And if it turns out that fluvoxamine is, in fact, about as useful as taking a dose of aspirin for treating covid-19? That the initial small-scale studies were not, in fact, accurate or reliable when it came to hundreds of thousands of patients?
It's all too easy to get outraged over a story you read, be that "there is a simple, cheap, sure cure and they're not letting us have it" or "quacks are taking advantage of desperate people to sell snake oil". Less yelling, more waiting and seeing, please!
Posting four replies to your own comment might just be the ACX equivalent of yelling.
The principle of charity is more important than ever in these uncertain times. Experts make mistakes, random internet commentators even more so. But I think most people are trying their best to make sense of the world - when they fail, compassion works better than derision to help them fix their worldview.
The fact that you're being sarcastic suggests you're not trying to help me understand your point of view (from my perspective, at least, it wasn't helpful). You seem to be venting your frustrations. Maybe you could do it somewhere else?
Members of the medical profession or just their professional associations? Because the people who make up the latter are self-selecting and will skew towards activism of various types; as such a tendency towards lgoing along with the currently popular political trends us hardly surprising. Professional bodies should not in matters such as this be seen as representative of their members so much as representative of the established political views of their time.
Are you not presupposing that puberty blockers are medically settled and therefore only given out for ideological reasons? Seems like quite the circular argument. PBs are unethical because they can cause sterilization, and sterilization is an unacceptable tradeoff because of ethics.
Now that's a bad-faith argument, come on. Context matters. Is it unethical to sterilize someone with ovarian or testicular cancer via removing the ovaries/testes? Of course not.
We have a cohort of pre- or mid-pubescent children who have a significantly higher rate of suicide. They self report that the dysphoria with their body is the main driver of these suicidal thoughts. A vast majority of the psychology establishment agrees that gender dysphoria is a condition that is heavily correlated with suicidal ideation. Doctors understand the statistics as well as the mechanism for puberty blockers to work. There is no slam-dunk evidence that starting puberty upon cessation of puberty blockers precludes eventual fertility.
And yet you ignore these possible positive aspects in favor only of a possible negative.
Doctors aren't giving in to the woke mob, they're just weighting the risk of sterilization against the risk of mental unease and potential suicide, using a different prior on the risk of sterilization than you are. Don't conflate your personal morals with some objective sort of "ethical issues".
> a doctor who _didn't_ believe that gender transition was the right path
Doctors do not always believe it's the right path - it depends on the specifics of the case. There are some pretty big hoops that you have to jump through if you want to gender transition (at least in all countries where I have any knowledge of the system).
I think what you're trying to suggest is that doctors who think gender transition is always the wrong path are silenced. This may be true on social media. However, I think the only obstacle to them publishing that hypothesis in an academic journal would be that they couldn't find evidence to support it.
But are suicidal thoughts and even gender dysphoria actually reason enough for using drugs with potentially major side effects? As I understand the objection to puberty blockers it is that that this is not the best treatment available due to potential side effects. The criticism (or at least the reasonable and probably Bayseian one) of puberty blockers is that they should not be an immediate choice as opposed to less potentially consequential treatments. You presumably know this, but your post does come across as puberty blockers versus no treatment, when any reasonable doctor has far more choices.
If one accepts that there are some proportion of gender dysphoria cases where the least-harm treatment is undergo hormone replacement therapy, then we are implicitly stating that for that proportion of people afflicted with gender dysphoria, continuing to produce the hormones of their assigned at-birth gender is more harmful than the potential side effects of HRT.
Once we decide that, it would of course have been better to undergo HRT prior to puberty caused an increase in the undesired sex hormone.
So are your (and trebuchet's) objections
(a) with my first if clause in this comment
(b) with the notion that I'm overestimating our predictive power of prospective puberty-blocker adolescents becoming future adult HRT cases
Because otherwise, Occam's razor seems to suggest to me that (more so trebuchet than you, based on your respective diction), the supposed ethical concerns are an post hoc argument
"who are not ideologically captured or living in fear of retribution from people who are ideologically captured before I agreed with it."
Sounds awfully post-hoc. It allows you to throw out the testimony of any medical professional who is in favor of PBs because they're "ideologically captured". It's a non-falsifiable argument.
"If so, would you feel any concern whatsoever about saying so, in public, under your real name, in front of your employer and all your friends?"
No I would not. In fact, online acquaintances of mine (so granted, not real names) have gone through exactly this. They had some degree of gender dysphoria, talked with a psychologist or therapist specializing in gender, and found that HRT would not be right for them, and their gender dysphoria was instead a manifestation of other mental conditions like social anxiety disorder/OCD/clinical depression.
The reason a doctor would be trashed online or by the "woke mob" would be their argument's wording, which social progressives would see through. Since I actually have trans acquaintances, my argument would show I actually understand the issue.
>Why shouldn't we have equal priors about both prior to examining any of the evidence, insofar as neither was developed for Covid and neither have super-clear mechanisms of action?
Even if you had a low prior on fluvoximine working, the TOGETHER trial seems like a good reason to update that prior higher, no?
>I will face the Devil in the future and I’ll fail again. Medicine is too big and complicated and scary to stray from the herd most of the time.
Here I've got a feeling that Scott is being somehow pressured to demonize ivermectin in front of his audience despite the evidence, and he is trying to communicate it in this sentence. Thus he probably agrees heartily with your reply but he will not answer.
"This guy I like secretly agrees with me despite saying the opposite" is a common trope. (Especially among fans of newbie politicians, where it's obvious, but it's the same thing here.)
He’s written a long post on ivermectin- his conclusion was that while there were studies showing that it worked, most were flawed and with the others the benefits were probably due to the deworming properties in countries where that is a problem, and where covid multiplied the problems caused by worms. 20% of people have worms in India.
Yeah, I didn't understand how he decided on a 90% probability ivermectin didn't work based on the worm theory. It might well just be worms, but 90% seemed too high to me (and if anything my bias ought to be against ivm since my former legal guardian just died "with" Covid after refusing to be vaccinated and my parents continue to refuse... but I'm okay with people doing both, get a vaccine and some ivermectin and fluvoxamine as Hail Maries.)
It's a tricky situation to be in, where my ability to make the case I am making depends on Scott's willingness to engage, when it's far easier for him to shift his attention elsewhere.
I've never been as blackpilled on the prospects of the rationality community as I am now. There simply is no way to get a proper conversation going despite my best efforts.
I wonder if Scott isn't slowly falling to the pressures of media income streams here. The chief economic mechanic that develops media echo chambers is outlets identifying their consumer base and playing to that consumer base for clicks or subscriptions. They know if they say X they'll lose subscribers, so it becomes impossible to say X whether X is true or untrue. The signal that makes the most money becomes the truth and the tail wags the dog.
If Scott subconsciously thinks he'd lose 10% of his subscriber base and become a less well regarded blogger by saying "IVM might work, and it's harmless, so there's no real reason not to try it since doctors literally have zero other things they can try right now in the case of an infection," then that sentence costs him a shit pile of money to say. If he makes a quarter million a year off of ACX, then that's a twenty five thousand dollar sentence.
If this was the SSC days, it's a sentence that costs nothing to type.
And let me tell you first hand, doctors right now still have absolutely *nothing* to even suggest you should do if you catch Covid. We're two years in and they're still saying "yeah, uhh, drink chicken broth and come to the hospital if you can't breathe." They're not even suggesting D and Zinc.
The thing is, though, that of every indie blogger or indie journo I've watched over the course of the last decade, the one thing they always end up doing is catering their content to a demo once they start getting paid. If Scott can resist this, then he will be one of the few, if any, I've seen do that.
ACX is not Razib Khan. C`mon, not paying for ACX costs you (and me) how much of the content? And the ACX still gets subscribers by a) being the one blog to read if you read anything at all - due to b) Scott's smarts&style PLUS c) Scott's OCH. H for honesty. That is his market. Not sure, he cornered it. ;) - I will subscribe when hitting my first 500k.
> since doctors literally have zero other things they can try right now in the case of an infection
You're commenting under a post literally about one such thing, no? Besides, there was a Pascalian medicine thing a few weeks ago about this "let's take zinc and D and everything else" idea.
A good friend of mine contracted Covid 6 days ago. Her doctor told her "umm chicken broth and come into the hospital if you can't breathe." Her sister is an MD and told her "umm chicken broth and come into the hospital if you can't breathe."
Let's pretend Luvox has a 60% chance of working (per this article) and IVM has a 10% chance of working (per the Worms article) and Scott is right about both. IVM's side effects are more benign than Luvox's. Why is the line being drawn where Scott is drawing it? Isn't 10% better than chicken broth? Couldn't Scott write this same article for IVM and wonder the same questions?
His direct response to me in the comment thread of the Worms article was approximately "yeah, I can see how taking IVM makes sense if you frame it that way." Yet here we are.
FWIW I rate IVM's chance of effectiveness even lower than Scott did in the Worms article, but still nonzero, so I still plan on taking it because I see no reason not to. I think the argument against IVM is basically social signaling at this point.
> My contention, and those of *all* of my friends who think deeply on this one, is basically "IVM is so incredibly safe why wouldn't I roll the dice on it being 10% effective? What's the drawback? There's no drawback. Why do we think there's a drawback?"
Scott replied:
> I think this is a pretty reasonable perspective.
But also added:
> I think it would result in you also taking HCQ, doxycycline, Vitamin D, and a few other things, but that's not necessarily a dealbreaker.
It would indeed lead me to take some of those. D3 is in the FLCCC protocol that's been used internationally with IVM, and I happen to have a shitpile of doxycycline in my cupboard from my wife's cancer, so I'll be taking both.
Curious - what will you do when you catch it? Chicken broth?
We enrolled my wife in a clinical trial for her colon cancer that probably had less than a 1% chance of working. If I went back and did the Pascalian Medicine analysis we wouldn't have done that. In the end she died anyway, but no doctor told us not to do it.
Expired tetracycline is nephrotoxic, so is minocycline. I'm not sure about doxycycline, some sites say it is, some say it isn't, I don't know enough chemistry to confirm which ones are right.
Your wife died, what, 2 and a half years ago? I might check the expiration date on those pills and do some research before taking them.
I just went back and re-read this, and I wouldn't consider the treatment "full." Or if it is full, it certainly doesn't convince me to not take IVM. In fact, the closing argument convinces me the opposite.
***quote***
Does Pascalian medicine beat our current strategy of only using drugs that are proven to work? I don't know. I think the current strategy makes sense on a social level, but I'm not sure that the Pascalian strategy wouldn't work for an individual. At least an individual who is able to reliably identify which low-but-nonzero-probability-of-benefit drugs really do have very few potential side effects (if you didn't already know about loa loa encephalopathy, consider that this might not be you; I am very much not-recommending that any reader here do this on their own).
After the worms article, I considered putting my family on ivermectin just in case anybody had worms. I think the chance of that is near zero, but seeing the picture of the worm freaked me out.
The stuff is super-safe, and I think we should probably just put every American on a course of it once a decade to see what gets cleared up by it.
But right now the stuff is hard to get, both because of people taking it in excess and because pharmacists are unwilling to trust that you really need it.
I don't think his position on ivermectin is "the chance of it working is zero". I think it's that the chance is too low to be worth anyone's time and money.
I don't think it's that deep. One of his common writing practices is to use tribal signals to appeal to the intended audience (Number 7 - https://slatestarcodex.com/2016/02/20/writing-advice/). In this essay, he wants to convince the type of doctors who only do things enthusiastically recommended by government agencies and other Authorities to prescribe fluvoxamine. This group almost certainly believes the mainstream disinformation about ivermectin. On the other hand, doctors with an open mind about ivermectin probably already have an open mind about fluvoxamine.
There are now two more things they can do, and one of them has an effectiveness of 89%.
I think you are misreading Scott. He might be worried about losing commenters — conversation here isn't as good as it was on SSC. He might be worried about people he respects thinking less of him. I don't think he is worried about losing a little money.
Fluvoxamine, as an antidepressant, is way easier for Scott's brain to category-map to the similar atypical usages / Devil encounters he had last year. A cocktail of guilt, math, reason, and courage is pushing him juuuust up and over the mountain of doubt.
The mountain of doubt that he describes in this article. The one that's kept a lot of doctors from considering HCQ or IVM *even before* the tar of social stigma and outrage culture became an even more prevalent factor.
Scott's making an interesting move here, to put chips on the table out in front of any third wave of media hysteria anti-"anti-vaxx." That's definitely courageous and could cost him dear if doctors/rationals/media/whomever don't rise up as a bloc in favor of fluvoxamine. But he's not quite all the way to full rationality on backpropagating this update towards other non-vaccine treatments. Maybe if IVM had been an anti-depressant it would have been a different story.
@Scott - what's your leading theory as to why case counts in Africa are so disproportionately lower than in South America or Southeast Asia?
His theory on IVM was "Worms as Confounder." Which might be true, but I've spoken directly to several doctors in South Africa who swear by the FLCCC methods so deeply that they quit their jobs when the FLCCC protocols were being banned from the top down, so they could proscribe them without international influence on their treatment suggestions.
I'm not a doctor, I just don't see any reason not to try IVM or fluvoxamine or anything else that seems like it has a nonzero chance of working, when the counterfactual from the doctors today, two years into the pandemic, is still "meh, chicken broth I guess."
I'LL DEFINITELY BE DOING THE CHICKEN BROTH TOO, hahaha. As it also has zero downside.
I went back and reviewed Scott's Pascalian Medicine article, and while it's well written, I still don't see where it makes a strong case against this approach.
The best it seems to offer is that this approach makes sense for the individual (me, you) but not for the medical community at large, due to economies of scale. That's a case that should be made mathematically, not grammatically, and he doesn't do the math.
We need some good studies on chicken broth. I don't say this glibly, it seems like it would be very interesting. Do we just get benefit from the hydration? Does the temperature matter (for example would cold soup be just as effective). Does the level of schmaltz matter? Does the amount of calories (how watered down the soup) or nutrients (quality bone broth + veggies) matter?
Compared to a control, of say, intravenous dextrose, what provides the best clinical outcome, for the appropriate range of diseases?
Bone broth is generally really good for you, and broth is going to replenish not just water but all the various salts you lose when sweating from a fever. Frankly chicken broth is probably something all of us should have more of even when healthy, I definitely wouldn't consider it a placebo.
Predictions : nutrient density matters a lot, calorie count matters a little (and level of schmaltz obviously affects this substantially), temperature only matters insofar as it ought to be at least warm - you don't want to have to burn calories heating up your food when ill.
It’s been clear for a long time that Scott has firmly conventional priors that are hard to move. That was evident in his Ivermectin post and in his post on non-pharmaceutical interventions where he bent over backward to find some effect for masking and lockdowns.
The NYT debacle did seem to scare Scott into having a ton of social desirability bias that he did not previously seem to possess. He wants to be seen as one of the Very Serious People so badly that it ruins his judgment.
You say "social desirability bias" - but I have seen Scott criticized more for being anti-ivermectin than for literally anything else. Is that not the opposite of social desirability?
Good point. I suspect those people were probably anti-ivermectin already.
Although it isn't social desirability bias, those paying subscribers do still represent an incentive to be pro- or at least open to ivermectin for covid.
I can tell you that we doctors prescribe things off label all day long. The problem is is that the doctors who chose to do this with other drugs were vilified and threatened and cajoled and are probably scared stiff to venture into these Waters without formal approval. You reap what you sow
Can you more details? It sounds like you're not talking about the drugs Scott says are very commonly prescribed off label: trazodone for sleep, gabapentin for nerve pain, etc. Or maybe you are. What are the off label prescriptions that lead to docs being vilified and threatened? What form do the vilifying and threatening take? Snotty remarks in the hall? Lawsuits?
yes by making such a huge issue of this , "horse dewrmer " etc and societies thrating removing licences people are on edge . But really ALL forms of care have been vilified or unsupported. What percent of patients get good daily FU with pulse oximetry if high risk? I will wager it is less than 10%.
He's talking about ivermectin, and how the news media will love to write about the quack doctor who says antidepressants can cure covid when "there is no evidence that it does"
As far as I can tell, whenever the media has mentioned fluvoxamine, it's been in the context of discussing trials saying that it *is* one weird trick that works.
I am reminded of Keynes' comment on bankers and banking, that failure is perfectly acceptable among bankers and results in no real consequences, as long as they fail in a strictly conventional way.
As a dude who might get covid at some point: is there any way to get this ten-day course of fluvoxamine for use just-in-case I get sick? Or do I need to wait until I'm already unambiguously sick, and then have the conversation with my doctor?
Current monoclonals don't seem to be holding up all that well against omicron. Why are you recommending a site that primarily seems to be concerned with getting people ivermectin to someone who's looking for fluvoxamine?
Thanks for the link to their full protocol. It seems like they might have doctors willing to prescribe fluvoxamine, given that. I do find it interesting that, with regards to the vaccine, this is their stance: "Vaccines have shown efficacy in preventing the most severe outcomes of COVID-19 and are an important part of a multimodal strategy that must also include early treatment. The decision to get a vaccine should be made in consultation with your health care provider." I'd avoid using them as an intellectual resource, given that snow job.
It's phrased in a way that's intended to lead the reader to the conclusion that the vaccine isn't a slam-dunk first-line preventative treatment, unlike their suggested prophylactics, and has more risks or other downsides compared to them.
I personally do not think it's particularly risky for a generally healthy dude to just pop Luvox for 10 days or so. While I'm not an MD, I'm in a field where I see lots of psychiatric drugs in use. I have seen hundreds of cases where docs put people in good-to-mediocre health on Luvox and other SSRI's -- including overweight, couch potato middle-aged people, people with asthma or incipient diabetes, people in their 60's, etc etc -- with no serious ill effects. So unless you have some unusual health problems I do not think it is particularly risky for you do just search in your friend group for someone who's on Luvox and ask them for a few
pills. I mean, sure, have tho convo w/ your doc first, but if doc is unresponsive, I really do not think there's much risk in just scoring some Luvox from friends. I am a professional with a sense of responsibility and a conscience, and I feel like I'm saying something members of my demographic and professional group are not supposed to say but -- yeah, fuckit, that's what I think.
On forums like this I am pseudonymous on general principle, even if I'm just sharing my opinions about poetry or brands of Irish whiskey. In person I would give the above advice to any friend or acquaintance. (Under those circumstances I would ask first what health problems they had, and if they had something unusual or serious going on I would recommend that they look into whether that problem made fluvoxamine risky for them -- or I might double check on that for them myself.) If I were a physician I would cheerfully sign my name to any document advocating for the use of fluvoxamine for covid.
My elderly parents are nervous about omicron, so I suggested they do exactly this and ask their doctor for a supply of fluvoxamine that they can use in the event of a positive test.
In case their doctor was skeptical or unfamiliar, I sent them the Lancet-published RCT. Also, my father is a retired psychiatrist who has decades of experience prescribing this kind of drug and understands the (minimal) side effects and (low) risks as well as anybody.
Their doctor is part of the UPenn system, so he asked Penn's infectious diseases unit if he should provide the prescription. They said "no." Not "come back after a positive test" or "we're protecting the supply for severe cases" or "this isn't in our standard treatment guidelines, but it's low-risk so let's defer to the patient."
So the answer to your question is it's possible, but to Scott's point, good like finding the doctor who will do it.
That drug still worries me. It is a psychotropic and I still think there are better alternatives.
Apart from the other therapeutics (monoclonals being a major one). I'm getting more interested in HCQ, which I was highly dismissive of under Trump, but as I look it more deeply (ignoring the several deeply flawed studies), may do some strong work if given in the first few days. Ivermectin? Who knows. I do think it also has promise.
We also keep ignoring zinc and D3, which are just amazing natural supplements in their ability to combat viruses.
This is a great article and I hope more doctors who treat Covid patients read it, but the FDA didn't approve fluvoxamine for depression. It's only approved for OCD, and used off-label for things like depression and anxiety.
Regarding fear of lawsuits, FDA approval isn't the only factor. Most doctors want to follow the "standard of care", which basically means doing what other doctors are doing. This leads to an obvious chicken-and-egg problem.
Many but not all docs exhibit a combo of entitlement and hyperconventionality that I find quite repellent. Jeez, it's not the worst combo in the world: Poor impulse control plus sexual attraction to adolescents is worse -- low capacity for empathy plus substantial power over others' welfare is worse -- stupidity plus having a bully pulpit is worse . . . But still, that doc combo enrages me every time.
"low capacity for empathy plus substantial power over others" sounds like a lot of PCP's I've visited. In thier defense, they are just responding to the incentives and shitty life experiences that the system pushes on them, but still.
I am going to be an asshole and say I first asked you about fluvoxaminne in the comments March 31st after the first small trial came out and 60 minutes did their report. The lack of cost benefit analysis from the FDA and CDC is absurdly frustrating.
You brought up a good point which is they FDA processes require a sponsor. Without a sponsor nothing happens. Someone needs to file the paperwork. If any rich people are reading best case is probably create a foundation, hire some regulatory professionals and get them to do it. Better yet get a pharma company to do it. I might ask my employer.
Scott wrote a while back about the baby IV fluid case where doctors had to do a PR shame campaign against a random pharma company that happened to own a bunch of generics, and eventually that company paid up to get it okayed in the US.
Your idea reminds me also of something either Scott or maybe another blogger explained about how the CDC has an associated nonprofit called the CDC Foundation which gives them money in emergencies because the money Congress gives them is very inflexible. Ties in to Scott's post from a while back about how billionaire philanthropy looks good when you compare it to government spending. I wonder what the per dollar return would be if you funded studied on off label uses for generics and got the new uses you find pushed through the FDA.
At least one rich person (inventor of the optical mouse) has tried to partner with a sponsoring drug company by offering to pay all fees without any success. He's also offered $2M to interview or debate any member of the NIH committee that voted to recommend that fluvoxamine be rated Neutral on their Covid Treatment Guidelines.
This reaction is the problem though. Up front, I'm strongly in favour of vaccines and strongly vaccinated, and think anti-vaccine positions are at best ill-informed, so this is not a defence of his position. But the point here is that a corrective to government failure is people using their own wealth to fund processes that would not otherwise happen. If we immediately take the knee-jerk position that it's not acceptable to do this outside a range of acceptable ideas we risk just recreating the problem we are trying to solve: the approval process only works for a subset of things that might be approved. If we instead foster a culture where all ideas can be tested and the silly ones can be publicly and demonstrably be found wanting, we'll be encouraging positive change and hopefully move away from the idea of government as the only source of legitimate wisdom in medicine to a position whereby government can verify a range of views. Therefore, to simply say that someone doing this is a nut because you disagree with him (correctly in my view) contradicts the rationale basis for wanting people to put their money where their mouth is. And also deprives us of the pleasure of seeing a proper analysis of the claims of the nuts of this world (not that I expect the outcomes of a proper assessment of whatever they are pushing would stop them, as that would just be government conspiracy again...).
Reputation effects aside, I think there's a lot of sense in rejecting claims - even claims of evidence - from people who have committed themselves to bizarre positions. There's a lot of subtle ways that data can be influenced or corrupted, so to some extent you need to assess the source as well as the content of a study. That's true of big pharma too, of course, but as large, long-standing companies, they have more at risk if they're caught in (overt) misconduct, and can generally be made to observe better standards.
Seems like that approach would just lead you to desperately cling to your priors, as you're doing now. "This person disagrees with me on one issue, so I won't even consider the possibility that they're correct on a separate issue." So the only way you would even consider a claim you don't currently agree with is if it is being presented by someone who you agree with on every issue? But by definition, you wouldn't agree with them on the claim they are presenting! And so you can never change your views.
> At least one rich person (inventor of the optical mouse) has tried to partner with a sponsoring drug company by offering to pay all fees without any success.
Oh, that's good.
> He's also offered $2M to interview or debate any member of the NIH committee
It is on both the doctors and the FDA. We could live in a world where people could just get fluvoxamine without a prescription and the consequences would fall on them. Instead the blame falls on the doctors or the FDA or the politicians and they behave too cautiously.
You could do a cost-benefit analysis comparing lives saved v. lives lost but I think it is more egregious to kill someone by preventing them having access to life saving medication than to let someone kill themselves by taking medicine they shouldn't for whatever reason. It seems like there isn't even a willingness to compare lives v. lives but a standard of safety that is probably too high in many situations. For example, considering withdrawal from SSRIs on one side while death is on the other.
Here in my country (western Europe), generalists have been strangely quasi absent from covid crisis, it was all urgency plus retirement home at the beginning, at after mass vaccination in new temporary structures, with a big state reservation / tracking system. It's not only prescribing strange (old) drugs, it's the individualized and decentralized medecine that is sidestepped. I wonder if it will permanent.
Hello sorry to have been gone so long, I owe some responses in past threads.
Regarding:
> It’s not illegal to prescribe fluvoxamine for COVID. It’s not even going to get you in any trouble. It might not get covered by insurance, but it only costs about $10 anyway. The problem is just that it’s weird.
Wrong. You can get in trouble. And you will. Applying this same logic to Ivermectin and Hydroxychloroquine, these too have the same right to be prescribed by a doctor for off-label use. However doctors who have in the last year, are punished, vilified and attacked, reprimanded and fired. I have many many examples, Dr Paul Marik being one, but you can easily find hundreds and probably thousands of examples of this on your own.
We've opened up the flood gates and "totally not put doctors in trouble" for prescribing things for off label use, except we have. The number doctors who feel "weird" prescribing things the NIH and FDA don't explicitly approve, will only increase, as we apply higher selection pressures for the system to vilify or remove any who go against it. Good luck finding doctors who will prescribe this.
What about patients (such as some of yours, no doubt) who are already taking SSRIs for depression? Would there be risks of adding fluvoxamine on top of that? Serotonin syndrome?
+1 on this. I was going to ask the same thing if somebody hadn't already. Also curious about non-SSRIs anti-depressants. Does this present enough of an upward shift in risks to offset the potential benefits?
Yes, but probably a fairly low risk. SSRIs all affect serotonin in the same way, so combining 2 of them is a bit like increasing the dose of the original SSRI.
Combining SSRIs with other drugs that increase serotonin but work in a different way (eg. MAOIs) is where you get the higher risk of serotonin syndrome.
The whole bloody system is set up for pharma, not for us - that's why. Why wouldn't there be widescale searching and trials for ALL possible helpful substances, not just pharmaceuticals, ala zinc and nigella sativa, from the very start?
One of the big knocks against ivermectin is the (lack of) obvious mechanism for it to work against covid at non-toxic doses.
But, like -- at least there *is* a mechanism! It has been shown to inhibit replication at (intolerably) high doses in vitro, and killing worms (which it definitely does) is *also* a potential mechanism.
What is the possible mechanism for a random SSRI to inhibit covid? It seems like many of the arguments that it's unlikely that a random dewormer would do anything apply in spades -- I am pretty ignorant on this, so maybe there's something obvious that I just don't know about -- but it seems like a weirdness that should be addressed. Otherwise given the mixed evidence from various ivermectin trials, the Insanity Wolf approach (just take everything) seems... kind of OK? (if a patient has covid and seems to be at high risk for bad outcomes, of course)
Fluvoxamine probably doesn't do anything to inhibit SARS-Cov-2 (the virus). What it has been long known to do is have an affect on the body's inflammatory response, and one of the major symptoms of COVID (the disease caused by SARS-Cov-2) is a massive inflammatory response. Moderate that symptom, and the symptom won't kill people.
By analogy, there are diseases that kill because they cause massive fevers that overheat the brain. You can lower mortality from those diseases by taking measures (at the crude level, just immersing the patient in cold water) that just treat the fever, even though they have no effect on the bacteria or virus that causes the disease.
I am not a doctor, but I understand that chlorpromazine is the front-line treatment for brain-eating amoeba, and also that nobody really knows why an dopamine agonist antipsychotic would be effective against amoebas.
No-one really knows the mechanism for SSRIs to help with depression either, but 10% of the population still takes them.
For Covid, fluvoxamine differs from other SSRIs in that it also binds to sigma receptors that are involved in coronavirus infection. One theory is basically that it blocks an important step of the virus lifecycle. There are several other drugs that bind to sigma receptors (most famously HCQ) but fluvoxamine seems to have the most evidence for effectiveness and relatively few side effects
But of course there's a lot of compounds that specifically interact with that receptor and don't have as many other effects limiting their maximum tolerable dose.
In that regard, it should be given much worse prior odds than hydroxychloroquine and ivermectin, which became well studied drugs due to their strong effect on parasites and weak effect on humans.
I strongly believe in what Scott calls the "meta-level heuristic that you need in order to practice good medicine".
Ivermectin seems to be a good argument for this. After being promoted by a bunch of people (the vast majority of whom meant well, I assume) and then becoming a political football, it's now so firmly lodged in people's minds that it takes massive institutional power to dislodge it. I don't understand how that's happened, but there are lots of other examples. And they will keep on emerging, and keep on distorting medicine. The only corrective that I can see is strong institutions. To give an analogy: they are signal-boosters that stop the signal being overwhelmed by massive noise. Even if institutions are imperfect signal boosters, they're still better than just the noise.
So I think doctors are right to follow the institutions as best they can most of the time. However, this post also seems to me to be pretty much the thing the internet was made for. This is what they promised us in the golden age of information: smart people pooling their knowledge for the greater good. I think these two intuitions are somewhat contradictory, and I have little hope of resolving this contradiction any time soon!
God that's depressing. It kind of says everything you need to know about the FDA that they're incapable of doing anything without a Pharma company with a suitcase full of money taking point.
I am going to be the Devil's advocate here and argue for why you should trust the Devil. It is because the consequences of not doing so are *illegible*. Like, what do you think will happen when you do this "slightly weird" thing? The worst case scenario isn't having to explain it to your colleagues, it's having it come up in conversation with someone a large amount of inferential distance away from where you are, but who you still respect the opinion of. (I don't know of a good example because I don't know what your social world, or the social world of a hypothetical person wanting but afraid to prescribe fluvoxamine, is like.) How are you going to justify yourself in that context, huh? (And you need to justify yourself, and not just defend yourself from threats, to protect your ego -- otherwise your mind will protect your ego with rationalizations, which are bad.)
The other worst case scenario is that you feel *yourself* the need to explain and justify your decision to someone, because that's how the human mind works. The decision of who to choose for this purpose can be made on many bases, such as previous trust, relevant expertise, and relevant domain knowledge. This post seems to point to Scott Alexander as an answer to the last question but doesn't say anything about the first two ("expertise" being thought of in a credentialed manner). In other words, talking to a representative of the Devil is easier and less scary than talking to Scott Alexander. Since fear usually represents some genuine danger that we should be worried about, this is an indication to trust the Devil.
I have said all of this as a Devil's advocate, or as a non-serious post. My serious reaction is that Scott is doing a good thing by providing his email for the purposes of having discussions on the psychology of providing fluvoxamine to patients. And I am defying the Devil myself somewhat by talking about His mechanisms. Hopefully I will not pay for it too badly :)
Yes, but you have to also take into account if they are "normal" or "weird" people. If you are accountable to "weird" people than you can violate consensus (of a group other than your own)
Someone can do all sorts of invisible damage all day, but someone who stops it but introduces a small amount of visible side effects will be destroyed for doing so.
Ah, you are saying the Devil wants (or at least wanted) us to break the window because its easily perceivable effects total positive, while a full accounting of all the effects totals negative. But I think in this case we can count on the Devil's short-sightedness even more: the first-order effect of breaking the window is clearly negative so we shouldn't do it. I don't know of anyone whose devil has convinced them to break windows due to the broken window fallacy.
There is something wonderfully different about listening to American discussions about medicines. I think it is because in Britain all advertising of prescription medicine is illegal, so we never get into these debates where we fire off the names of what sound like summaries of the latest Star Wars movie.
Five years ago, I could definitely have tagged this onto the SW Wikipedia page and got away with it for a few days.... "At the battle of Covid 19, the forces of the Fluvoxamine Alliance face the combined might of Sith Lord Darth Luvox, and the Ivermectin insurgents..."
I assume that there is some cross over between pulp sci fi authors and drug marketeers.
On another note, if you outsource all your medical knowledge to doctors you're going to have a bad time, unless your doctors are way better educated than ours. Then again, _our_ skilled doctors emigrate to the UK and only the bad ones stay so...
Advertising usually happens for on-patent medicines, or brand-names of OTC medications. There are approximately no ads for generic prescription medications because it doesn't make financial sense to do so.
This is politicized because the Establishment decided to do everything they could to oust Trump, which involved denigrating everything he said.
This is a bit off-topic, but how come an antidepressant can treat COVID ? I'm no doctor nor a biologist, so it sounds to me like saying that "ice cream can be used as an effective shaped explosive", i.e. somewhat surprising.
One of fluvoxamine's well-known secondary effects is on inflammation response. One of the major and dangerous symptoms of COVID is massive inflammatory response.
So it's a bit closer to "plant fertilizer can be used as an explosive"; the fact that ammonium nitrate is both plant food and can go boom is a coincidence, but its high availability and low cost as fertilizer makes it a convenient explosive.
It's only partially a coincidence. Ammonium nitrate works as fertilizer because it's a very dense source of bioavailable nitrogen. "Dense source of nitrogen" is also a big facet of what makes it boomable, as part of the "things that want to very suddenly turn back into N2 gas" class of explosives.
It is still partially a coincidence, since there are other dense sources of bioavailable nitrogen that don't go boom readily, most notably urea and ammonia. I think the other secret ingredient for ammonium nitrate going boom is that it's a salt of a oxidizer and a reducer, while ammonia is a pure reducer which needs access to an oxidizer to turn back into elemental nitrogen. Atmospheric oxygen does the trick, but surface area limits the speed of the reaction to burning instead of exploding.
At some level, sure, the chemical properties of nitrogen that make it suitable for an explosive, and make it necessary for plants as they evolved, AND that keep plants as they evolved from just sucking it in from the atmosphere they're soaking in are not accidental, but causally related.
But there is no particularly legible path from "plants on Earth need compounds of this element to be in the soil" and "compounds of this element are often explosive" short of encyclopedic knowledge of both chemistry and Earth biology; the presence of both properties in a single compound is very much a "co-incidence" of the properties.
I would still say not entirely. The kind of chemical that is essential for life is usually the kind of chemical that is highly unstable (think O2), because instability is a good sign of having lots of free energy, and also predicts scarcity.
I suspect that "bioavailable nitrogen" being scarce enough to be a limiting factor on plant growth is also linked to nitrogen's utility as a backbone for explosive compounds: the low energy state of N2 relative to other nitrogen compounds both provides a steep energy gradient for nitrogen compounds that can react to yield N2, and leads to a need for specialized metabolic pathways to fix N2 into compounds that can be readily used for cellular processes.
The other atmospheric gases that supply major elemental components organic molecules (H2O, CO2, and O2) are all less common than N2, but the cellular machinery for fixing them into organic molecules is far more ubiquitous than nitrogen fixation. Hydrogen "fixation" is ubiquitous enough that biologists don't seem talk about it as such, and oxygen "fixation" is nearly universal in eukaryotes and fairly common in bacteria. Carbon fixation is a bit more specialized, but still nearly universal in plants and algae. Nitrogen fixation, however, seems to be limited to certain varieties bacteria and archaea, with most plants reliant on organic nitrogen already being present in their growing media, or at most providing a hospitable symbiotic niche for nitrogen-fixing bacteria to move in to.
In addition to what Eric Rall said: The chemical relation is also a reason why this kind of chemical fertilizers got so widely available in the 50s. At least in Europe there were a lot of chemical plants build to produce explosives during WWII that could easily repurposed to produce fertilizers after the war.
To follow up on a real dog's remark, "among the SSRIs, the order of affinity for sigma-1 receptors is as follows: fluvoxamine > sertraline > fluoxetine > escitalopram > citalopram >> paroxetine." https://pubmed.ncbi.nlm.nih.gov/28315270/
Since I'm on citalopram, I'm bummed about this list, but there we are.
Amazing, so you alone debunked the snake oil option and discovered the real thing, no one was talking about. You really are the smartest of them all, i knew it.
Is the evidence that Luvox helps purely empirical - of the "people threw lots of things at the wall and one stuck a little" variety? Is there a plausible mechanism by which Luvox should help with COVID?
Luvox has known effects on inflammation. COVID causes massive, dangerous inflammation. I don't know of any particularly detailed model of exactly how Luvox affects COVID-caused inflammations, but it's the suspected mechanism.
If you want to do something even slightly unusual you get a lot of nonsensical opposition from senior clinicians. finding even a single example of a hospital anywhere in the country doing it already is like a magical key.
Also it seems the UK's solution is NICE. Their job explicitly includes sorting out treatment protocols and recommending likely treatments to doctors
You mentioned before about doctors in the US being a bit blind to stuff in the same field abroad.
You might find the NICE page on covid drugs interesting.
Ya, The National Institute for Health and Care Excellence.
That sort of naming isn't so uncommon.
Also, as a rule of thumb, if you're ever wondering about the QALY impact of a drug or treatment there's a good chance that NICE have a page with the details of their analysis which tend to be pretty high quality.
They're a "non departmental public body" like the "Office for National Statistics" or "Office of Tax Simplification"
So I presume that if they basically "approve" it, fluvoxamine gets that "(patients given rapid access)" parenthetical next to it which the fifty other random things on the list don't have. Do you know why hasn't that happened yet? I feel like widespread prescription in a culturally familiar country would help persuade American doctors.
Thank you for opening up about the moral dilemmas here which apply in all areas of life and especially where reputations and careers appear to be at stake. The price we pay for society is becoming clearer by the day and some of those age-old bargains are looking a little threadbare
Then you should read the Screwtape letters, which are basically a whole novel of this kind of moral and psychological analysis, with the plot twist that the letters are written by a literal demon.
This is really two posts. One about whether doctor should prescribe fluvoxamine for COVID (Yes)
The other is an aside but really much more important, it’s a problem with the basic set up of DFA that goes back to why it was founded. FDA is there to keep quack medicines and medical devices from being widely sold. There are some Libertarians who disagree with that goal but Scott does not and it’s not what he is writing about here.
There is also a critique of FDA that its procedures for keeping quack drugs off the market are flawed, that it pays too much attention to possible costs (including the cost of delay) and not enough to benefits (including the benefits beyond those to the recipient to others in the case of vaccines) of new drugs. I suspect that is true and it’s a long-standing problem, but that is not exactly what Scott is addressing, either.
Rather, it’s that the DFA is entirely reactive. If there is not a market player pushing DFA for a regulatory action – the issue here is changing the label of fluvoxamine to include COVID as a possible use – it does not happen. But this was the problem with screening test kits early on. There was no market “demand” for gazillions of kits whose use would be to screen lots of asymptomatic people so they would self-isolate. [FDA also dragged its feet on approving cheap fast for which there WAS demand but that was the long-standing problem of over-weighing risks relative to benefits.] Another example was the non-decision to use fractional doses of vaccines and to delay second doses to allow more first doses. There was no one pushing for that decision and it did not get consideration.
Is there any reason you don't ask the question "why do we require prescriptions for medicine that's already approved?"
Doesn't "prescriptions are optional for legal substances" just make this _entire problem_ go away if we let people make their own choice and suffer the consequences if they choose poorly?
As I understand it, we have four classes of medications in the United States. There's the kind that is just stocked on shelves, and people can pick up and buy (things like aspirin and vitamin D); there's the kind that you have to go ask a pharmacist for and they will just give you a limited amount (things like pseudoephedrine and other amphetamine precursors); there's the kind that you need a prescription from a physician before asking the pharmacist for; and there's the kind that physicians aren't even allowed to prescribe. Given that different chemicals have different levels of risk, and different types of risk that consumers would be more or less likely to underestimate, it seems to me to make sense to have these kinds of gradations. It might even make sense to have a further gradation within the prescription medicines - ones that physicians are allowed to prescribe for whatever use they see fit, and ones that physicians are only allowed to prescribe "on-label". It would probably be useful to move many medications down a notch on this scale. But it seems to me that if you think it's worthwhile at all to have an approval process for drugs, then you should think that some drugs could reach a point where it's reasonable to have them be physician-prescribed, while others get approved to the over-the-counter level.
On one hand, I spent my entire life until my mid-20s in a depressed fog, barely able to manage graduating at all (let alone fulfill all the wild dreams of researching this and that thing, writing that or this thing, tackling this or that ambition, etc etc).
The only reason I did manage to graduate, in fact — that I managed to *keep going* — was that I found fantastic reserves of joy and energy through hydrocodone, oxycodone, morphine, and the rest. When the choice was "become addicted or kill yourself", well...
On the other hand, this quickly became a nightmare too: super addicted, as predicted; could no longer afford enough; could no longer find suppliers; withdrawing all the time...
I had thought, before, that I'd rather be dependent upon opioids and alive than sober and dead, but I hadn't thought about what might happen if I couldn't get them any more. I was very bitter back then: "it's like $10 for a month's supply at the goddamn pharmacy; why can I not just be prescribed some weak opioid and *I'll* deal with the dependence?!"
I can see why the caution, of course. Once I started, I couldn't stop. My life is great now, and I have almost everything I've ever wanted — because I finally did get that prescription (for buprenorphine); even after friends dying from opioid abuse, even after all the heartache, I couldn't stop without the substitute of bupe.
But also... I don't think I regret it. I spent a decade in therapy and trying every possible drug, even ketamine; I even managed to charm a Desoxyn script (+ alprazolam!) out of my psychiatrist to trial it just for a month; and... nothing. I was ready to die. Opioids are the only thing that helped.
Do I have a point here? Uh... Yes, but the margins of this comment are too small to contain it.
Hah! Fellow math nerd here. Also, do you think your opioid dependence could have made you less susceptible to ketamine treatment? I have no knowledge of how medicine works and am shooting out of my ass here.
This is something I wanted to ask as early as the IVM post, but the comments on it flew very fast and I thought it would be unlikely anyone would see it.
I work and have academic background in social sciences, an area strongly removed from medicine and/or biostatistics. In our field, no one would treat you with any degree of seriousness if you were to propose any kind of solution to any problem based purely on empirics without any sort of model that explains why what you are doing should work (not just a model in the rationalist sort of sense, you'd be expected to present a system of equations and how they relate to each other). In medicine, this seems very widespread - I opened 20 random Wikipedia pages on medicines that are on the WHO Essential list, and close to half of them have "no well understood" or "a subject of discussion" mechanisms of action, although their effects are empirically well studied.
I don't propose that our way of doing things is better than the medical way of doing things. But what's the reason there's such a big difference between fields in this?
As an academic coming from physics, that’s really surprising to hear. Which of the social sciences are you coming from? Could you give an example or two of mathematical models underlying a social intervention?
You don't need to have a *mathematical* model to have a model. For a basic example, just consider the idea that prices are set by an interplay between supply (which drives prices down) and demand (which drives prices up). This model already tells you a lot about which interventions would be predicted to affect prices in which direction, even if it doesn't tell you how much. It's true that much economics in the last few decades has involved trying to make mathematical models to calculate these things in greater detail, but those models are much more controversial, and haven't been validated in detail. It's standard practice for politicians to do things to try to increase supply or decrease demand if they think a price is rising more quickly than people want. However, it would *not* be standard practice for a politician to say something like, "we've observed that the price of beans is correlated with the price of gasoline, and thus to affect gas prices, we will increase supply of beans and decrease demand of beans", no matter how strong the observed correlation. You'd want *some* sort of mechanism.
I think mostly it boils down to biology being so damn complicated that if we weren't willing to act on empirics absent theory we wouldn't have most medicine. Everything has 50 different relevant interactions, half of which act at cross-purposes to each other, and if you're really lucky the main effect is consistent across mammals so you can do mouse studies - if you're unlucky it's not even consistent between different humans.
Scott, I am not a doctor, but people who are doctors have complained to me about things called "carepaths" where there are relatively strongly entrenched algorithms for treating X, and if the doctor deviates from them, insurance won't cover it, their hospitals might get angry with them, and sometimes pharmacists (citing a relatively recent law perhaps designed to prevent overuse of opiods?) won't fill the prescriptions. Do you think this has any effect? (non-rhetorical, I am genuinely curious)
> and sometimes pharmacists (citing a relatively recent law perhaps designed to prevent overuse of opiods?) won't fill the prescriptions
I expect government reaction against opioid abuse is part of the issue here, but it may also go deeper than that. Pharmacists are trained to be medical practicioners in their own right, not just pill dispensers, as a line of defense against doctor error and as an initial point of contact for patients with drug reactions.
The central cases of doctor errors that pharmacists are supposed to watch out for are things like confusing the intended medication for one with a similar name (e.g. the doctor write a prescription for tramadol when they meant trazodone), miscalculating the dosage to be either dangerously high or uselessly low, or overlooking an interaction with another medication the patient is taking (possibly prescribed by a different doctor). Deviating from carepaths seems apt for a vigilant pharmacist to mistake it for one of the first two classes of errors they're supposed to be guarding against.
Sure, and obviously I am fine with pharmacists checking with the doc to ensure it's the right drug/dosage/etc... and even with keeping an eye on "well this doc prescribes tons of opiods to someone who doesn't seem to require it," I am talking about (perhaps only hypothetical?) situations where a doc prescribes drug Y and the pharmacist calls them to say "are you sure you meant Y" the doc says "yes, totally, I know it's not on the carepath but I think with my medical judgement it will work" and the pharmacist says "nope, not filling it."
From what I know, that only happens if there are real ethical concerns: the Dr. is a pill mill or the medication is really, really dangerous. (They have their own liability concerns). Approximately nobody is going to care if the doctor writes a non-approved prescription for something generally-uninteresting. Doctor wants to write a script for metformin as a part of cancer treatment? *Shrug*.
I noticed the dosages in the TOGETHER trial (100mg, 2x daily for 10 days after positive test) are in line with a typical adult dose of fluvoxatine for OCD/depression.
The on-label treatment assumes the patient will use the drug indefinitely, so tolerance for side effects is pretty low. Nobody wants nausea, emotional blunting, or sexual side effects long-term if they can be avoided.
It seems like side effect tolerance for a ten day treatment against a potentially deadly disease would be very different, so maybe higher dosages might make sense?
I think it's reasonable to be cautious given the unknowns, so I don't want to suggest people should start self-medicating with 10x doses or anything. Just wondering though if larger dosages are being studied and if we know anything about anti-inflammatory effects at higher dosages or significant escalation of risks?
Has anyone suggested a biological mechanism by which fluvoxamine helps treat COVID? I know almost nothing about pharmaceuticals, but what little I do know about SSRIs makes me think that they mostly affect brain chemistry. But COVID is a respiratory disease. Am I wrong about SSRIs?
If it really works, then it really works, but I would love to know more about why. Maybe this is the weird thing that Scott was alluding to in the article?
"Anti-Inflammatory Effect of Fluvoxamine and Rationale for Use in COVID-19
In a murine sepsis model, fluvoxamine was found to bind to the sigma-1 receptor on immune cells, resulting in reduced production of inflammatory cytokines. In an in vitro study of human endothelial cells and macrophages, fluvoxamine reduced the expression of inflammatory genes. Ongoing studies are establishing whether the anti-inflammatory effects of fluvoxamine observed in nonclinical studies also occur in humans and are clinically relevant in the setting of COVID-19."
I'm not particularly left-leaning, or even very anal about word choice. But Scott using "man up" at the end made me uncomfortable, and not least because he is addressing female (and other non-binary) doctors too. I hope he's using it ironically in a way that I'm too stupid to understand.
My wife, with pretty reliable feminist cred - when I met her she was a millwright in an iron mine - replies, “Give me a break.” She’s smiling but really, we are passing into nutty sensitivity at times.
I no more object to being told to "man up" than I object to male-identifying persons being told not to be "a pissy little bitch".
Some terms have outgrown specific gendered connotations and are de facto if not de jure gender-neutral. In the same way that nowadays when calling someone a bastard, you do not intend anyone to take it that your contention with them is on the grounds of them having been born outside of wedlock, men can be bitches too and women can need to grow a pair.
Then again, I don't object to terms like "guys" being used to address a mixed audience. Some people may be exquisitely sensitive to the use of language and this grates on their ears more than it does mine.
I find 'guys' fascinating! There was one particular author – Douglas Hofstadter – that mostly persuaded me 'guys' was bad, so I tried to avoid it myself. But it sure seems like the conventional usage is _entirely_ gender-neutral, e.g. it's used for all 'female' groups too. I'm a little surprised that it wasn't 'policed' like so many other words/phrases.
I think they're trying to police it, I see recommendations that one should use "people" or "folks" or "y'all" instead (which are fifty times worse, if you are not in fact a bred-and-buttered Southerner in whose mouth such usages are natural), but I was educated in an all-girls' school where we routinely addressed the group as "lads", so there you go.
There are worse things to fight over. It's okay to swap out "fireman" for "firefighter", that's not too bad. But getting bent out of shape about "someone said 'hey guys' when addressing a mixed audience" is a little too sensitive.
I haven't seen any evidence of policing – not at the level where 'normies' are policing or being policed (or just towing the line). I'm surprised that I haven't seen evidence of people getting bent out of shape about 'guys'. I'm sure it's happening somewhere, but I thought it'd be _everywhere_ by now.
I remember that! He wrote that he regretted not writing one of his characters (the tortoise I think?) as a woman, because he thought he would have been perceived as a radical if he did. But by not doing it he was upholding the status quo.
I was hoping to see a short consideration of ongoing drug trials for fluvoxamine. They could help hesitant doctors thread the needle. They don't have to stake a claim for whether they think it works. They give their patients that have COVID and want something a "something." They help contribute to science!
I don't know how common it is for a doctor to recommend clinical drug trials to patients in most settings. Anecdotally, it's never happened to me. But there are a couple trials actively recruiting in the US that doctors could talk to patients about. (Note, I have no affiliation with either of these trials, but I saw them mentioned on Twitter.)
I was wondering about the potential for one of more of the large health insurance companies (United, Aetna, Cigna) to act as the sponsor for a drug like fluvoxamine. It seems like they would be have the money and proper incentives to play the role. If a cheap generic like this actually works, it could save them a fortune in hospital claims that they would otherwise be on the hook for. Seems like they could create a foundation, hire experienced people from pharma companies who have shepherded drugs through the process, and get to work.
I’m sure there’d be some pushback since everyone seems to hate on insurance companies but it’s hard for me to see how they would be any more conflicted than the pharma companies who make and profit off the drugs directly. I mean, at least they are on the hook for claims if there are side effects or situations where it doesn’t work. Unlike the drug companies, they only profit if it works and saves them claims down the line.
Vox is much more of a mixed bag than any other media source I'm aware of. They have some stuff that is much better than any other media source, and some stuff that is much worse. They have an unusual mix of left-wing and neo-liberal bias, likely a remnant of the influence of Matthew Yglesias and Ezra Klein, and their mostly young very-online staff.
Yes. That's why I don't trust her. And I'm not willing to say more, because that would be re-litigating an old, over and done with fight, but while Sleazy E may be rather too forthright in his estimation of her credibility, he's not alone.
I do have one big thing, but I don't want to disinter that corpse from the shallow grave in which it restlessly slumbers. Just an example of how people can indeed be partial when it comes to their own sacred cows, which is only human, but when you're setting up as "giving advice on thinking correctly and overcoming natural biases" it doesn't sit well alongside it.
Come on – just link to whatever it is you're hinting at. If it helps, I promise not to disturb the corpse. (I just want to try to identify it.)
Your generic argument doesn't make sense – you writeoff anyone giving advice that isn't already perfect? I don't completely agree with Kelsey but I think she's unusually _talented_ at explaining her thinking and I appreciate that more than being (accidentally) 'correct'.
This is exactly the problem here. If I just said "yeah I agree with Sleazy E", people (not unnaturally) would want to know why. But I honestly don't want to rake up an old debate, so I'm shutting up now. I'm not saying anything more than that I have that opinion and this need not be taken as Gospel truth; those who think Kelsey Piper is a good guide are not wrong, so far as it goes.
Scott trusts KP enough that they are housemates, which actually is a fact he might have mentioned here -- he did mention it a few months ago. (Or, trusts her because she's a housemate; either way, that's what pro-forma disclosures are for.)
What are some examples of Vox being shitty? I've found them really reliable in my experience, and have mad respect for several of their reporters and alumni.
Your anecdote about ketamine is the reason I've never pursued a medical degree. I can give people who have treatment-resistant depression ketamine and shrooms. I can give MDMA to people with PTSD. I have done so many times with great success and it's a wonderful feeling. If I were an accredited doctor then doing all that stuff would cause me to lose my license at best.
"Earlier this month, Pfizer said it expects to manufacture 180,000 treatment courses by the end of this year and at least 50 million courses by the end of next year, including 21 million in the first half of 2022.
"We can right now commit to 80 million doses ... thanks to our manufacturing machine," Bourla told CNBC."
And they're going to allow generic versions of it in poorer countries:
" Pfizer Inc (PFE.N) said on Tuesday it will allow generic manufacturers to supply its experimental antiviral COVID-19 pill to 95 low- and middle-income countries through a licensing agreement with international public health group Medicines Patent Pool (MPP).
The voluntary licensing agreement between Pfizer and the MPP will allow the UN-backed group to grant sub-licences to qualified generic drug manufacturers to make their own versions of PF-07321332. Pfizer will sell the pills it manufactures under the brand name Paxlovid."
So it's just that they can't crank it out fast enough, not that anyone has been forcing them to hold off on manufacturing it while waiting for the final approval. Not the FDA's fault that bulk manufacturing processes take time to scale up.
If it's any consolation, the engineers' budget ventilator approach probably wouldn't have been very helpful; in the early days especially, we were short on fancy vents, the kind that could do advanced modes of ventilation to treat ARDS. Being on a vent is generally bad for COVID, but if you're going to be on the vent you should ideally be on the kind of computerized ventilation that can micromanage pressures, not the kind of simple machine that runs on gas pressure. Effective mechanical ventilation is an esoteric art that even many MDs don't understand, and there was some serious miscommunication going on in the early days of COVID as to what was needed. In purely consequentialist terms, I doubt you did any significant harm.
(I'm a respiratory therapist, though I was still in school when COVID hit)
Here is the thing, and my understanding of this is quite imperfect. There are multiple purposes the FDA serves. One purpose, which is pretty important and actually takes a lot of work but is viewed as boring and taken for granted by many, is to make sure the actual manufacturing of drugs is done correctly. That every pill of your generic aspirin constains exactly the same dose as the label says even though dozens of generic companies are making the low margin drug trying to keep costs as low as they can.
For a new drug, something doctors have no experiences with, the fear level can be high and the FDA I think does serve as providing a blessing. A doctor can say "I don't know anything about this drug for shingles but the FDA says this drug works for patients in this group so I'm not just taking the word of the 20-something drug rep". Since drug companies are only allowed to market drugs they have approval from the FDA for and they can only market for indications that are on the FDA approved label, there's an obvious profit incentive for them to spend the money to go out and do the studies to establish the bona fides of the new drug or to prove a drug that is already approved for one thing also works for something else.
But older drugs are a bit different. Doctors presumably have real life experience with patients on older drugs so they should feel more open to trying them if there's reason to believe they may work in an unexpected place. If some study said low dose aspirin helped certain types of depression, you should not feel a huge amount of fear trying it on your patients 'just to see'. Yes if some generic aspirin manufacturer spent $75M to run a clinical trial and submit it to the FDA for a label expansion you'd feel better, but is that the best use of resources? I'm not sure.
So I'm not sold on the idea that the FDA should go from passive entity here to active. By passive I mean companies come to the FDA asking if they can market a new drug or add something to the label of their existing drug. The FDA convenes the advisory boards with experts on the disease area and evaluates their evidence but they do the work of collecting the evidence, hoping for the best.
But should the FDA go active? Going out and trying to find new labels for old drugs? Picking up studies others did to try to add to the label rather than waiting for people to ask them to do it? The FDA does have limited resources and it isn't like you can just throw money to quickly expand it to infinity. It's not like disease experts grow on trees after all.
More importantly if the FDA did start doing this, I would fear that it could lead to the less formal knowledge generating institutions of the medical field starting to atrophy. Medicine form my impression is a combination of theretical and practical knowledge. Doctors combine a lot of information from less formal sources. These include the experiences of other doctors, articles in the literature (not just highly controlled RCT's but case reports, the chatter at conventions and meetings, etc. I suspect making the FDA pro-active in going out to find label expansions for existing drugs will cause doctors to pay less attention to these others areas of knowledge generation and they will atrophy.
Now that being said, doctors have seemed to be totally willing to write a lot of scripts to try to fight Covid. How many ivermectin and HCQ scripts were written? OK the FDA did give HCQ temporary approval but still, those scripts are still being written. I recall when the first cases happened news reports said doctors were trying tamiflu. Yet tamiflu isn't approved for Covid and even for the flu it only does good if you start it early but they were clearly trying anything that seemed like it may have a plausible path to working.
As I see it, the purpose of the FDA is not in question and I agree that the FDA shouldn't randomly test old drugs for different diseases.
But it could be worth to have some kind of public fund to take care of researching promising treatments that are not profitable enough for big pharma to care.
Another thing could be to examine the approval process if it can be simplified but still serving it's purpose.
This could be a case of regulatory capture: big pharma paying some think tank or NGO to lobby for stricter rules for approval at the FDA in the name of public safety. But this makes the process more expensive driving many competitors out of the market and all the startups with good concepts in their arms.
I think it is worthwhile to test old drugs to see if they can do new things, however I'm not sure it's a great idea to do this with FDA approval of the new indication as the endpoint. Think about driving a car and the manual. Most of your knowledge of driving comes from your actual experience doing that. Odds are you haven't read your car's manual unless it's to find how to use some feature you don't use often or you're a bit bored one day.
When something is brand new, all you may have is the manual (label). As time goes on doctors get a feel for how the drug works in real life. If then research indicates it has some other use, doctors can apply it to those patients or learn from other doctors who have. My gut feeling is that norm is probably pretty optimal.
If we change the norm to "don't do anything unless the FDA blesses" I worry that would dramatically increase the work on the FDA which I think might be better spent looking at the totally new drugs who lack real life experience and which doctors will rely much more on the manual. Deeper I think that might disrupt the informal knowledge generation process with a more formal one.
Formalizing informal knowledge generation is not a bad thing. Something as simple as keeping a food log with a diary of how you feel each day is an example of how a little bit of formalization can help you find patterns that your 'hunches' only imperfectly captured. But couldn't we have more strategic ways to leverage the gain by formalizing informal knowledge? For example, what if we could data mine off-label and on-label use more efficiently to spot relationships?
I think the systemic issue goes beyond the FDA. There are many other institutions that influence what doctors feel comfortable prescribing, and in principle that makes sense: individual doctors can't conduct large-scale medical research on their own, so they really need to be able to trust what's coming out of institutions. As well as the FDA, we should look at:
1. Popular medical resources like Uptodate, which provide information on common treatments including off-label prescribing. Lots of doctors consult this many times a day. Its article on fluvoxamine begins with a warning about Covid treatment that says there is "insufficient data to recommend for or against." I think persuading the editors of Uptodate to actually update their article in light of the TOGETHER trial could make a big difference.
2. Insurance companies, which put barriers in the way of unusual (or expensive) treatment. Refusing pointblank to cover something can get them into trouble so they're usually more devious, requiring a doctor to fill out a long form called a "prior authorization" that details all the other treatments a patient has already tried. The point of these forms seems to be to deter patients from filling their prescriptions, as getting the form and then getting the doctor to complete it can take a lot of time and effort. Patients usually don't know about this requirement until they get to the pharmacy (and doctors can't keep track of the constantly changing requirements of all the different insurance companies).
I'm not aware of any insurance companies requiring this for fluvoxamine, but the ~$10 cost Scott mentions is only at specific pharmacies using a coupon from somewhere like Goodrx. Thanks to our ridiculous drug pricing system, the walk-up cost is closer to $100.
3. State regulators, which have threatened to take away the medical licenses of doctors who write inappropriate mask or vaccine exemptions. I think the state boards are probably right to do this on balance, but it still makes doctors very reluctant to deviate from the consensus on Covid.
4. Large hospital systems and medical groups, which heavily influence the prescribing decisions of the doctors who work for them. The people in charge of these are usually far removed from clinical practice.
5. Supply chain issues, which resulted in shortages of HCQ last year. Do pharmacies have enough fluvoxamine to give it to everyone with Covid? There is a very obvious long-term solution if Covid is going to be endemic, but it could be a problem in the current surge.
The thing is, early reports come out and immediately everyone hops on "it's a miracle cure!" train and starts writing enthusiastic blog posts and then moving on to "why isn't the FDA approving this, they have BLOOD ON THEIR HANDS, THE DEATHS OF MILLIONS WILL BE DUE TO THEM".
And then the average idiot (yr. obdt. svt.) goes online looking for some further details, and sites like the NIH say "yeah, but those early studies are all over the place, it's not as rosy as it sounds, if you want the drug eh okay but it's on your own head".
So are they being too cautious, or are the miracle-cure merchants being too optimistic? Remember all the hype around ivermectin, which I thought at the time was probably mostly getting good results because it's an anti-parasitic and where it was being used, and Scott's post vindicated me in my opinion. So maybe fluvoxamine *is* a miracle cure! Or maybe it works to ameliorate the worst of the disease in certain high-risk patients if you get it early enough, but it's not a miracle cure, and the FDA is not in fact a bunch of HANDS DRIPPING WITH THE BLOOD OF SLAUGHTERED MILLIONS organisation.
My basic life experience is 'never trust a hype' and even in the unlikely event of finding a miracle cure you should always be careful and not over-use it (e.g. antibiotics).
This also was making me careful when in the beginning of COVID everyone put all their stakes and hopes on vaccines and almost ignored other treatment.
They just approved Paxlovid. The initial trials had been stopped because it was so effective that withholding it from the control group was deemed unethical — but the FDA continued to withhold it from everyone else. If there were enough pills available, which I don't know, withholding approval cost something over five hundred lives a day.
When they finally approved a beta blocker, the FDA estimated that it would save eight to ten thousand lives a year. It had been in use in Europe by then for over ten years, so they were confessing to about a hundred thousand unnecessary deaths. That doesn't add up to slaughtered millions, but it's a step in that direction.
There is insufficient evidence for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of fluvoxamine for the treatment of COVID-19.
The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for fluvoxamine. The studies summarized below are the randomized clinical trials that have had the greatest impact on the Panel’s recommendations.
TOGETHER is an adaptive platform, double-blind randomized placebo-controlled trial conducted in Brazil.5 Nonhospitalized adults with COVID-19 and a known risk factor for progression to severe disease were randomized to fluvoxamine 100 mg twice daily (n = 741) or placebo (n = 756) for 10 days. Fluvoxamine use was associated with a lower risk of the primary composite outcome of retention in the emergency department for >6 hours or admission to a tertiary hospital (79 of 741 participants [11%] in the fluvoxamine arm vs. 119 of 756 participants [16%] in the placebo arm [relative risk 0.68; 95% CrI, 0.52–0.88]). Of note, 87% of the primary outcome events were hospitalizations. There was no statistically significant difference between study arms for the secondary outcomes of need for hospitalization or time to symptom resolution. There was no significant difference in mortality between study arms in the intention-to-treat (ITT) population (17 of 741 participants [2%] in the fluvoxamine arm vs. 25 of 756 participants [3%] in the placebo arm [OR 0.69; 95% CI, 0.36–1.27]). In a secondary, per-protocol analysis of participants who received >80% of possible doses, death was the outcome for 1 of 548 participants (<1%) in the fluvoxamine arm versus 12 of 618 participants (2%) in the placebo arm (OR 0.09; 95% CI, 0.01–0.47). Participants in the fluvoxamine arm were less likely to present to an emergency setting for COVID-19 for any duration, although this analysis was not prespecified. Compared with those in the placebo arm, participants who received fluvoxamine were less adherent to therapy and discontinued therapy due to intolerance more often.
While fluvoxamine treatment significantly reduced the primary composite outcome in the TOGETHER trial (i.e., retention in the emergency department for >6 hours or admission to a tertiary hospital), the difference in hospitalizations between arms was not significant. Defining the clinical relevance of the >6 hour emergency department observation time endpoint is difficult, especially its applicability to practice settings in different countries. Moreover, the endpoint has not been used in other studies of interventions for nonhospitalized patients at high risk for hospitalization and death. While a per-protocol analysis found a significant treatment effect for mortality in patients taking >80% of possible doses (assessed by patient self-report), no such benefit was found in the primary ITT analysis. The 80% threshold has no clear justification, and only 74% of participants in the fluvoxamine arm reached this level of adherence. Since per-protocol analyses are not randomized comparisons, they can introduce bias when adherence is associated with factors that influence the outcome; this bias cannot be excluded in this study. Notably, mortality in the placebo arm was substantially higher in those with ≤80% adherence than in those with >80% adherence, suggesting that factors other than adherence differed in the per-protocol population. Finally, including only participants who could tolerate fluvoxamine does not reflect the actual effectiveness of the drug, since intolerance and adherence appeared to be related."
Talking of early treatments, doctors going off protocol but researching themselves and treatments that don't get the funding to gather the large studies that are usually required in medicine:
Have anyone here already heard of Dr. Chetty (South Africa) and his findings? For me as a rational thinker without medical background this sounds really plausible and the way practical medicine should work.
Is there any obvious flaw i didn't get? I'm only speaking of medical or logical reasons. If he perhaps gave Interviews to the wrong people doesn't change the facts he has seen or done on his patients.
To be a little fairer to the FDA, they do seem to be aware of the drug trials but don't think there's enough evidence that fluvoxamine does make enough of a difference (EDIT not the FDA, it's the NIH):
"Anti-Inflammatory Effect of Fluvoxamine and Rationale for Use in COVID-19
In a murine sepsis model, fluvoxamine was found to bind to the sigma-1 receptor on immune cells, resulting in reduced production of inflammatory cytokines.1 In an in vitro study of human endothelial cells and macrophages, fluvoxamine reduced the expression of inflammatory genes.2 Ongoing studies are establishing whether the anti-inflammatory effects of fluvoxamine observed in nonclinical studies also occur in humans and are clinically relevant in the setting of COVID-19.
Recommendation
There is insufficient evidence for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of fluvoxamine for the treatment of COVID-19.
Rationale
Three randomized trials have studied the use of fluvoxamine for the treatment of nonhospitalized patients with COVID-19. In STOP COVID, a contactless, double-blind randomized placebo-controlled trial conducted in the United States among nonhospitalized adults with mild COVID-19 diagnosed within 7 days of symptom onset, fluvoxamine (100 mg up to 3 times daily for 15 days) reduced clinical deterioration at Day 15.3 Clinical deterioration was defined as shortness of breath plus oxygen saturation (SpO2) <92% or hospitalization plus SpO2 <92%. This was a small study (≤80 participants per arm) with limited cases of clinical deterioration and a short follow-up period. In addition, 24% of participants stopped responding to surveys prior to Day 15.
The subsequent STOP COVID 2, a Phase 3 randomized controlled trial (ClinicalTrials.gov Identifier NCT04668950) that enrolled >700 participants in the United States and Canada, was stopped for futility by a data safety monitoring board after lower than expected case rates and treatment effect were observed.4
TOGETHER is an adaptive platform, double-blind randomized placebo-controlled trial conducted in Brazil.5 Nonhospitalized adults with COVID-19 and a known risk factor for progression to severe disease were randomized to fluvoxamine 100 mg twice daily (n = 741) or placebo (n = 756) for 10 days. Fluvoxamine use was associated with a lower risk of the primary composite outcome of retention in the emergency department for >6 hours or admission to a tertiary hospital (79 of 741 participants [11%] in the fluvoxamine arm vs. 119 of 756 participants [16%] in the placebo arm [relative risk 0.68; 95% CrI, 0.52–0.88]). Of note, 87% of the primary outcome events were hospitalizations. There was no statistically significant difference between study arms for the secondary outcomes of need for hospitalization or time to symptom resolution. There was no significant difference in mortality between study arms in the intention-to-treat (ITT) population (17 of 741 participants [2%] in the fluvoxamine arm vs. 25 of 756 participants [3%] in the placebo arm [OR 0.69; 95% CI, 0.36–1.27]). In a secondary, per-protocol analysis of participants who received >80% of possible doses, death was the outcome for 1 of 548 participants (<1%) in the fluvoxamine arm versus 12 of 618 participants (2%) in the placebo arm (OR 0.09; 95% CI, 0.01–0.47). Participants in the fluvoxamine arm were less likely to present to an emergency setting for COVID-19 for any duration, although this analysis was not prespecified. Compared with those in the placebo arm, participants who received fluvoxamine were less adherent to therapy and discontinued therapy due to intolerance more often.
While fluvoxamine treatment significantly reduced the primary composite outcome in the TOGETHER trial (i.e., retention in the emergency department for >6 hours or admission to a tertiary hospital), the difference in hospitalizations between arms was not significant.5 Defining the clinical relevance of the >6 hour emergency department observation time endpoint is difficult, especially its applicability to practice settings in different countries. Moreover, the endpoint has not been used in other studies of interventions for nonhospitalized patients at high risk for hospitalization and death. While a per-protocol analysis found a significant treatment effect for mortality in patients taking >80% of possible doses (assessed by patient self-report), no such benefit was found in the primary ITT analysis. The 80% threshold has no clear justification, and only 74% of participants in the fluvoxamine arm reached this level of adherence. Since per-protocol analyses are not randomized comparisons, they can introduce bias when adherence is associated with factors that influence the outcome; this bias cannot be excluded in this study. Notably, mortality in the placebo arm was substantially higher in those with ≤80% adherence than in those with >80% adherence, suggesting that factors other than adherence differed in the per-protocol population. Finally, including only participants who could tolerate fluvoxamine does not reflect the actual effectiveness of the drug, since intolerance and adherence appeared to be related.
Additional studies are needed to provide more specific, evidence-based guidance on the role of fluvoxamine for the treatment of COVID-19. Further details of the studies discussed are provided in Table 4c."
That sounds less like "we can't find anyone willing to be responsible for this" and more "if some study comes out with yes yes yes it works!!!, then we'll approve it". Right now, they seem to think the studies are "meh, it's kinda okay".
The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for fluvoxamine. The studies summarized below are the randomized clinical trials that have had the greatest impact on the Panel’s recommendations.
"Key Limitations:
The >6-hour emergency setting observation endpoint has not been used in other studies of interventions for nonhospitalized patients who are at high risk for hospitalization and death
As this was an adaptive platform trial where multiple investigational treatments or placebos were being evaluated simultaneously, not all patients in the placebo arm received a placebo that was matched to fluvoxamine by route of administration, dosing frequency, or duration of therapy
PP analyses are not randomized comparisons, and they introduce bias when adherence is associated with factors that influence the outcome
Adherence was self-reported and not verified
Interpretation:
Fluvoxamine reduced the proportion of patients who met the composite endpoint of COVID-19-related hospitalization or retention in an emergency setting for >6 hours.
The use of fluvoxamine did not impact the incidence of COVID-19-related hospitalizations.
It is difficult to define the clinical relevance of the >6-hour emergency setting observation endpoint and apply it to practice settings in different countries.
Fluvoxamine did not have a consistent impact on mortality.
Fluvoxamine did not impact time to symptom resolution."
STOP-COVID (as you might guess from the rah-rah name, this one was run in the USA not Brazil):
"Key Limitations:
Small sample size
Short follow-up period
Ascertaining clinical deterioration was challenging because all assessments were done remotely
24% of patients stopped responding to follow-up prior to Day 15 but were included in the final analysis
Interpretation:
Fluvoxamine reduced the proportion of patients who experienced clinical deterioration.
Due to significant limitations, it is difficult to draw definitive conclusions about the efficacy of using fluvoxamine to treat COVID-19."
Are there good studies on post-SSRI sexual dysfunction (including less visible symptoms like libido loss in women)? Wondering about the basis for Scott's characterization of the side effect as "very rare." I have some medical contacts who focus on those issues and believe that they're under-scrutinized and under-researched
I think you are correct. Many of the doctors who denied the existence of PSSD (and therefore had no need to discuss it with patients) are now saying that it is 'rare' (and therefore have no need to discuss it with patients). There is barely any research on PSSD. I was talking to a urologist who sees men whose sex lives have been ruined by SSRIs: "We have no idea of its prevalence. It is entirely possible that SSRIs cause low level sexual dysfunction in people and they don't really notice." It's a horrifying situation.
Scott, I like to print out your essays to read with a cup of coffee as a break from my computer. Your writing is so good that I always enjoy them hugely, whether I'm interested in the subject matter or not.
But when I print them out from my web browser, the last paragraph of the first page is always obscured by a big 'Publish on Substack' advert, which only appears in the printed version, I don't see any such thing on the page in the web browser at all, it's only on the printout. And I can't find any way to work around this.
I realise that this is nothing to do with you, and indeed probably a bug in the Linux version of Firefox, but I wondered if you had the clout with Substack to get them to fix their button so it doesn't do this?
Let's say, purely hypothetically, that you have two octogenarian grandparents whom you love dearly. They're both vaccinated and boostered. One has recently finished bladder cancer treatment, another has a history of heart rate issues, beyond that and their age they have no major COVID comorbidities. What steps would or could you, their grandchild, take today to improve the odds that they can obtain a Fluxov prescription in the event that either one contracts COVID?
Just to point the 30% number in perspective, this is roughly equivalent to the estimated effect size for going from 0% masked -> 100% surgical masked from the Bangladesh study.
Unfortunately fluvoxamine only impacts your risk from Covid and has no real impact on psychological safety so it is utterly irrelevant to our societal response.
>The VA system took 35,000 high-risk older patients off of an unusually-likely-to-cause-QT-syndrome SSRI in 2011, and were unable to find any evidence that this prevented even a single case of the syndrome, let alone any negative outcome!
Is there a role for the physician organizations? Because I know for our kid, the recommendations about things like car seats and avoiding SIDS and stuff generally come from the American Association of Pediatrics, not the FDA but nor do individual pediatricians have to decide what to say about a lot of issues. And when my wife was pregnant we kept hearing about recommendations from the American College of Obstetricians and Gynecologists. So could one of the professional medical associations give physicians the okay to do this and know they aren’t being unprofessional?
"That is, FDA procedures usually assume there is a pharma company sponsoring a drug. But fluvoxamine is cheap and off-patent and no pharma company is involved in repurposing it for COVID. Nobody has a procedure for a drug without a sponsor, so they won’t do anything."
I'm mildly amused by the happenstance that this is pretty much the same thing Weinstein et al. were saying about getting Ivermectin re-labeled as a prophylactic for COVID.
No reflection on the virtues of fluxovamine, since I am not a doctor of any sort.
I find it very frustrating that a lot of the NPIs are justified in order to keep hospitals from being overwhelmed, and here is a treatment which would increase hospital capacity by 30% (or is it 43%?), which would probably have done more than any NPI to keep hospitals from being overwhelmed, but we aren't using it because there is no one to pay for marketing it.
So these doctors and nurses we see in the media who complain about how overloaded they are, they don't know about it?
I've been single for too long because asking people out would require me to do something potentially awkward.
"For some reason the same experts who don’t mind prescribing SSRIs when people have mild depression freak out about prescribing them when they’re the only evidence-based oral medication for a deadly global pandemic. "
While I agree wholeheartedly with the sentiment, correction: dexamethasone is oral.
While we're on the subjects of steroids and "flu-" drugs that 10 million Americans already use without issues, why not fluticasone inhalers to treat Covid? They're extremely safe (far fewer side effects than oral steroids) and for me they clear up all my respiratory inflammation completely within 12-48 hours depending on how bad it was before I started. A hypothetical downside is that it might stop working in a part of the lung that is filled with fluid, but as a prophylactic against pneumonia as soon as you test positive for covid it would work great (80% confidence). Maybe I'm just seeing it through rose-tinted glasses because i'm a super-responder to it. I have occasional inflammation in my lungs, not very bad. It usually stays under control with far less than the recommended 2 puffs of 110mcg twice a day. One puff once on days when I feel like I need it is usually sufficient. When I had covid in May 2020, I raised my dosage back up to what was prescribed (2 puffs twice a day) and got through it without letting my SPO2 dip below 95%. It lasted 10 days and was milder than some flus. Fluticasone inhaler was the only thing I was taking.
Scott, you shouldn't beat yourself up for not doing something which seems unlikely in retrospect to have mattered, or for hesitating to take steps which were probably legal until you had more Bayesian evidence thereof.
You should beat yourself up for not trying to convince the FDA to authorize vaccines for new variants under the precautionary principle, which seems like an iron-clad argument according to premises they might accept.
Also, stop using a technique of anti-epistemology which successfully stitches together anthropomorphism with dehumanization. FDA bureaucrats drag their feet on needed medicine because they don't understand the difference between their behavior and the archetypal young student standing up to the anti-controls expert in front of a crowd. It's almost like traditional rationality places too much emphasis on avoiding false claims, or being less wrong.
About that Bayes formula on the bottom in your subscribe thing... Bayes formula doesn't tend to give 60/40 odds.
Here's how it works: "prior probability", P(A) that a random drug is effective for COVID, is very very small, that should be understandable, right? P(A|B) is the posterior probability given the trial(B) .
The P(B) is probability of finding the drug to be effective whether it works or not. Which for this study is woefully high - there's a number of red flags (the stranger the end point, the more effective the drug was at it; non strange end points not even statistically significant). Note that P(B|A) is less than 1 (but presumably, close to 1), and to get a greater P(A|B) than P(A) you need P(B) to be small.
The end result is that your P(A) is small (fractions of percent) and your P(A|B) is higher, but still very small (fractions of percent).
To get odds close to 50/50 (like your 60/40), would require a rare numerical coincidence; the P(B) needs to be approximately equal to P(A) . That doesn't occur often, because people who could get P(B) to be this low, shoot to make it even lower.
To clarify, for your odds, it has to be the case that Brazilian study was approximately as unlikely to find an ineffective drug to be effective, as the probability that a drug chosen completely at random from your medicine cabinet would be effective. I think it should be intuitively clear to anyone that the probability of guessing the drug is far lower than probability that another study in Brazil screws up.
If 3 is an issue, isn't the solution writing up some social permissions slips and handing them out to as many doctors as you can get them to?
It sounds like all you need to do is let doctors have the line "I know a bunch of other doctors that are prescribing patients with fluvoxamine for covid" and they'll start doing it themselves too.
And if it turns out that fluvoxamine is, in fact, about as useful as taking a dose of aspirin for treating covid-19? That the initial small-scale studies were not, in fact, accurate or reliable when it came to hundreds of thousands of patients?
It's all too easy to get outraged over a story you read, be that "there is a simple, cheap, sure cure and they're not letting us have it" or "quacks are taking advantage of desperate people to sell snake oil". Less yelling, more waiting and seeing, please!
> What yelling? Are you projecting?
Posting four replies to your own comment might just be the ACX equivalent of yelling.
The principle of charity is more important than ever in these uncertain times. Experts make mistakes, random internet commentators even more so. But I think most people are trying their best to make sense of the world - when they fail, compassion works better than derision to help them fix their worldview.
The fact that you're being sarcastic suggests you're not trying to help me understand your point of view (from my perspective, at least, it wasn't helpful). You seem to be venting your frustrations. Maybe you could do it somewhere else?
Members of the medical profession or just their professional associations? Because the people who make up the latter are self-selecting and will skew towards activism of various types; as such a tendency towards lgoing along with the currently popular political trends us hardly surprising. Professional bodies should not in matters such as this be seen as representative of their members so much as representative of the established political views of their time.
Are you not presupposing that puberty blockers are medically settled and therefore only given out for ideological reasons? Seems like quite the circular argument. PBs are unethical because they can cause sterilization, and sterilization is an unacceptable tradeoff because of ethics.
Now that's a bad-faith argument, come on. Context matters. Is it unethical to sterilize someone with ovarian or testicular cancer via removing the ovaries/testes? Of course not.
Doctors are members par excellence of the Professional Managerial Class.
What percentage of doctors do this? Is it higher or lower than the percentage of doctors who prescribe HCQ or IVM off-label?
I thought we were supposed to be Bayesians here.
We have a cohort of pre- or mid-pubescent children who have a significantly higher rate of suicide. They self report that the dysphoria with their body is the main driver of these suicidal thoughts. A vast majority of the psychology establishment agrees that gender dysphoria is a condition that is heavily correlated with suicidal ideation. Doctors understand the statistics as well as the mechanism for puberty blockers to work. There is no slam-dunk evidence that starting puberty upon cessation of puberty blockers precludes eventual fertility.
And yet you ignore these possible positive aspects in favor only of a possible negative.
Doctors aren't giving in to the woke mob, they're just weighting the risk of sterilization against the risk of mental unease and potential suicide, using a different prior on the risk of sterilization than you are. Don't conflate your personal morals with some objective sort of "ethical issues".
> a doctor who _didn't_ believe that gender transition was the right path
Doctors do not always believe it's the right path - it depends on the specifics of the case. There are some pretty big hoops that you have to jump through if you want to gender transition (at least in all countries where I have any knowledge of the system).
I think what you're trying to suggest is that doctors who think gender transition is always the wrong path are silenced. This may be true on social media. However, I think the only obstacle to them publishing that hypothesis in an academic journal would be that they couldn't find evidence to support it.
"The mob is uninformed" is not an argument that the mob is wrong.
Social media companies' mismanagement of them is horrnedous, but they're right about this one (assuming we're talking the same mob)
But are suicidal thoughts and even gender dysphoria actually reason enough for using drugs with potentially major side effects? As I understand the objection to puberty blockers it is that that this is not the best treatment available due to potential side effects. The criticism (or at least the reasonable and probably Bayseian one) of puberty blockers is that they should not be an immediate choice as opposed to less potentially consequential treatments. You presumably know this, but your post does come across as puberty blockers versus no treatment, when any reasonable doctor has far more choices.
If one accepts that there are some proportion of gender dysphoria cases where the least-harm treatment is undergo hormone replacement therapy, then we are implicitly stating that for that proportion of people afflicted with gender dysphoria, continuing to produce the hormones of their assigned at-birth gender is more harmful than the potential side effects of HRT.
Once we decide that, it would of course have been better to undergo HRT prior to puberty caused an increase in the undesired sex hormone.
So are your (and trebuchet's) objections
(a) with my first if clause in this comment
(b) with the notion that I'm overestimating our predictive power of prospective puberty-blocker adolescents becoming future adult HRT cases
Because otherwise, Occam's razor seems to suggest to me that (more so trebuchet than you, based on your respective diction), the supposed ethical concerns are an post hoc argument
"who are not ideologically captured or living in fear of retribution from people who are ideologically captured before I agreed with it."
Sounds awfully post-hoc. It allows you to throw out the testimony of any medical professional who is in favor of PBs because they're "ideologically captured". It's a non-falsifiable argument.
"If so, would you feel any concern whatsoever about saying so, in public, under your real name, in front of your employer and all your friends?"
No I would not. In fact, online acquaintances of mine (so granted, not real names) have gone through exactly this. They had some degree of gender dysphoria, talked with a psychologist or therapist specializing in gender, and found that HRT would not be right for them, and their gender dysphoria was instead a manifestation of other mental conditions like social anxiety disorder/OCD/clinical depression.
The reason a doctor would be trashed online or by the "woke mob" would be their argument's wording, which social progressives would see through. Since I actually have trans acquaintances, my argument would show I actually understand the issue.
>Why shouldn't we have equal priors about both prior to examining any of the evidence, insofar as neither was developed for Covid and neither have super-clear mechanisms of action?
Even if you had a low prior on fluvoximine working, the TOGETHER trial seems like a good reason to update that prior higher, no?
>I will face the Devil in the future and I’ll fail again. Medicine is too big and complicated and scary to stray from the herd most of the time.
Here I've got a feeling that Scott is being somehow pressured to demonize ivermectin in front of his audience despite the evidence, and he is trying to communicate it in this sentence. Thus he probably agrees heartily with your reply but he will not answer.
"This guy I like secretly agrees with me despite saying the opposite" is a common trope. (Especially among fans of newbie politicians, where it's obvious, but it's the same thing here.)
+1 to this
Guilty!
He’s written a long post on ivermectin- his conclusion was that while there were studies showing that it worked, most were flawed and with the others the benefits were probably due to the deworming properties in countries where that is a problem, and where covid multiplied the problems caused by worms. 20% of people have worms in India.
Yeah, I didn't understand how he decided on a 90% probability ivermectin didn't work based on the worm theory. It might well just be worms, but 90% seemed too high to me (and if anything my bias ought to be against ivm since my former legal guardian just died "with" Covid after refusing to be vaccinated and my parents continue to refuse... but I'm okay with people doing both, get a vaccine and some ivermectin and fluvoxamine as Hail Maries.)
To my knowledge, Scott's article remains uncorrected, and is the basis for mainstream media coverage like this: https://twitter.com/MythinformedMKE/status/1471197859664044035?t=B8pJwTatFkvFaFgSWuVMCA&s=19
It's a tricky situation to be in, where my ability to make the case I am making depends on Scott's willingness to engage, when it's far easier for him to shift his attention elsewhere.
I've never been as blackpilled on the prospects of the rationality community as I am now. There simply is no way to get a proper conversation going despite my best efforts.
I wonder if Scott isn't slowly falling to the pressures of media income streams here. The chief economic mechanic that develops media echo chambers is outlets identifying their consumer base and playing to that consumer base for clicks or subscriptions. They know if they say X they'll lose subscribers, so it becomes impossible to say X whether X is true or untrue. The signal that makes the most money becomes the truth and the tail wags the dog.
If Scott subconsciously thinks he'd lose 10% of his subscriber base and become a less well regarded blogger by saying "IVM might work, and it's harmless, so there's no real reason not to try it since doctors literally have zero other things they can try right now in the case of an infection," then that sentence costs him a shit pile of money to say. If he makes a quarter million a year off of ACX, then that's a twenty five thousand dollar sentence.
If this was the SSC days, it's a sentence that costs nothing to type.
And let me tell you first hand, doctors right now still have absolutely *nothing* to even suggest you should do if you catch Covid. We're two years in and they're still saying "yeah, uhh, drink chicken broth and come to the hospital if you can't breathe." They're not even suggesting D and Zinc.
It was not an accusation as much as a question.
The thing is, though, that of every indie blogger or indie journo I've watched over the course of the last decade, the one thing they always end up doing is catering their content to a demo once they start getting paid. If Scott can resist this, then he will be one of the few, if any, I've seen do that.
ACX is not Razib Khan. C`mon, not paying for ACX costs you (and me) how much of the content? And the ACX still gets subscribers by a) being the one blog to read if you read anything at all - due to b) Scott's smarts&style PLUS c) Scott's OCH. H for honesty. That is his market. Not sure, he cornered it. ;) - I will subscribe when hitting my first 500k.
> since doctors literally have zero other things they can try right now in the case of an infection
You're commenting under a post literally about one such thing, no? Besides, there was a Pascalian medicine thing a few weeks ago about this "let's take zinc and D and everything else" idea.
A good friend of mine contracted Covid 6 days ago. Her doctor told her "umm chicken broth and come into the hospital if you can't breathe." Her sister is an MD and told her "umm chicken broth and come into the hospital if you can't breathe."
Let's pretend Luvox has a 60% chance of working (per this article) and IVM has a 10% chance of working (per the Worms article) and Scott is right about both. IVM's side effects are more benign than Luvox's. Why is the line being drawn where Scott is drawing it? Isn't 10% better than chicken broth? Couldn't Scott write this same article for IVM and wonder the same questions?
The recommendations exist, but doctors are unaware of them.
I have the NIH paper Scott linked open in another tab. A few weeks ago jstr linked this one, also from the NIH, https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC7833340/figure/fig1/ which said to take antihistamines.
Thanks for this link btw, bookmarking it.
"This guy whose writing I like is super-smart and good at dealing with his biases. But, disagrees with me about something important! My theories are:
1. I am wrong
2. He is biased.
Yeah, #2 is the ticket."
His direct response to me in the comment thread of the Worms article was approximately "yeah, I can see how taking IVM makes sense if you frame it that way." Yet here we are.
FWIW I rate IVM's chance of effectiveness even lower than Scott did in the Worms article, but still nonzero, so I still plan on taking it because I see no reason not to. I think the argument against IVM is basically social signaling at this point.
You said
> My contention, and those of *all* of my friends who think deeply on this one, is basically "IVM is so incredibly safe why wouldn't I roll the dice on it being 10% effective? What's the drawback? There's no drawback. Why do we think there's a drawback?"
Scott replied:
> I think this is a pretty reasonable perspective.
But also added:
> I think it would result in you also taking HCQ, doxycycline, Vitamin D, and a few other things, but that's not necessarily a dealbreaker.
This was "why not take all the things all the time?" which got a full treatment in https://astralcodexten.substack.com/p/pascalian-medicine
It would indeed lead me to take some of those. D3 is in the FLCCC protocol that's been used internationally with IVM, and I happen to have a shitpile of doxycycline in my cupboard from my wife's cancer, so I'll be taking both.
Curious - what will you do when you catch it? Chicken broth?
We enrolled my wife in a clinical trial for her colon cancer that probably had less than a 1% chance of working. If I went back and did the Pascalian Medicine analysis we wouldn't have done that. In the end she died anyway, but no doctor told us not to do it.
Expired tetracycline is nephrotoxic, so is minocycline. I'm not sure about doxycycline, some sites say it is, some say it isn't, I don't know enough chemistry to confirm which ones are right.
Your wife died, what, 2 and a half years ago? I might check the expiration date on those pills and do some research before taking them.
I just went back and re-read this, and I wouldn't consider the treatment "full." Or if it is full, it certainly doesn't convince me to not take IVM. In fact, the closing argument convinces me the opposite.
***quote***
Does Pascalian medicine beat our current strategy of only using drugs that are proven to work? I don't know. I think the current strategy makes sense on a social level, but I'm not sure that the Pascalian strategy wouldn't work for an individual. At least an individual who is able to reliably identify which low-but-nonzero-probability-of-benefit drugs really do have very few potential side effects (if you didn't already know about loa loa encephalopathy, consider that this might not be you; I am very much not-recommending that any reader here do this on their own).
After the worms article, I considered putting my family on ivermectin just in case anybody had worms. I think the chance of that is near zero, but seeing the picture of the worm freaked me out.
The stuff is super-safe, and I think we should probably just put every American on a course of it once a decade to see what gets cleared up by it.
But right now the stuff is hard to get, both because of people taking it in excess and because pharmacists are unwilling to trust that you really need it.
If we did that, wouldn't the worms just evolve to be resistant to ivermectin?
I don't think his position on ivermectin is "the chance of it working is zero". I think it's that the chance is too low to be worth anyone's time and money.
+1
I don't think it's that deep. One of his common writing practices is to use tribal signals to appeal to the intended audience (Number 7 - https://slatestarcodex.com/2016/02/20/writing-advice/). In this essay, he wants to convince the type of doctors who only do things enthusiastically recommended by government agencies and other Authorities to prescribe fluvoxamine. This group almost certainly believes the mainstream disinformation about ivermectin. On the other hand, doctors with an open mind about ivermectin probably already have an open mind about fluvoxamine.
There are now two more things they can do, and one of them has an effectiveness of 89%.
I think you are misreading Scott. He might be worried about losing commenters — conversation here isn't as good as it was on SSC. He might be worried about people he respects thinking less of him. I don't think he is worried about losing a little money.
My theory:
Fluvoxamine, as an antidepressant, is way easier for Scott's brain to category-map to the similar atypical usages / Devil encounters he had last year. A cocktail of guilt, math, reason, and courage is pushing him juuuust up and over the mountain of doubt.
The mountain of doubt that he describes in this article. The one that's kept a lot of doctors from considering HCQ or IVM *even before* the tar of social stigma and outrage culture became an even more prevalent factor.
Scott's making an interesting move here, to put chips on the table out in front of any third wave of media hysteria anti-"anti-vaxx." That's definitely courageous and could cost him dear if doctors/rationals/media/whomever don't rise up as a bloc in favor of fluvoxamine. But he's not quite all the way to full rationality on backpropagating this update towards other non-vaccine treatments. Maybe if IVM had been an anti-depressant it would have been a different story.
@Scott - what's your leading theory as to why case counts in Africa are so disproportionately lower than in South America or Southeast Asia?
https://www.bbc.com/news/world-51235105
His theory on IVM was "Worms as Confounder." Which might be true, but I've spoken directly to several doctors in South Africa who swear by the FLCCC methods so deeply that they quit their jobs when the FLCCC protocols were being banned from the top down, so they could proscribe them without international influence on their treatment suggestions.
I'm not a doctor, I just don't see any reason not to try IVM or fluvoxamine or anything else that seems like it has a nonzero chance of working, when the counterfactual from the doctors today, two years into the pandemic, is still "meh, chicken broth I guess."
Your contempt for chicken broth is strange. For all we know it might also have a nonzero chance of working. :)
I'LL DEFINITELY BE DOING THE CHICKEN BROTH TOO, hahaha. As it also has zero downside.
I went back and reviewed Scott's Pascalian Medicine article, and while it's well written, I still don't see where it makes a strong case against this approach.
https://astralcodexten.substack.com/p/pascalian-medicine
The best it seems to offer is that this approach makes sense for the individual (me, you) but not for the medical community at large, due to economies of scale. That's a case that should be made mathematically, not grammatically, and he doesn't do the math.
We need some good studies on chicken broth. I don't say this glibly, it seems like it would be very interesting. Do we just get benefit from the hydration? Does the temperature matter (for example would cold soup be just as effective). Does the level of schmaltz matter? Does the amount of calories (how watered down the soup) or nutrients (quality bone broth + veggies) matter?
Compared to a control, of say, intravenous dextrose, what provides the best clinical outcome, for the appropriate range of diseases?
Bone broth is generally really good for you, and broth is going to replenish not just water but all the various salts you lose when sweating from a fever. Frankly chicken broth is probably something all of us should have more of even when healthy, I definitely wouldn't consider it a placebo.
Predictions : nutrient density matters a lot, calorie count matters a little (and level of schmaltz obviously affects this substantially), temperature only matters insofar as it ought to be at least warm - you don't want to have to burn calories heating up your food when ill.
It’s been clear for a long time that Scott has firmly conventional priors that are hard to move. That was evident in his Ivermectin post and in his post on non-pharmaceutical interventions where he bent over backward to find some effect for masking and lockdowns.
The NYT debacle did seem to scare Scott into having a ton of social desirability bias that he did not previously seem to possess. He wants to be seen as one of the Very Serious People so badly that it ruins his judgment.
You say "social desirability bias" - but I have seen Scott criticized more for being anti-ivermectin than for literally anything else. Is that not the opposite of social desirability?
Has he been criticized by his social circle or the people he looks up to?
Good point. I suspect those people were probably anti-ivermectin already.
Although it isn't social desirability bias, those paying subscribers do still represent an incentive to be pro- or at least open to ivermectin for covid.
I can tell you that we doctors prescribe things off label all day long. The problem is is that the doctors who chose to do this with other drugs were vilified and threatened and cajoled and are probably scared stiff to venture into these Waters without formal approval. You reap what you sow
Can you more details? It sounds like you're not talking about the drugs Scott says are very commonly prescribed off label: trazodone for sleep, gabapentin for nerve pain, etc. Or maybe you are. What are the off label prescriptions that lead to docs being vilified and threatened? What form do the vilifying and threatening take? Snotty remarks in the hall? Lawsuits?
I'm pretty sure he's referring to HCQ and ivermectin for COVID.
yes by making such a huge issue of this , "horse dewrmer " etc and societies thrating removing licences people are on edge . But really ALL forms of care have been vilified or unsupported. What percent of patients get good daily FU with pulse oximetry if high risk? I will wager it is less than 10%.
He's talking about ivermectin, and how the news media will love to write about the quack doctor who says antidepressants can cure covid when "there is no evidence that it does"
As far as I can tell, whenever the media has mentioned fluvoxamine, it's been in the context of discussing trials saying that it *is* one weird trick that works.
I am reminded of Keynes' comment on bankers and banking, that failure is perfectly acceptable among bankers and results in no real consequences, as long as they fail in a strictly conventional way.
It makes me sad how precisely on point this comment is. It's the institutionally acceptable choice.
It's not just institutions, although they play a role. It's also individual reputation and self-view.
Eric Falkenstein has a book about basically that idea https://www.overcomingbias.com/2009/08/no-risk-premium.html
this seems accurate - add doctors and FDA drug approvers to that list
No one ever got fired for buying ~~IBM~~ Microsoft
Preach, brother!
Remember to tell your doctor you're feeling depressed about having COVID, to clear his conscience.
+1
+2
+3
As a dude who might get covid at some point: is there any way to get this ten-day course of fluvoxamine for use just-in-case I get sick? Or do I need to wait until I'm already unambiguously sick, and then have the conversation with my doctor?
It's the second thing, isn't it?
Current monoclonals don't seem to be holding up all that well against omicron. Why are you recommending a site that primarily seems to be concerned with getting people ivermectin to someone who's looking for fluvoxamine?
Thanks for the link to their full protocol. It seems like they might have doctors willing to prescribe fluvoxamine, given that. I do find it interesting that, with regards to the vaccine, this is their stance: "Vaccines have shown efficacy in preventing the most severe outcomes of COVID-19 and are an important part of a multimodal strategy that must also include early treatment. The decision to get a vaccine should be made in consultation with your health care provider." I'd avoid using them as an intellectual resource, given that snow job.
It's phrased in a way that's intended to lead the reader to the conclusion that the vaccine isn't a slam-dunk first-line preventative treatment, unlike their suggested prophylactics, and has more risks or other downsides compared to them.
Believe there's one monoclonal that's holding up well -- something called sotrovimab
https://www.washingtonpost.com/health/2021/12/16/monoclonal-antibody-sotrovimab/
I personally do not think it's particularly risky for a generally healthy dude to just pop Luvox for 10 days or so. While I'm not an MD, I'm in a field where I see lots of psychiatric drugs in use. I have seen hundreds of cases where docs put people in good-to-mediocre health on Luvox and other SSRI's -- including overweight, couch potato middle-aged people, people with asthma or incipient diabetes, people in their 60's, etc etc -- with no serious ill effects. So unless you have some unusual health problems I do not think it is particularly risky for you do just search in your friend group for someone who's on Luvox and ask them for a few
pills. I mean, sure, have tho convo w/ your doc first, but if doc is unresponsive, I really do not think there's much risk in just scoring some Luvox from friends. I am a professional with a sense of responsibility and a conscience, and I feel like I'm saying something members of my demographic and professional group are not supposed to say but -- yeah, fuckit, that's what I think.
Thank you for being willing to say it. How much of your willingness to speak up here is due to your pseudonymity?
On forums like this I am pseudonymous on general principle, even if I'm just sharing my opinions about poetry or brands of Irish whiskey. In person I would give the above advice to any friend or acquaintance. (Under those circumstances I would ask first what health problems they had, and if they had something unusual or serious going on I would recommend that they look into whether that problem made fluvoxamine risky for them -- or I might double check on that for them myself.) If I were a physician I would cheerfully sign my name to any document advocating for the use of fluvoxamine for covid.
My elderly parents are nervous about omicron, so I suggested they do exactly this and ask their doctor for a supply of fluvoxamine that they can use in the event of a positive test.
In case their doctor was skeptical or unfamiliar, I sent them the Lancet-published RCT. Also, my father is a retired psychiatrist who has decades of experience prescribing this kind of drug and understands the (minimal) side effects and (low) risks as well as anybody.
Their doctor is part of the UPenn system, so he asked Penn's infectious diseases unit if he should provide the prescription. They said "no." Not "come back after a positive test" or "we're protecting the supply for severe cases" or "this isn't in our standard treatment guidelines, but it's low-risk so let's defer to the patient."
So the answer to your question is it's possible, but to Scott's point, good like finding the doctor who will do it.
That drug still worries me. It is a psychotropic and I still think there are better alternatives.
Apart from the other therapeutics (monoclonals being a major one). I'm getting more interested in HCQ, which I was highly dismissive of under Trump, but as I look it more deeply (ignoring the several deeply flawed studies), may do some strong work if given in the first few days. Ivermectin? Who knows. I do think it also has promise.
We also keep ignoring zinc and D3, which are just amazing natural supplements in their ability to combat viruses.
This is a great article and I hope more doctors who treat Covid patients read it, but the FDA didn't approve fluvoxamine for depression. It's only approved for OCD, and used off-label for things like depression and anxiety.
Regarding fear of lawsuits, FDA approval isn't the only factor. Most doctors want to follow the "standard of care", which basically means doing what other doctors are doing. This leads to an obvious chicken-and-egg problem.
Many but not all docs exhibit a combo of entitlement and hyperconventionality that I find quite repellent. Jeez, it's not the worst combo in the world: Poor impulse control plus sexual attraction to adolescents is worse -- low capacity for empathy plus substantial power over others' welfare is worse -- stupidity plus having a bully pulpit is worse . . . But still, that doc combo enrages me every time.
"low capacity for empathy plus substantial power over others" sounds like a lot of PCP's I've visited. In thier defense, they are just responding to the incentives and shitty life experiences that the system pushes on them, but still.
I am going to be an asshole and say I first asked you about fluvoxaminne in the comments March 31st after the first small trial came out and 60 minutes did their report. The lack of cost benefit analysis from the FDA and CDC is absurdly frustrating.
You brought up a good point which is they FDA processes require a sponsor. Without a sponsor nothing happens. Someone needs to file the paperwork. If any rich people are reading best case is probably create a foundation, hire some regulatory professionals and get them to do it. Better yet get a pharma company to do it. I might ask my employer.
Scott wrote a while back about the baby IV fluid case where doctors had to do a PR shame campaign against a random pharma company that happened to own a bunch of generics, and eventually that company paid up to get it okayed in the US.
Your idea reminds me also of something either Scott or maybe another blogger explained about how the CDC has an associated nonprofit called the CDC Foundation which gives them money in emergencies because the money Congress gives them is very inflexible. Ties in to Scott's post from a while back about how billionaire philanthropy looks good when you compare it to government spending. I wonder what the per dollar return would be if you funded studied on off label uses for generics and got the new uses you find pushed through the FDA.
At least one rich person (inventor of the optical mouse) has tried to partner with a sponsoring drug company by offering to pay all fees without any success. He's also offered $2M to interview or debate any member of the NIH committee that voted to recommend that fluvoxamine be rated Neutral on their Covid Treatment Guidelines.
https://stevekirsch.substack.com/p/do-you-know-why-there-isnt-an-eua
Uh, possibly because that dude is a nut who thinks that the vaccines kill you?
This reaction is the problem though. Up front, I'm strongly in favour of vaccines and strongly vaccinated, and think anti-vaccine positions are at best ill-informed, so this is not a defence of his position. But the point here is that a corrective to government failure is people using their own wealth to fund processes that would not otherwise happen. If we immediately take the knee-jerk position that it's not acceptable to do this outside a range of acceptable ideas we risk just recreating the problem we are trying to solve: the approval process only works for a subset of things that might be approved. If we instead foster a culture where all ideas can be tested and the silly ones can be publicly and demonstrably be found wanting, we'll be encouraging positive change and hopefully move away from the idea of government as the only source of legitimate wisdom in medicine to a position whereby government can verify a range of views. Therefore, to simply say that someone doing this is a nut because you disagree with him (correctly in my view) contradicts the rationale basis for wanting people to put their money where their mouth is. And also deprives us of the pleasure of seeing a proper analysis of the claims of the nuts of this world (not that I expect the outcomes of a proper assessment of whatever they are pushing would stop them, as that would just be government conspiracy again...).
Sure, but there’s also a lot of harm that could be done by having that guy be the public face of fluvoxamine
So don't make him the public face, just take his money under a confidentiality agreement.
Reputation effects aside, I think there's a lot of sense in rejecting claims - even claims of evidence - from people who have committed themselves to bizarre positions. There's a lot of subtle ways that data can be influenced or corrupted, so to some extent you need to assess the source as well as the content of a study. That's true of big pharma too, of course, but as large, long-standing companies, they have more at risk if they're caught in (overt) misconduct, and can generally be made to observe better standards.
Seems like that approach would just lead you to desperately cling to your priors, as you're doing now. "This person disagrees with me on one issue, so I won't even consider the possibility that they're correct on a separate issue." So the only way you would even consider a claim you don't currently agree with is if it is being presented by someone who you agree with on every issue? But by definition, you wouldn't agree with them on the claim they are presenting! And so you can never change your views.
So you think Lisa Shaw is alive?
> At least one rich person (inventor of the optical mouse) has tried to partner with a sponsoring drug company by offering to pay all fees without any success.
Oh, that's good.
> He's also offered $2M to interview or debate any member of the NIH committee
Oh, that's bad.
Accepting thinly veiled bribes seems both stupid and illegal, especially from dude that is especially unhanged antivaxer?
I would also not partner with someone like that.
It is on both the doctors and the FDA. We could live in a world where people could just get fluvoxamine without a prescription and the consequences would fall on them. Instead the blame falls on the doctors or the FDA or the politicians and they behave too cautiously.
You could do a cost-benefit analysis comparing lives saved v. lives lost but I think it is more egregious to kill someone by preventing them having access to life saving medication than to let someone kill themselves by taking medicine they shouldn't for whatever reason. It seems like there isn't even a willingness to compare lives v. lives but a standard of safety that is probably too high in many situations. For example, considering withdrawal from SSRIs on one side while death is on the other.
Here in my country (western Europe), generalists have been strangely quasi absent from covid crisis, it was all urgency plus retirement home at the beginning, at after mass vaccination in new temporary structures, with a big state reservation / tracking system. It's not only prescribing strange (old) drugs, it's the individualized and decentralized medecine that is sidestepped. I wonder if it will permanent.
Sorry - draft reply somehow got posted...
Could a large part of it be the doctors don't even know? What percentage of doctors even know about this do you figure?
Hello sorry to have been gone so long, I owe some responses in past threads.
Regarding:
> It’s not illegal to prescribe fluvoxamine for COVID. It’s not even going to get you in any trouble. It might not get covered by insurance, but it only costs about $10 anyway. The problem is just that it’s weird.
Wrong. You can get in trouble. And you will. Applying this same logic to Ivermectin and Hydroxychloroquine, these too have the same right to be prescribed by a doctor for off-label use. However doctors who have in the last year, are punished, vilified and attacked, reprimanded and fired. I have many many examples, Dr Paul Marik being one, but you can easily find hundreds and probably thousands of examples of this on your own.
We've opened up the flood gates and "totally not put doctors in trouble" for prescribing things for off label use, except we have. The number doctors who feel "weird" prescribing things the NIH and FDA don't explicitly approve, will only increase, as we apply higher selection pressures for the system to vilify or remove any who go against it. Good luck finding doctors who will prescribe this.
https://edition.cnn.com/2021/08/26/us/covid-ivermectin-arkansas-doctor/index.html and https://www.nbcnews.com/news/us-news/texas-doctor-touted-ivermectin-covid-treatment-suspended-rcna5588 : Much better examples than Paul Marik, who was reprimanded for prescribing oxycontin to a non-patient.
Ah yeah. Thanks for the examples. So yeah, you can't just prescribe what you feel is right as a doctor anymore. must have "federal approval"
What about patients (such as some of yours, no doubt) who are already taking SSRIs for depression? Would there be risks of adding fluvoxamine on top of that? Serotonin syndrome?
+1 on this. I was going to ask the same thing if somebody hadn't already. Also curious about non-SSRIs anti-depressants. Does this present enough of an upward shift in risks to offset the potential benefits?
Yes, but probably a fairly low risk. SSRIs all affect serotonin in the same way, so combining 2 of them is a bit like increasing the dose of the original SSRI.
Combining SSRIs with other drugs that increase serotonin but work in a different way (eg. MAOIs) is where you get the higher risk of serotonin syndrome.
Given whatever SSRI you're taking, you can check if it interacts dangerously at https://www.drugs.com/drug-interactions/fluvoxamine-index.html
The whole bloody system is set up for pharma, not for us - that's why. Why wouldn't there be widescale searching and trials for ALL possible helpful substances, not just pharmaceuticals, ala zinc and nigella sativa, from the very start?
One of the big knocks against ivermectin is the (lack of) obvious mechanism for it to work against covid at non-toxic doses.
But, like -- at least there *is* a mechanism! It has been shown to inhibit replication at (intolerably) high doses in vitro, and killing worms (which it definitely does) is *also* a potential mechanism.
What is the possible mechanism for a random SSRI to inhibit covid? It seems like many of the arguments that it's unlikely that a random dewormer would do anything apply in spades -- I am pretty ignorant on this, so maybe there's something obvious that I just don't know about -- but it seems like a weirdness that should be addressed. Otherwise given the mixed evidence from various ivermectin trials, the Insanity Wolf approach (just take everything) seems... kind of OK? (if a patient has covid and seems to be at high risk for bad outcomes, of course)
Fluvoxamine probably doesn't do anything to inhibit SARS-Cov-2 (the virus). What it has been long known to do is have an affect on the body's inflammatory response, and one of the major symptoms of COVID (the disease caused by SARS-Cov-2) is a massive inflammatory response. Moderate that symptom, and the symptom won't kill people.
By analogy, there are diseases that kill because they cause massive fevers that overheat the brain. You can lower mortality from those diseases by taking measures (at the crude level, just immersing the patient in cold water) that just treat the fever, even though they have no effect on the bacteria or virus that causes the disease.
I am not a doctor, but I understand that chlorpromazine is the front-line treatment for brain-eating amoeba, and also that nobody really knows why an dopamine agonist antipsychotic would be effective against amoebas.
No-one really knows the mechanism for SSRIs to help with depression either, but 10% of the population still takes them.
For Covid, fluvoxamine differs from other SSRIs in that it also binds to sigma receptors that are involved in coronavirus infection. One theory is basically that it blocks an important step of the virus lifecycle. There are several other drugs that bind to sigma receptors (most famously HCQ) but fluvoxamine seems to have the most evidence for effectiveness and relatively few side effects
I think the idea is that it may have an anti inflammatory effect due to interaction with "sigma-1 receptor on immune cells", (from https://www.covid19treatmentguidelines.nih.gov/therapies/immunomodulators/fluvoxamine/ ).
But of course there's a lot of compounds that specifically interact with that receptor and don't have as many other effects limiting their maximum tolerable dose.
In that regard, it should be given much worse prior odds than hydroxychloroquine and ivermectin, which became well studied drugs due to their strong effect on parasites and weak effect on humans.
I strongly believe in what Scott calls the "meta-level heuristic that you need in order to practice good medicine".
Ivermectin seems to be a good argument for this. After being promoted by a bunch of people (the vast majority of whom meant well, I assume) and then becoming a political football, it's now so firmly lodged in people's minds that it takes massive institutional power to dislodge it. I don't understand how that's happened, but there are lots of other examples. And they will keep on emerging, and keep on distorting medicine. The only corrective that I can see is strong institutions. To give an analogy: they are signal-boosters that stop the signal being overwhelmed by massive noise. Even if institutions are imperfect signal boosters, they're still better than just the noise.
So I think doctors are right to follow the institutions as best they can most of the time. However, this post also seems to me to be pretty much the thing the internet was made for. This is what they promised us in the golden age of information: smart people pooling their knowledge for the greater good. I think these two intuitions are somewhat contradictory, and I have little hope of resolving this contradiction any time soon!
God that's depressing. It kind of says everything you need to know about the FDA that they're incapable of doing anything without a Pharma company with a suitcase full of money taking point.
I am going to be the Devil's advocate here and argue for why you should trust the Devil. It is because the consequences of not doing so are *illegible*. Like, what do you think will happen when you do this "slightly weird" thing? The worst case scenario isn't having to explain it to your colleagues, it's having it come up in conversation with someone a large amount of inferential distance away from where you are, but who you still respect the opinion of. (I don't know of a good example because I don't know what your social world, or the social world of a hypothetical person wanting but afraid to prescribe fluvoxamine, is like.) How are you going to justify yourself in that context, huh? (And you need to justify yourself, and not just defend yourself from threats, to protect your ego -- otherwise your mind will protect your ego with rationalizations, which are bad.)
The other worst case scenario is that you feel *yourself* the need to explain and justify your decision to someone, because that's how the human mind works. The decision of who to choose for this purpose can be made on many bases, such as previous trust, relevant expertise, and relevant domain knowledge. This post seems to point to Scott Alexander as an answer to the last question but doesn't say anything about the first two ("expertise" being thought of in a credentialed manner). In other words, talking to a representative of the Devil is easier and less scary than talking to Scott Alexander. Since fear usually represents some genuine danger that we should be worried about, this is an indication to trust the Devil.
I have said all of this as a Devil's advocate, or as a non-serious post. My serious reaction is that Scott is doing a good thing by providing his email for the purposes of having discussions on the psychology of providing fluvoxamine to patients. And I am defying the Devil myself somewhat by talking about His mechanisms. Hopefully I will not pay for it too badly :)
My takeaway here is that the more people you are accountable to, the less likely you are to do anything that violates of 'group consensus'.
Yes, but you have to also take into account if they are "normal" or "weird" people. If you are accountable to "weird" people than you can violate consensus (of a group other than your own)
Frederic Bastiat as relevant as ever
Just read the lede of of his wiki article, but could not tell: what do you see as the relevance?
"What is seen and what is not seen."
Someone can do all sorts of invisible damage all day, but someone who stops it but introduces a small amount of visible side effects will be destroyed for doing so.
Ah, you are saying the Devil wants (or at least wanted) us to break the window because its easily perceivable effects total positive, while a full accounting of all the effects totals negative. But I think in this case we can count on the Devil's short-sightedness even more: the first-order effect of breaking the window is clearly negative so we shouldn't do it. I don't know of anyone whose devil has convinced them to break windows due to the broken window fallacy.
There is something wonderfully different about listening to American discussions about medicines. I think it is because in Britain all advertising of prescription medicine is illegal, so we never get into these debates where we fire off the names of what sound like summaries of the latest Star Wars movie.
Five years ago, I could definitely have tagged this onto the SW Wikipedia page and got away with it for a few days.... "At the battle of Covid 19, the forces of the Fluvoxamine Alliance face the combined might of Sith Lord Darth Luvox, and the Ivermectin insurgents..."
I assume that there is some cross over between pulp sci fi authors and drug marketeers.
I think Pokemon are a closer match.
https://preview.redd.it/gqsk407lx2n21.jpg?width=640&crop=smart&auto=webp&s=11d6065a9ac145db9a6d1bab84e976cc2d0d8f5d
On another note, if you outsource all your medical knowledge to doctors you're going to have a bad time, unless your doctors are way better educated than ours. Then again, _our_ skilled doctors emigrate to the UK and only the bad ones stay so...
Similar https://pixelastic.github.io/pokemonorbigdata/
Advertising usually happens for on-patent medicines, or brand-names of OTC medications. There are approximately no ads for generic prescription medications because it doesn't make financial sense to do so.
This is politicized because the Establishment decided to do everything they could to oust Trump, which involved denigrating everything he said.
This is a bit off-topic, but how come an antidepressant can treat COVID ? I'm no doctor nor a biologist, so it sounds to me like saying that "ice cream can be used as an effective shaped explosive", i.e. somewhat surprising.
It's biology, I ain't gotta explain shit.
Apparently via sigma-1 receptors, which is orthogonal to fluvoxamine's action as an SSRI.
One of fluvoxamine's well-known secondary effects is on inflammation response. One of the major and dangerous symptoms of COVID is massive inflammatory response.
So it's a bit closer to "plant fertilizer can be used as an explosive"; the fact that ammonium nitrate is both plant food and can go boom is a coincidence, but its high availability and low cost as fertilizer makes it a convenient explosive.
It's only partially a coincidence. Ammonium nitrate works as fertilizer because it's a very dense source of bioavailable nitrogen. "Dense source of nitrogen" is also a big facet of what makes it boomable, as part of the "things that want to very suddenly turn back into N2 gas" class of explosives.
It is still partially a coincidence, since there are other dense sources of bioavailable nitrogen that don't go boom readily, most notably urea and ammonia. I think the other secret ingredient for ammonium nitrate going boom is that it's a salt of a oxidizer and a reducer, while ammonia is a pure reducer which needs access to an oxidizer to turn back into elemental nitrogen. Atmospheric oxygen does the trick, but surface area limits the speed of the reaction to burning instead of exploding.
At some level, sure, the chemical properties of nitrogen that make it suitable for an explosive, and make it necessary for plants as they evolved, AND that keep plants as they evolved from just sucking it in from the atmosphere they're soaking in are not accidental, but causally related.
But there is no particularly legible path from "plants on Earth need compounds of this element to be in the soil" and "compounds of this element are often explosive" short of encyclopedic knowledge of both chemistry and Earth biology; the presence of both properties in a single compound is very much a "co-incidence" of the properties.
I would still say not entirely. The kind of chemical that is essential for life is usually the kind of chemical that is highly unstable (think O2), because instability is a good sign of having lots of free energy, and also predicts scarcity.
I suspect that "bioavailable nitrogen" being scarce enough to be a limiting factor on plant growth is also linked to nitrogen's utility as a backbone for explosive compounds: the low energy state of N2 relative to other nitrogen compounds both provides a steep energy gradient for nitrogen compounds that can react to yield N2, and leads to a need for specialized metabolic pathways to fix N2 into compounds that can be readily used for cellular processes.
The other atmospheric gases that supply major elemental components organic molecules (H2O, CO2, and O2) are all less common than N2, but the cellular machinery for fixing them into organic molecules is far more ubiquitous than nitrogen fixation. Hydrogen "fixation" is ubiquitous enough that biologists don't seem talk about it as such, and oxygen "fixation" is nearly universal in eukaryotes and fairly common in bacteria. Carbon fixation is a bit more specialized, but still nearly universal in plants and algae. Nitrogen fixation, however, seems to be limited to certain varieties bacteria and archaea, with most plants reliant on organic nitrogen already being present in their growing media, or at most providing a hospitable symbiotic niche for nitrogen-fixing bacteria to move in to.
In addition to what Eric Rall said: The chemical relation is also a reason why this kind of chemical fertilizers got so widely available in the 50s. At least in Europe there were a lot of chemical plants build to produce explosives during WWII that could easily repurposed to produce fertilizers after the war.
To follow up on a real dog's remark, "among the SSRIs, the order of affinity for sigma-1 receptors is as follows: fluvoxamine > sertraline > fluoxetine > escitalopram > citalopram >> paroxetine." https://pubmed.ncbi.nlm.nih.gov/28315270/
Since I'm on citalopram, I'm bummed about this list, but there we are.
Amazing, so you alone debunked the snake oil option and discovered the real thing, no one was talking about. You really are the smartest of them all, i knew it.
Is the evidence that Luvox helps purely empirical - of the "people threw lots of things at the wall and one stuck a little" variety? Is there a plausible mechanism by which Luvox should help with COVID?
Luvox has known effects on inflammation. COVID causes massive, dangerous inflammation. I don't know of any particularly detailed model of exactly how Luvox affects COVID-caused inflammations, but it's the suspected mechanism.
Is it better than just giving steroids to the patient?
I work with a lot of clinicians.
If you want to do something even slightly unusual you get a lot of nonsensical opposition from senior clinicians. finding even a single example of a hospital anywhere in the country doing it already is like a magical key.
Also it seems the UK's solution is NICE. Their job explicitly includes sorting out treatment protocols and recommending likely treatments to doctors
You mentioned before about doctors in the US being a bit blind to stuff in the same field abroad.
You might find the NICE page on covid drugs interesting.
https://www.nice.org.uk/covid-19/rapid-c-19-treatments-currently-monitored
What the Frak? They actually in reality named that organization "NICE"?
Ya, The National Institute for Health and Care Excellence.
That sort of naming isn't so uncommon.
Also, as a rule of thumb, if you're ever wondering about the QALY impact of a drug or treatment there's a good chance that NICE have a page with the details of their analysis which tend to be pretty high quality.
They're a "non departmental public body" like the "Office for National Statistics" or "Office of Tax Simplification"
See also: the National Institute of Coordinated Experiments
Yes, but it’s the name of a horribly sinister organization in CS Lewis’s _That Hideous Strength_.
So I presume that if they basically "approve" it, fluvoxamine gets that "(patients given rapid access)" parenthetical next to it which the fifty other random things on the list don't have. Do you know why hasn't that happened yet? I feel like widespread prescription in a culturally familiar country would help persuade American doctors.
Thank you for opening up about the moral dilemmas here which apply in all areas of life and especially where reputations and careers appear to be at stake. The price we pay for society is becoming clearer by the day and some of those age-old bargains are looking a little threadbare
I think Lewis's "Inner Ring" is one of the best things ever written.
Then you should read the Screwtape letters, which are basically a whole novel of this kind of moral and psychological analysis, with the plot twist that the letters are written by a literal demon.
He was a very skilled writer, and it was written when he was at the top of his game (just after WWII by the sound of it).
This is really two posts. One about whether doctor should prescribe fluvoxamine for COVID (Yes)
The other is an aside but really much more important, it’s a problem with the basic set up of DFA that goes back to why it was founded. FDA is there to keep quack medicines and medical devices from being widely sold. There are some Libertarians who disagree with that goal but Scott does not and it’s not what he is writing about here.
There is also a critique of FDA that its procedures for keeping quack drugs off the market are flawed, that it pays too much attention to possible costs (including the cost of delay) and not enough to benefits (including the benefits beyond those to the recipient to others in the case of vaccines) of new drugs. I suspect that is true and it’s a long-standing problem, but that is not exactly what Scott is addressing, either.
Rather, it’s that the DFA is entirely reactive. If there is not a market player pushing DFA for a regulatory action – the issue here is changing the label of fluvoxamine to include COVID as a possible use – it does not happen. But this was the problem with screening test kits early on. There was no market “demand” for gazillions of kits whose use would be to screen lots of asymptomatic people so they would self-isolate. [FDA also dragged its feet on approving cheap fast for which there WAS demand but that was the long-standing problem of over-weighing risks relative to benefits.] Another example was the non-decision to use fractional doses of vaccines and to delay second doses to allow more first doses. There was no one pushing for that decision and it did not get consideration.
Is there any reason you don't ask the question "why do we require prescriptions for medicine that's already approved?"
Doesn't "prescriptions are optional for legal substances" just make this _entire problem_ go away if we let people make their own choice and suffer the consequences if they choose poorly?
This would mean to say to a deadly ill person: "It's you own fault!" and let him die after 2 weeks of suffering, despite it would be easy to help.
1) This will never happen without a real emergancy, humans al way too empathic.
2) Nobody would like to live in a society akting like this.
3) This will could be misused to get rid of people. Better to err in the other direction.
As I understand it, we have four classes of medications in the United States. There's the kind that is just stocked on shelves, and people can pick up and buy (things like aspirin and vitamin D); there's the kind that you have to go ask a pharmacist for and they will just give you a limited amount (things like pseudoephedrine and other amphetamine precursors); there's the kind that you need a prescription from a physician before asking the pharmacist for; and there's the kind that physicians aren't even allowed to prescribe. Given that different chemicals have different levels of risk, and different types of risk that consumers would be more or less likely to underestimate, it seems to me to make sense to have these kinds of gradations. It might even make sense to have a further gradation within the prescription medicines - ones that physicians are allowed to prescribe for whatever use they see fit, and ones that physicians are only allowed to prescribe "on-label". It would probably be useful to move many medications down a notch on this scale. But it seems to me that if you think it's worthwhile at all to have an approval process for drugs, then you should think that some drugs could reach a point where it's reasonable to have them be physician-prescribed, while others get approved to the over-the-counter level.
Opioids are hard.
On one hand, I spent my entire life until my mid-20s in a depressed fog, barely able to manage graduating at all (let alone fulfill all the wild dreams of researching this and that thing, writing that or this thing, tackling this or that ambition, etc etc).
The only reason I did manage to graduate, in fact — that I managed to *keep going* — was that I found fantastic reserves of joy and energy through hydrocodone, oxycodone, morphine, and the rest. When the choice was "become addicted or kill yourself", well...
On the other hand, this quickly became a nightmare too: super addicted, as predicted; could no longer afford enough; could no longer find suppliers; withdrawing all the time...
I had thought, before, that I'd rather be dependent upon opioids and alive than sober and dead, but I hadn't thought about what might happen if I couldn't get them any more. I was very bitter back then: "it's like $10 for a month's supply at the goddamn pharmacy; why can I not just be prescribed some weak opioid and *I'll* deal with the dependence?!"
I can see why the caution, of course. Once I started, I couldn't stop. My life is great now, and I have almost everything I've ever wanted — because I finally did get that prescription (for buprenorphine); even after friends dying from opioid abuse, even after all the heartache, I couldn't stop without the substitute of bupe.
But also... I don't think I regret it. I spent a decade in therapy and trying every possible drug, even ketamine; I even managed to charm a Desoxyn script (+ alprazolam!) out of my psychiatrist to trial it just for a month; and... nothing. I was ready to die. Opioids are the only thing that helped.
Do I have a point here? Uh... Yes, but the margins of this comment are too small to contain it.
Hah! Fellow math nerd here. Also, do you think your opioid dependence could have made you less susceptible to ketamine treatment? I have no knowledge of how medicine works and am shooting out of my ass here.
This is something I wanted to ask as early as the IVM post, but the comments on it flew very fast and I thought it would be unlikely anyone would see it.
I work and have academic background in social sciences, an area strongly removed from medicine and/or biostatistics. In our field, no one would treat you with any degree of seriousness if you were to propose any kind of solution to any problem based purely on empirics without any sort of model that explains why what you are doing should work (not just a model in the rationalist sort of sense, you'd be expected to present a system of equations and how they relate to each other). In medicine, this seems very widespread - I opened 20 random Wikipedia pages on medicines that are on the WHO Essential list, and close to half of them have "no well understood" or "a subject of discussion" mechanisms of action, although their effects are empirically well studied.
I don't propose that our way of doing things is better than the medical way of doing things. But what's the reason there's such a big difference between fields in this?
As an academic coming from physics, that’s really surprising to hear. Which of the social sciences are you coming from? Could you give an example or two of mathematical models underlying a social intervention?
You don't need to have a *mathematical* model to have a model. For a basic example, just consider the idea that prices are set by an interplay between supply (which drives prices down) and demand (which drives prices up). This model already tells you a lot about which interventions would be predicted to affect prices in which direction, even if it doesn't tell you how much. It's true that much economics in the last few decades has involved trying to make mathematical models to calculate these things in greater detail, but those models are much more controversial, and haven't been validated in detail. It's standard practice for politicians to do things to try to increase supply or decrease demand if they think a price is rising more quickly than people want. However, it would *not* be standard practice for a politician to say something like, "we've observed that the price of beans is correlated with the price of gasoline, and thus to affect gas prices, we will increase supply of beans and decrease demand of beans", no matter how strong the observed correlation. You'd want *some* sort of mechanism.
I think mostly it boils down to biology being so damn complicated that if we weren't willing to act on empirics absent theory we wouldn't have most medicine. Everything has 50 different relevant interactions, half of which act at cross-purposes to each other, and if you're really lucky the main effect is consistent across mammals so you can do mouse studies - if you're unlucky it's not even consistent between different humans.
Scott, I am not a doctor, but people who are doctors have complained to me about things called "carepaths" where there are relatively strongly entrenched algorithms for treating X, and if the doctor deviates from them, insurance won't cover it, their hospitals might get angry with them, and sometimes pharmacists (citing a relatively recent law perhaps designed to prevent overuse of opiods?) won't fill the prescriptions. Do you think this has any effect? (non-rhetorical, I am genuinely curious)
> and sometimes pharmacists (citing a relatively recent law perhaps designed to prevent overuse of opiods?) won't fill the prescriptions
I expect government reaction against opioid abuse is part of the issue here, but it may also go deeper than that. Pharmacists are trained to be medical practicioners in their own right, not just pill dispensers, as a line of defense against doctor error and as an initial point of contact for patients with drug reactions.
The central cases of doctor errors that pharmacists are supposed to watch out for are things like confusing the intended medication for one with a similar name (e.g. the doctor write a prescription for tramadol when they meant trazodone), miscalculating the dosage to be either dangerously high or uselessly low, or overlooking an interaction with another medication the patient is taking (possibly prescribed by a different doctor). Deviating from carepaths seems apt for a vigilant pharmacist to mistake it for one of the first two classes of errors they're supposed to be guarding against.
Sure, and obviously I am fine with pharmacists checking with the doc to ensure it's the right drug/dosage/etc... and even with keeping an eye on "well this doc prescribes tons of opiods to someone who doesn't seem to require it," I am talking about (perhaps only hypothetical?) situations where a doc prescribes drug Y and the pharmacist calls them to say "are you sure you meant Y" the doc says "yes, totally, I know it's not on the carepath but I think with my medical judgement it will work" and the pharmacist says "nope, not filling it."
From what I know, that only happens if there are real ethical concerns: the Dr. is a pill mill or the medication is really, really dangerous. (They have their own liability concerns). Approximately nobody is going to care if the doctor writes a non-approved prescription for something generally-uninteresting. Doctor wants to write a script for metformin as a part of cancer treatment? *Shrug*.
I noticed the dosages in the TOGETHER trial (100mg, 2x daily for 10 days after positive test) are in line with a typical adult dose of fluvoxatine for OCD/depression.
The on-label treatment assumes the patient will use the drug indefinitely, so tolerance for side effects is pretty low. Nobody wants nausea, emotional blunting, or sexual side effects long-term if they can be avoided.
It seems like side effect tolerance for a ten day treatment against a potentially deadly disease would be very different, so maybe higher dosages might make sense?
I think it's reasonable to be cautious given the unknowns, so I don't want to suggest people should start self-medicating with 10x doses or anything. Just wondering though if larger dosages are being studied and if we know anything about anti-inflammatory effects at higher dosages or significant escalation of risks?
Has anyone suggested a biological mechanism by which fluvoxamine helps treat COVID? I know almost nothing about pharmaceuticals, but what little I do know about SSRIs makes me think that they mostly affect brain chemistry. But COVID is a respiratory disease. Am I wrong about SSRIs?
If it really works, then it really works, but I would love to know more about why. Maybe this is the weird thing that Scott was alluding to in the article?
"Has anyone suggested a biological mechanism by which fluvoxamine helps treat COVID?"
Going by the NIH page on it, the mechanism is thought to be anti-inflammatory:
https://www.covid19treatmentguidelines.nih.gov/therapies/immunomodulators/fluvoxamine/
"Anti-Inflammatory Effect of Fluvoxamine and Rationale for Use in COVID-19
In a murine sepsis model, fluvoxamine was found to bind to the sigma-1 receptor on immune cells, resulting in reduced production of inflammatory cytokines. In an in vitro study of human endothelial cells and macrophages, fluvoxamine reduced the expression of inflammatory genes. Ongoing studies are establishing whether the anti-inflammatory effects of fluvoxamine observed in nonclinical studies also occur in humans and are clinically relevant in the setting of COVID-19."
I'm not particularly left-leaning, or even very anal about word choice. But Scott using "man up" at the end made me uncomfortable, and not least because he is addressing female (and other non-binary) doctors too. I hope he's using it ironically in a way that I'm too stupid to understand.
My wife, with pretty reliable feminist cred - when I met her she was a millwright in an iron mine - replies, “Give me a break.” She’s smiling but really, we are passing into nutty sensitivity at times.
haha those are reliable credentials. I suppose to each their own. I was just shocked on reading it.
You don't have to do this to yourself.
As Larry David would say, "Eh".
I didn't love "man up" either; I tend to use "grow a spine" in similar circumstances. But I'm not going to get bent out of shape about it.
Yeah. I was shocked by how shocked I was on reading it.
I no more object to being told to "man up" than I object to male-identifying persons being told not to be "a pissy little bitch".
Some terms have outgrown specific gendered connotations and are de facto if not de jure gender-neutral. In the same way that nowadays when calling someone a bastard, you do not intend anyone to take it that your contention with them is on the grounds of them having been born outside of wedlock, men can be bitches too and women can need to grow a pair.
Then again, I don't object to terms like "guys" being used to address a mixed audience. Some people may be exquisitely sensitive to the use of language and this grates on their ears more than it does mine.
I find 'guys' fascinating! There was one particular author – Douglas Hofstadter – that mostly persuaded me 'guys' was bad, so I tried to avoid it myself. But it sure seems like the conventional usage is _entirely_ gender-neutral, e.g. it's used for all 'female' groups too. I'm a little surprised that it wasn't 'policed' like so many other words/phrases.
I think they're trying to police it, I see recommendations that one should use "people" or "folks" or "y'all" instead (which are fifty times worse, if you are not in fact a bred-and-buttered Southerner in whose mouth such usages are natural), but I was educated in an all-girls' school where we routinely addressed the group as "lads", so there you go.
There are worse things to fight over. It's okay to swap out "fireman" for "firefighter", that's not too bad. But getting bent out of shape about "someone said 'hey guys' when addressing a mixed audience" is a little too sensitive.
I haven't seen any evidence of policing – not at the level where 'normies' are policing or being policed (or just towing the line). I'm surprised that I haven't seen evidence of people getting bent out of shape about 'guys'. I'm sure it's happening somewhere, but I thought it'd be _everywhere_ by now.
Metamagical Themas?
I remember that! He wrote that he regretted not writing one of his characters (the tortoise I think?) as a woman, because he thought he would have been perceived as a radical if he did. But by not doing it he was upholding the status quo.
He made a point of using feminine pronouns in MT too. It’s a great book. First place I heard the word ‘meme’.
It had an intro to the Turing Test and how he was pranked by a fake Turing Machine.
I believe he touched on the programming language LISP there too.
I’ve lost my copy somewhere along the way. I need to get another one and find a good space on for it.
Maybe! It was one of the non-GEB books.
+1: I am also pretty easy going with language, and "man up" reads as shockingly old-fashioned and inappropriate to me.
I was hoping to see a short consideration of ongoing drug trials for fluvoxamine. They could help hesitant doctors thread the needle. They don't have to stake a claim for whether they think it works. They give their patients that have COVID and want something a "something." They help contribute to science!
I don't know how common it is for a doctor to recommend clinical drug trials to patients in most settings. Anecdotally, it's never happened to me. But there are a couple trials actively recruiting in the US that doctors could talk to patients about. (Note, I have no affiliation with either of these trials, but I saw them mentioned on Twitter.)
https://covidout.umn.edu/
https://activ6study.org/
Thanks for the links. I tested positive yesterday and am seeking fluvoxamine - if I can't get a prescription I'll join one of the studies.
I wound up joining activ-6, which did let me opt out of the other 2 study arms. So I've either got fluvoxamine or a placebo. Thanks again!
I was wondering about the potential for one of more of the large health insurance companies (United, Aetna, Cigna) to act as the sponsor for a drug like fluvoxamine. It seems like they would be have the money and proper incentives to play the role. If a cheap generic like this actually works, it could save them a fortune in hospital claims that they would otherwise be on the hook for. Seems like they could create a foundation, hire experienced people from pharma companies who have shepherded drugs through the process, and get to work.
I’m sure there’d be some pushback since everyone seems to hate on insurance companies but it’s hard for me to see how they would be any more conflicted than the pharma companies who make and profit off the drugs directly. I mean, at least they are on the hook for claims if there are side effects or situations where it doesn’t work. Unlike the drug companies, they only profit if it works and saves them claims down the line.
Why isn’t this happening?
I'd like to know this as well
Vox is one of the shittiest sources you could possibly listen to. They're just awful. I wouldn't trust Kelsey Piper further than I could chuck her.
Have you read anything she has written?
Vox is much more of a mixed bag than any other media source I'm aware of. They have some stuff that is much better than any other media source, and some stuff that is much worse. They have an unusual mix of left-wing and neo-liberal bias, likely a remnant of the influence of Matthew Yglesias and Ezra Klein, and their mostly young very-online staff.
"Have you read anything she has written?"
Yes. That's why I don't trust her. And I'm not willing to say more, because that would be re-litigating an old, over and done with fight, but while Sleazy E may be rather too forthright in his estimation of her credibility, he's not alone.
Do you have an specific examples of things she's written that make you not trust her? I've written Vox entirely _except_ for Kelsey.
I do have one big thing, but I don't want to disinter that corpse from the shallow grave in which it restlessly slumbers. Just an example of how people can indeed be partial when it comes to their own sacred cows, which is only human, but when you're setting up as "giving advice on thinking correctly and overcoming natural biases" it doesn't sit well alongside it.
Come on – just link to whatever it is you're hinting at. If it helps, I promise not to disturb the corpse. (I just want to try to identify it.)
Your generic argument doesn't make sense – you writeoff anyone giving advice that isn't already perfect? I don't completely agree with Kelsey but I think she's unusually _talented_ at explaining her thinking and I appreciate that more than being (accidentally) 'correct'.
This is exactly the problem here. If I just said "yeah I agree with Sleazy E", people (not unnaturally) would want to know why. But I honestly don't want to rake up an old debate, so I'm shutting up now. I'm not saying anything more than that I have that opinion and this need not be taken as Gospel truth; those who think Kelsey Piper is a good guide are not wrong, so far as it goes.
Scott trusts KP enough that they are housemates, which actually is a fact he might have mentioned here -- he did mention it a few months ago. (Or, trusts her because she's a housemate; either way, that's what pro-forma disclosures are for.)
https://astralcodexten.substack.com/p/open-thread-181
Ah. In that case I hope her life improves to the point where she can work for an entity less worthless than Vox.
What are some examples of Vox being shitty? I've found them really reliable in my experience, and have mad respect for several of their reporters and alumni.
Your anecdote about ketamine is the reason I've never pursued a medical degree. I can give people who have treatment-resistant depression ketamine and shrooms. I can give MDMA to people with PTSD. I have done so many times with great success and it's a wonderful feeling. If I were an accredited doctor then doing all that stuff would cause me to lose my license at best.
How much of this is that the doctors know Paxlovid is right around the corner?
*Do* they know that?
Also, we're going to be extremely quantity-limited on Paxlovid. But I guess that's not the doctor's fault. 🤷
Pfizer is getting the doses ready as fast as they can, they are just waiting for (and anticipating) final approval:
https://www.reuters.com/business/healthcare-pharmaceuticals/pfizer-expects-produce-80-mln-courses-covid-19-antiviral-pill-cnbc-reporter-2021-11-29/
"Earlier this month, Pfizer said it expects to manufacture 180,000 treatment courses by the end of this year and at least 50 million courses by the end of next year, including 21 million in the first half of 2022.
"We can right now commit to 80 million doses ... thanks to our manufacturing machine," Bourla told CNBC."
And they're going to allow generic versions of it in poorer countries:
https://www.reuters.com/business/healthcare-pharmaceuticals/pfizer-allow-generic-versions-its-covid-19-pill-95-countries-2021-11-16/
" Pfizer Inc (PFE.N) said on Tuesday it will allow generic manufacturers to supply its experimental antiviral COVID-19 pill to 95 low- and middle-income countries through a licensing agreement with international public health group Medicines Patent Pool (MPP).
The voluntary licensing agreement between Pfizer and the MPP will allow the UN-backed group to grant sub-licences to qualified generic drug manufacturers to make their own versions of PF-07321332. Pfizer will sell the pills it manufactures under the brand name Paxlovid."
So it's just that they can't crank it out fast enough, not that anyone has been forcing them to hold off on manufacturing it while waiting for the final approval. Not the FDA's fault that bulk manufacturing processes take time to scale up.
If it's any consolation, the engineers' budget ventilator approach probably wouldn't have been very helpful; in the early days especially, we were short on fancy vents, the kind that could do advanced modes of ventilation to treat ARDS. Being on a vent is generally bad for COVID, but if you're going to be on the vent you should ideally be on the kind of computerized ventilation that can micromanage pressures, not the kind of simple machine that runs on gas pressure. Effective mechanical ventilation is an esoteric art that even many MDs don't understand, and there was some serious miscommunication going on in the early days of COVID as to what was needed. In purely consequentialist terms, I doubt you did any significant harm.
(I'm a respiratory therapist, though I was still in school when COVID hit)
I agree. Early communication about these shortages was lacking on the details, and ultimately incorrect about the level of need.
Social acceptability is a helluva drug. Even compared to ketamine.
Here is the thing, and my understanding of this is quite imperfect. There are multiple purposes the FDA serves. One purpose, which is pretty important and actually takes a lot of work but is viewed as boring and taken for granted by many, is to make sure the actual manufacturing of drugs is done correctly. That every pill of your generic aspirin constains exactly the same dose as the label says even though dozens of generic companies are making the low margin drug trying to keep costs as low as they can.
For a new drug, something doctors have no experiences with, the fear level can be high and the FDA I think does serve as providing a blessing. A doctor can say "I don't know anything about this drug for shingles but the FDA says this drug works for patients in this group so I'm not just taking the word of the 20-something drug rep". Since drug companies are only allowed to market drugs they have approval from the FDA for and they can only market for indications that are on the FDA approved label, there's an obvious profit incentive for them to spend the money to go out and do the studies to establish the bona fides of the new drug or to prove a drug that is already approved for one thing also works for something else.
But older drugs are a bit different. Doctors presumably have real life experience with patients on older drugs so they should feel more open to trying them if there's reason to believe they may work in an unexpected place. If some study said low dose aspirin helped certain types of depression, you should not feel a huge amount of fear trying it on your patients 'just to see'. Yes if some generic aspirin manufacturer spent $75M to run a clinical trial and submit it to the FDA for a label expansion you'd feel better, but is that the best use of resources? I'm not sure.
So I'm not sold on the idea that the FDA should go from passive entity here to active. By passive I mean companies come to the FDA asking if they can market a new drug or add something to the label of their existing drug. The FDA convenes the advisory boards with experts on the disease area and evaluates their evidence but they do the work of collecting the evidence, hoping for the best.
But should the FDA go active? Going out and trying to find new labels for old drugs? Picking up studies others did to try to add to the label rather than waiting for people to ask them to do it? The FDA does have limited resources and it isn't like you can just throw money to quickly expand it to infinity. It's not like disease experts grow on trees after all.
More importantly if the FDA did start doing this, I would fear that it could lead to the less formal knowledge generating institutions of the medical field starting to atrophy. Medicine form my impression is a combination of theretical and practical knowledge. Doctors combine a lot of information from less formal sources. These include the experiences of other doctors, articles in the literature (not just highly controlled RCT's but case reports, the chatter at conventions and meetings, etc. I suspect making the FDA pro-active in going out to find label expansions for existing drugs will cause doctors to pay less attention to these others areas of knowledge generation and they will atrophy.
Now that being said, doctors have seemed to be totally willing to write a lot of scripts to try to fight Covid. How many ivermectin and HCQ scripts were written? OK the FDA did give HCQ temporary approval but still, those scripts are still being written. I recall when the first cases happened news reports said doctors were trying tamiflu. Yet tamiflu isn't approved for Covid and even for the flu it only does good if you start it early but they were clearly trying anything that seemed like it may have a plausible path to working.
As I see it, the purpose of the FDA is not in question and I agree that the FDA shouldn't randomly test old drugs for different diseases.
But it could be worth to have some kind of public fund to take care of researching promising treatments that are not profitable enough for big pharma to care.
Another thing could be to examine the approval process if it can be simplified but still serving it's purpose.
This could be a case of regulatory capture: big pharma paying some think tank or NGO to lobby for stricter rules for approval at the FDA in the name of public safety. But this makes the process more expensive driving many competitors out of the market and all the startups with good concepts in their arms.
I think it is worthwhile to test old drugs to see if they can do new things, however I'm not sure it's a great idea to do this with FDA approval of the new indication as the endpoint. Think about driving a car and the manual. Most of your knowledge of driving comes from your actual experience doing that. Odds are you haven't read your car's manual unless it's to find how to use some feature you don't use often or you're a bit bored one day.
When something is brand new, all you may have is the manual (label). As time goes on doctors get a feel for how the drug works in real life. If then research indicates it has some other use, doctors can apply it to those patients or learn from other doctors who have. My gut feeling is that norm is probably pretty optimal.
If we change the norm to "don't do anything unless the FDA blesses" I worry that would dramatically increase the work on the FDA which I think might be better spent looking at the totally new drugs who lack real life experience and which doctors will rely much more on the manual. Deeper I think that might disrupt the informal knowledge generation process with a more formal one.
Formalizing informal knowledge generation is not a bad thing. Something as simple as keeping a food log with a diary of how you feel each day is an example of how a little bit of formalization can help you find patterns that your 'hunches' only imperfectly captured. But couldn't we have more strategic ways to leverage the gain by formalizing informal knowledge? For example, what if we could data mine off-label and on-label use more efficiently to spot relationships?
I think the systemic issue goes beyond the FDA. There are many other institutions that influence what doctors feel comfortable prescribing, and in principle that makes sense: individual doctors can't conduct large-scale medical research on their own, so they really need to be able to trust what's coming out of institutions. As well as the FDA, we should look at:
1. Popular medical resources like Uptodate, which provide information on common treatments including off-label prescribing. Lots of doctors consult this many times a day. Its article on fluvoxamine begins with a warning about Covid treatment that says there is "insufficient data to recommend for or against." I think persuading the editors of Uptodate to actually update their article in light of the TOGETHER trial could make a big difference.
2. Insurance companies, which put barriers in the way of unusual (or expensive) treatment. Refusing pointblank to cover something can get them into trouble so they're usually more devious, requiring a doctor to fill out a long form called a "prior authorization" that details all the other treatments a patient has already tried. The point of these forms seems to be to deter patients from filling their prescriptions, as getting the form and then getting the doctor to complete it can take a lot of time and effort. Patients usually don't know about this requirement until they get to the pharmacy (and doctors can't keep track of the constantly changing requirements of all the different insurance companies).
I'm not aware of any insurance companies requiring this for fluvoxamine, but the ~$10 cost Scott mentions is only at specific pharmacies using a coupon from somewhere like Goodrx. Thanks to our ridiculous drug pricing system, the walk-up cost is closer to $100.
3. State regulators, which have threatened to take away the medical licenses of doctors who write inappropriate mask or vaccine exemptions. I think the state boards are probably right to do this on balance, but it still makes doctors very reluctant to deviate from the consensus on Covid.
4. Large hospital systems and medical groups, which heavily influence the prescribing decisions of the doctors who work for them. The people in charge of these are usually far removed from clinical practice.
5. Supply chain issues, which resulted in shortages of HCQ last year. Do pharmacies have enough fluvoxamine to give it to everyone with Covid? There is a very obvious long-term solution if Covid is going to be endemic, but it could be a problem in the current surge.
The thing is, early reports come out and immediately everyone hops on "it's a miracle cure!" train and starts writing enthusiastic blog posts and then moving on to "why isn't the FDA approving this, they have BLOOD ON THEIR HANDS, THE DEATHS OF MILLIONS WILL BE DUE TO THEM".
And then the average idiot (yr. obdt. svt.) goes online looking for some further details, and sites like the NIH say "yeah, but those early studies are all over the place, it's not as rosy as it sounds, if you want the drug eh okay but it's on your own head".
So are they being too cautious, or are the miracle-cure merchants being too optimistic? Remember all the hype around ivermectin, which I thought at the time was probably mostly getting good results because it's an anti-parasitic and where it was being used, and Scott's post vindicated me in my opinion. So maybe fluvoxamine *is* a miracle cure! Or maybe it works to ameliorate the worst of the disease in certain high-risk patients if you get it early enough, but it's not a miracle cure, and the FDA is not in fact a bunch of HANDS DRIPPING WITH THE BLOOD OF SLAUGHTERED MILLIONS organisation.
My basic life experience is 'never trust a hype' and even in the unlikely event of finding a miracle cure you should always be careful and not over-use it (e.g. antibiotics).
This also was making me careful when in the beginning of COVID everyone put all their stakes and hopes on vaccines and almost ignored other treatment.
They just approved Paxlovid. The initial trials had been stopped because it was so effective that withholding it from the control group was deemed unethical — but the FDA continued to withhold it from everyone else. If there were enough pills available, which I don't know, withholding approval cost something over five hundred lives a day.
When they finally approved a beta blocker, the FDA estimated that it would save eight to ten thousand lives a year. It had been in use in Europe by then for over ten years, so they were confessing to about a hundred thousand unnecessary deaths. That doesn't add up to slaughtered millions, but it's a step in that direction.
"I think persuading the editors of Uptodate to actually update their article in light of the TOGETHER trial could make a big difference"
The problem is, you have the NIH saying that this trial is not trustworthy enough to recommend fluvoxamine:
https://www.covid19treatmentguidelines.nih.gov/therapies/immunomodulators/fluvoxamine/
https://www.covid19treatmentguidelines.nih.gov/therapies/immunomodulators/fluvoxamine/clinical-data/
"Recommendation
There is insufficient evidence for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of fluvoxamine for the treatment of COVID-19.
The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for fluvoxamine. The studies summarized below are the randomized clinical trials that have had the greatest impact on the Panel’s recommendations.
TOGETHER is an adaptive platform, double-blind randomized placebo-controlled trial conducted in Brazil.5 Nonhospitalized adults with COVID-19 and a known risk factor for progression to severe disease were randomized to fluvoxamine 100 mg twice daily (n = 741) or placebo (n = 756) for 10 days. Fluvoxamine use was associated with a lower risk of the primary composite outcome of retention in the emergency department for >6 hours or admission to a tertiary hospital (79 of 741 participants [11%] in the fluvoxamine arm vs. 119 of 756 participants [16%] in the placebo arm [relative risk 0.68; 95% CrI, 0.52–0.88]). Of note, 87% of the primary outcome events were hospitalizations. There was no statistically significant difference between study arms for the secondary outcomes of need for hospitalization or time to symptom resolution. There was no significant difference in mortality between study arms in the intention-to-treat (ITT) population (17 of 741 participants [2%] in the fluvoxamine arm vs. 25 of 756 participants [3%] in the placebo arm [OR 0.69; 95% CI, 0.36–1.27]). In a secondary, per-protocol analysis of participants who received >80% of possible doses, death was the outcome for 1 of 548 participants (<1%) in the fluvoxamine arm versus 12 of 618 participants (2%) in the placebo arm (OR 0.09; 95% CI, 0.01–0.47). Participants in the fluvoxamine arm were less likely to present to an emergency setting for COVID-19 for any duration, although this analysis was not prespecified. Compared with those in the placebo arm, participants who received fluvoxamine were less adherent to therapy and discontinued therapy due to intolerance more often.
While fluvoxamine treatment significantly reduced the primary composite outcome in the TOGETHER trial (i.e., retention in the emergency department for >6 hours or admission to a tertiary hospital), the difference in hospitalizations between arms was not significant. Defining the clinical relevance of the >6 hour emergency department observation time endpoint is difficult, especially its applicability to practice settings in different countries. Moreover, the endpoint has not been used in other studies of interventions for nonhospitalized patients at high risk for hospitalization and death. While a per-protocol analysis found a significant treatment effect for mortality in patients taking >80% of possible doses (assessed by patient self-report), no such benefit was found in the primary ITT analysis. The 80% threshold has no clear justification, and only 74% of participants in the fluvoxamine arm reached this level of adherence. Since per-protocol analyses are not randomized comparisons, they can introduce bias when adherence is associated with factors that influence the outcome; this bias cannot be excluded in this study. Notably, mortality in the placebo arm was substantially higher in those with ≤80% adherence than in those with >80% adherence, suggesting that factors other than adherence differed in the per-protocol population. Finally, including only participants who could tolerate fluvoxamine does not reflect the actual effectiveness of the drug, since intolerance and adherence appeared to be related."
Talking of early treatments, doctors going off protocol but researching themselves and treatments that don't get the funding to gather the large studies that are usually required in medicine:
Have anyone here already heard of Dr. Chetty (South Africa) and his findings? For me as a rational thinker without medical background this sounds really plausible and the way practical medicine should work.
https://youtu.be/2T7KlrzPAYY
Is there any obvious flaw i didn't get? I'm only speaking of medical or logical reasons. If he perhaps gave Interviews to the wrong people doesn't change the facts he has seen or done on his patients.
Just as an aside, I hate that that CS Lewis link forces javascript in order to read a piece of text.
To be a little fairer to the FDA, they do seem to be aware of the drug trials but don't think there's enough evidence that fluvoxamine does make enough of a difference (EDIT not the FDA, it's the NIH):
https://www.covid19treatmentguidelines.nih.gov/therapies/immunomodulators/fluvoxamine/
"Anti-Inflammatory Effect of Fluvoxamine and Rationale for Use in COVID-19
In a murine sepsis model, fluvoxamine was found to bind to the sigma-1 receptor on immune cells, resulting in reduced production of inflammatory cytokines.1 In an in vitro study of human endothelial cells and macrophages, fluvoxamine reduced the expression of inflammatory genes.2 Ongoing studies are establishing whether the anti-inflammatory effects of fluvoxamine observed in nonclinical studies also occur in humans and are clinically relevant in the setting of COVID-19.
Recommendation
There is insufficient evidence for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of fluvoxamine for the treatment of COVID-19.
Rationale
Three randomized trials have studied the use of fluvoxamine for the treatment of nonhospitalized patients with COVID-19. In STOP COVID, a contactless, double-blind randomized placebo-controlled trial conducted in the United States among nonhospitalized adults with mild COVID-19 diagnosed within 7 days of symptom onset, fluvoxamine (100 mg up to 3 times daily for 15 days) reduced clinical deterioration at Day 15.3 Clinical deterioration was defined as shortness of breath plus oxygen saturation (SpO2) <92% or hospitalization plus SpO2 <92%. This was a small study (≤80 participants per arm) with limited cases of clinical deterioration and a short follow-up period. In addition, 24% of participants stopped responding to surveys prior to Day 15.
The subsequent STOP COVID 2, a Phase 3 randomized controlled trial (ClinicalTrials.gov Identifier NCT04668950) that enrolled >700 participants in the United States and Canada, was stopped for futility by a data safety monitoring board after lower than expected case rates and treatment effect were observed.4
TOGETHER is an adaptive platform, double-blind randomized placebo-controlled trial conducted in Brazil.5 Nonhospitalized adults with COVID-19 and a known risk factor for progression to severe disease were randomized to fluvoxamine 100 mg twice daily (n = 741) or placebo (n = 756) for 10 days. Fluvoxamine use was associated with a lower risk of the primary composite outcome of retention in the emergency department for >6 hours or admission to a tertiary hospital (79 of 741 participants [11%] in the fluvoxamine arm vs. 119 of 756 participants [16%] in the placebo arm [relative risk 0.68; 95% CrI, 0.52–0.88]). Of note, 87% of the primary outcome events were hospitalizations. There was no statistically significant difference between study arms for the secondary outcomes of need for hospitalization or time to symptom resolution. There was no significant difference in mortality between study arms in the intention-to-treat (ITT) population (17 of 741 participants [2%] in the fluvoxamine arm vs. 25 of 756 participants [3%] in the placebo arm [OR 0.69; 95% CI, 0.36–1.27]). In a secondary, per-protocol analysis of participants who received >80% of possible doses, death was the outcome for 1 of 548 participants (<1%) in the fluvoxamine arm versus 12 of 618 participants (2%) in the placebo arm (OR 0.09; 95% CI, 0.01–0.47). Participants in the fluvoxamine arm were less likely to present to an emergency setting for COVID-19 for any duration, although this analysis was not prespecified. Compared with those in the placebo arm, participants who received fluvoxamine were less adherent to therapy and discontinued therapy due to intolerance more often.
While fluvoxamine treatment significantly reduced the primary composite outcome in the TOGETHER trial (i.e., retention in the emergency department for >6 hours or admission to a tertiary hospital), the difference in hospitalizations between arms was not significant.5 Defining the clinical relevance of the >6 hour emergency department observation time endpoint is difficult, especially its applicability to practice settings in different countries. Moreover, the endpoint has not been used in other studies of interventions for nonhospitalized patients at high risk for hospitalization and death. While a per-protocol analysis found a significant treatment effect for mortality in patients taking >80% of possible doses (assessed by patient self-report), no such benefit was found in the primary ITT analysis. The 80% threshold has no clear justification, and only 74% of participants in the fluvoxamine arm reached this level of adherence. Since per-protocol analyses are not randomized comparisons, they can introduce bias when adherence is associated with factors that influence the outcome; this bias cannot be excluded in this study. Notably, mortality in the placebo arm was substantially higher in those with ≤80% adherence than in those with >80% adherence, suggesting that factors other than adherence differed in the per-protocol population. Finally, including only participants who could tolerate fluvoxamine does not reflect the actual effectiveness of the drug, since intolerance and adherence appeared to be related.
Additional studies are needed to provide more specific, evidence-based guidance on the role of fluvoxamine for the treatment of COVID-19. Further details of the studies discussed are provided in Table 4c."
That sounds less like "we can't find anyone willing to be responsible for this" and more "if some study comes out with yes yes yes it works!!!, then we'll approve it". Right now, they seem to think the studies are "meh, it's kinda okay".
The NIH are very not enthusiastic about the TOGETHER trial:
https://www.covid19treatmentguidelines.nih.gov/tables/fluvoxamine-data/
The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for fluvoxamine. The studies summarized below are the randomized clinical trials that have had the greatest impact on the Panel’s recommendations.
"Key Limitations:
The >6-hour emergency setting observation endpoint has not been used in other studies of interventions for nonhospitalized patients who are at high risk for hospitalization and death
As this was an adaptive platform trial where multiple investigational treatments or placebos were being evaluated simultaneously, not all patients in the placebo arm received a placebo that was matched to fluvoxamine by route of administration, dosing frequency, or duration of therapy
PP analyses are not randomized comparisons, and they introduce bias when adherence is associated with factors that influence the outcome
Adherence was self-reported and not verified
Interpretation:
Fluvoxamine reduced the proportion of patients who met the composite endpoint of COVID-19-related hospitalization or retention in an emergency setting for >6 hours.
The use of fluvoxamine did not impact the incidence of COVID-19-related hospitalizations.
It is difficult to define the clinical relevance of the >6-hour emergency setting observation endpoint and apply it to practice settings in different countries.
Fluvoxamine did not have a consistent impact on mortality.
Fluvoxamine did not impact time to symptom resolution."
STOP-COVID (as you might guess from the rah-rah name, this one was run in the USA not Brazil):
"Key Limitations:
Small sample size
Short follow-up period
Ascertaining clinical deterioration was challenging because all assessments were done remotely
24% of patients stopped responding to follow-up prior to Day 15 but were included in the final analysis
Interpretation:
Fluvoxamine reduced the proportion of patients who experienced clinical deterioration.
Due to significant limitations, it is difficult to draw definitive conclusions about the efficacy of using fluvoxamine to treat COVID-19."
Are there good studies on post-SSRI sexual dysfunction (including less visible symptoms like libido loss in women)? Wondering about the basis for Scott's characterization of the side effect as "very rare." I have some medical contacts who focus on those issues and believe that they're under-scrutinized and under-researched
I think you are correct. Many of the doctors who denied the existence of PSSD (and therefore had no need to discuss it with patients) are now saying that it is 'rare' (and therefore have no need to discuss it with patients). There is barely any research on PSSD. I was talking to a urologist who sees men whose sex lives have been ruined by SSRIs: "We have no idea of its prevalence. It is entirely possible that SSRIs cause low level sexual dysfunction in people and they don't really notice." It's a horrifying situation.
Scott, I like to print out your essays to read with a cup of coffee as a break from my computer. Your writing is so good that I always enjoy them hugely, whether I'm interested in the subject matter or not.
But when I print them out from my web browser, the last paragraph of the first page is always obscured by a big 'Publish on Substack' advert, which only appears in the printed version, I don't see any such thing on the page in the web browser at all, it's only on the printout. And I can't find any way to work around this.
I realise that this is nothing to do with you, and indeed probably a bug in the Linux version of Firefox, but I wondered if you had the clout with Substack to get them to fix their button so it doesn't do this?
Typo: But But CS Lewis
Let's say, purely hypothetically, that you have two octogenarian grandparents whom you love dearly. They're both vaccinated and boostered. One has recently finished bladder cancer treatment, another has a history of heart rate issues, beyond that and their age they have no major COVID comorbidities. What steps would or could you, their grandchild, take today to improve the odds that they can obtain a Fluxov prescription in the event that either one contracts COVID?
Thank you, taking a look at those now.
So, speaking practically rather than legally, is there a way one can get one's hands on fluvoxamine?
Just to point the 30% number in perspective, this is roughly equivalent to the estimated effect size for going from 0% masked -> 100% surgical masked from the Bangladesh study.
Unfortunately fluvoxamine only impacts your risk from Covid and has no real impact on psychological safety so it is utterly irrelevant to our societal response.
>The VA system took 35,000 high-risk older patients off of an unusually-likely-to-cause-QT-syndrome SSRI in 2011, and were unable to find any evidence that this prevented even a single case of the syndrome, let alone any negative outcome!
Is it just me or is this phrasing quite like the "no evidence" phrasing from https://astralcodexten.substack.com/p/the-phrase-no-evidence-is-a-red-flag?
4. If people believe there is a safe and relatively effective treatment for COVID, they might be less likely to bother with a weird GMO vaccine.
Is there a role for the physician organizations? Because I know for our kid, the recommendations about things like car seats and avoiding SIDS and stuff generally come from the American Association of Pediatrics, not the FDA but nor do individual pediatricians have to decide what to say about a lot of issues. And when my wife was pregnant we kept hearing about recommendations from the American College of Obstetricians and Gynecologists. So could one of the professional medical associations give physicians the okay to do this and know they aren’t being unprofessional?
"That is, FDA procedures usually assume there is a pharma company sponsoring a drug. But fluvoxamine is cheap and off-patent and no pharma company is involved in repurposing it for COVID. Nobody has a procedure for a drug without a sponsor, so they won’t do anything."
I'm mildly amused by the happenstance that this is pretty much the same thing Weinstein et al. were saying about getting Ivermectin re-labeled as a prophylactic for COVID.
No reflection on the virtues of fluxovamine, since I am not a doctor of any sort.
I find it very frustrating that a lot of the NPIs are justified in order to keep hospitals from being overwhelmed, and here is a treatment which would increase hospital capacity by 30% (or is it 43%?), which would probably have done more than any NPI to keep hospitals from being overwhelmed, but we aren't using it because there is no one to pay for marketing it.
So these doctors and nurses we see in the media who complain about how overloaded they are, they don't know about it?
I love this post!
I've been single for too long because asking people out would require me to do something potentially awkward.
"For some reason the same experts who don’t mind prescribing SSRIs when people have mild depression freak out about prescribing them when they’re the only evidence-based oral medication for a deadly global pandemic. "
While I agree wholeheartedly with the sentiment, correction: dexamethasone is oral.
While we're on the subjects of steroids and "flu-" drugs that 10 million Americans already use without issues, why not fluticasone inhalers to treat Covid? They're extremely safe (far fewer side effects than oral steroids) and for me they clear up all my respiratory inflammation completely within 12-48 hours depending on how bad it was before I started. A hypothetical downside is that it might stop working in a part of the lung that is filled with fluid, but as a prophylactic against pneumonia as soon as you test positive for covid it would work great (80% confidence). Maybe I'm just seeing it through rose-tinted glasses because i'm a super-responder to it. I have occasional inflammation in my lungs, not very bad. It usually stays under control with far less than the recommended 2 puffs of 110mcg twice a day. One puff once on days when I feel like I need it is usually sufficient. When I had covid in May 2020, I raised my dosage back up to what was prescribed (2 puffs twice a day) and got through it without letting my SPO2 dip below 95%. It lasted 10 days and was milder than some flus. Fluticasone inhaler was the only thing I was taking.
There's a preregistered study in progress, still recruiting: https://clinicaltrials.gov/ct2/show/NCT05054322
10% of Americans being on SSRIs is my personal “I don’t know anybody who voted for Nixon” moment.
I don’t even know anyone who sees a therapist except for the people in our drug treatment court which I work with.
Are people’s primary doctors handing these out?
Probably: https://www.youtube.com/watch?v=BNlyZSvsNjw&ab_channel=ComedyCentralStand-Up
Dr. Faust is a name I can believe in.
12/23/21 Update:
"Ontario becomes the first province to list fluvoxamine as a COVID-19 treatment to consider"
https://www.ctvnews.ca/health/coronavirus/ontario-becomes-the-first-province-to-list-fluvoxamine-as-a-covid-19-treatment-to-consider-1.5717489
Scott, you shouldn't beat yourself up for not doing something which seems unlikely in retrospect to have mattered, or for hesitating to take steps which were probably legal until you had more Bayesian evidence thereof.
You should beat yourself up for not trying to convince the FDA to authorize vaccines for new variants under the precautionary principle, which seems like an iron-clad argument according to premises they might accept.
Also, stop using a technique of anti-epistemology which successfully stitches together anthropomorphism with dehumanization. FDA bureaucrats drag their feet on needed medicine because they don't understand the difference between their behavior and the archetypal young student standing up to the anti-controls expert in front of a crowd. It's almost like traditional rationality places too much emphasis on avoiding false claims, or being less wrong.
Which of the three is your reason to not prescribe [Desoxyn](https://astralcodexten.substack.com/p/know-your-amphetamines)?
About that Bayes formula on the bottom in your subscribe thing... Bayes formula doesn't tend to give 60/40 odds.
Here's how it works: "prior probability", P(A) that a random drug is effective for COVID, is very very small, that should be understandable, right? P(A|B) is the posterior probability given the trial(B) .
The P(B) is probability of finding the drug to be effective whether it works or not. Which for this study is woefully high - there's a number of red flags (the stranger the end point, the more effective the drug was at it; non strange end points not even statistically significant). Note that P(B|A) is less than 1 (but presumably, close to 1), and to get a greater P(A|B) than P(A) you need P(B) to be small.
The end result is that your P(A) is small (fractions of percent) and your P(A|B) is higher, but still very small (fractions of percent).
To get odds close to 50/50 (like your 60/40), would require a rare numerical coincidence; the P(B) needs to be approximately equal to P(A) . That doesn't occur often, because people who could get P(B) to be this low, shoot to make it even lower.
To clarify, for your odds, it has to be the case that Brazilian study was approximately as unlikely to find an ineffective drug to be effective, as the probability that a drug chosen completely at random from your medicine cabinet would be effective. I think it should be intuitively clear to anyone that the probability of guessing the drug is far lower than probability that another study in Brazil screws up.
Read RFK Jr.’s book and all becomes painfully obvious.
If 3 is an issue, isn't the solution writing up some social permissions slips and handing them out to as many doctors as you can get them to?
It sounds like all you need to do is let doctors have the line "I know a bunch of other doctors that are prescribing patients with fluvoxamine for covid" and they'll start doing it themselves too.