FDA committee votes 14-1 to dismiss clozapine REMS

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wish i was at the lake

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wish i was at the lake said:
Unclear, sounds like there is still potential for required monitoring during initiation / higher risk time periods
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I'd be fine with fairly strict monitoring (weekly or bi-weekly) for the first 2-4 months. Typically patients who are severe enough to start clozapine are hopefully going to have closer monitoring during those periods anyway. The need for 6 months of weekly monitoring, then 6 more months of bi-weekly monitoring is just punitive (which was the point in the first place) and there's no reason to not move to monthly monitoring after a couple months. Would essentially move them to a schedule for LAI patients, which they probably need anyway if they're requiring clozapine.
 
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Good riddance to REMS for clozapine.

Looks like it was a 14-1 vote.

brosa said:
I always thought rems was made to stop people from prescribing clozapine. It's a feature, not a bug. Pharma would lose a lot of money if clozapine was more often prescribed.
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Well I looked up the one vote in opposition - Walter Dunn MD, PhD (UCLA), and came up with this link:


"Nature of Disqualifying Financial Interest The disqualifying financial interest at issue arises from your financial interests in the ownership of publicly traded common stocks in These companies have been identified as competing firms by the Center for Drug Evaluation and Research (CDER). At the writing of this waiver, the aggregate market value of your financial interests in the common stocks of all firms, is between $17,500 and $37,500. "

This is for a separate committee meeting (from 2022). Not saying its directly related but I'm always skeptical of anyone with any financial links to big pharma.
 
REMS or not, the patient population who can actually use this drug will remain small. To really use it you need a strong community engagement team that goes out and actually collects blood samples and runs CBCs in the patient's home or tent. This exists throughout Europe, but it's not a thing in the US. For the small, small number of patients who have family who care about them and will help them get the bloodwork done, this is really nice.
 
comp1 said:
REMS or not, the patient population who can actually use this drug will remain small. To really use it you need a strong community engagement team that goes out and actually collects blood samples and runs CBCs in the patient's home or tent. This exists throughout Europe, but it's not a thing in the US. For the small, small number of patients who have family who care about them and will help them get the bloodwork done, this is really nice.
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I think that is the point. If rems is gone, I will not be requiring serial blood draws from my patients. The true rate of agranulocytosis is around 10-14 per 10,000 cases. That is far less than severe problems from other medications, and does not support burdensome testing. China doesn't bother and they are not all dying from severe infections - they START people with schizophrenia on clozapine as first line.

If REMS is gone, american psychiatrists will have to ask themselves - why wouldn't I start treatment with clozapine? Or at least do it as 2nd agent after a single failure.
 
comp1 said:
REMS or not, the patient population who can actually use this drug will remain small. To really use it you need a strong community engagement team that goes out and actually collects blood samples and runs CBCs in the patient's home or tent. This exists throughout Europe, but it's not a thing in the US. For the small, small number of patients who have family who care about them and will help them get the bloodwork done, this is really nice.
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Yeah as noted above this monitoring was a function of the REMS requirements, not something people would have generally required otherwise. The rate of agranulocytosis is so low that even people on in psychosis clinics might only see a few cases in their whole career unless you're literally starting every patient on clozapine, much less actual harm or death from this.

This is going to be super helpful for general outpatient as well where after someone fails 1-2 antipsychotics, it'll be way easier to start them on clozapine where it wouldn't have even been a consideration before due to the infrastructure you'd need to be compliant with REMS.
 
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REMS may have been the concrete barrier, but we'll need actual position statements from US specialty organizations (or better, the FDA) to claim that the community standard changed. I'm not sure that "this is how China does things" will hold up when the prescribing information still clearly says what it says.
 
comp1 said:
REMS may have been the concrete barrier, but we'll need actual position statements from US specialty organizations (or better, the FDA) to claim that the community standard changed. I'm not sure that "this is how China does things" will hold up when the prescribing information still clearly says what it says.
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I do not practice defensive psychiatry. I practice evidence-based medicine. EBM supports that clozapine is a superior treatment. I am part of your community and this is my standard. I use clozapine currently and will utilize it more if the restrictions are lessened.
 
comp1 said:
REMS may have been the concrete barrier, but we'll need actual position statements from US specialty organizations (or better, the FDA) to claim that the community standard changed. I'm not sure that "this is how China does things" will hold up when the prescribing information still clearly says what it says.
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The FDA is who required REMS. If the FDA abolishes the requirement for constant blood draws, then this is the FDA saying constant blood draws are not required.

The moment that happens I am sure the manufacturers are capable of editing a LaTex document and printing new inserts.
 
Removing REMS does not remove the blood draw requirement in the prescribing information. It removes the requirement to report those required blood draws to a central agency. There's nothing here to suggest that the FDA will change the blood draw requirements that I'm seeing.
 
comp1 said:
Removing REMS does not remove the blood draw requirement in the prescribing information. It removes the requirement to report those required blood draws to a central agency. There's nothing here to suggest that the FDA will change the blood draw requirements that I'm seeing.
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I promise you that the blood draws are in the prescribing information because the FDA requires they be in the prescribing information. The FDA advisory committee voted against having any requirements for collection, monitoring or documenting of neutrophil counts.

'The FDA says it's not necessary' is actually a great defense against the allegation that not doing something is per se negligence as far as medications go.
 
comp1 said:
There is nothing changing practically here. If the patient gets neutropenia and then dies, you'll still be liable for not following the FDA's completely unchanged recs.
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Lol there's "nothing changing practically" with REMS going away?

I'll let you mull over what "practically" means.
 
Okay, I'll be fair, I'm in the VA and our REMS involved absolutely nothing for physicians to do beyond ordering the meds and labs we still have to do. I assume it was much worse elsewhere, like a lot of other things.
 
comp1 said:
There is nothing changing practically here. If the patient gets neutropenia and then dies, you'll still be liable for not following the FDA's completely unchanged recs.
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There is a huge swath of people for whom the CBC has been ordered but the patient does not get it drawn. I think it would be extremely reasonable to argue the benefits of staying on the clozapine outweigh the risks of DCing the medication due to inability to get a CBC regularly drawn when properly documented in notes. Also the rate of which CBCs were needed are wild, if you get them actually completed a bit less frequently you can still be resting just fine at night.
 
comp1 said:
Removing REMS does not remove the blood draw requirement in the prescribing information. It removes the requirement to report those required blood draws to a central agency. There's nothing here to suggest that the FDA will change the blood draw requirements that I'm seeing.
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I agree. This is obviously an unpopular opinion because everyone hates REMS and wonders if the truly burdensome degree of monitoring is justified, but we will need some sort of consensus on what degree of monitoring is required before I will be comfortable deviating substantially from the prior recommendations. Yes, the absolute risk of agranulocytosis is small, but it is catastrophic. If you decide to come up with your own monitoring scheme and it is significantly different to the REMS protocol which the FDA still recommends, and the family of your patient who died from agranulocytosis sues you, it is not going to be particularly persuasive to claim that people in China do it your way.

In practical terms, one of the best defenses to an allegation that you deviated from standard of care is to show that you followed the guidelines of regulatory authorities or professional organizations. As burdensome as REMS was, it was pretty protective in a medicolegal sense as long as you were following the guidelines. I don’t disagree that reducing the monitoring frequency might be good and improve access to care, but we should really pressure APA to release practice guidelines on this before substantially changing our practice.

Just my two cents.
 
sloop said:
I agree. This is obviously an unpopular opinion because everyone hates REMS and wonders if the truly burdensome degree of monitoring is justified, but we will need some sort of consensus on what degree of monitoring is required before I will be comfortable deviating substantially from the prior recommendations. Yes, the absolute risk of agranulocytosis is small, but it is catastrophic. If you decide to come up with your own monitoring scheme and it is significantly different to the REMS protocol which the FDA still recommends, and the family of your patient who died from agranulocytosis sues you, it is not going to be particularly persuasive to claim that people in China do it your way.

In practical terms, one of the best defenses to an allegation that you deviated from standard of care is to show that you followed the guidelines of regulatory authorities or professional organizations. As burdensome as REMS was, it was pretty protective in a medicolegal sense as long as you were following the guidelines. I don’t disagree that reducing the monitoring frequency might be good and improve access to care, but we should really pressure APA to release practice guidelines on this before substantially changing our practice.

Just my two cents.
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Sure, but pretty much every country other than Japan has less stringent monitoring frequency for clozapine than the US does. Idk how protective that would be from a medico-legal standpoint, but there are plenty of regulatory bodies that can be referenced if that is argued.

Also, if you inform the patient/their guardians that the recommendation is to get weekly CBCs for monitoring d/t the risk of agranulocytosis for the first 3 months and they choose not to have labs drawn then that's on them just like if they go against recommendations with any other med. Imo this can be easily mitigated by just documenting that the patient was educated about this and chose to not follow these recommendations. Let's also not pretend like we don't prescribe meds that are just as dangerous or more dangerous without this onerous level of monitoring. I've never heard of anyone being sued for agranulocytosis or aplastic anemia d/t carabamazepine despite that risk being higher.
 
Great news for psych patients and their families!

Keep the cuts coming president Elon! :cigar:
 
Stagg737 said:
Sure, but pretty much every country other than Japan has less stringent monitoring frequency for clozapine than the US does. Idk how protective that would be from a medico-legal standpoint, but there are plenty of regulatory bodies that can be referenced if that is argued.

Also, if you inform the patient/their guardians that the recommendation is to get weekly CBCs for monitoring d/t the risk of agranulocytosis for the first 3 months and they choose not to have labs drawn then that's on them just like if they go against recommendations with any other med. Imo this can be easily mitigated by just documenting that the patient was educated about this and chose to not follow these recommendations. Let's also not pretend like we don't prescribe meds that are just as dangerous or more dangerous without this onerous level of monitoring. I've never heard of anyone being sued for agranulocytosis or aplastic anemia d/t carabamazepine despite that risk being higher.
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Standard of care is determined by that care which reasonably prudent physician would provide under similar circumstances in your particular community. What is done in other countries is not particularly relevant (besides, my understanding is that in several places like the UK and Australia, there is still a recommendation for weekly labs for a significant period of time and monthly labs indefinitely, so it’s not like there are no monitoring requirements).

You also cannot necessarily get around the requirement to provide standard of care by saying that you informed them of the risk. That might be somewhat relevant in contributory negligence jurisdictions, but you’re still on the hook in most jurisdictions if it is determined that a reasonably prudent psychiatrist in your area would have discontinued the medication.

I don’t disagree that it would be good to reduce the monitoring. I’m just saying that standard of care isn’t really about what seems reasonable to you. If you don’t have something like practice guidelines implying a change in standard of care and there is a bad outcome when you did something different than what the FDA still recommends and what the conservative clozapine clinic the next town over does, you’re not on great footing.
 
sloop said:
You also cannot necessarily get around the requirement to provide standard of care by saying that you informed them of the risk. That might be somewhat relevant in contributory negligence jurisdictions, but you’re still on the hook in most jurisdictions if it is determined that a reasonably prudent psychiatrist in your area would have discontinued the medication.
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But how will the bolded be proven? This recommendation is just going into effect. How would we knnow that reasonably prudent psychiatrists (seemingly everyone on this board) would prefer a severely psychotic patient stay on the medication even if they weren't getting lab draws? I get what you're saying, but I also think that the standard of care has changed as evidenced by the following wording from the FDA's announcement:

"Although the risk of severe neutropenia with clozapine still exists, FDA has determined that the REMS program for clozapine is no longer necessary to ensure the benefits of the medicine outweigh that risk. Eliminating the REMS is expected to decrease the burden on the health care delivery system and improve access to clozapine. FDA has notified the manufacturers that the clozapine REMS must be eliminated. FDA has instructed the clozapine manufacturers to formally submit a modification to eliminate the Clozapine REMS and to update the prescribing information, including removing mandatory reporting of ANC blood tests to the REMS program.

In the coming months, FDA will work with the clozapine manufacturers to update the prescribing information and eliminate the Clozapine REMS."
 
sloop said:
Standard of care is determined by that care which reasonably prudent physician would provide under similar circumstances in your particular community. What is done in other countries is not particularly relevant (besides, my understanding is that in several places like the UK and Australia, there is still a recommendation for weekly labs for a significant period of time and monthly labs indefinitely, so it’s not like there are no monitoring requirements).

You also cannot necessarily get around the requirement to provide standard of care by saying that you informed them of the risk. That might be somewhat relevant in contributory negligence jurisdictions, but you’re still on the hook in most jurisdictions if it is determined that a reasonably prudent psychiatrist in your area would have discontinued the medication.

I don’t disagree that it would be good to reduce the monitoring. I’m just saying that standard of care isn’t really about what seems reasonable to you. If you don’t have something like practice guidelines implying a change in standard of care and there is a bad outcome when you did something different than what the FDA still recommends and what the conservative clozapine clinic the next town over does, you’re not on great footing.
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I think it's a fair concern to want to make sure good psychiatrists are protected medicolegally, but you can pry the clozapine script out of my cold, dead hands for my chronically psychotic suicidial patient. Having seen the lifesaving effects of this medication that many (even good) psychiatrists simply don't prescribe due to the difficulty of REMS compliance this was long overdue. Hopefully there is some better forward guidance on monitoring that is less regular than current REMS requirements moving forward.
 
comp1 said:
Okay, I'll be fair, I'm in the VA and our REMS involved absolutely nothing for physicians to do beyond ordering the meds and labs we still have to do. I assume it was much worse elsewhere, like a lot of other things.
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If the thing between you and going home has never been that godforsaken website, which was bad and then made worse recently, you are fortunate indeed, but it also means you really have no basis for understanding why it is in fact a big deal to no longer need to do an entirely separate, lengthy beurocratic process on a broken website just to get a patient a life saving medication arguably no riskier than several other things on the market not tagged with historic bias.

I haven't prescribed clozapine since residency and the memory of the unadulterated rage I felt every time I was stymied in providing the patient their medication--often WHEN WE HAD THE LABS, but due to some bull**** related to the website is still fresh. The problems with logging in. With certifying your training. With cross covering if a patient needed a refill but wasn't on your panel so you had to re-enter them into REMS. And then the website updated, it somehow got worse, and all of us who didn't absolutely have to never bothered to re register.

One of the privileges of being a consult attending is that if I decide to start someone on cloz I get to kick the hassles of dealing with the REMS to a trainee, but there's a very long list of better things they could be doing.

Getting rid of REMS won't change a thing about what frequency of monitoring I will require if I prescribe it. It will only eliminate a pointless, unnecessary, harmful source of friction in providing mental health care to some of the sickest patients.

I hope anyone defending REMS also advocates for providers to have to hand-enter any prescriptions for stimulants or benzos above standard dose ranges into a barely functioning website once a month, because THAT would probably prevent a lot more patient harm than REMS ever did.

Anyone dumb enough to put someone on cloz and not monitor for neutropenia is presumably the same batch of incompetents doing things like putting people on lithium for weak indications and then not checking level or kidney function for years. REMS is not what stands between those people and causing harm. They always find a way.
 
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Stagg737 said:
But how will the bolded be proven? This recommendation is just going into effect. How would we knnow that reasonably prudent psychiatrists (seemingly everyone on this board) would prefer a severely psychotic patient stay on the medication even if they weren't getting lab draws? I get what you're saying, but I also think that the standard of care has changed as evidenced by the following wording from the FDA's announcement:

"Although the risk of severe neutropenia with clozapine still exists, FDA has determined that the REMS program for clozapine is no longer necessary to ensure the benefits of the medicine outweigh that risk. Eliminating the REMS is expected to decrease the burden on the health care delivery system and improve access to clozapine. FDA has notified the manufacturers that the clozapine REMS must be eliminated. FDA has instructed the clozapine manufacturers to formally submit a modification to eliminate the Clozapine REMS and to update the prescribing information, including removing mandatory reporting of ANC blood tests to the REMS program.

In the coming months, FDA will work with the clozapine manufacturers to update the prescribing information and eliminate the Clozapine REMS."
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The announcement also says “FDA still recommends that prescribers monitor patients’ ANC according to the monitoring frequencies described in the prescribing information.”

I mean, it’s pretty obvious how they will prove it. They will do it like they do in almost every med mal case. They will get some psychiatrist, probably from your state, to say that they continue to monitor as described in REMS, that this is still the recommendation from the FDA, and that you violated standard of care. They will then impeach you with the decade of REMS practice and the guidance from the FDA. It might go something like this:

“Doctor, are you familiar with the role the FDA plays in regulating the safety of medications?”

“Do you believe that, if the FDA says certain blood tests are recommended for a medication, those blood tests should be done?”

“Is it true that, between 2015 and 2025, the FDA required that prescribers obtain an ANC on a certain schedule and report those lab results?”

“Is it true that those recommendations included [insert relevant frequency here]?”

“Is it also true that, when the FDA stopped the REMS program in 2025, they recommended that prescribers continue to monitor the ANC according to the prescriber information provided for clozapine?”

“Is it true that that prescriber information also recommends monitoring the ANC at [insert relevant frequency]?”
 
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sloop said:
The announcement also says “FDA still recommends that prescribers monitor patients’ ANC according to the monitoring frequencies described in the prescribing information.”

I mean, it’s pretty obvious how they will prove it. They will do it like they do in almost every med mal case. They will get some psychiatrist, probably from your state, to say that they continue to monitor as described in REMS, that this is still the recommendation from the FDA, and that you violated standard of care. They will then impeach you with the decade of REMS practice and the guidance from the FDA. It might go something like this:

“Doctor, are you familiar with the role the FDA plays in regulating the safety of medications?”

“Do you believe that, if the FDA says certain blood tests are recommended for a medication, those blood tests should be done?”

“Is it true that, between 2015 and 2025, the FDA required that prescribers obtain an ANC on a certain schedule and report those lab results?”

“Is it true that those recommendations included [insert relevant frequency here]?”

“Is it also true that, when the FDA stopped the REMS program in 2025, they recommended that prescribers continue to monitor the ANC according to the prescriber information provided for clozapine?”

“Is it true that that prescriber information also recommends monitoring the ANC at [insert relevant frequency]?”
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Sure, and to be blunt I think all of those points are easily refutable and many psychiatrists (myself included) would testify so. The most difficult of those questions imo is the last one, I could see that one being problematic but is also easily explained if one understands the history of how clozapine was approved in the US.

Again, there’s a reason the REMS program is being stopped and that is something I think couldn’t be ignored in court. Will be interesting if a case comes up, but I don’t think this is as open and shut as you’re suggesting.
 
Stagg737 said:
Sure, and to be blunt I think all of those points are easily refutable and many psychiatrists (myself included) would testify so. The most difficult of those questions imo is the last one, I could see that one being problematic but is also easily explained if one understands the history of how clozapine was approved in the US.

Again, there’s a reason the REMS program is being stopped and that is something I think couldn’t be ignored in court. Will be interesting if a case comes up, but I don’t think this is as open and shut as you’re suggesting.
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I’m not saying it is open and shut, but you have to remember that these cases are presented in front of juries of ordinary people who will hear that some poor patient died or was seriously injured, that you didn’t follow the guidelines of the government agency that approves medications, and that at least one other psychiatrist thinks that you should have.

The reality is that ANC monitoring in clozapine is a unique case where the standard of care was perfectly defined with 100% certainty for the last decade, and that doesn’t change overnight because the reporting system goes away. This is particularly true when the FDA, in the same breath, says you should monitor according to the prescriber information (which is basically a carbon copy of the REMS handbook). Maybe practice should change, but this is a time for professional organizations to step up and provide some recommendations to support our progress towards a new standard.
 
I dont care about med/mal. I will prescribe clozapine and not monitor ANC like it used to be monitored. I have reviewed the data myself and believe it was pure fiction. A rate way less than a much more lethal and frequent problem (toxic megacolon).

I will only check if symptoms show up. I will fight it in court if it happens.
 
sloop said:
I’m not saying it is open and shut, but you have to remember that these cases are presented in front of juries of ordinary people who will hear that some poor patient died or was seriously injured, that you didn’t follow the guidelines of the government agency that approves medications, and that at least one other psychiatrist thinks that you should have.

The reality is that ANC monitoring in clozapine is a unique case where the standard of care was perfectly defined with 100% certainty for the last decade, and that doesn’t change overnight because the reporting system goes away. This is particularly true when the FDA, in the same breath, says you should monitor according to the prescriber information (which is basically a carbon copy of the REMS handbook). Maybe practice should change, but this is a time for professional organizations to step up and provide some recommendations to support our progress towards a new standard.
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True, but the other side of this reality is that the monitoring as outlined has been completely inappropriate since it's inception and that clozapine as been repeatedly demonized by the FDA and big pharma (which a jury is likely not going to be too supportive of given the current attitude toward healthcare in our country) to the point that we don't require the same monitoring on drugs that have higher rates of severe side effects like this (carbamazepine). The fact that clozapine was forced into what is still the most stringent Phase 3 trial in FDA history (in any field) speaks to this and a decent psychiatrist and lawyer should absolutely highlight that.

This would easily be argued in court. Whether the judge and jury buy that is a different story, but I really think saying that we shouldn't deviate from the previous standard becuase it was legally protective when it was also clinically unnecessary after the first 1-2 months is excessive.
 
I see this being a net gain for hospitals and inpatient providers (I'm looking at you NPs and certain doctors with a reputation in the community of starting patient on the same mindless regimen because, "It worka da best!"), at possibly the expense of patients, and definitely at the expense of outpatient psychiatrists. Pump up the Clozaril on the psych wards, get a CBC, then dump them on outpatient psychiatry, and utilization review and the hospital suits high five each other.


mistafab said:
If REMS is gone, american psychiatrists will have to ask themselves - why wouldn't I start treatment with clozapine? Or at least do it as 2nd agent after a single failure.
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The typical psychotic inpatient loves to say they've tried everything, nothing works, etc. But antipsychotic failures are extremely rare, and almost always due to medication non-compliance.

Also, as above, be prepared for a wave of patients suddenly on Clozaril from NPs because... reasons.


Stagg737 said:
Sure, but pretty much every country other than Japan has less stringent monitoring frequency for clozapine than the US does. Idk how protective that would be from a medico-legal standpoint, but there are plenty of regulatory bodies that can be referenced if that is argued.
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First, you can't really sue doctors in many countries. Second, malpractice is based on standard of care and case law. For example, there is no FDA recommendation for duty to warn. If someone needs to be on Clozaril, ANC still needs to be monitored, especially during the first few months. Severe a granulocytosis is rare but it does happen. When it does happen, it is a beast to get a patient to get daily ANC draws while trying to not destabilize while quickly cross tapering them off Clozaril.

Anyway, if someone has been stable on Clozaril for years, then the lack of REMS is a benefit that outweighs risks.
 
Stagg737 said:
True, but the other side of this reality is that the monitoring as outlined has been completely inappropriate since it's inception and that clozapine as been repeatedly demonized by the FDA and big pharma (which a jury is likely not going to be too supportive of given the current attitude toward healthcare in our country) to the point that we don't require the same monitoring on drugs that have higher rates of severe side effects like this (carbamazepine). The fact that clozapine was forced into what is still the most stringent Phase 3 trial in FDA history (in any field) speaks to this and a decent psychiatrist and lawyer should absolutely highlight that.

This would easily be argued in court. Whether the judge and jury buy that is a different story, but I really think saying that we shouldn't deviate from the previous standard becuase it was legally protective when it was also clinically unnecessary after the first 1-2 months is excessive.
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I’m really not sure why we are still arguing this. I don’t actually disagree that the monitoring was excessive. I’ve made that clear numerous times and you keep beating the same dead horse. My only point is that this is a time where it would be helpful for professional organizations to issue some guidelines if we are to argue that practice should change. Until that happens, anyone trying to trailblaze with respect to this is somewhat vulnerable medicolegally. You are trying to apply a purely data-driven approach to the legal considerations here, which mostly tells me you have little direct experience with the legal system. The legal system has its own process. Ideally, this would directly track evidence and data, but it often doesn’t. If you want to go ahead and start people on clozapine with like monthly monitoring, be my guest, but don’t pretend it will not be a potential if someone points out that your dead patients was not monitored in the way the FDA recommends and in the way that was universally mandatory until a few days ago.
 
Candidate2017 said:
The typical psychotic inpatient loves to say they've tried everything, nothing works, etc. But antipsychotic failures are extremely rare, and almost always due to medication non-compliance.
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Do you have a source for this? This is at substantial variance with the literature, which suggests that a significant fraction (30-40%ish) of patients with a schizophrenia diagnosis get minimal if any benefits from a lot of neuroleptics. This is supported by the PET data that suggests that most of these people actually have perfectly unremarkable dopamine synthesis capacity etc. The problem of people with psychosis who dopamine antagonism does nothing for is a really well-documented problem in the field that has been recognized for decades at this point.

I don't disagree that there are also a lot of instances of "treatment failures" that are more about treatment self-discontinuation, but the fact remains that patients do not infrequently actually take these things more or less as prescribed and still don't get any better.

EDIT:

Literally published just this month:

psychiatryonline.org

Continuous Dopamine D2 Receptor Blockade and Long-Term Outcome in First-Episode Schizophrenia | American Journal of Psychiatry

Objective: It is not known what proportion of patients experience relapse in first-episode schizophrenia despite continuous dopamine D2 receptor blockade and whether breakthrough psychosis is attributable to long-term use of D2-blocking antipsychotics. Using data from a Finnish nationwide...
psychiatryonline.org psychiatryonline.org


The money quote from their discussion: "About 40%–50% of patients with first-episode schizophrenia will relapse despite continuous D2 blockade . . ."
 
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sloop said:
I’m really not sure why we are still arguing this. I don’t actually disagree that the monitoring was excessive. I’ve made that clear numerous times and you keep beating the same dead horse. My only point is that this is a time where it would be helpful for professional organizations to issue some guidelines if we are to argue that practice should change. Until that happens, anyone trying to trailblaze with respect to this is somewhat vulnerable medicolegally. You are trying to apply a purely data-driven approach to the legal considerations here, which mostly tells me you have little direct experience with the legal system. The legal system has its own process. Ideally, this would directly track evidence and data, but it often doesn’t. If you want to go ahead and start people on clozapine with like monthly monitoring, be my guest, but don’t pretend it will not be a potential if someone points out that your dead patients was not monitored in the way the FDA recommends and in the way that was universally mandatory until a few days ago.
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Completely agree with the bolded. My point is just that I don't think that the potential medico-legal liability should prevent us from prescribing clozapine to patients who need it even if they're not going to get labs. You're right that my experience with the legal system is lacking compared to those who are forensically trained or do significant forensic work, but I do have a basic enough understanding that even with the previous system in place one could easily make a very strong argument for prescribing it to the appropriate patients even without any monitoring at all.
 
Stagg737 said:
Completely agree with the bolded. My point is just that I don't think that the potential medico-legal liability should prevent us from prescribing clozapine to patients who need it even if they're not going to get labs. You're right that my experience with the legal system is lacking compared to those who are forensically trained or do significant forensic work, but I do have a basic enough understanding that even with the previous system in place one could easily make a very strong argument for prescribing it to the appropriate patients even without any monitoring at all.
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I wonder how the Covid years may impact this. When REMS requirements were suspended I had quite a few cases who refused to get labs for quite awhile and did fine. That’s by no means the standard of care today but I think would be a good defense, let alone good evidence, that monitoring intervals should be let up on.
 
Setting aside for the moment the growing body of evidence that ANC monitoring is wholly unnecessary after the first year of treatment
and not a hill worth dying on even during treatment initiation, for patients who are unable or unwilling but nevertheless need clozapine.
pubmed.ncbi.nlm.nih.gov

Evaluating the epidemiology of clozapine-associated neutropenia among people on clozapine across Australia and Aotearoa New Zealand: a retrospective cohort study - PubMed

None.
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov

I am genuinely baffled by the fear of getting sued for doing one's level best to treat people with treatment resistant schizophrenia. In the ridiculously rare event of a neutropenia related death, what are the odds of the patient having a family member invested enough to sue you, who isn't instead just grateful to you for the care you have provided to their loved one in good faith? I suppose it's always possible some litigious and opportunistic long lost family member could do that. I just cannot imagine letting that remote possibility impact my willingness to prescribe anl life-saving medication for someone who needs it, now that the FDA isn't tying my hands behind my back anymore. I became a doctor to help people, not to avoid getting sued at all costs.
 
bashir said:
Setting aside for the moment the growing body of evidence that ANC monitoring is wholly unnecessary after the first year of treatment
and not a hill worth dying on even during treatment initiation, for patients who are unable or unwilling but nevertheless need clozapine.
pubmed.ncbi.nlm.nih.gov

Evaluating the epidemiology of clozapine-associated neutropenia among people on clozapine across Australia and Aotearoa New Zealand: a retrospective cohort study - PubMed

None.
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov

I am genuinely baffled by the fear of getting sued for doing one's level best to treat people with treatment resistant schizophrenia. In the ridiculously rare event of a neutropenia related death, what are the odds of the patient having a family member invested enough to sue you, who isn't instead just grateful to you for the care you have provided to their loved one in good faith? I suppose it's always possible some litigious and opportunistic long lost family member could do that. I just cannot imagine letting that remote possibility impact my willingness to prescribe anl life-saving medication for someone who needs it, now that the FDA isn't tying my hands behind my back anymore. I became a doctor to help people, not to avoid getting sued at all costs.
Click to expand...

I mean, this is all fair and people can make whatever decisions they feel are justified based on their risk tolerance. I don’t want my concerns misconstrued. My main point isn’t that we should all be so terrified of being sued that we don’t follow evidence in our practice. My main point is really that some guidance is useful when something of this magnitude changes. I’m not sure why it is so controversial to say that it would be helpful for the APA to work on some practice guidelines for the post-REMS monitoring of ANC with clozapine. As I said, I’m all for moving towards a new standard of care in this country, but it would be better if we were moving that way with some degree of visible consensus.
 
clausewitz2 said:
The money quote from their discussion: "About 40%–50% of patients with first-episode schizophrenia will relapse despite continuous D2 blockade . . ."
Click to expand...

Relapse is the norm, but relapse =/= failure.

I can't get the full article, but how did they determine "continuous D2 blockade"?

Past studies show a relapse rate of about 20% in treated schizophrenia, so 40-50% relapse quoted in this study is much higher. And do we even know the dosages these patients received? Given the higher relapse rate, I suspect a significant portion of patients did not receive maximum therapeutic doses or even treated with polyantipsychotics, which has been shown to much more effective.
 
Candidate2017 said:
Relapse is the norm, but relapse =/= failure.

I can't get the full article, but how did they determine "continuous D2 blockade"?

Past studies show a relapse rate of about 20% in treated schizophrenia, so 40-50% relapse quoted in this study is much higher. And do we even know the dosages these patients received? Given the higher relapse rate, I suspect a significant portion of patients did not receive maximum therapeutic doses or even treated with polyantipsychotics, which has been shown to much more effective.
Click to expand...

By continuous administration of LAIs during the study period.
 
sloop said:
I mean, this is all fair and people can make whatever decisions they feel are justified based on their risk tolerance. I don’t want my concerns misconstrued. My main point isn’t that we should all be so terrified of being sued that we don’t follow evidence in our practice. My main point is really that some guidance is useful when something of this magnitude changes. I’m not sure why it is so controversial to say that it would be helpful for the APA to work on some practice guidelines for the post-REMS monitoring of ANC with clozapine. As I said, I’m all for moving towards a new standard of care in this country, but it would be better if we were moving that way with some degree of visible consensus.
Click to expand...
I totally agree that APA guidance would/will be useful. I have heard they are actively working on developing guidelines. And I wasn't responding to anyone in particular, more a general statement of my opinion that getting sued for a bad outcome with clozapine seems very unlikely, and I personally don't feel it necessary to wait for APA guidance to do what seems to be in my patient's best interest.
 
The pharmacy I use still requires me to upload into the REMS, even though when I log into the REMS it reminds me I don't have to. Lol.
 
*People should take the risk of being sued serious. Grieving families are upset... and one could simply look at the Daniel Penny case in NYC where the father has the audacity to try for a civil suit - or they are simply chasing an "easy" dollar.
**People in the past 20-30 years are simply more emotional, labile. One only need to reference TDS and the over emphasis of feelings as examples that set people on edge.
*** Volk v. DeMeerleer (Majority and Dissent) This case basically blew the lid off psychiatric liability [at minimum in the state of WA] wherein if your stable patients go on a murder suicide rampage, you are liable because, well, the feelings someone else must take responsibility...
 
You don't need to go down the terrifying rabbit hole of Volk here or invoke anything about emotions. This is narrow and quite different. The FDA is still very clear that nothing has changed clinically; the standard of care remains the same in terms of neutrophil checks. You don't require a runaway judiciary to rule against you here. The FDA doesn't define what a "propensity to dangerousness" is, but with clozapine it's all crystal clear. As such, my clozapine prescribing (or general lack thereof) will also remain unchanged unless and until the FDA says there is some sort of lesser requirement for neutrophil checks.
 
Exactly. This is pomp, and show. On one hand they say sure, our bad, we screwed up, but they stopped short of making real world change.

Just like they did with circling back to ECT because it predated FDA, and now ECT docs have to talk about "brain damage" ... Thanks FDA.

And of course there is the joke of celexa and QTc... Thanks FDA.

Oh, and then recently the reduction of SSRI and Suicide risk black box being only downgraded to warning or whatever... another failed attempt, only to virtue signal to us rank and file docs in the trenches but missing the mark... thanks FDA.

I'm sure there's more.
 
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