Starting clozaril in a patient with low baseline neutropenia

[sweetlenovo88]

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Patient wants clozaril and is on high dose seroquel at this time. ANC has been at 1.9 all year, am I justified in not starting a titration given the low baseline?

 

[Merovinge]

Patient wants clozaril and is on high dose seroquel at this time. ANC has been at 1.9 all year, am I justified in not starting a titration given the low baseline?

No, minimum to start is 1.5 unless they have known BEN in which case it is 1.0. I am amazed a patient is asking for Clozapine, that in and of itself is quite the story. Clozapine is SO much better a drug than anything else we have for schizophrenia, give your patient a chance at it, it's worth the extra headache to improve their life.

https://www.clozapinerems.com/CpmgClozapineUI/home.u

That site will give you all the guidelines and let you sign up if you have not already.

P.S. The draconian rules USA has over clozapine is such a huge impairment since the only psychiatrists prescribing it are willing to do a bunch of extra unpaid work to give their patient the most effective drug. Near #1 petpeeve of mine.

 

[sweetlenovo88]

No, minimum to start is 1.5 unless they have known BEN in which case it is 1.0. I am amazed a patient is asking for Clozapine, that in and of itself is quite the story. Clozapine is SO much better a drug than anything else we have for schizophrenia, give your patient a chance at it, it's worth the extra headache to improve their life.

https://www.clozapinerems.com/CpmgClozapineUI/home.u

That site will give you all the guidelines and let you sign up if you have not already.

P.S. The draconian rules USA has over clozapine is such a huge impairment since the only psychiatrists prescribing it are willing to do a bunch of extra unpaid work to give their patient the most effective drug. Near #1 petpeeve of mine.

I know minimum is 1.5, but I don't feel comfortable given he is already at 1.9 and at under 1.5 it is discontinued. Am I being too cautious?

 

[PistolPete]

You can try it and see what happens to his ANC. You can also give low dose lithium (300mg) to increase his white count if he's close to the cutoff and responding very well to the clozapine.

 

[sweetlenovo88]

You can try it and see what happens to his ANC. You can also give low dose lithium (300mg) to increase his white count if he's close to the cutoff and responding very well to the clozapine.

Thanks for the suggestion, he said he had side effects to lithium

 

[Merovinge]

I know minimum is 1.5, but I don't feel comfortable given he is already at 1.9 and at under 1.5 it is discontinued. Am I being too cautious?

If he/she is a good candidate for clozapine AND requesting it then certainly worth it. You can leave the Seroquel pretty much alone at low doses of clozapine and slowly cross titrate, you should know within a few months if they will tolerate it. Its obviously a pain but it could be a game-changer for the patient.

 

[Neuro111]

I don't have a ton of experience with Clozapine, but I have worked under an attending who is doing research on BEN ( and loves clozaril). Obviously I am not sure what race your patient is, but 1.9 is perfectly reasonable to start clozapine. I know a lot of people start Lithium to increase the ANC count, but after reading multiple articles and talking to the said attending, I don't think it is necessary to add lithium. In fact, I would actively discourage using Lithium because it is masking their true ANC values.

 

[Blitz2006]

Stupid question time.

How long does it take for clozaril to 'adversely' impact the Neutrophil count? Is it a matter of hours after taking medication? Days? Weeks?

 

[Merovinge]

Stupid question time.

How long does it take for clozaril to 'adversely' impact the Neutrophil count? Is it a matter of hours after taking medication? Days? Weeks?

Not a stupid question. It has clearly been found at any point in time in treatment (hence monthly CBC in perpetuity) but is much more likely early on in treatment, first few months are the highest risk time.

 

[clozareal]

P.S. The draconian rules USA has over clozapine is such a huge impairment since the only psychiatrists prescribing it are willing to do a bunch of extra unpaid work to give their patient the most effective drug. Near #1 petpeeve of mine.

#1 pet peeve of mine too. is there any systematic way to start loosening these regulations? is it through research? congress? organized medicine? creating a new drug that acts on the same receptors that clozapine does but not on neutrophils? I know they recently loosened regulations in 2015 when they lowered the ANC and allowed some physician ability to override that ANC recommendation. I will literally dedicate a portion of my time in residency doing so if there's a logical way to do so.

 

[Jules A]

#1 pet peeve of mine too. is there any systematic way to start loosening these regulations? is it through research? congress? organized medicine? creating a new drug that acts on the same receptors that clozapine does but not on neutrophils? I know they recently loosened regulations in 2015 when they lowered the ANC and allowed some physician ability to override that ANC recommendation. I will literally dedicate a portion of my time in residency doing so if there's a logical way to do so.

Although deaths are rare and I continue to prescribe it due to its exceptional efficacy I think the need for a healthy respect for agranulocytosis remains. I will never forget an incident years ago on the acute unit involving a patient who was being tested weekly when their neutrophils tanked. The patient was quickly transferred to medicine and was dead within a few days. That tragedy although one of the rare cases gave me pause because I had erroneously believed monitoring labs provided a sufficient safety net which afforded me time to reduce or stop the med if things were going south.

 

[birchswing]

#1 pet peeve of mine too. is there any systematic way to start loosening these regulations? is it through research? congress? organized medicine? creating a new drug that acts on the same receptors that clozapine does but not on neutrophils? I know they recently loosened regulations in 2015 when they lowered the ANC and allowed some physician ability to override that ANC recommendation. I will literally dedicate a portion of my time in residency doing so if there's a logical way to do so.

There was an attempt to bind clozapine to DHA so that it would act mostly in the brain lowering systemic side effects but it was discontinued (for reasons unknown to me):
https://en.wikipedia.org/wiki/DHA-clozapine

 

[Shikima]

On a side note, any one had any success with Clozaril for difficult to control mania?

 

[Blitz2006]

Although deaths are rare and I continue to prescribe it due to its exceptional efficacy I think the need for a healthy respect for agranulocytosis remains. I will never forget an incident years ago on the acute unit involving a patient who was being tested weekly when their neutrophils tanked. The patient was quickly transferred to medicine and was dead within a few days. That tragedy although one of the rare cases gave me pause because I had erroneously believed monitoring labs provided a sufficient safety net which afforded me time to reduce or stop the med if things were going south.

Wow, sad times. Obviously we read about it, but hits you when it actually happens in real life...

 

[PistolPete]

Although deaths are rare and I continue to prescribe it due to its exceptional efficacy I think the need for a healthy respect for agranulocytosis remains. I will never forget an incident years ago on the acute unit involving a patient who was being tested weekly when their neutrophils tanked. The patient was quickly transferred to medicine and was dead within a few days. That tragedy although one of the rare cases gave me pause because I had erroneously believed monitoring labs provided a sufficient safety net which afforded me time to reduce or stop the med if things were going south.

Wow, that quick? ANC fell and less than a week later they're dead? I'm curious, how long had they been on clozaril before this happened?

 

[Jules A]

Wow, that quick? ANC fell and less than a week later they're dead? I'm curious, how long had they been on clozaril before this happened?

Patient had been on it before with positive effect stopped due to noncompliance but was later in a group home setting where medications were administered and followups for labs etc. would be handled by staff. The plan was re-start due to the severity of psychosis and that other meds trialed were ineffective. It was within a couple of weeks of initiation. There was no other explanation offered that I was privy to during the ensuing investigation. I discussed it with the experienced and conscientious attending who cared for the patient and was left with the sentiment that it was one of those rare but horrific things than can happen.

 

[Crayola227]

Although deaths are rare and I continue to prescribe it due to its exceptional efficacy I think the need for a healthy respect for agranulocytosis remains. I will never forget an incident years ago on the acute unit involving a patient who was being tested weekly when their neutrophils tanked. The patient was quickly transferred to medicine and was dead within a few days. That tragedy although one of the rare cases gave me pause because I had erroneously believed monitoring labs provided a sufficient safety net which afforded me time to reduce or stop the med if things were going south.

Yeah, you really gotta respect the bone marrow.

Your case is exactly why these drugs are the big deal they are to Rx. The risk isn't high, but when it happens, unforeseeable sudden irreversible death in someone otherwise tolerating a medication, is what it is. I think of a lot of the biologics and the risk of PML, here as well.

To Rx these is to acknowledge this risk, and to proceed is to say that in the case of death, you will still feel justified in hindsight at the cost/benefit value you assessed.

 

[Merovinge]

Although deaths are rare and I continue to prescribe it due to its exceptional efficacy I think the need for a healthy respect for agranulocytosis remains. I will never forget an incident years ago on the acute unit involving a patient who was being tested weekly when their neutrophils tanked. The patient was quickly transferred to medicine and was dead within a few days. That tragedy although one of the rare cases gave me pause because I had erroneously believed monitoring labs provided a sufficient safety net which afforded me time to reduce or stop the med if things were going south.

I certainly wouldn't want to do away with all monitoring, but the reality is that Clozaril is saving more lives with psychosis (by far) than it's costing. It would never be a first or second line treatment because the weight gain, difficulty titrating from orthostasis/sedation, and troubles coming on/off it at higher doses; but it could avoid being 10th line and actually get used 3rd line if folks could miss a single CBC here and there without apocalypse coming. It's like being on dialysis-lite to be clozapine. There's a balance somewhere between what we have and what China has, I just wish folks could help us get there.

Clozapine story of the day - 19 yo M, 2 year hx of schizophrenia, had spent nearly 12 of the last 24 months inpatient, I think 4 atypical and Haldol trials to date with stark-raving-mad hallucinations/delusions. Multiple attempts at self harm/suicide. Finally got started on clozapine as part of an ACT team. I saw him about 12 months later. He was working 40 hours a week at an auto shop. His A1C got up to 19!?! He started working out 10 hours/week and had help with his diet, repeat A1C was 10.2 I think 3 months later? Maybe the first one was an error. Suffice to say, he felt the SE were worth it enough to go from 0 min a day in the gym to 10 hours. I still use his case to this day to motivate people with DM2.

 

[slappy]

I know minimum is 1.5, but I don't feel comfortable given he is already at 1.9 and at under 1.5 it is discontinued. Am I being too cautious?

That's wrong. You don't discontinue it unless it's less than 0.5, although most people would stop it at less than 1.

 

[PistolPete]

Patient had been on it before with positive effect stopped due to noncompliance but was later in a group home setting where medications were administered and followups for labs etc. would be handled by staff. The plan was re-start due to the severity of psychosis and that other meds trialed were ineffective. It was within a couple of weeks of initiation. There was no other explanation offered that I was privy to during the ensuing investigation. I discussed it with the experienced and conscientious attending who cared for the patient and was left with the sentiment that it was one of those rare but horrific things than can happen.

Dang. I was asking because the risk of agranulocytosis is highest in the first 4 weeks.

 

[birchswing]

I was kind of curious about this and did some reading and found that at a population level in Finland people were more likely to die on the newer atypical antipsychotics than on clozapine:

http://www.reuters.com/article/us-schizophrenia-drugs-idUSTRE56C15Z20090713

I'm not sure if the same source is being cited in this article which mentions a Lancet paper said people on Seroquel can develop heart failure:

http://www.abc.net.au/news/2013-11-27/growing-concerns-over-side-effects-of-seroquel/5120554

I tried finding the Lancet article (I currently don't have access to an academic library) and only came across this site which mentions a couple of case studies of heart failure with Seroquel but doesn't have any reference to the aforementioned Lancet article (it does reference a different Lancet article about cardiomyopathy with clozapine):

https://www.nzma.org.nz/journal/read-the-journal/all-issues/2010-2019/2011/vol-124-no-1337/cc-coffey

Does anyone know the title of that article? Looking at an abstract on PubMed would suffice for me.

I'm curious to know if heart failure is a recognized side effect or a fluke with Seroquel.

 

[HarryMTieboutMD]

On a side note, any one had any success with Clozaril for difficult to control mania?

Yes! And there is good literature on it too.

Patient wants clozaril and is on high dose seroquel at this time. ANC has been at 1.9 all year, am I justified in not starting a titration given the low baseline?

In addition to the above responses, the best data coming from John Kane's study in the 1980s show that Clozapine works better than other antipsychotics when they fail (ie, so called "treatment resistant schizophrenia"). More specifically, the Kane started the patients on Haldol with adequate dose and duration, watched them fail, stopped Haldol, and started Clozapine.

In a generic sampling of SCZ patients (ie, treatment resistance is not a priori evaluated), Clozapine does about as well as the others https://www.ncbi.nlm.nih.gov/pubmed/26842482

So, has the patient been on a higher potency D2 blocking neuroleptic? Why does he want clozapine?

 

[st2205]

Yes! And there is good literature on it too.

I don't see much literature on it. What are you referring to?

I'm also curious if there's literature showing that it's having any better outcomes relative to agranulocytosis rather than improving the way the ANC looks on a lab? My phone resumption is that it works by demarginalization so does this treat the condition or give us false security?

 

[clausewitz2]

I don't see much literature on it. What are you referring to?

I'm also curious if there's literature showing that it's having any better outcomes relative to agranulocytosis rather than improving the way the ANC looks on a lab? My phone resumption is that it works by demarginalization so does this treat the condition or give us false security?

Lithium appears to actually promote erythropoesis selectively and lead to a true increase in production of neutrophils, so really not the kind of pseudoleukocytosis associated with steroids. In vitro studies show that Li actually promotes colony-stimulating factor secretion and maaaay directly promote preferential proliferation of specific granulocytic precursors.

 

[HarryMTieboutMD]

I don't see much literature on it. What are you referring to?

I'm also curious if there's literature showing that it's having any better outcomes relative to agranulocytosis rather than improving the way the ANC looks on a lab? My phone resumption is that it works by demarginalization so does this treat the condition or give us false security?

Not GREAT literature but the aggregate of literature including some open label studies that were rather well designed in terms of patient selection, randomization, etc suggest it works well
https://www.ncbi.nlm.nih.gov/pubmed/10831480
https://www.ncbi.nlm.nih.gov/pubmed/10450255

Lithium appears to actually promote erythropoesis selectively and lead to a true increase in production of neutrophils, so really not the kind of pseudoleukocytosis associated with steroids. In vitro studies show that Li actually promotes colony-stimulating factor secretion and maaaay directly promote preferential proliferation of specific granulocytic precursors.

THIS. Too many people believe the myth that Li promotes demargination, but looking at the heme literature suggests otherwise. . So before the Clozapine guidelines changed, if one were to use Lithium to boost ANC, it would reflect a true leukopoesis. Here is a nice review of the subject
https://www.ncbi.nlm.nih.gov/pubmed/18809733

 

[st2205]

Not GREAT literature but the aggregate of literature including some open label studies that were rather well designed in terms of patient selection, randomization, etc suggest it works well
https://www.ncbi.nlm.nih.gov/pubmed/10831480
https://www.ncbi.nlm.nih.gov/pubmed/10450255



THIS. Too many people believe the myth that Li promotes demargination, but looking at the heme literature suggests otherwise. . So before the Clozapine guidelines changed, if one were to use Lithium to boost ANC, it would reflect a true leukopoesis. Here is a nice review of the subject
https://www.ncbi.nlm.nih.gov/pubmed/18809733

Thanks. I'll take a peak. I was a little confused when I opened the first two links that had nothing to do with lithium, then I went back and realized you were saying there was good evidence for mania and was assuming the discussion was lithium.

 

[Trismegistus4]

Low neutropenia? Is that related to elevated leukocytosis?