Here is one explanation - link1 , link2
"Fluvoxamine is a stronger Sigma1 agonist than any other SSRI. That is why we chose to test it for COVID rather than the others. Makes sense to also test some of the others in RCTs though."
Fluvoxamine has the strongest sigma-1 receptor affinity out of the SSRI drugs, as this paper indicates. The receptor affinities of these drugs are in this order of strength:
Fluvoxamine > sertraline > fluoxetine > escitalopram > citalopram >> paroxetine
However, we do not know for sure that sigma-1 receptor agonism is the reason fluvoxamine has benefits for COVID. So it would be risky to assume that other sigma-1 receptor drugs would work. So for the moment, fluvoxamine would seem the best choice, until we get further studies which indicate the mechanism by which fluvoxamine is beneficial for COVID.
The benefits of fluvoxamine for COVID appear to be very substantial: this article says that fluvoxamine 100 mg given twice daily for 10 days reduces COVID deaths by 90% if taken early enough, which means fluvoxamine reduces death by a factor of 10, which is incredible. We need replication studies of course to confirm this, but so far it is looking very good. The fluvoxamine study itself is here.
If confirmed this would make the efficacy of fluvoxamine similar to that of the vaccines (the latest vaccine data indicates that for the delta variant, the Pfizer vaccine reduces death by a factor of 10).
I bought my fluvoxamine from the excellent and very reliable prescription-free pharmacy Buy-Pharma. It's not as cheap as some are making out though: I paid around $36 for 30 x 100 mg tablets.
If it does turn out that sigma-1 receptor agonism is the reason for the COVID benefits, then there are quite a few other sigma-1 agonists that might also work, including dextromethorphan, which is found in some over-the-counter tickly/dry cough medicines (dextromethorphan would be a great way to treat COVID, as it would suppress the incessant cough at the same time).
However, it's not that easy to calculate the in vivo strength of the dextromethorphan sigma-1 agonism compared to fluvoxamine, so again, at this point, substituting fluvoxamine with dextromethorphan may not be a good idea. Although if dextromethorphan is all you have, it might be worth taking it if you were hit with COVID.
Digging into the binding affinities a bit more, I found this paper which details the binding affinities:
The order of potency for SSRIs at sigma-1 receptor is as follows:
fluvoxamine Ki = 17 nM
sertraline Ki = 31.6 nM
fluoxetine Ki = 191.2 nM
escitalopram Ki = 288.3 nM
citalopram Ki = 403.8 nM
paroxetine Ki = 2041 nM
Note that a lower Ki number signifies a higher affinity. So fluvoxamine has the strongest binding to the receptor.
Remember that the binding affinity to a receptor tells you how strongly a drug is attracted to and sticks onto a receptor, but it does not tell you whether the drug acts as an agonist or antagonist at the receptor. It turns out that all the above are agonists — except possibly for sertraline.
The paper goes on to say that sertraline may act as an antagonist of sigma-1 receptor. This Wikipedia list of sigma-1 receptor agonists and antagonists also puts sertraline into the antagonist category.
As for dextromethorphan, this paper provides the sigma-1 receptor binding affinity:
dextromethorphan Ki = 205 nM
So dextromethorphan has a roughly similar receptor binding affinity to fluoxetine (Prozac).
However, binding affinity is just part of the picture. To determine the actual in vivo strength of agonism that a drug achieves when you take it orally, you also have to take into consideration the blood concentrations of the drug that are attained, using pharmacokinetic data.
A quick Google search for pharmacokinetic data shows that 50 mg of oral fluvoxamine achieves a peak blood concentration (Cmax) of 15 ng/ml in young people, and 31 ng/ml in elderly people. Plasma protein binding of fluvoxamine is 77%.
This article says the peak blood concentration (Cmax) of 20 mg of oral fluoxetine (Prozac) is about 12 ng/ml. Plasma protein binding of fluoxetine is 94%.
So the blood concentrations of fluvoxamine are a little higher than fluoxetine, and the plasma protein binding of fluvoxamine is lower, and both these facts will actually serve to make free fluvoxamine more concentrated in the blood than free fluoxetine. So the pharmacokinetics favor fluvoxamine.
And we know fluvoxamine blows fluoxetine out of the water in terms of fluvoxamine's much higher sigma-1 receptor affinity. So all in all, oral fluvoxamine is going to have a much stronger effect on sigma-1 than fluoxetine (Prozac).
So in summary: if the benefits for COVID do indeed come from sigma-1 receptor agonism, fluoxetine (Prozac) would make a poor substitute for fluvoxamine.
Edited by Hip, 05 November 2021 - 04:33 PM.
