Antidepressants - Going Backwards: What is Depression?

Ethan: I would say that the general public in America has been put under the impression that depression is related to a deficiency in serotonin, which is so obviously an extremely reductionistic way of explaining the origin of depression. The recent paper on the serotonin theory of Depression, like it was this big revelation that maybe there's more to depression than serotonin. Freud described it as a psychological response to loss, others have related it to inherent temperaments. Can you give us your overarching view of what depression is? Why do human beings, of all the animals in the world, why do we kill ourselves when it's so counterintuitive evolutionarily to do.

Ken: Lemmings do it

Ethan: Not with the same intentionality.

Ken: Good point. Good point. I don't think I profess to have any kind of reasonable answer to that question. What I would say is from a point of view of a practicing medically orientated psychiatrist, what I'm interested in is how do we define that group of patients which are going to respond to medication? There clearly is all sorts of evidence that suggest that illnesses and drugs can emulate part or all of the typical picture that we call serious biological depressive illness. Like, for instance, most patients with Parkinson's develop at least a partial depressive syndrome. And, an arbitrary definition of depression is reached for a much greater proportion of patients with Parkinson's than a comparable sample of the general population, et cetera, et cetera. And it's associated with various other different things. Dopamine-depleting drugs like Tetrabenazine and Reserpine cause at least a partial depressive syndrome, et cetera, et cetera. So there's all sorts of evidence that something called depression has an underlying biological basis. So that was the kind of depression that I'm interested in. As a doctor, you've got social workers and psychologists to deal with all the other problems that might cause people to be discontent, unhappy and whatever with life. I don't think medicine should have anything to do with that; that's up to society and the government to deal with poverty, deal with housing, deal with this, that and the other, and people will be happier. But it's not a psychiatric problem.

I think failure to delineate the difference between those things, failure for doctors to clearly delineate that difference, has been a major problem. The serious question is how reliably can we predict which patients are going to respond to the various different interventions that we've got? And I think the DSM that you mentioned before has been a profoundly negative influence on that because, of course, it's lumped all different kinds of depressive syndromes into a kind of severity continuum and not taken account of psychomotor retardation and what Professor Gordon Parker defines as the core symptoms, which, I've agreed with Gordon for the whole of my career. And again, that meshes in with what we were saying earlier, Ethan, which is that drug companies have got no incentive in producing better rating scales and helping with the problem of defining these things. So that area's been somewhat neglected. The number of research groups that have done research similar to Gordon Parker's group is extremely small.

Ethan: I really liked Gordon Parker's response to the article, ‘Is depression overdiagnosed? No.’ And his response, ‘Is depression overdiagnosed? Yes.’

Ken: Essentially what you were saying I completely agree with and that is that essentially it was a complete Strawman argument. As far as I was concerned, no psychopharmacologist that I respected held the view that serotonin deficiency was the key to depression. And even more important than that, from a practical trial point of view, it seemed to me to be blindingly obvious right from the beginning when those drugs first came in, that they were not antidepressants. Let's have a bit more history here. I'm addressing this question to your listeners. What was the first SSRI, Serotonin Reuptake Inhibitor drug that was marketed? Most people I'm sure would answer Prozac. Actual fact, it wasn't the first serotonin reuptake inhibitor at all. The first serotonin reuptake inhibitor was Zimelidine, was it called? And what's really interesting to know about that is Zimelidine was developed from the nucleus of the antihistamine Chlorpheniramine, I think is the official name for that now, and that is a significant serotonin uptake inhibitor. When these drugs were developed from the nucleus of methylene blue, that produced the antihistamines, the tricyclic antidepressants, and the original Chlorpromazine-like neuroleptics, which was almost all the drugs in psychiatry back in the fifties and sixties. They were all that same three-ring nucleus.

In those days, their ability to ascertain their neuropharmacology profile at the different receptors, half of which, of course, weren't even recognized then, was very crude. And so, the categorization of these drugs was less than properly scientific. For instance, Doxepin, which we now know is the most specific and potent antihistamine in the world, still 50, 60 years later, that was classified as an antidepressant. Chlorpheniramine, which is actually quite a potent serotonin reuptake inhibitor, was classified as an antihistamine. Need I say more. So that helps you to understand why everything was something of a muddle.

Arvid Carlsson, the Nobel Prize winning pharmacologist from Karolinska, he developed Zimelidine from the nucleus of Chlorpheniramine, and that was marketed, I remember using it in London way back, in the seventies. That was the first marketed SSRI. Sadly, it was associated with the development of Guillen-Barre Syndrome. And it was taken off the market quite soon; I don't think we used it for more than 6 or 12 months, if I recall. But the point of the story is that Carlsson didn't describe SSRIs as antidepressants. He regarded them as anxiety-reducing drugs, and the reason they were marketed as antidepressants; it wasn't pharmacological, it wasn't doctors and pharmacologists that determined it, it was marketing. So when the Eli Lilly people came to market it, of course they said if we call them anxiolytics, then people are gonna think they're gonna be addictive, like benzodiazepines and after the barbiturate story and then the Librium and Valium story and people being paranoid about getting hooked on those kinds of drugs. They wanted to steer clear of that so that's why they called them antidepressants. There was nothing to do with their pharmacological action or the scientific evidence for them being effective for depression. It was just because they got over the finishing line for the FDA with 2.5 points on the Hamilton rating scale. And so they decided to call them antidepressants. What a triumph of marketing. And again, the medical profession swallowed it hook, line, and sinker without question. When I started using them, whenever they came to Australia, I didn't start using them; patients I had on Clomipramine, which is an extremely effective SNRI antidepressant, half the patients I had in those days were on Clomipramine. Some clever GP, who wanted to big-note himself to his patients by using the very latest drug, would say, ‘Oh we got these wonderful new drugs, we'll give you those instead.’ And then of course they'd come back to me 3 or 6 months later saying, ‘These don't work. Can I go back on Clomipramine please?’ And when you've seen 20 patients like that in a row it doesn't take much to convince you that, nevermind what the randomized controlled trials are supposed to say, people who have taken Clomipramine and got better who go onto those drugs, 19 out of 20 of them, just get worse again. When you put them back on Clomipramine, they get better again. You don't have to be Einstein to figure out what's going on there.

Therein lies a powerful argument about the inappropriateness of RCTs. I was going to say to you when I was talking about, you know, Lasagna and Walter Modell back in the sixties, and how they rapidly decided that RCTs had gone too far. I think the irony of that is, of course, I dunno who started this nonsense about them being the gold standard, but it really has become common parlance hasn't it, to call RCT the gold standard. I sarcastically pointed out in something I wrote quite recently that, has it escaped people's notice that the gold standard was actually abandoned by all Western countries in the 1930s?

Ethan: It makes me wonder, in comparison to the serotonin toxicity, is depression this spectrum that we are all on, and there is a bar that we consider to be depressed enough that, again, has just continued to move further and further, or less restrictive, diagnostically, and it just is a determinant of how many insults or how many hits do you have genetically that predisposes you to biologic depression?

Ken: Look, what a fascinating question. What that reminds me of is the relationship between depression and post-natal onset of depression in ladies who've given birth. And what's fascinating, and again, this is an area of research that I think seems to have been somewhat neglected. But, if you look at people who have their first episode of depression post-natally and who've never had depression before, the recurrence rate is lower than people who have postnatal depression, who'd had an episode of depression previously. Now, you'd think it might be the opposite. My teaching, and I don't know how widespread this is, was always that postpartum psychosis was a particularly severe form of the illness, which was more likely to relapse. And of course, what I've told you suggests that in fact, the opposite is true. Now, my explanation relates to exactly what you were just saying, that it's a question of genetic thresholds. And, of course, it must be the case. Surely, all the things we know about genetics suggest that there would be many different genetic changes that occur, which determine the severity and the course of people's depression. It's not just one genetic abnormality. So you can picture it as a threshold effect. The more genetic insults you have, the more easily you get depressed. And either the worse or the longer it goes on, or whatever it is, and that fits with that model of postnatal depression, because of course, if your threshold is relatively high and you haven't had depression until you get pregnant, we know that, postpartum period is the greatest risk for precipitating depression that you ever encounter. So that fits with that model.

Ethan: One of the biggest mysteries in my training was, I kept seeing peri- and post-menopausal women on inpatient units with postmenopausal psychosis. Most of those women had postpartum depression as well, not to the severity that the symptoms present after menopause, delusional paranoia, thinking that their entire families are dead. It adds uncertainty to the discussion of what is depression and how we understand it. But I was just curious to hear your commentary on that because they're in this period of life where estrogen gradually declines, then all of a sudden they develop psychotic symptoms when they are 55, 60 years old and they've never had a psychotic symptom or seen a psychiatrist in their life.

Ken: Yep. Look, that's what makes you feel that the distinction between triggering factors and contributing factors and exacerbating factors hasn't really had the attention paid to it that it might have done. Are the hormonal changes that are taking place, are they triggering factors like they seem to be in postnatal depression? It's interesting, isn't it? Throughout the whole of my career, there's been all sorts of evidence, increases or decreases of one hormone or another, might be associated with symptoms and precipitating stuff. But the picture hasn't become clearer. There's been no clarification of exactly what's going on as far as I can see in all that time. We must be looking at it wrong, mustn't we? Otherwise, we would've understood more about it by now. And maybe it is to do with triggering factors rather than causal factors or exacerbating factors or whatever. And they're all subtly different, aren't they?

Ethan: When I would bring this up to my attending psychiatrists, I would be sent to the literature and there's not any clear literature, and I'm like, but are you seeing the obvious and common sense trend that is happening in front of you? How do you make sense of that? Can you help me to critically think about why this is happening in this population? Obviously there's not a good answer out there or else we would know how to treat it better, but of course everybody here is so afraid to give women estrogen after menopause due to the risk of certain cancers. But if people could see, if the general public could see, the state that some women are in when estrogen is withdrawn in menopause, it is worth the slightly elevated risk of a cancer to treat them, but it doesn't happen nearly as often as I think it should because of litigation

Ken: I can imagine that's the case