What we’ve said about Clozapine

“It's two failed antipsychotic treatments for an adequate time, and typically that's about six weeks. And then the antipsychotic needs to be at an adequate dose. And there we're talking about 600 thorazine equivalents”

“make sure you save it for treatment-resistant schizophrenia because you don't want to get too loosey-goosey. And we're going to be talking about the reasons why that is”

“when we're talking about treatment-resistant schizophrenia, it works about 60% of the time. And that's even more impressive when you consider how ineffective other antipsychotics are at that point. So other drugs work about 5% of the time”

“I don't believe in stronger antipsychotics. There is only one stronger antipsychotic, and it's clozapine. And so if you can do clozapine, you should try clozapine. But most people can't because of the monitoring, and a lot of people don't like the side effects”

“Those are the two medications that have shown to have evidence in reducing suicidality. Lithium for bipolar and clozapine for schizophrenic patients has shown to actually reduce suicidality”

“schizophrenia with persistent aggression, which is related to the fact that it helps with violence, it's independent of its antipsychotic defect. So it's not just that you're treating the psychosis and then the aggression goes away”

“most of the other antipsychotics cause problems with regards to the fact they worsen negative symptoms, something that we call neurolepsis. So clozapine actually helps in that regard”

“schizophrenia is a syndrome that comes with positive symptoms, negative symptoms, and cognitive symptoms. So when you're treating schizophrenic patients, you're not just stopping hallucinations and then saying your job's done”

“whereas all the other antipsychotics block at least 60% of the D2 receptor in order to work, clozapine still works when it's only blocking like 30% to 40%. So we know that something else is involved”

“I've actually seen patients with BPD who don't really seem complicated by other, you know, have any other comorbid condition actually get better with clozapine or at least evidence some significant improvement with clozapine”

“If the patient's been off of it for more than 48 hours, you need to restart the titration. The REM requirements have gone away, so you don't need to log into the database. That doesn't mean that the monitoring has gone away”

“You have to wait five days after dose change before the levels are appropriate in their blood. The typical target plasma range is 350 to 600. You can go above 600, but there's really diminishing returns above 1,000”

“you can also check it whenever you add new medications to sort of make sure there's not interactions. And there's things you wouldn't expect, like if a patient's drinking orange juice and they switch to grapefruit juice, that can impact their levels a lot”

“people need to remember they took away the REMS. They didn't take away the recommendation. So technically, anytime you don't do the classical REMS monitoring, you are outside the standard of care and you're putting your license on the line”

“the first half of the year, you do it weekly. Then the second half of the year, you do it every two weeks. And then after one year, you do it monthly”

“the earlier you're taking the medication, the higher the risk. So it peaks within the first six months, especially the first 18 weeks. And then after one year, the risk is very, very low”

“it's considered mild if the count is 1,000 to 1,500. It's moderate if it's 500 to 1,000. And then severe is less than 500”

“If it's severe, you stop the clozapine and you discontinue it until the ANC is greater than 1,000. And then you check it three times per week until it's greater than 1,500”

“Sometimes the number it spits it out, you actually have to multiply it by 1,000 because I remember my lab would just spit out like 3.5, so it would be like 3,500”

“the gist of benign ethnic neutropenia, essentially their ANC is going to be lower and still be functional. So it's not a problem as much for them. So the cutoff kind of bumps down”

“there's a bunch of other problems that are just as bad as severe neutropenia. So more patients actually die each year from the constipation issues than they do from the severe neutropenia”

“the constipation... the ileus, the small bowel risk, those are all the same thing, just kind of progression of the worsening constipation and having sequelae”

“a normal time for a person is 24 hours. You could feel free to run the experiments yourself. but if you take clozapine it slows things down to 110 hours which is pretty significant”

“Only other one I'll add is make sure, you know, consider starting a bowel regimen prophylactically and ask the patients if they're pooping”

“it's the myocarditis and the tachycardia that actually leads the cardiomyopathy. So that's the long-term thing”

“The two big things you're looking for are the flu-like symptoms and cardiac symptoms. So if you see any sort of fever, fever is often the first sign, also along with like things like fatigue, muscle ache”

“if a troponin is greater than two times the upper limit or the CRP is greater than 100, those are big red flags. If the troponin is abnormal, that's a sign of myocardial injury. And you really need to stop the clozapine”

“the one that they use the most is atenolol. I think it's because it doesn't cross the blood brain barrier. So it doesn't cause any sort of psychological mental slowing. There it's pretty common to use atenolol 12.5 milligrams”

“the biggest risk factor is how quickly you titrate the clozapine. So the faster you titrate it, the higher the risk there is of dropping the seizure threshold. The risk is dose-dependent”

“Myoclonic jerks are a warning sign before they get a seizure. So... Another thing is you don't necessarily have to stop the clozapine just because the patient gets a seizure. So typically Depakote is what's going to be used to treat it”

“clozapine and olanzapine are probably the two worst drugs we have in regards to metabolic risk in terms of weight gain. It's more significant in non-white patients. It's very reasonable to start metformin from day one”

“Don't titrate the metformin too fast. So it does cause a lot of DGI distress. So start low. Typically the dose is the same as if they had diabetes”

“when you're at the point that you're using clozapine, you're a little bit less worried about those other risks because of the benefit and necessity that clozapine kind of offers”

“The orthostatic hypotension is due to the alpha-1 blockade. Super common, 20% incidence. And that's why we have to titrate slowly because you don't want to zonk the patient”

“You encourage hydration. You increase sodium intake if it's possible. If it's possible, you should avoid other alpha-1 blockers, avoid benzos”

“it's believed that the metabolite nor clozapine has muscarinic agonist properties. And that's possibly what leads to the clozapine drooling”

“Do not use glycopyrrolate first line. So you do not want to increase the muscarinic burden of these patients. So glycopyrrolate, which is a systemic anti-muscarinic medication”

“some of the antipsychotics can actually worsen OCD. I think clozapine and olanzapine are the most likely”

“histamine H, alpha-1A, and muscarinic M. So the ham receptors... And a lot of the second-gen antipsychotics block these receptors. And they're pesky receptors”

“a lot of the TCAs have a lot of anti-muscarinic activity. Paroxetine is very anticholinergic. The anti-Parkinsonian medications, the meds that treat overactive bladder and that are bladder relaxants. Benadryl is a big one”

“100 milligrams of clozapine is actually equal to 2 milligrams of benztropine. And this can be helpful to know because if you ever need to stop the clozapine suddenly”

“With clozapine, you wouldn't expect EPS, so it didn't make a lot of sense for me why he would be on cogettin if he didn't overtly have some weird EPS. He never noticed any difference, and I think I saved him some cognitive problems in the future”

“CYP1A2 is doing the majority of metabolism. The second one, which is a less significant pathway but still impacts levels, is CYP2D6. So for CYP1A2, the strong inducers, which lowers levels like 50%, the big one is smoking”

“Any CYP1A2 substrates, smoking, burning leaf has the potential to induce CYP1A2. So it will decrease the levels of olanzapine and clozapine. Important to consider, patient goes inpatient, isn't smoking, then they go outpatient and all of a sudden the medication is not working as much. Always ask if they're smoking cigarettes”

“So strong inhibitors, they can increase levels like 5 to 10 times. they're the big medications we worry about so cipro the antibiotic so there's a real interaction there that can raise levels significantly luvox fluvoxamine”

“it doesn't count as a trial if someone just doesn't take the medication. So I would see this all the time in the hospital. We would call it, someone would call it treatment resistant schizophrenia because the patient kept coming back to the hospital”

“The monitoring requirements basically make it impossible to use. Also, the titration requirements similarly make it extremely hard to use because who has that amount of time to get somebody stable these days? It essentially self-selects for patients who are lower acuity”

“The patient who says, I don't have schizophrenia, but I take my clozapine every day has better outcomes than the patient who says, I have schizophrenia, I hate those meds, I'm not taking them”

“there's studies showing that patients subjectively really like clozapine. And we think of it as this messy drug with all these problems, but patients are reporting that they really like it”