Clozapine 101

Armin Moradi

Clozapine is a serotonin-dopamine antagonist and is considered to be an atypical antipsychotic, it was in fact the first atypical antipsychotic
most complex pharmacologic profile of any of the atypical antipsychotics
It's generally dosed to occupy less than 60% of D2 receptors, for unknown reasons and under serious debate. It's pretty effective at 40-50% binding, whereas haloperidol is effective at 80% binding
it's suspected that this reduced binding is why clozapine rarely, if ever, causes EPS symptoms
new bindings? cluster of bindings? who known? stay tuned!
it does have higher binding potency for non-D2 receptors vs other antipsychotics, so maybe that's the reason?
And here we have a whole long list of receptors that clozapine touches
interestingly, 5HT2A and D2 which we always read about with antipsychotics don't show up as high potency targets of clozapine
in fact, look at D2 down so far down
BUT, only D2 and 5HT2A have known effects insofar as clozapine is concerned
this, amigos, is one of the most complex binding portfolios in the entirety of psychopharmacology

The gold standard of treatment in schizophrenia
it's used when other antipsychotics fail
it's unlikely that only the 5HT(2A) antagonism is the mechanism by which clozapine prevails
other antipsychotics also have that action, so it appears there is more to the story of clozapine than meets the eye
but clozapine is so good, that in the rare occasion, patients can return to near-normal cognitive and social functioning
it's also particularly effective for treating aggression and violence in psychotic patients
and most importantly, it's the only, and I repeat, the only antipsychotic known to reduce risk of suicide in schizophrenia
and given its actions, it can actually reduce tardive dyskinesia in patients who do have it already, especially in long-term treatments
it's also indicated in EPS intolerance patients and treatment-resistant mania/OCD/autism
that said, on its own, clozapine can induce, very rarely, OCD symptoms

most common: N/V, ECG, hypotension, tachycardia, dizziness, syncope
agranulocytosis 0.5-2%
neutropenia 1st 2.3% 2nd 0.6%
seizures - dose-dependent
sedation, salivation (dose-dependent), ?bowel obstruction, myocarditis, weight gain
greatest cardiometabolic profile - insulin, triglycerides

let's get the most common side effects out of the way: N/V, ECG changes, hypotension, tachycardia, dizziness, and syncope are the most common
clozapine is the antipsychotic associated with agranulocytosis, 0.75% during first year, about 1% get fever
neutropenia 2.32% and 0.69% during first and second year respectively
regular bloodwork is required, weekly at first, then monthly bloodwork
at high doses, it puts patients at increased risk of seizures, about 4% of patients at doses greater than 600mg/day
other side effects include sedation, salivation, myocarditis, and weight gain
in fact it has the greatest cardiometabolic side effect profile of any antipsychotic
so, lots of pain, lots of gain, but it's not first line because we don't like to kill people
the mechanism of development of agranulocytosis, myocarditis, and seizures is unknown
weight gain is thought to be linked to blockade of 5HT2C and H1 histamine receptors
sedation is likely linked to potent M1 muscarinic, H1 histamine and alpha 1 adrenergic receptor blockade
M1,2,3 muscarinic blockade can also yield excessive salivation, even resulting in constipation and even bowel obstruction
and cardiometabolically, it increases insulin resistance and fasting triglycerides, for unknown reasons