Key moments, in order
The FDA took away the REMS, not the recommendation. People still get severe neutropenia, so ANC monitoring continues on the exact same schedule; you just no longer report to a central registry. Skip the classic monitoring and you are outside the standard of care, with your license on the line.
Every other antipsychotic needs to block at least 60% of D2 receptors to work; clozapine works at 30% to 40%, so something else is involved.
The histamine, alpha-1 and muscarinic ("HAM") receptors are the pesky ones that many second-generation antipsychotics block.
Treatment-resistant schizophrenia means two failed antipsychotic trials, each for an adequate time (typically about six weeks) at an adequate dose (about 600 chlorpromazine equivalents).
It does not count as a trial if the patient just does not take the medication. We saw this all the time in the hospital: a patient got called treatment resistant because they kept coming back.
More patients die each year from bowel obstruction than from severe neutropenia, yet the whole REMS infrastructure was built around neutropenia. Ask every patient about their bowels.
In treatment-resistant schizophrenia it works about 60% of the time, against about 5% for other drugs at that point.
Save clozapine for treatment-resistant schizophrenia; do not get too loosey-goosey with it.
It reduces suicide. Clozapine in schizophrenia and lithium in bipolar disorder are the two medications shown to reduce suicidality, and clozapine is the only one with the FDA nod for suicide reduction in schizophrenia. When ideation comes from schizophrenia and the patient is appropriate, don't forget clozapine.
It helps schizophrenia with persistent aggression, and that effect is independent of its antipsychotic effect: it is not just that the psychosis is treated and the aggression goes away.
Most other antipsychotics worsen negative symptoms (neurolepsis); clozapine actually helps.
It is a syndrome of positive, negative and cognitive symptoms. Stopping the hallucinations does not mean your job is done.
We think of it as a messy drug, but studies show patients subjectively really like clozapine.
Neutropenia risk is highest early, peaking in the first six months and especially the first 18 weeks. After one year, the risk is very, very low.
An easy schedule to remember: weekly for the first half of the year, every two weeks for the second half, then monthly after one year.
Check the lab's units. A printed 3.5 may mean 3,500.
If the patient has been off it for more than 48 hours, restart the titration from 12.5 mg. You can probably go quicker than the first time, since you know they tolerate it. The REMS database is gone, but the monitoring is not.
Neutropenia is mild at an ANC of 1,000 to 1,500, moderate at 500 to 1,000, and severe below 500.
Stop clozapine until the ANC is above 1,000, then check it three times a week until it is above 1,500.
In benign ethnic neutropenia the ANC runs lower and is still functional, so the cutoffs bump down. With consistently low ANCs in a patient from that population, you can reasonably assume it.
Constipation, ileus and small bowel obstruction are one progression of worsening constipation.
Normal colonic transit takes about 24 hours; on clozapine it slows to about 110 hours.
Start a bowel regimen prophylactically and ask patients if they are pooping. Docusate should be started in pretty much every patient; some guidelines start with an osmotic laxative like polyethylene glycol (MiraLAX).
Myocarditis and tachycardia are what lead to cardiomyopathy, the long-term cardiac risk.
For myocarditis, watch for flu-like and cardiac symptoms. Fever is often the first sign, along with fatigue and muscle aches.
A troponin above twice the upper limit or a CRP above 100 is a big red flag. An abnormal troponin means myocardial injury, and you need to stop the clozapine.
For tachycardia, atenolol is used most, probably because it does not cross the blood-brain barrier and so causes no mental slowing. 12.5 mg is a common dose.
Seizure risk is dose-dependent, and the biggest risk factor is how quickly you titrate.
Clozapine and olanzapine are probably the two worst drugs for metabolic risk and weight gain, more so in non-white patients. Starting metformin from day one is very reasonable.
Metformin: start low and titrate slowly because of GI distress. The dose is the same as for diabetes.
By the time you are using clozapine, you worry a little less about those risks because of the benefit and necessity it offers.
Orthostatic hypotension comes from alpha-1 blockade and is super common (about 20%), which is why we titrate slowly.
For orthostasis, encourage hydration, increase sodium if possible, and avoid other alpha-1 blockers and benzodiazepines.
Drooling is thought to come from norclozapine, a metabolite with muscarinic agonist properties.
For drooling, do not use glycopyrrolate first line; it is a systemic anti-muscarinic and adds to an already heavy muscarinic burden. First line is atropine drops, one to three swished and swallowed (not in the eyes); second line is ipratropium nasal spray.
100 mg of clozapine is roughly equal to 2 mg of benztropine, which helps if you ever need to stop clozapine suddenly.
Minimize other anti-muscarinic drugs: many TCAs, paroxetine, anti-parkinsonian medications, bladder relaxants for overactive bladder, and diphenhydramine is a big one.
Check a level five days after a dose change. The typical target plasma range is 350 to 600; you can go above 600, but there are diminishing returns above 1,000.
Also check a level when you add new medications, and after unexpected changes: switching from orange juice to grapefruit juice can affect levels a lot.
CYP1A2 does most of the metabolism, with CYP2D6 a lesser pathway. Smoking is the big inducer and lowers levels by about 50%.
Always ask about smoking. A patient who does not smoke on the inpatient unit and starts again after discharge can lose response, and no one knows why.
Strong CYP1A2 inhibitors can raise levels 5 to 10 times. The big ones are ciprofloxacin and fluvoxamine.
Each moment is a point made in the episode, linked to the second it was said. The topic links open everything the podcast has said on that topic.