Antidepressants - Going Backwards: EXTRA: Serotonin Toxicity, NOT Syndrome

Ethan: I actually came across your work listening to David Puder's podcast, and I wish you could have seen the look of joy on my face when I heard you criticize the term ‘Serotonin Syndrome’. Why is it a syndrome? That makes it sound like there's a cutoff point to where you all of a sudden have serotonin syndrome, even though, in reality, it is just an increasing amount of serotonin exposure until you get to a level of toxicity, which again would be on a spectrum of toxicity.

Ken: All I can say to that, Ethan, is that was very perspicacious of you because even a majority, I would say, of people writing about this in journals haven't understood that crucial distinction. Indeed, we are actually finalizing a letter in response to something that was published in a journal only a few weeks ago. One of the opening statements started off by saying, ‘Serotonin toxicity is a syndrome or a form of toxicity.’ And I thought, ‘That's not a very good start,’ because my argument would be those two things are mutually exclusive as clearly you have understood.

But look, so many of these terminologies are either not very well defined in the first place or they're used very carelessly. So I'm afraid psychiatry, medicine perhaps generally, but I think possibly psychiatry is more guilty of this than other disciplines. So many of the concepts and words that are used are only used even verging on meaningless. Like, for instance, serotonergic. Strictly speaking, serotonergic means having to do with the serotonin system. It doesn't insinuate it's an elevation or a blockade of serotonin. So using the words serotonergic drug, especially in the context of a drug toxicity, is completely inappropriate, because the only thing we're interested in as far as this business of, serotonin syndrome, which shouldn't be used, Serotonin Toxicity, is that it is a form of toxicity. And it's to-do with elevation of serotonin, Neuroscience-based nomenclature. This is something that a number of leaders in the field, like Dave Nutt, and Steven Stahl, Zohar, and other eminent international psychopharmacologists, have written about recently. And that is the importance of using proper neuroscience-based nomenclature. And indeed, some of the journals now specify that they won't accept papers unless the authors define what they propose or suppose the actual actions of the drugs they're talking about are. It's no good calling them anxiolytics or antidepressants or blah, blah, blah. They've got to specify what their mechanism of action is in what they're writing.

Ethan: We had an episode talking about benzodiazepines, which have had a very large arc of what they've been called or what drug class they belong to that has transitioned over time from anti-epileptics to hypnotics, to tranquilizers to anxiolytics. It creates confusion and there is vested interest in that confusion, both for the consumer and for folks in our position. The last little tidbit about serotonin syndrome. When I talk to patients or colleagues about it, I always like to use the parallel of alcohol. You can drink alcohol and you can have a degree of toxicity. It's not just a situation where you're drunk or you're not drunk. You are a certain level of drunk. And the same applies to serotonin toxicity. You can have mild toxicity or you can have really severe life-threatening toxicity. It's weird how many different ways that I use the examples of alcohol to make a point. Maybe I should find another parallel.

Ken: I sympathize with you. The analogy that we've started using, because it is so crucial, we've found looking at these various unhelpful publications, and there's so much duplication of scientific writing in the literature nowadays. In the old days, if you submitted a paper, you sometimes got a thing back saying, ‘There's nothing original here, people have written about this already. No thank you. We don't want it.’ But now, I mean, there's a tsunami of review papers about serotonin syndrome/toxicity. Most people are still calling it syndrome. It's hopeless. Professor White and I, 20 years ago, started trying to persuade everybody to call it toxicity. But changing the course of the ship of medical knowledge is a slow business, isn't it?

Ethan: Yeah.

Ken: So we started using the analogy of lithium toxicity. And I thought everybody knows about that. People wouldn't say, ‘Oh, this patient's got lithium syndrome.’ Everybody would look at you and think, ‘What on Earth do you mean, lithium syndrome? It's lithium poisoning.’ And serotonin toxicity is exactly the same. And it's a crucial difference. As you said, but perhaps for our listeners, we said how things aren't terribly well defined in medicine sometimes, but generally speaking, the term syndrome is used to describe a collection of symptoms and signs that seem to occur together more frequently than you would expect by chance, and therefore recognized as a kind of group, but they don't describe any known condition or pathophysiology. So there's no exact cause or whatever. It's a fairly vague, general term, whereas toxicity, especially the word toxodrome, which I don't know who actually coined that term, but I know the Hunter Area Toxicology Service, HATS, is the abbreviation in the literature. That's Professor White's group and the database that he started way back in the late 1990s. And I was involved in that right at the beginning helping a little bit for them to define what they ought to be looking for in terms of examining patients for serotonin toxicity because they were particularly interested in it. So I went down to talk to them when the database was more or less being set up, and they have ever since then, been recording appropriate clinical data on all forms of toxicity, because they're a general toxicology service. But particularly, of course, poisonings with antidepressant drugs and lithium and so on. So they were particularly interested in serotonin toxicity and wanted to make sure that they understood it and were examining patients appropriately, so that's how it all started.

And they've now accumulated, oh, it'll be more than 5,000 cases of single drug overdoses, of Serotonin Reuptake Inhibitor-type drugs. And they've published a whole suite of papers on this. I dunno how many, it's probably close to 20 by now. And of course, most of these reviews that I started to talk about a minute or two ago, they're not really reviews at all because they don't look at the original scientific data that's in the literature, whether it be from experiments on animals, or whether it be from in vitro experiments, measuring in test tubes the potency of drugs for various different properties. And that's something which has expanded tremendously over the latter part of my career, the last 20 or 30 years. It's possible to do huge panels of receptor assays that give you the potency of drugs at a whole range of different receptors and enzymes, and heaven knows what else. And they're very valuable. It's not always easy to relate the potency in test tubes to what actually happens in humans, but at least it's a very good start in giving you an idea of whether drugs are likely to have an effect on system A, B or C, etc, etc. So these review papers, they're not reviewing that kind of data, which might be valuable, they're just reproducing what other reviews have said. So when you look at the references they give, they're not referencing original studies. They're referencing what somebody else who wrote another review like them said. That's completely pointless. A review shouldn't be a review of what other people have said, it should be a review of the original data. And we've got, as I said, a tsunami of these papers.