Thank you for that! The anti-muscarinic paradox with Olanzapine and Quetiapine has bothered me for some time.
I find the 5HT2a hypothesis very compelling. It should be interesting to examine it via some mechanisms described in the paper by Nutt and Carhart-Harris "Serotonin and brain function: a tale of
two receptors" (https://journals.sagepub.com/doi/pdf/10.1177/0269881117725915) and through the lens of the entropic brain hypothesis - maybe the delirious brain is in a more entropic state which can be (kind of) specifically attenuated by 5HT2a antagonism?
I’d say your pick of diphenhydramine over quetiapine doesn’t compute for me, I also have questions about its efficacy in other disorders specifically how it is first like in Parkinson’s psychosis with little chemical “antipsychotic” effect. A mystery drug to be sure.
It's mostly premised on the fact that there is a much clearer pharmacologic rationale for H1 antagonism than M1 antagonism. We use H1 antagonists all the time for their sleep promoting actions (doxepin is the poster-child for this), so we know they're sedating. M1 antagonism's utility is not so clear, so better to avoid it so you have less confounders.
Hydroxyzine is a relatively pure H1 antagonist (Ki ~10), followed by 5HT2A (Ki ~170) antagonism. It seems like a good pick if you're willing to go with the idea that H1 antagonism may be useful, but you're not so sure about all of the other things that quetiapine might be doing.
Thank you for that! The anti-muscarinic paradox with Olanzapine and Quetiapine has bothered me for some time.
I find the 5HT2a hypothesis very compelling. It should be interesting to examine it via some mechanisms described in the paper by Nutt and Carhart-Harris "Serotonin and brain function: a tale of
two receptors" (https://journals.sagepub.com/doi/pdf/10.1177/0269881117725915) and through the lens of the entropic brain hypothesis - maybe the delirious brain is in a more entropic state which can be (kind of) specifically attenuated by 5HT2a antagonism?
I’d say your pick of diphenhydramine over quetiapine doesn’t compute for me, I also have questions about its efficacy in other disorders specifically how it is first like in Parkinson’s psychosis with little chemical “antipsychotic” effect. A mystery drug to be sure.
Did you mean hydroxyzine?
Yes.
Sure, let me explain the idea.
It's mostly premised on the fact that there is a much clearer pharmacologic rationale for H1 antagonism than M1 antagonism. We use H1 antagonists all the time for their sleep promoting actions (doxepin is the poster-child for this), so we know they're sedating. M1 antagonism's utility is not so clear, so better to avoid it so you have less confounders.
Hydroxyzine is a relatively pure H1 antagonist (Ki ~10), followed by 5HT2A (Ki ~170) antagonism. It seems like a good pick if you're willing to go with the idea that H1 antagonism may be useful, but you're not so sure about all of the other things that quetiapine might be doing.
I don't know much about this, but I enjoy the article, because no one else knows either.