those things would all help. Try to reduce adverse childhood experiences if it all possible. Those would be beneficial, but remember, this is an illness which is 80% genetically determined, 20% environmentally determined. Right. So if you improve all of the environmental things, you can reduce risk by 20,000. 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 percent well it's interesting well i think that the uh if not anything else if you had a genetic type that you kind of label 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. Yeah.

That seems like a viable option for me as well. I don't know if you thought about that. Just like... Yeah, I'll certainly, again, if we got better. at predicting who's at risk, we could then monitor them much more carefully. Any idea on how, because we have the genes that are abnormal, I mean, do we have a risk calculator? Is that been developed? No, we don't. It should be, part of it is the genetics of the illness are so complicated altogether, if you just count a number of gene sites that appear

to be related to schizophrenia or the risk for developing schizophrenia. There are 240. Now, in those, you have 108 of those are single nucleotide polymorphisms. Now, if you do the gene-wide association study 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. What we really need is we need like one of these countries, the U.S. would be a gamer, some European

country to do genome mapping on all of their whole population. Yeah. And that I think will be the next step because 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. 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, in the way it is, if you had a gene map for everyone in the population and you had, 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? 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. The problem with that is the psychological weight that that puts on a parent. And so I feel like you almost need to increase 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. 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.

Yeah, so I think that's my other thought is like, okay, this can feel really weighty to a population. So it's like, how do you allow this to be something that's a positive and not like a detriment? Yeah, we're going to have to get a lot better at genetic. counseling. Are the, the, the intellectual knowledge of the, um, the average person is going to have to increase when 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, um, for very complex topics like this to be widely adopted.

So. Yes. All right, guys. Hopefully we will get there. Well, we will leave it there today. Hopefully you enjoyed this conversation with Dr. Cummings. If you did, let me know. I'm on X.

You can tweet 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. Okay. Thank you. For your continued wisdom. I really appreciate you.

And we'll leave it there for today. Okay. Thanks.