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The Life Cycle of Medical Ideas


About five years ago, an Italian surgeon with the unlikely name of Dr. Zamboni posited the theory that multiple sclerosis was caused by blockages in venous return from the brain causing various complicated downstream effects which eventually led to the immune system attacking myelinated cells. The guy was a good surgeon, nothing about the theory contradicted basic laws of biology, and no one else had any better ideas, so lots of people got excited.

As far as I can tell, the medical community responded exactly one hundred percent correctly. They preached caution, urging multiple sclerosis patients not to develop false hope. But at the same time, they quickly launched studies investigating Zamboni’s experiments and used newly gathered data to test the theory. All the results that came back made the idea look less and less likely, so that to my understanding by now it is pretty much discredited. Having successfully spent hundreds of thousands of dollars to empirically disconfirm Zamboni’s hypothesis, we can now reflect at leisure on the reasons it was kind of dumb and we should have realized it all along.


About five years ago, two Israel doctors named Gat and Goren posit the theory that benign prostatic hyperplasia, a prostate disease that affects millions of older men, is caused by incompetence of the spermatic veins. They claim they can treat it surgically, and show off rows of smiling patients with glowing testimonials. Once again, the guys are good doctors, nothing about their theory contradicts basic laws of biology, and no one else has any better ideas.

I shamefacedly admit I want this one to be true. There’s so much “well, everything is a complicated combination of genes, biomolecules, biopsychosocial stressors and immune modulators that we may never really understand” going on in medicine today that it would be super gratifying if this one mysterious disease turned out to just be plumbing going in the wrong direction. And although the prostate is about as far from my area of expertise as it is possible to be, I have to say that from a physiological standpoint their theory seems to have that rare and much-sought scientific elegance, where everything comes together in a pretty package.

On the other hand, it sounds a whole lot like the Zamboni debacle transposed to a different organ, and Gat and Goren don’t have much evidence other than a pretty theory and their own anecdotal success.

As far as I can tell, the medical community has totally ignored this one. Gat and Goren have published their hypothesis and their apparent excellent results in peer-reviewed medical journals. It has garnered praise from prestigious figures in the field (bonus points for calling it “seminal”, especially if the pun was intentional). As far as I know, no one has attacked it or even formally expressed doubt. Yet as far as I know, it has gone nowhere.

Does everyone mutually assume that if something this revolutionary were true, someone would have noticed beyond a single article in a urology journal? Do they just decide it needs further research, and hope that this research will be conducted by someone else? Or do they think that it would end up like Zamboni’s MS cure, with hundreds of thousands of dollars wasted, dozens of unnecessary surgeries performed, and nothing to show but yet another fringe medical idea that sounded good at the time?


Minocycline is a relatively boring umpteenth-line antibiotic sometimes used to treat acne. About five years ago, some Japanese doctors noticed that their schizophrenic patients with acne seemed to be getting better. This was especially bizarre because some of these patients had “negative symptoms”, a set of schizophrenia symptoms considered totally untreatable and which the super-advanced next-generation antipsychotics being pumped out by drug companies can’t even touch. They started wondering – can minocycline, an uninspiring antibiotic from the early 1970s, do what all of these psychiatric medications can’t?

Once again the medical community responded correctly. They launched a couple of double-blind placebo-controlled studies of minocycline, and sure enough, the stuff was shown to work again and again.

And yet the psychiatrists I know have never heard of it, and I am not aware of any psychiatric hospital in the world where minocycline is routinely given to schizophrenic patients with negative symptoms outside of a clinical trial.

It’s not like this is some kind of experimental drug that might kill the patient and isn’t even legal yet and we have to wait for further research. If the schizophrenic patient happens to get acne, the psychiatrist will be perfectly happy to send them to the nearest CVS Pharmacy to pick up a bottle of minocycline, which they will no doubt have in droves. It’s just the schizophrenia connection that isn’t there.

I’m totally in favor of waiting for all the research to come in and not jumping to conclusions. The problem is that I don’t understand exactly what the process is. If the rule was “We must wait for NIMH to fund a study with greater than 2,000 subjects, and after that everyone will prescribe it, and NIMH is currently working on crunching the data, so just hold your horses,” this would sound totally reasonable to me. The problem is that I don’t know what we’re waiting for and I’m not sure there actually is a thing we’re waiting for except a spontaneous change in the zeitgeist, which could take forever.


When people blame drug companies for suppress any promising medications they can’t make a profit off of, those people are missing the point.

The drug companies don’t suppress promising medications. Promising medications start off pre-suppressed. In some cases they are suppressed by regulation that says a drug has to go through crazy expensive trials before it can be approved. In other cases, they are suppressed simply by the burden of proof: even without the government, doctors aren’t going to prescribe something they don’t know is safe and effective, and they’re not going to know it’s safe and effective without studies, which as I may have mentioned are crazy expensive. In still other cases, the medications are suppressed by medical conservativism: most doctors very reasonably don’t want to use a drug unless they know other doctors they respect are using the drug, so unless the drug impresses itself onto the consciousness of the entire medical community at once it will fizzle out.

What drug companies do, as best I understand it, is put billions of dollars and millions of man-hours of effort into un-suppressing those particular drugs it is in their financial interest to un-suppress. They are doing a great service. It’s just a very selective one.

I’m not sure how it works in surgery. As far as I know, there aren’t companies that patent surgical procedures and then popularize them. If there were, maybe one of them would pick up Gat-Goren and give it a fair try to stand or fall on its own merits. As it is, it looks like it will have to wait for some university or charitable group to pick it up – and let’s face it, “my eighty year old grandpa gets up to piss half a dozen times a night” isn’t quite as sexy as multiple sclerosis.

In medicine, drugs are usually approved for specific indications. Doctors are allowed to prescribe them for other indications, but there are trivial inconveniences and minor legal hurdles and in practice most of them rarely do. Some pharmaceutical company was nice enough to get minocycline approved for acne back in the ’70s, but since then it’s gone off patent and no one owns it enough to say “Hey, start the process to approve this drug of mine for schizophrenia!” The medical community is pretty smart and I bet there’s a process by which this will eventually happen, but I also bet it will take a long time and be overly complicated and a whole lot of schizophrenics will have to suffer from negative symptoms long after the vanguard of the medical community has satisfied itself that these are treatable.

(I can imagine the look on my attending’s face if I suggested we treat one of our schizophrenic patients with minocycline. I expect I would get a lecture on how We Have To Be Responsible And Ethical, and then we would give them one of the same three drugs we give all schizophrenics. I might have more luck painting little fake acne pustules on my schizophrenic patients’ faces, but most of the ones I have now are Paranoid-Type and I really can’t imagine them going along with that. I’ll just have to wait until I get someone catatonic.)

Which is why it sucks that the other really interesting drug that might revolutionize the treatment of schizophrenia is an antihypertensive from the 1950s.


I find the life cycle of medical ideas really interesting.

I was always taught that there were two kinds of medicine. Real medicine, which has been proven to work by studies. And alternative medicine, which has been proven not to work by studies but people still use it anyway because they are stupid.

This dichotomy leaves out the huge grey area of “things that seem like they will probably work, and a few smaller studies have shown very promising results, but no one has bothered to do larger studies, or if they have they have never really been incorporated into medical practice for reasons I can’t put my finger on.”

Some of this grey medicine, like Zamboni’s MS treatment, are doomed to eventually fall back into the abyss of alternative medicine. Others, like the Gat-Goren procedure, teeter in the middle, threatening to go either way. Still others, like minocycline, have already been sanctified and dressed in robes of white, and the only thing preventing them from entering Evidence Based Heaven is some sort of weird bureaucratic snafu at the Pearly Gates.

I am encouraged that all three of the examples of grey medicine cited in this article are about five years old. It suggests that there’s a certain window of time during which grey medicine is well-known but hasn’t yet been well-studied. Maybe most of the newer stuff I don’t know about, and most of the older stuff has been successfully proven or disproven. It seems possible to me that the current system does have the optimal combination of safety and innovation, or at least the best we can do without a Science Czar. As I immerse myself in Medical Culture, I look forward to finding out whether there are some hidden processes for dealing with this, or whether the situation is really as dire as it looks.

But I am also hopeful that some new organizations like Microryza and MetaMed might, totally independent of justified or unjustified medical conservativism, be able to speed the process along.

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25 Responses to The Life Cycle of Medical Ideas

  1. Jack says:

    It’s fascinating to see how this works. Presumably some of the effect is waiting until new advice makes it into medical schools. Or people like you grow up, become senior, and start trying it??

    My other thoughts are: It’s ok to WANT something to be true, it’s probably healthy to acknowledge it, that may hopefully make it more clearly distinct from trying to think it’s true.

    And it’s ironic that “a simple widely-spread existing antibiotic will cure you but doctors refuse to tell you about it” is something you find it hard to convince someone suffering from paranoia of 🙂

  2. Rachael says:

    Can you apply for funding and do a study on the minocycline thing, and raise both its and your profile? Or are you too junior and/or busy with other things?

    • Scott Alexander says:

      Too junior and busy. It’s possible in two or three years I might have that chance, but I don’t know if I’m allowed to do studies where I give people experimental drugs without way more trouble than I’m willing to go through.

      But the bigger problem is that even if I did get permission, as someone in a medium-sized non-academic hospital I’d only have access to my own patient population, and I’d be lucky to gather even a few dozen consenting schizophrenics with negative symptoms. This would then add to the existing pool of small studies supporting minocycline which are shelved away and ignored.

      The problem doesn’t seem to be studies – people have already done much better studies on this than I ever could. The problem seems to be that the existing studies are being ignored. A very large and definitive study might be one solution, but there’s no way I or any non-government non-university entity could muster one of those.

  3. Andrew says:

    Could you go into a little more detail on the trivial inconveniences and minor legal hurdles that prevent drugs from being prescribed for other indications?

    I mean, I assume it’s not for lack of evidence that your attending would ignore your suggestion, or you’d just take 10 minutes to present said evidence (unless your position precludes you from doing even that).

    • Scott Alexander says:

      I don’t know too much about this field, but my understanding is that you lose some legal protection.

      If doctors use a drug the way the FDA approved it, they have two good defenses in court: “The FDA said it was okay” and “All the other doctors use it this way”.

      If doctors use a drug off-label, they lose the first defense. If they use it off-label in a novel way, they lose the second defense too.

      This is bad not just in the case where the doctor miscalculated and the drug has more side effects than they thought, but also in the case where the drug has a normal side effect and you get unlucky (a lot of different things can cause life-threatening reactions in one in a million people), and even in the case where someone is put on a drug, gets a normal non-drug related cancer, and the prosecutor manages to select a jury who don’t understand that correlation isn’t always causation.

      But I’m glad you asked that, because in looking for better legal information I read through Wikipedia’s page on off label use and there really is a lot of it. That makes me wonder why minocycline is falling through the off-label cracks. Right now my best guess is that the two indications are so different that the doctors who would use it for Indication 2 aren’t already familiar with it from Indication 1 and so have a natural and reasonable reluctance to use a drug they’re not already trained in. Compare this to gabapentin working for both migraines and seizures, where it’ll probably be the same neurologist giving it both times.

  4. Mark says:

    Thanks for posting. In the hundred or so feeds I have there are few that are as consistently gems as your posts.

    It seems like in the Minocycline, a graduate student would be able to get the resources needed to actually test it properly. Is one of the reasons progress seems to have slowed that 70 years ago, a graduate student could have said, “I’m going to go and try this” and been able to do it. Whereas today, there’s so much bureaucratic hassle that no one bothers?

    • Scott Alexander says:

      But the thing is, it has been tested pretty well, at least to the degree a graduate student could do it. One of those trials I linked to was on 120 or so patients, which is well above what the average grad student could get their hands on.

      The problem doesn’t seem to be that no one has done the small studies, it seems to be that, the small studies having turned up positive, no one knows where to go from there.

      • Deiseach says:

        It’s possibly because it’s so weird, no-one can come up with a plausible reason why something that treats acne should help schizophrenia.

        Which, in combination with what you say about the hypertension medication, makes me wonder if some of the symptoms associated with schizophrenia might be down to something crazy like ‘brain inflammation’ (I’m sure there’s a proper medical term for it). Relieve the inflammation/pressure on a certain area, and the symptoms clear up.

        The way that stomach ulcers used to be ascribed to stress and an unhealthy lifestyle, then someone came along with the crazy notion that you got ulcers because of a bacterial infection, and here’s Heliobacter pylori smiling and waving at us.

        alternative medicine, which has been proven not to work by studies but people still use it anyway because they are stupid

        That’s the attitude that drives me nuts. Yes, a lot of ‘alternative medicine’ is woo-woo stuff; yes, a lot of it is ‘old wives’ tales’; yes, a lot of it is things that used to work okay but now we have better and safer drugs that do the job instead.

        But people don’t take cures because they’re stupid, it’s because (a) they don’t have access to anything better or (b) they’ve tried everything else and this is last-gasp desperation. The way people used to take St. John’s Wort to the eye-rolling and patronising smiles of the medical profession, until somebody tested it, found out “Holy crap, it does have an effect” and it was hauled off the shelves of all the health food stores because now it was An Official Drug and now you need a prescription for it.

  5. Shmi Nux says:

    There is something suspicious about the schizo-acne story. Something else must be going on.

    There is a potentially enormous upside to an effective anti-schizophrenia medication. Drug companies spend billions on synthesizing new compounds, yet in this case they could take an existing off-patent med, modify the formula a bit in safe and non-essential ways, patent, test and market it as a new drug, specifically for treating schizophrenia, with a side effect of curing acne. Creating derivative drugs is a pretty standard approach, by the way.

    This would accomplish “put billions of dollars and millions of man-hours of effort into un-suppressing those particular drugs it is in their financial interest to un-suppress” rather cost-effectively: negligible research costs, almost guaranteed safety, almost guaranteed efficacy. Jackpot!

    Even if the old off-patent drug is just as effective, without proper marketing it cannot compete with a brand-name patented drug (it cannot compete even now, with no competition at all).

    This hasn’t happened, why?

    • >This hasn’t happened, why?

      Scott says all of these are newer than 5 years. Perhaps it is currently happening?

      Perhaps the process at drug companies is optimized for more original-research-heavy stuff? Like maybe they have a small department scouring for derivative-opportunites, and a large department marketing the results of the research department?

    • Scott Alexander says:

      I’m actually wondering that myself.

      I briefly considered the possibility that maybe if a drug company worries that if it created a similar molecule and marketed it, that would raise the profile of minocycline, and all the doctors prescribing this newfangled drug would realize they’re being conned and switch to minocycline instead.

      Then I laughed hysterically and got back to searching for the real reason.

      • Douglas Knight says:

        Are drug companies ever so creative as to game the patent system that way? They do isolate chiral forms and pretend that the original dose was limited by the other isomer, but other than that one trick, I don’t see it. (They do, all the time, make small changes to existing treatments, but then the FDA makes them do head-to-head comparisons, so they probably think that they’re actually improving the drug, not gaming the system.)

        If only the original acne doctor had gotten a use patent, rather than utopically giving away knowledge, we’d be home free.

  6. I remember some OB/LW posts to the effect that we probably over-regulate drugs right now, putting too much weight on people not dying from new drugs and too little on the people that will die from new drugs not being approved fast enough. Your thoughts on this? Guess as to the likely effects of weakening regulations?

  7. Athrelon says:

    “And yet the psychiatrists I know have never heard of it, and I am not aware of any psychiatric hospital in the world where minocycline is routinely given to schizophrenic patients with negative symptoms outside of a clinical trial.”

    Where did you happen to run across this; did it just turn up in the course of random journal browsing?

  8. Fantastic post. To your specific point about how drug companies “un-suppress” drugs (great term by the way, I’m going to use that) – I’ve frequently tried to explain that the profit motive behind the biomedical industry does not cause them to lie (distort data), but does cause them to exercise editorial control in terms of what kinds of treatments that pursue in the first place (what kind of data they spend time and money producing in the first place).

    But your larger point about what is the process by which tools get into our hands to help patients is well-taken. My guess, and it’s exactly that, is that they get approved by a committee informing insurance and institutional formularies, while simultaneously thought leaders are presenting things at conferences and gradually changing medical standard of care. The first one of those two is probably more systematic.

    • Scott Alexander says:

      I don’t know nearly as much about insurance formularies as I should. Are they just a list of drugs, or do they also give indications (for example, list whether minocycline has a psychiatric indication)?

      I was actually thinking of the term “thought leader” as I wrote this article, but it’s so fuzzy that I think it raises more questions than it answers.

      You said that at your institution people were talking about minocycline? Do you mind relaying what they said? If professors and attendings are discussing this kind of thing, the content of their discussions seems to be exactly the sort of information I would need to educate myself on how this process goes ahead.

      Also, I am really happy to discover that you exist. I’d never heard of you or your blog before, and it will be very nice to have another rationalist psychiatry resident to talk to, question, and occasionally rant at. I have subscribed to your blog and I look forward to reading more of your stuff.

      (that genetic test on clozapine seems like another example of something important people don’t know about)

      And although I appreciate the need to debunk hysterical claims about how evil drug companies are, saying that they don’t distort data goes a little far – this is my go-to example.

  9. Malcolm says:

    Does everyone mutually assume that if something this revolutionary were true, someone would have noticed beyond a single article in a urology journal?

    Sounds to me like institution-level bystander effect.

  10. Doug S. says:

    Minocycline does seem to be getting more attention:

  11. Sabio Lantz says:

    Fantastic tour of three examples. I totally agree that conservatism and lack-of-imaginable-profit give us bias challenges in medicine. And that these biases are covered with the sanctimony of “Science” is a shame.

    Minocycline gave me horrible vertigo, but I’d trade that for paranoid delusions! 😉

  12. JPH says:

    So here’s a idea your post semi-incubated:

    SkinChance: a Massively Multi-Patient Medical Study (Proposal)

    Try Everything – Pay to Participate

    Vitiligo is a condition that occurs when the cells responsible for skin pigmentation are unable to function. The root cause of vitiligo is unknown, and recommended treatments for the condition are require either specialist intervention in the form of skin grafts, or increase the likelihood of skin cancer by using UV photo therapy. All currently know treatments have highly variable success rates.

    We propose a massively multi-patient study where worldwide patients are pay a nominal fee to participate (in the order of $10 + personal medicine costs) through crowdfunding, agree to test selected medicine on themselves for the trial period, and share results with the wider patient group in exchange for early access to the trials collated data.

    This would give the opportunity and incentive to try a wider range of medicines than possible with geographically and personal schedule limiting hospital based studies. All forms of topical medication should initially be considered, but for scope purposes given for a trial group of 5000 patients/partcipants, testing in the order of 500 existing topical medications could be feasible. Specifically designing a study for in many cases using “off-label” local topical medication has risks, and weighted consideration between dosage, accessibility and availability of the existing medication, previous success factors, and known side effects must be considered. Motivating the patient/participant to keep to a prescribed treatment schedule, and accurately self report result is another risk for the study.

    But hey,… why not? Thoughts?

  13. Pingback: Friday Links | Meta Rabbit

  14. Phil Goetz says:

    There is an older and more-important example than these: Genetic tests for diseases. I don’t mean testing the patient’s genes; I mean taking a biopsy and finding out what foreign genes are in it. You can do this with PCR, hybridization microarrays, or gene sequencing. (Well, you always use PCR, but you would use it differently if you were going to follow up with a microarray or sequencing.)

    Many people die every year from undiagnosed bacterial infections. We’ve known for 25 years how to quickly, easily, and cheaply diagnose most bacterial infections with such tests. But you can’t patent use of PCR for testing, as it is too obvious to patent. And nobody could afford the trials needed to get FDA approval anyway, because the FDA insists on having a separate trial for each strain being tested for.

    The method is generic: Choose the genome you want to detect and use an algorithm to design a set of probes for it. Download Genbank, let your computer crank away it it over the weekend, and you’ll have your set of primers or probes to test for the presence of every genome in Genbank. You might choose just 382 of the most-likely ones, to put on a 384-well microplate.

    But the FDA wants a separate study for each of those 382 primers. Nobody could afford that even if they could patent the method. So hospitals keep using immunological assays, which are slow, unreliable, expensive, and can test for only one thing at a time.