How fast can you titrate clozaril

[Chrismander]

I started clozaril for the first time ever (Yipee! and someone said this was supposed to be a useless rotation that I'm on), and followed the dosing guidelines listed on the registry website. So far so good. But my attending was asking me if we could go any faster on the titration. I know there's a risk of hypotension and cardiovascular collapse during the initiation of it, so is this titration regimen the fastest one could go? In this case the patient had previously tolerated 500 mg clozaril a day in divided doses (has been off ~1 month or more), would that factor into your decision making at all? Thanks for all your help!

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[whopper]

I've given Clozaril dozens of times. I only had a handful of Clozaril patients until I worked in a long-term facility. There, you see a very different patient population vs. the regular short term facility most medical hospitals have.

I would not go faster than the recommended guidelines. If anything goes wrong, and a lot can go wrong even when following the recommended guidelines, you're just going to open yourself up to (possibly jusftified) criticisms. The criticisms may unfairly connect the accelerated titration with the problem whether or not it would've happened due to the accelerated titration (and how the heck would you be able to figure that out?)

I don't know why your attending wants to go faster than the recommended titration rate. If he/she has any insights into that you should ask him/her.

I know there's a risk of hypotension and cardiovascular collapse

Another big thing to factor is the ANC. Going too much too fast could cause the ANC to plummet. Some theorize (though I've never seen data to back it up) that titrating too much too fast may drop the ANC to the point where you'd have to stop the Clozaril but if you did it at a slow and steady pace, the bone marrow may have been able to compensate and tolerate the Clozaril.

There is some data suggesting that Clozaril suppression of bone marrow's production of blood cells may be permanent. E.g. ANC levels may not return to where they were before it started, stopping Clozaril in some and restarting it later may have accelerated drops in ANC not seen before.

Seizure is another thing to worry about. Although the product guidelines don't mention this, several mention that someone on Clozaril need to be put on a anti-seizure medication.

Another factor is that while titrating up, there are specific milestone events that the doctor should consider. E.g. several texts recommend that once the patient's Clozaril level reaches 400 mg a day, that the patient be put on Depakote to prevent seizures. Some recommend that serum Clozaril levels be taken and used as a factor in the determination in the titration.

But my attending was asking me if we could go any faster on the titration.

Again don't know why he/she is asking you. It's not out of the ordinary for a psychiatrist, even with several years of experience, to have little experience with Clozaril patients because you only start accumulating treatment resistant patients in specific settings such as a long term facility.

 

[psychattending]

I started clozaril for the first time ever (Yipee! and someone said this was supposed to be a useless rotation that I'm on), and followed the dosing guidelines listed on the registry website. So far so good. But my attending was asking me if we could go any faster on the titration. I know there's a risk of hypotension and cardiovascular collapse during the initiation of it, so is this titration regimen the fastest one could go? In this case the patient had previously tolerated 500 mg clozaril a day in divided doses (has been off ~1 month or more), would that factor into your decision making at all? Thanks for all your help!

It is an issue of building up tolerance to the side effects - mainly sedation and hypotension. I have gone up more quickly in re-exposure patients especially if they are acutely ill. One would have to monitor side effects very closely.

 

[kugel]

I have gone up slightly faster in a few pts who have previously tolerated clozapine without problems, but only when I can document clear understanding of the risks/benefits by the patient or the legal guardian. I put it to the patient (or guardian) as a decision he gets to make. "So, we may be able to decrease the time getting back to full dose. But I can't be sure that's true. You could get low blood pressure and that could possibly kill you, or you could possibly lose your white blood cells that fight infection and you could die from that, or you could get seizures. We'll monitor you, so that if you do get such problems we can probably catch it before it becomes serious, but I can't guarantee that. Of course, if I go slow, you suffer the symptoms longer. Do you want me to go fast or do you want me to go slow?"

I'm not necessarily advocating this approach. Whopper is an expert.

 

[whopper]

I don't know if it's fair to call me an expert.

I can tell you that a specific forensic facility in Ohio had specific guidelines on Clozaril that are actually better than that in the package insert. Unfortunately I only have it in print format. One of the doctors that helped formulate those guidelines used to be my boss and we talked about the subject quite a bit because when I first started working at a forensic facility I had my first Clozapine patients without an attending to oversee me and I felt green.

Those guidelines specifically state Depakote or another seizure med must be given. I've never seen that before until I worked with him. Many of those guidelines were directly from experts such a Paul Keck but they are not regularly incorporated in most practice.

I've also seen some PRNs I've never seen before to treat some of the symptoms such as hyper-salivation.

There are also some techniques one could try to preven the ANC plummet such as an antioxidant rich diet and vitamin supplementation. This does have in-vitro studies backing it up, but no one so far has been able to exploit that in a living animal to my knowledge to prevent the ANC drop. The theory is that Clozapine when it reacts with some enzyme systems (myeloperoxidase and NADPH-oxidase), it forms a very potent free-radical that damages bone marrow. Nice theory but I've only seen one study where they tried to use it to preven ANC drops (in animals not humans by giving Vit C supplementation) and the results did not prove anything one way or another.

Another thing to factor is men of African descent have lower ANCs. I kid you not about this and I've seen this quite a bit in clinical practice. I was, in fact, going to write a paper on it because I didn't know this phenomenon was brought out to medical science. I won't because I just found out about 3 months ago that someone beat me to it.

It's called Benign Ethnic Neutropenia. It's been cited in several medical journals but few in America are willing to bring it out to the open, IMHO, becuase of PC. This is known and discussed in the UK, in fact in the UK, Clozapine registries maintain a seperate males of African descent registry and different dosing guidelines (at least from some sources I've read) because of that phenomenon. (Now do you understand why I came up with my opinion?). It's not out of the ordinary to get an African-American male with an ANC of close to 2.0 or even lower than it. Most people of a different sex and race don't have that going on. This can make treating a male of Africa-American descent with treatment resistant psychosis with Clozapine more complicated.

Another problem, I've learned, and this is anectdotal and something I was thinking of publishing but I haven't encountered a case of it yet, is according to an IM doctor that worked at the forensic facility, those on Clozapine often have delayed inflammatory reactions to infections. Makes sense when you consider they have an impaired Neutrophil production, but it's one of those things you don't think about until you see a case of an ear infection turned into an abscess and the patient didn't experience ear pain at all. She told me she's seen it actually several times. If I ever encounter such a case I will try to publish it.

That becomes especially more difficult if the person is psychotic to the point where they will not bring this problem up and on Clozapine. She told me that when doing a physical examination and interview of patients on Clozapine, you have to be much more sensitive to the possibility of them having a bacterial infection.

I bet you by now I treated over 10x more people on Clozaril than the PD of the residency program I graduated. At any point in time, at the forensic facility I work at, I have at around 1-5 patients on Clozaril. Like I said, I've seen attendings that have practiced for decades and they may have only had about 10 Clozaril patients EVER.

I mentioned before in other posts that a residency program with more clinical rotations will give you a better clinical education. This is exactly a reason why. I didn't have a long term or forensic facility available except as an elective at my residency program.