Antidepressants - Going Backwards: Revealed: The Train Wreck of Medical Publishing

Ethan: We have a pretty bad opiate epidemic here that is now just a total drug epidemic. But in the mid 1980s, a couple of researchers, Porter and Jick, published a 4-line COMMENT in the New England Journal of Medicine stating that after reviewing 12,000 cases in a medical system, that 4 people got addicted to opiates. This was just a comment in the New England Journal of Medicine. It wasn't part of a larger study. This was cited some 300 times in the next couple of decades as evidence that opiates, including Oxycontin, are not addictive. Which is, absolute horseshit. And, it contributed heavily to the epidemic that we still find ourselves in. We're still losing more and more people in America every year, citing, in that case, not any actual decent information to begin with. People don't realize that research can't be trusted at face value. You have to have nuance in your understanding and reading the methodology and knowing where the researchers sources come from.

Ken: This business of publication and the reliability of data - it might be useful for listeners to be aware of that rather long commentary I've written on the website called, ‘Medical Science Publishing a Slow Motion Train Wreck.’ It's something if people are interested, they need to read about and see the evidence. That commentary has got a hundred references, probably most of which are from eminent researchers and in eminent journals, not from the borderlands of sanity. It's a really important topic for general listeners. It's very important to understand that sadly, modern science, but especially medicine, has become tremendously influenced by the huge financial weight of the pharmaceutical companies. There really is a hegemony of influence and power in the whole medical education space, to an extent, which many doctors still don't fully understand. Almost everything that doctors are exposed to is heavily influenced by the power of pharmaceutical companies. Now don't presume when I say that, that I'm necessarily suggesting that's all bad. Of course it isn't. But it is important to understand that their motivation is quite different to the motivation of what I would call a proper ethical clinician, which I hope people would consider I am.

Ethan: I agree with you. I think I probably come off as anti-big pharma. Big Pharma has allowed us to create a lot of novel drugs that, without all of that money backing it, we probably would not have created. But the reality is that most of the drugs they develop don't work. And then they're behind the eight ball and they have to recoup all of the money that they spent on research and development. Drugs that maybe are moderately or mildly effective tend to be marketed as wildly effective.

Ken: In view of what we were saying concerning Train Wreck of Medical Publishing, a very quick version of the story about the publishing of the benchmark paper on the tricyclic antidepressants. I had a very eminent neurologist who was a kind of mentor for me because there were not many psychiatrists who it was helpful to go to, to discuss psychopharmacology. He happened to be an epileptologist who was doing research on Sodium Valproate and because I was starting to use that in mania I hooked up with him. And he was a very widely published and eminent academic. And that paper on tricyclics, he thought it was a good paper, and he said you must get this published in the most eminent journal possible. So we chose the British Journal of Pharmacology, which in those days was probably about the most prestigious journal you could get a paper like that published in. When I got it back from the referees, both the two referees produced very short reports. One said, basically, nothing interesting here, nothing new. Nobody uses these drugs anymore, waste of space. And the other fellow said something somewhat similar.

As many people well know, that perhaps not all your listeners will appreciate, then and now, arguing with editors is a complete waste of time. Most editors probably don't even look at most of the papers that pass supposedly across their desk. It's all done by computer. So I didn't expect that my letter of protest would even get a reply, but I wrote a short letter of protest saying the first referee said nothing new. Out of the 160 references in this paper, actually a hundred of them are in the last five years, so that kind of rebuts that point a bit, doesn't it? And then, second point, nobody uses them anymore. Actually, if you look at the usage, they're used in this, this, this, this, and this, and the sales figures are still quite substantial. So saying nobody uses them anymore is also pretty incorrect. I suspect these two referees you've picked are aligned with drug companies. And, to my great surprise, I got a letter back from the editor saying, ‘Your points are well made. I will send the paper out to be re-refereed, and I will make sure that I pick referees who are not aligned with drug companies.’ And both those referees said, ‘Excellent paper, publish it right away.’ And they did. And you know what? A year later, to my great surprise, I got a letter from the editor of the British Journal of Pharmacology, said, ‘Dear Dr. Gilman, I think after all that's happened, you would be interested to know that your paper was the most downloaded review paper from the Journal last year.’ And I thought, how gracious of him, not just to do what he did, but then remember that and a year later say, ‘Yep, it was good, wasn't it?’ I was really chuffed. And that paper, it's the only significant review paper in that field in the last three decades.

To help the younger members of the profession understand this more, another aspect of this, which strikes me quite powerfully. I was involved in rating scales and designing rating scales right at the beginning of my career. And it always struck me that most of the rating scales were absolutely awful. Stuart Montgomery who designed the MADRS, he was around when I was there, back in the day. I did think that the MADRS was a slight improvement cause it was better geared to measuring degrees of change with treatment. And of course, the Hamilton Rating Scale was never really designed for the purpose it's used for. And it has just got stuck in the literature because it's the go-to reference scale. People who've tried to design better scales to measure anhedonia and anergia, and things like that, which are really the core symptoms of depression, not the anxiety/sleep-type symptoms that are so often the major part of the Hamilton Rating Scale.

And I digress for a moment. If you look at an online Hamilton Rating Scale for Depression, you'll realize very quickly that you only have to sleep a little bit better and have a little bit less anxiety in order to get the drug approved as an antidepressant. So you can make almost any Valium/sedative-type drug become an antidepressant by that because it improves the score on the Hamilton scale by enough to get over the line. And it's called an antidepressant. That's nothing to do with pharmacology and medicine, that's just to do with marketing. The whole thing's topsy-turvy.

But the even more important point is that drug companies aren't going to fund work to produce better rating scales. They've got no interest in doing that. So because 90% of all the published studies are funded by the drug companies, I actually had the figures for this from a reference I had quite recently, and I was staggered. The 200,000 antidepressant trials that have been done, huge proportion of course, have been funded by the drug companies. That helps you to understand why the methodology and the means of measuring improvement haven't changed in 40 years, because the money isn't interested in doing that. The money is interested in just getting them a couple of points over the finish line for FDA and away you go. Thank you very much. And then we forget about it and move on to the next one. We're not interested in following up for medium or long-term side effects. I produced a sarcastic aphorism a little while ago that the number of side effects recognized for a drug is inversely proportional to the time for which it's been in use, Gilman's Axiom number 13. It's absolutely true, isn't it? The longer a drug's been in use, the more side effects people realize it has. And that's why it's so easy to demonstrate that new drugs are better, because of course, you do short term trials and you failed to pick up all the side effects. The rating scales aren't designed to pick up side effects. And so you can't fail.

Ethan: That's especially true when the 20-year patent runs out. And companies have created a new class, and all of a sudden they go from not telling you so much about the side effect profile of the previous class to labeling them as very problematic. We need to get out of that class of medications because they're damaging to you. When we look at the classification system for diagnosing depression, you gotta meet five out of nine criteria. Whether you're thinking about killing yourself or whether you have impaired concentration and attention, those carry the same weight in the D S M in terms of diagnostic criteria to diagnose depression, which is ridiculous.

Ken: History is so important with all of this and especially for our younger medical people, in the early part of their career. We've got this culture of ‘Everything that's new must be better.’ And of course, that's an inevitable product of profit motive. If you introduce a new drug, you've got to say it's better than the old drug. And that necessarily almost inevitably means you've got to badmouth the old drug and say it was worse, more dangerous, less effective, whatever. You can twist the statistics to persuade people is true.

So that's a huge influence. And that influence started after the last World War. From the history point of view, most scientific publications in those days were the records of learned societies, whether it was the Royal Society or the Linean Society, or the BMJ or the American Medical Association. Back in the day, they were much less affected by those kinds of things. And what was published was, they paid for it, their members contributed to it, and it was written for their members. But that very rapidly changed. What comes around goes around. I love this. It changed because of Ghislaine Maxwell, the lady who's in jail now because she helped that rich financier in America who committed suicide in prison. What was his name?

Ethan: Jeffrey Epstein.

Ken: Jeffrey Epstein. That's it. She was his mistress and procurer, I suspect.

But do you realize who her father was? Robert Maxwell. Robert Maxwell was, to cut a long story short, a spy at the end of the second World War. Sorry, he was a soldier. But at the end of the war in Germany, when they were debriefing everybody, he became involved in the secret-service type stuff. They set him up as a publisher in Berlin where he got into medical publishing and he was a ruthless, psychopathic character. And it was Maxwell who produced essentially the whole modern method of scientific publishing. And what he did was to proliferate the number of different journals so everybody felt important by being an editor of a journal and blah, blah, blah and used all the usual techniques that those kind of business were used to - hype everything up. And so he made an enormous amount of money. He became a member of Parliament in the UK. And he owned a football team and he bought the famous newspaper in England, the Daily Mail, I think it was. And then he tried to, in competition with Rupert Murdoch, who's still staggering on, him and Murdoch had a bidding war for one of the papers in New York, which of course Murdoch won.

And Maxwell eventually faded out of scene and of course died having fallen off his yacht somewhere off the Canary Islands just before he was about to be pulled in front of one or two different committees and charged with embezzlement cuz in fact he'd embezzled the equivalent of a billion dollars from his companies. So that was Ghislaine Maxwell's father, and he was the fellow who was responsible for the modern model of medical publishing. But the point of understanding that is that is what's generated this whole atmosphere as we call it of quantity rather than quality. It's all profit driven. Medical publishing houses, you know, Elvira and all the rest of them, their profit margins are higher than any other Fortune 500 company. They put the drug companies to shame. They're highly profitable enterprises. And of course part of the reason they've become so profitable is cuz they've managed to hive off all the work onto the doctors and researchers, and do very little themselves. They make us do all the work and then they charge us for the result of it. What a fantastic business model! It's the only business model I can think of in the world where they're producing a greater quantity of a worse product, that actually gives you more profit. What businessman wouldn't like that