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Joanna Moncrieff: Depression, Serotonin, SSRIs, Psychiatry & Social Media | #88

Full episode transcript below. Beware of typos!

Nick Jikomes

are a psychiatrist with an academic position? Yeah. And you came onto my radar relatively recently with the paper that you did that got a lot of attention that we'll talk about. But you've you've been studying depression and discussing and writing about it for quite some time. Yes.

Joanna Moncrieff 6:44

Yes. On psychiatric drugs across antidepressants and other psychiatric drugs. Yeah.

Nick Jikomes 6:50

So how I mean, how long has you know, in my own lifetime, right? I've I've just always lived in a time where depression was this, you know, official psychiatric illness that people talk about? It's medically recognized. But how long going back? You know, it is deep in history as as necessary. How long is something like major depression been formally recognized by the medical community or whoever the leaders of society were? Is this sort of a 20th century phenomenon? Or does it go further back than that?

Joanna Moncrieff 7:22

So I actually wrote a paper on this, I would say that our modern concept of depression dates to the 1960s, and was really formulated in the context of the development and marketing of the first generation of antidepressants back then. Now prior to that, going back for centuries, there's always been a concept of something very similar to depression, but probably much more serious, more severe than what most people would refer to as depression nowadays, and often it was referred to as melancholia. So melancholia or severe depression goes back much longer. But our our current conception of depression as a relatively common problem, that doesn't necessarily end you know, end up with someone being admitted to a hospital, it dates to the 1960s. Even they're even after then, even after that, it was not necessarily thought to be terribly common. And it was really in the 1990s, with their promotion of the SSRIs, that lots more people start to get diagnosed with depression and prescribe antidepressants. And we end up with a sort of situation that we have today, where in the UK, or in England, at least, latest figures suggest that one in 17 adults, sorry, 17% of adults, almost one in six of the population are taking an antidepressant.

Nick Jikomes 8:56

I see. And can you give us like a synopsis of the history here with respect to the drug treatments that have been used historically? So we go back to the 60s, and we roll forward to the present? What were some of the major drug classes that were used? And that came up along the way? And how do those differ? And why? Why have why has there been an evolution there? Why have we used new drugs every, you know, a few years or a few decades?

Joanna Moncrieff 9:22

Good question. And the short answer to the last part of your of your question is probably because it makes money to bring in new new drugs all the time. But going back, so in the 1960s, actually going back to the 1950s, the first drugs that were proposed to maybe have some specific action on depression were actually drugs that were being used for tuberculosis at the time, and they were in a class of drugs called monoamine oxidase inhibitors, but they were quite toxic so they were never widely used. And then after them A class of drugs called the tri cyclic antidepressants came along. These were drugs that were actually related to the early anti psychotic drugs micropro Amazeen that were being being used and developed at that time. And then, after that various other, various other drugs come along with more drugs that are classed as monoamine oxidase inhibitors. But the big drugs the big sellers during this period, the 1960s, and 70s, were not branded as antidepressants. They were the benzodiazepines. And they were targeted. Mainly at anxiety, they were called anti lytic drugs or anti anxiety drugs. And it's in the late 1980s, that the pharmaceutical industry introduced a new range of antidepressants, most of which are targeted at serotonin. And these are known as the selective serotonin reuptake inhibitors, or the for short the SSRIs that we're now very familiar with.

Nick Jikomes 11:07

And so when you went from MAOIs, to try psychedelics that was in large part due to the fact that Mao is the strong sort of pharmaceutical grade MAOIs that did get prescribed. Those are pretty gnarly drugs that have a lot of very, very serious side effects. So is it fair to say that the transition from Mao is to try cyclex was primarily to avoid how much of it was to avoid those severe side effects of the immune wise and how much of it was the effectiveness of the try side clicks?

Joanna Moncrieff 11:36

So that's a good question. I can't say that I'm an expert on all the things that drove the transition from try site clicks to SSRIs. But you're right to say that one of them was definitely the fact that both tried psychedelics and monoamine oxidase inhibitors mo ma allies have have considerable side effects. So the tri cyclic antidepressants, some of which are still prescribed like amitriptyline are cardiotoxic and dangerous and overdose. And even even taking at ordinary prescribed doses can have some cardiotoxic effects. And the MOI, M ay oh ay drugs had other problems. And so yes, it so one of the drivers of developing new antidepressants was was to find drugs that had lower side effect profiles. But other drivers, I think, are the collapse of the market for benzodiazepines. After the after it became apparent that these drugs were dependence forming, even though they'd initially been marketed as not being dependence forming. And when it became apparent that they were being, you know, doled, out, doled out left, right, and center to all sorts of people with all sorts of mainly social and personal problems. So so the benzodiazepine market collapsed. And the the new antidepressants were launched, I believe, with an intention of stepping into that market, but in a different sort of way with a different message.

Nick Jikomes 13:19

I see. And when can I meet? You know, you mentioned that the benzodiazepines were originally marketed as not being having risk of dependency. But of course, we know that they do. In fact, they're, they're one of the big ones there. And one can immediately think of many analogies of this kind of thing, right? We're a drug is marketed for a certain reason, it does something that helps with something, it also doesn't have certain liabilities. But of course, we learn later, or in some cases we knew at the time, but for nefarious reasons, people said that it didn't have some of these liabilities. So when we get to the point where SSRIs are coming onto the scene, I think in the 80s, what, how are they being talked about there in terms of their risks and benefits.

Joanna Moncrieff 14:04

So, so the big the big difference when the SSRIs come along, or that the big story is the story of the chemical imbalance. So, so SSRIs are marketed from the start alongside this narrative that depression is caused by a chemical imbalance. The particular chemical involved with serotonin and SSRIs can work because they reverse this imbalance they help to boost the underlying low levels of serotonin. And that narrative was introduced, I believe, because it was a very different narrative from the narrative that had gone along with the marketing of benzodiazepines. benzodiazepines are quite sedative drugs, and they were obviously they will obviously changing people's normal mental state in the same way that alcohol would. And in fact, they have, you know, similar similar effects to alcohol in some ways. And so they obviously weren't treating the cause of the problem. They were numbing people out relaxing people. But, but not, but it was difficult to argue that they were really getting to the underlying physiological or biological cause. And, and the, and the widespread use of benzodiazepines plus the fact that they were recognized to be dependent dependence forming really brought that sort of drug use into disrepute in the late 1980s. And therefore, I believe this narrative of the chemical imbalance was brought in to overcome the reluctance that people were beginning to feel about using drugs to deal with emotional problems. And so so this was a really a key part, a key part of selling antidepressants in those early days was putting out this message that depression is caused by a chemical imbalance, and the drugs are being prescribed to reverse it. There, there was, of course, other evidence to support their use, the drug companies were doing the standard randomized control trials, comparing antidepressants to placebo drugs. And showing then, as you can show now that there are small differences between these drugs and placebo. So that was that was the sort of scientific evidence base on which these drugs were being used. And, as you mentioned earlier, some evidence that their side effect profile was better than than the previous drug side effects, side effect profiles. But they were also being marketed Alongside this, this narrative that people had a chemical imbalance, and that's why they should take them.

Nick Jikomes 17:02

Okay, so this narrative forms. And in a nutshell, it's saying, Not only is this class of drugs going to treat the symptoms of this illness, but it's actually doing so in a way that directly speaks to the underlying biological cause that we think is driving depression. So if we if we just take a moment to, so set aside sort of the marketing and the pharmaceutical company in the profit motive side of this, why, why SSRIs at the time, why did they even start doing trials with selective serotonin reuptake inhibitors? In the scientific research world? Why was serotonin, a focus here as opposed to some other transmitter or something else?

Joanna Moncrieff 17:42

So I'm sorry, I can't answer that question. In the 1960s. And through most of the 70s, the main focus had actually been on noradrenaline. That was that was thought to be the key chemical in depression, but people had suggested people had been suggested, suggesting that serotonin had a role back in the 1960s, as well, why it was that in the late 1980s, the drug companies decided serotonin was the one to focus on. I don't know, the had the there had been SSRI drugs released back in the 1970s. As far back as the 1970s. There was one that was released briefly and then taken off the market because it was found to be toxic. Forget the name at the moment. So they had they had been developing some serotonin targeting drugs all along. But why they took that decision to really focus on them at that time. I don't know.

Nick Jikomes 18:42

I see. So is it fair to say that, you know, in at this time, if you were, say, a scientist, a psychopharmacologist, and you were well versed in the scientific literature at the time, that it wasn't crystal clear that serotonin and elevating serotonin would have been the obvious choice to make?

Joanna Moncrieff 19:00

No, absolutely not, as I say the main interested actually previously been on noradrenalin.

Nick Jikomes 19:06

I see. And you mentioned, you know, obviously, at the time, they were doing randomized controlled trials, all of this stuff has to go through the normal drug development process. So there's data there, there's double blind placebo controlled studies showing some positive effect. Can you talk a little bit about the specifics there? How big of an effect compared to placebo? Were they seeing what kind of people were they studying? You know, representative samples of the population? What was the strength of that evidence?

Joanna Moncrieff 19:32

Yes. So this is a really important question because because in the in the debate that's followed my paper that the main criticism has been the main point people are made is that antidepressants work, and when they say that, what they are referring to are these randomized control trials. Now, what they involve is they involve recruiting people. Well, the first thing to say is that most of them almost All of them have been done by the drug companies in order to test the drugs that they are developing. And what they usually involve is advertising for people who think they might have depression, come along and enroll in a study the studies, randomized people either to be put on an antidepressant or to be put on a placebo, having having confirmed that they can be diagnosed as having some form of depression. And then they follow people up for a few weeks. Some of them involve some of them, do what's called a placebo wash out. So they actually start by giving everyone a placebo. And then anyone who responds to the placebo they exclude, because they say, Oh, well, you know, we won't, we won't be able to see an effect with these people. And then they just take the people who haven't responded to the placebo, and randomize them either to have the antidepressant or to have or to continue with with the placebo. And these trials usually last six to eight weeks. And then and then the researchers come along and do a depression rating scale with the people who are involved. And then the statisticians compare the scores on the depression rating scales between the people who were allocated to take the antidepressant and the people who were allocated to take the placebo. And

Nick Jikomes 21:30

so, So to clarify, a lot of these randomized controlled trials were done looking specifically at people who had depression and did not initially respond to a placebo.

Joanna Moncrieff 21:44

Yes, yes, as I say, this thing called a placebo washout is is a very common procedure. Another thing to mention is that many of them will have involved people who are already taking antidepressants, most of them do not exclude people who were already taking antidepressants. So you're also going to have some people entering the trial who have previously been on medication, and then then it taken off it to go into the study. So but another point to emphasize is they're very short term, so six to eight weeks, whereas we know that most people take antidepressants for months, and many people end up taking them for years. So that's a real gap in our knowledge. But that, coming back to the results, so what the main results are is this comparison, in the scores on depression rating scales between people who are taking the antidepressant and people who are taking the placebo, depression rating scale scores are just collections of typical symptoms of depression, they, they've not been particularly well validated in the sense that we don't really know whether they really correlate with with disability or impairment or not being able to go to work or, or anything like that. They're, they're just what people report about their their current symptoms. But anyway, putting that aside, what the studies show is that if you, especially if you add in all the studies that are if you look at all that take an overall view of all the studies that are published, and the studies that are not published, because we know that the ones that get published are more likely to find positive effects of the drug. But if you add in all the published and unpublished ones together, what you find is that there is a very small difference in depression rating scale scores between people taking an antidepressant, and people taking a placebo, the people on the antidepressant do a little bit better. Now, the most commonly used rating scale is called the Hamilton rating scale for depression. And its maximum, the maximum you can score on that is 52 points. Typically, people going into a trial will have 28 to 30 be scoring 28 to 30 points. The difference between antidepressants and placebo that is found at the end of these studies, is two points, two points, two points. So it's it's a very small difference. People improve people generally improve by around eight to 10 points in these trials. But the difference in improvement rates between the antidepressant group, and the group of people who take placebo is around two points. In fact, in fact, in the really big meta analysis that had been done recently a bit less than two points. So it's, it's very small, it's a very small difference.

Nick Jikomes 24:44

Very small difference, and it's compared to placebo. This is not a random sub sample of the population or even a random sub sample of the population of people with depression. It's you've got this placebo wash up phenomenon and the effect Is that I mean, I didn't actually know it was that small. So if someone is taking the SSRI and one arm of the trial, they might say improved by eight to 10 points on the scale. But on average, the people taking the placebo, the non SSRI, placebo, are going to be improving by six to eight points or something like that.

Joanna Moncrieff 25:16

Exactly. That's exactly, yes, yeah. So absent that there are, there are other methodological features of these trials, which mean that possibly even that small differences are not a real difference. And one of the, one of the problems with these trials that that creates that, that may explain that difference is that it's a different experience taking an antidepressant from taking a placebo. Therefore, some people can guess, accurately whether they have been allocated to the placebo or to the drug, which of course, completely undermined the whole point of using a placebo, you're using a placebo, to try and control for the fact that we know that if you give someone a tablet, even just a dummy tablet, you are likely to get see some improvement in their mood, because you've given them some hope. And and we know that giving people hope does does help to improve depression. And

Nick Jikomes 26:22

so I mean, this is particularly a problem when you're when you're testing something that's a psychoactive drug, right? Because the whole point of it being psychoactive is you can feel the effects of it. And so it comes to this question of what do you choose? Is the placebos something truly inert? Or do you pick a placebo that is itself psychoactive, but in a different way? And so what was typically the placebo identity in these types of trials?

Joanna Moncrieff 26:45

So that's, that's an interesting question. So in recent antidepressant trials, by recent I mean, going all the way back to the 1990s, and into the 1980s. All the trials have only used a completely inert placebo. So you're comparing an active drug with an inert placebo. And there are there are lots of studies showing that people can guess more accurately than, than would be predicted by chance, whether they're getting the active drug or placebo, not in every study. And because the side effects of of antidepressants are lower, they're, they're less less strongly psychoactive drugs than some of the older antidepressant so. So not everyone is guessing correctly. But certainly, in some studies, more people can guess them correctly than you would predict by chance. Going back to the 1960s, and into the 1970s. A few trials were set up using an active placebo. They these trials used a low dose of something that produced a dry mouth, so it wasn't like a psychoactive placebo, but it was something that gave people some side effects. And so so it suggested to people that they might be on a on a on a real drug rather than in a, in a tablet. And those studies by and large, found no difference between the drug and the placebo.

Nick Jikomes 28:12

Interesting, so you get to the 90s, you find these positive results, but as you're telling us right now, the important caveat there is these are very, very small effects in a non random sample of the general population. And nonetheless, the SSRIs take off from a commercial perspective. Now bring us to the present day, how many people are on these things? And, you know, today, what is our understanding of like the percentage of people that see some improvement with SSRIs, with or without therapy?

Joanna Moncrieff 28:45

So, yes, so as you say, they've absolutely taken off. Prescriptions have, since the early 90s, at least quadrupled in the UK. We've now got one in six people using antidepressants, we've got increasing rates of younger people using antidepressants. Antidepressants used to be well still are predominantly prescribed to middle aged and older people, but but their rates of use in younger people are creeping up and up, especially in the last decade or so. And and this is a phenomena you see worldwide and in the US that the last data I'm aware of showed about 12% of people were using antidepressants, but that's that's back from about that's, that's probably about 10 years old now. So I should think it's quite a lot, a lot higher than that now. So they're being very widely used.

Nick Jikomes 29:43

And can you start to talk a little bit now about the recent paper that you published, what kind of study was this and how did it work? How did you do it? And then what were the basic findings?

Joanna Moncrieff 29:56

Yes, so So the paper we just published was looking at the evidence for links between serotonin and depression, particularly, we wanted to test out the theory that depression is caused by low serotonin levels. And we did this because I've been aware that this, this idea that this is the cause of serotonin has been very widely accepted by members of the public. And the promotion of this idea has gone hand in hand, as I was saying earlier, with the increase in use of antidepressants. And and that is not a coincidence, that's because they were marketed on, you know, in the context of promoting this idea. So, and I was also aware, at the same time as being aware of how widely accepted this idea was, I was also aware that many leading psychiatrists recognize that there actually was not convincing evidence to support this idea. But although this seemed to be recognized, no one had really got all the research together so that you could take an overview and really come to a conclusion either way, well, is it supported? Or isn't it supported? That was just really the sort of rumor that really, actually there isn't, there isn't the evidence base for it. So what I did was get a team together. And we identified first of all the main areas of research that have attempted to look at possible links between serotonin and depression. Now, you can't stick needles into the brains of human beings to measure the serotonin levels in the brain directly. So the research that's been done with human beings, and it's argued, arguably, I would say it's only human beings that feel depression. So it's only really valid way of looking at depression. The research that's been done with human beings has been looking at indirect ways of trying to assess levels of serotonin in people with depression and in compared with people who don't have depression. So we identified six main areas of research, and got together overviews of the research and all those main areas in order to in order to come to a conclusion about whether there was evidence supporting this idea that depression is caused by low serotonin or not. So I could go through those different areas of research. I don't know if people would be interested in that in that, yeah.

Nick Jikomes 32:31

Why don't you just try and concisely summarize that for people to give people a basic sense of the markers that you were looking at it and what you saw.

Joanna Moncrieff 32:39

So we looked at studies that had looked at serotonin levels in blood and urine, and other body fluids. We looked at research that had looked at levels of the serotonin metabolite, and that's been done particularly in the cerebral spinal fluid. So this is the fluid that covers the brain and the spinal column. We looked at levels of serotonin receptors. These are the receptors on the ends of cells that serotonin links to in order to, in order to have its exert its action in the brain. We looked at the levels of something called the serotonin transporter protein. This is the protein that transports serotonin out of the gap between the nerve cells, the signups where it has its action, so the serotonin transporter protein effectively deactivates or remove serotonin from can be active. And then we looked at a set of experiments that gave people a drink that lacks the molecule that's used to make serotonin. And then a few hours later, measures people's mood to see whether this drink, apparently, and evidence suggests that it does reduce levels of serotonin. And so the studies have been looked at be looked at whether this whether this, taking this drink, causes people to be depressed or causes people's mood to decline significantly. And then finally, we looked at genetic studies, there have been a lot of studies recently of the gene for the serotonin transporter protein. They've been looking at whether having a particular mutation of that gene predict the onset of depression. And studies have also looked at whether having that gene predicts the onset of depression in the context of adverse life events, whether there's an interaction between having the drug and having adverse life events. And basically, across all those areas, there was no convincing evidence of a link link between or any link between serotonin and depression, if anything, there was a little bit of evidence from some studies, particularly the receptor studies, that and the transporter studies that higher levels of serotonin might be linked with depression. But the most likely explanation for this was that many of the participants in these studies had taken SSRI drugs, which we know which we know, modify the serotonin system, and they've been taking these drugs either during the time at which the experiments are done just before that time. And we also know that the effects of these drugs can be quite long lasting as well. Yeah.

Nick Jikomes 35:42

So So basically, if it's, if it was true, that depression is causally linked to serotonin, that people who have depression have lower serotonin levels and need to boost it, which would be the explanation for why something like SSRIs are supposed to be working. You have all these expectations, right? People with depression should have lower serotonin levels on average, they should should go up after SSRI use. As you go from having depression to recovering from depression or developing depression. As you go from starting your SSRI dosing, and so forth, you expect all of these things to change in a certain way, right? You expect serotonin levels to go up or down, depending on which way we're moving. You expect serotonin receptors and transporters. And those types of proteins to go up or down depending on, you know, if you're recovering from depression are developing it depending on if you're elevating serotonin levels, with your SSRIs, and so forth. And basically, the expectation that you would have, if it's true that low serotonin drove depression, you're saying you did not see that basically, anywhere you looked?

Joanna Moncrieff 36:45

No, no, exactly. And I mean, we only we looked at the evidence we looked at and none of that indicated that there was a deficiency of serotonin in people with depression compared to compared to people who didn't have depression, we found a couple of other interesting things. One was that the genetic studies in particular showed that there was no effect of the of having this mutation of the serotonin transporter gene. And there was no interaction of the gene with adverse life events, but there was a very strong effect of adverse life events on your risk of developing depression or not, which is consistent with other research on adverse life events. And the other finding that we've that was interesting, and I would put just this is this is just a tentative finding that came out of some of the studies was that people on long term antidepressants showed some indications of actually having lower levels of serotonin in particular, lower levels of serotonin in the blood in the in the study that in the meta analysis that we looked at looked at blood levels of serotonin and and there are other studies also showing that blood levels of serotonin are reduced and people with depression. So I we didn't you know, that wasn't something that we set out to look at particularly. And there are various possible explanations, but one possible explanation is that, that although serotonin although SSRI drugs may boost serotonin in the short term, it may be that the body reacts and over compensates for their action, and therefore you actually end up with lower levels of serotonin.

Nick Jikomes 38:33

Is this the idea of a compensatory change? So So for example, you take an SSRI acutely you start taking it today, and you take it for some days or weeks, that's going to elevate serotonin levels in your synapses. But then, you know, the idea would be that the brain is detecting Oh, hey, there's there's higher levels of serotonin around, let's compensate for that by bringing things down. Is that the basic idea? And is that what you would expect to see with the chronic use of a drug like this?

Joanna Moncrieff 38:58

So, yes. Well, that that effect has been shown with other drugs. Certainly, we know, we know that's the case with opioids for example, we know that, you know, the body reacts to oppose the the effects of the opioids. And there's some evidence that it can overshoot so that people who are on long term opioids may actually start experiencing even more pain than they had before they started the opioids because the body's you know, got it's got its homeostatic mechanism a bit wrong. It's overshot and it's actually making people more sensitive to pain. So there may be something similar going on with SSRIs. But I would say that the the evidence on quite what SSRIs do and how they're affecting how they are affecting the serotonin system is confusing and inconclusive at the moment.

Nick Jikomes 39:54

I see. And so what can you talk a little bit more about what is known what is known today? And what has been known since SSRIs, were originally coming onto the scene about the potential long term effects of chronic use.

Joanna Moncrieff 40:11

So, so when nurses first came onto the scene, there was very little interest. I mean, shockingly, now looking back very little interest in whether they had any long term effects. And I think this comes back to this idea that they were reversing an underlying abnormality that sounds like such a good thing to do, that it didn't seem obvious that we should really be, you know, be too worried about any long term effects. If you, if you think about that, you know, if you don't take that model, and if you think about them differently, if you think about them as psychoactive drugs, as you described them earlier, which I would, you know, completely go along with that description. They are drugs that change the normal state of the brain and therefore change our normal mental states. If you think about them in that way, then it becomes obvious that we do have to have some concern about what the what the long term effects of using them on a daily basis for weeks and months and years might be. And we have good evidence now that they are dependence forming in the same way that benzodiazepines are dependence forming. They they don't cause that they don't cause people to get high. Their effects are not particularly pleasant when people take them. So they're different from benzodiazepines and opiates and alcohol in that way. But they are similar in the sense that when people try and stop them, they experience physical withdrawal symptoms, physical symptoms, including things like dizziness, nausea, but also anxiety. Hi hypersensitivity to, to, to sound and other sensations, typically, these with some antidepressants, these electric shock sensations that people get in the brain and that's also a symptom of benzodiazepine withdrawal. And there's probably I would think, an indicate all these drugs are probably benzodiazepines are definitely sedatives. Antidepressants probably also have some sort of restricting effect on nervous nervous activity, the activity of the nervous system. And these symptoms like these electric shock symptoms, and benzodiazepines also cause tinnitus during withdrawal sometimes, and as I say, you know, increased sensitivity to sound, all these things, I think, indicate a brain that is on the rebound from being suppressed. Yes, so it's become hypersensitive, you've, you've suppressed the sensitivity. And, and antidepressants do that, to some extent, we can see that, for example, in the way that they have these sexual side effects that these are very well recognized and and have been, have been acknowledged, since they were introduced. They they cause all sorts of sexual dysfunction, but one of the types of sexual dysfunction is reduced sensitivity, reduced sexual responsiveness which may be linked to these reports that they are have these emotional numbing effects as well. And so I think what's happening when people come off them is you're getting this rebound in sensitivity. There's heightened sensitivity or awareness of sound and other stimuli and, and an emotional lability people become also sort of more emotional than they were previously. When the drugs were suppressing their emotions. Yeah. Yeah.

Nick Jikomes 44:02

Yeah. I mean, it makes perfect sense. I mean, there's many, many examples of this in biology and in psychopharmacology, you take a drug that has some effect, in this case, something that's dampening, at least to some extent, certain types of brain activity. And if you're, you know, if you're dampening what the brain is trying to do, so to speak, then when you release that constraint, there's going to be this, this overshooting or this rebound, you know, sort of just like pulling a rubber band or something, and then and then suddenly, suddenly letting it go. Yeah.

Joanna Moncrieff 44:35

So I think that's definitely happening. But I think it's probably not all that is happening. And I've, over the last few years, I've come to appreciate that. The limitations of what we know about the long term effects of drugs, especially drugs that affect the brain, and that's partly because some of the symptoms people get during an To depressant withdrawal are not necessarily related to this rebound effect. And it's also related to the fact that this this sexual dysfunction effect so. So as I said, sexual dysfunction is well recognized as an acute side effects of taking antidepressants. But it's increasingly being reported that even when people stop taking antidepressants, the sexual dysfunction can continue. And often what continues is reduced libido, reduced sensitivity. And so this suggests that when people stopped, sometimes instead of getting a rebound, they're actually getting a continuation of the symptom that they had when they were taking the antidepressants.

Nick Jikomes 45:48

So another way of saying that is that there are long term persistent side effects that come that can come from chronic use. Yes, yes,

Joanna Moncrieff 45:55

absolutely. And so these there are these persistent sexual side effects. And also, when people withdraw it, you know, I think I think we used to think certainly, I had the impression that after people withdrew from a drug, you know, you'd get unpleasant side effects, which might go on for a few weeks, but then they would stop and you'd be back to normal. I think increasingly, we're appreciating certainly with some sorts of drugs, that people don't go back to normal and that sort of timespan. And it may take very much longer. And there are these basically persistent withdrawal symptoms that can go on for years. And some people, particularly with antidepressants, but they're also reported with, they've also been known about for a long time as benzodiazepines.

Nick Jikomes 46:41

And I suppose that also just sets you up for a kind of vicious cycle. Because if you have negative side effects that are persisting long after you discontinue the use of one drug, you've now got a new set of symptoms that you're going to want to treat. And it's plausible that you're going to try and treat them with other drugs, and you can just kind of like cycle cycle in that way.

Joanna Moncrieff 47:01

Yes, and I think this is one of the problems from the fact that antidepressant withdrawal symptoms weren't really widely acknowledged until quite recently, I'm sure that there are many people who tried to come off antidepressants, experienced withdrawal symptoms, and thought that they were having a relapse of their underlying condition, and then did back up back on their antidepressant when maybe they didn't need to, but maybe also ended up back on ended up taking a you know, another drug like a so called mood stabiliser, or a benzodiazepine or an anti psychotic or something else because of the persistent symptoms they were having. And the fact that anxiety is one of the one of the main symptoms is obviously going to make that particularly likely. And I think the anxiety again, is, is related to this fact that the drugs are suppressing nervous activity. And so I think the anxiety is a rebound effect. But But obviously, especially if people were a bit anxious to begin with, they might not might not recognize it as that, especially if no one's suggesting it, and might therefore just think they're having a relapse.

Nick Jikomes 48:11

Yeah, that's interesting that you know, and this, this phenomenon comes up in other areas with other drugs as well, where you, you form a dependency on a drug, you try to come off of it, the withdrawal symptoms, or being mistaken by the person having them as a relapse or something like that. And then that just incentivizes them to stay on the drug.

Joanna Moncrieff 48:30

Yeah, yeah, absolutely. I think that, that I'm sure that's been happening a lot. Another thing to say about that is, I think, I also think that type people, I think that that people become very worried about stopping taking an antidepressant. I mean, if you've, you know, if you've taken this drug, and you have started to feel better, and you think that this is, it's the drug that has had this effect, and it's the drug that's keeping you well, you can understand that when you start trying to come off the drug, you might become very anxious. And, and if you're getting a few odd symptoms, that might make you even more anxious. So I think there's a psychological component as well to this, which is not to say that people are making it up in any way, but just saying it to emphasize that people often feel very vulnerable when they're coming off a medication, and therefore will, you know, be even more likely to interpret any symptoms they have as a relapse as a catastrophe, and therefore think that they need to go back on the medication.

Nick Jikomes 49:38

Yeah, I mean, if you're taking something for a period of time, and you perceive that it has helped you to some extent, and you are considering going off of it, you're naturally going to have some uncertainty or some anxiety about that, and that would, you know, one would expect that that's just going to predispose you to be more sensitive to the withdrawal symptoms you're going to feel which are itself going to include things like anxiety or just sort of mood instability?

Joanna Moncrieff 50:01

Yeah, absolutely. And of course, you know, in many cases, the doctors will think this as well. So people will get the same message from their doctor, okay, of course you feel a bit, you know, you're not feeling so good that shows you must be relapsing.

Nick Jikomes 50:14

So going back to this notion of the chemical imbalance, if the original idea here is that SSRIs are correcting a chemical imbalance, specifically that depression is being driven by low serotonin levels, you're boosting serotonin levels with the drug. And that's, that's why these SSRIs are having the very small effects that you told us that they were having in the original trials, in principle, what other kinds of explanations for what's driving depression are out there in terms of the underlying biology.

Joanna Moncrieff 50:46

So there are there are lots of different theories about the biological origins of depression. People are talking about it being to do with there not being the nerves not making enough connections between other nerves. People are talking about it being due to a deficiency of glutamate or a dysfunction of the opioid system. Most of these speculations are in the context of new drugs that are being marketed for depression. So opioid dysregulation has started to be talked about as some opioid drugs are being developed for the treatment of depression, believe it or not. And the glutamate hypothesis has been linked to ketamine and esketamine, which are being marketed for the treatment of depression at the moment. And this idea of depression and being due to

deficiency of nervous connections or, or even as I've seen, put on the John hot Johns Hopkins website, due to brain damage, they're suggesting depression is a process of brain damage. This is in the context of the use of both ketamine and psychedelics, which are being suggested to possibly work by increasing the number of connections that occur between different nerve cells in different parts of the brain. I, I would like to emphasize that all these are entirely speculative. They're all coming up in the context of new treatments. So they are all new ways of trying to persuade people to take new medicate new new drugs for depression. And I think that this is the wrong way to think about depression, I think thinking about depression as a biological condition, is the wrong way to think about it. And indeed, the reason that the pharmaceutical industry needed to run a campaign to persuade us all that depression is due to a chemical imbalance is because we do not naturally think of depression in that way. That's not to say that, you know, things aren't aren't going on in the brain when people are depressed. Of course they are, it's not that the brain is out of the picture or irrelevant. But it's just to say that maybe that's not the best place to understand depression, maybe looking in the brain is not not the best place to understand it. And our, you know, natural understanding of depression and of other emotions is as a reaction to our life circumstances, which is, of course, colored by the person we are by all our developmental experiences by our genes, which also helped to, you know, mold our personality. But, so it's influenced by these things, but it's nevertheless a reaction to things that are going on around us. And I think that's a much more plausible and natural way of thinking about depression. Doesn't mean it's not going to be affected by by drugs.

Nick Jikomes 54:00

Absolutely. But what you're saying is basically, everything that's going on in terms of the ideation going on in the research community around what drugs are working here, and how they're working, is that there's a lot of motive motivated reasoning, that is apt to happen because, you know, if you've got the chemical imbalance idea to do with serotonin, that's happening in the current context of you having an interest in the SSRIs working if you are trying to argue that this is a neuro plastic deficiency, and there needs to be physical rewiring, that the psychedelics or ketamine can help, you know, that's in the context of developing those as medicines that can be marketed and used. So if you could wave a magic wand, let's say you had the entire budget of the NIH in the US or whatever you had, effectively, unlimited resources, and your charter was to understand the origins of depression in the brain. What kind of research would you like to see get done?

Joanna Moncrieff 54:57

Okay, I will answer that question. But first of all, just just To start to go back to your point. So you're absolutely right that these specific theories about the biology of depression are arising in the context of, of the marketing of new of new products. But there's, but there's a more general understanding in the psychiatric community about, about the, so most psychiatrists and researchers, researchers in psychiatry assume that depression must be some biological entity that must be amenable in some way to drugs or other sorts of interventions on the brain. And that is an assumption in itself that that which is not necessarily tied to a specific drug or a specific product, but is tied to I believe the psychiatric recycler the profession of psychiatrists need to see mental health problems as biological brain based problems. I don't think they need to be seen like that. And you can give me all the money you like, I don't think that it's worthwhile looking in the brain to find the cause of depression, I absolutely don't, I think I think we have a perfectly good ordinary understanding of depression as a, as an ordinary human reaction to adverse circumstances. Some people react more strongly to things than other people do that that's true across the board. There are individual differences. But I don't, I don't even say, you know, I don't think that they have much to do with the brain or with biology, either, although, although your genetic makeup is going to play some role in them. So you know, so in order to help people with depression, I don't think looking at the brain is is going to achieve that, I think we need a different understanding of depression, we need to see it as a reaction to life circumstances, and we need to work out how to help people. First of all, we need to work out how to make a better world in which fewer people are distressed and unhappy, in are in circumstances that make them feel distressed and unhappy, and would make anyone feel distressed and unhappy. And secondly, we need to help people who maybe are more sensitive to things than others find ways of, of dealing with with situations and managing managing their the ups and downs of emotions in a in a better way. And so,

Nick Jikomes 57:40

yeah, so the basic idea here, that is that depression is, you know, if you just think of a human being as a bunch of inputs, and then their behavior, behavioral and affective output being how they're feeling and what they're doing. There's many inputs in our lives, right? There's your diet, and what you're eating, there's your sleep schedule, there's your personal relationships, and how healthy they are, how stressful your work is, you know, these are all inputs. And if the inputs are, you know, in a certain constellation, that's going to drive a tendency towards depression, like behaviors. And, of course, there's individual differences that that, you know, in our genetics and other things that make us more or less sensitive to having that kind of depressive output in response to the environmental inputs that are that are composing our life. So the name of the game is you have to teach people through therapy or some other means to either change what those inputs are by changing, you know, how you're working, what your relationships are, and so on and so forth, or reacting to them differently. And I think what you're saying is that, certainly, various drugs might modulate your ability to change those inputs or react to them differently. But ultimately, the cause is not, you know, something, you know, bubbling up from inside of you. It's this constellation of environmental inputs that's causing you to feel a certain way on a day to day basis.

Joanna Moncrieff 58:59

Yes, absolutely. That's what that puts it very well, I think. You've got inputs, and you've got outputs. What goes on in between, is, I think, probably unknowable, and not useful anyway, even if we could know it. So deal with is the inputs, as you've said.

Nick Jikomes 59:17

And so with all of that in mind, sort of going back to the notion, I want to talk a little bit more about the notion that SSRIs are having this kind of general numbing effect. They're making one less sensitive to their environment and their own emotions. To what extent do we know that that's actually happening? Because I know a lot of people say that they sort of feel that way on us, this rise to the highest current aren't quite as high and the lows aren't quite as low. But in general, there's the sort of effect of dwelling that the SSRIs tend to have, how, how firm is our knowledge that that's in fact happening? And does that explain the perceived benefit they're having? They're just sort of numbing you to all of those inputs in your environment that made you depressed, but of course that just allows you to persist in, in not addressing those inputs. Yeah.

Joanna Moncrieff 1:00:05

So. So we have some, you know, scientific evidence published in in peer reviewed journals of emotional numbing. Then there is some, then there was some papers by people who've been trying to investigate that a bit further. And they suggest that No, it's not due to the drugs, it's due to the underlying depression. And I don't think those two things have been perfectly well teased out. But there are a lot of people who describe emotional numbing, and to me, I suppose the most convincing thing is this link with the well recognized sexual effects of SSRIs. So there are a couple of papers, one done by me, showing that people who report emotional numbing are also reporting the same sort of sexual side effects. So there seems to be a correlation between these. And as I say, the, you know, the sexual side effects are very well recognized. So it just seems sort of plausible that the drugs might be having a similar effect on, on on our general sensitivity to the environment, which would include our emotions. So yeah, I don't think it's like 100% secure, but but, but evidence on adverse effects or effects that aren't the main focus of research is often is, is often not very good, because it's not been the focus of research. And so no one has, I mean, you, you could actually fairly easily set up a volunteer study where you gave volunteers a, an antidepressant or an SSRI or a placebo, followed them up for, you need to follow them up for a good few weeks, that would be the only thing certainly people who are happy to take the drugs for a few weeks, in case this numbing effect, it takes sort of time to get going is a bit cumulative. And and then you could, you know, then you could ask them about their emotions, you'd need to do quite detailed, you know, quite a detailed assessment, I would say, because emotion numbing is quite a subtle sort of concept. But that would be one way to do it. And as far as I know, no one's no one's done that. So our evidence comes mainly from people who have experienced depression or anxiety, who may therefore also have had some, you know, emotional numbing as part of their original condition. So it is a bit difficult to tease out. But I think it probably is a real effect. And, you know, it is reported by lots and lots of people, I suppose the other bit of evidence that's quite convincing is it's reported by a lot of a lot of people who are otherwise very positive about taking antidepressants, it's not just reported by people who are, you know, feel that they're a bad thing and being harmful to them. And, and, obviously, if, if, if antidepressants are causing that effect, and the difference in, as we've said, the difference between an antidepressant and a placebo in these controlled trials is very small, then, you know, then a certain amount of emotional numbing may well, it would seem to me account for that difference. But, but I think it's not just about the emotional numbing, I think, thinking about that difference. It's also important to just think about these drugs as psychoactive drugs, they are drugs that change people's normal mental state, they change the normal state of the brain, though, some of the antidepressants have quite subtle effects. But nevertheless, some people will be feeling just slightly different. And, you know, if you, if you are depressed, and you go out and have a few drinks of alcohol, you may well not be depressed after you've had those drinks, because you're just in a different sort of state. It's not necessarily that you know, that, that alcohol is particularly dampening your emotions, you're just in a different sort of state. So you're not so aware of being depressed anymore. So it may be it may be that that's happening, that you're in a different sort of mental state, you're not therefore so in touch with your underlying emotions, as you would be if you were not under the influence of this substance.

Nick Jikomes 1:04:33

Yeah, no, I think that's that's an interesting area to think about, like how much of people feeling better on a day to day basis when they have depression, whether or not they're on an SSRI is just how frequently they're moving from one emotional state to the other. If you're, if your days and weeks are very homogenous, it gives you a lot of space to really ruminate in any depression like symptoms you may having. But if you're, if your life is more dynamic, because you're socializing frequently When you're going out and doing sports, this, that and the other, you're constantly being moved around, you know, emotional affective space. And there's probably something really powerful just about that not not any particular thing you might be doing, or drink you may be having or whatever, but just the fact that you're, you're not always in the same emotional space, day by day, moment by moment.

Joanna Moncrieff 1:05:21

So I think I think that's a really good point about the nature of depression, that depression is, it's like a vicious circle, you know, people start feeling depressed, therefore do less, therefore, start to ruminate have less, fewer of the positive experiences that will take them out of that low mood, because they're not, you know, opening themselves up to experience they're, you know, they're withdrawn, they're, they're becoming inactive, and therefore, it can spiral, you know, and become more and more severe. And I think that's, that's, you know, a useful way of thinking how depression sort of develops.

Nick Jikomes 1:05:57

Yeah. And I want to ask to about, so more and more people over time are being diagnosed with depression and being prescribed antidepressants. To what extent do we know that that's, you know, how much of that is due to us just like lowering the bar for what qualifies the depression, and being more liberal in prescribing these drugs? And how much of it is actually people are becoming more depressed over time? And so something about our environment is actually driving that?

Joanna Moncrieff 1:06:26

Yes, that's, that's a good question. And the other possibility is that we are calling we call depression, we now call distress depression, but we would have had, we had other words for it going back not putting not phrasing that very, very well,

Nick Jikomes 1:06:46

well, growing more and more things depression, that we used to call by another name, that we

Joanna Moncrieff 1:06:50

used to call anxiety or distress or neurosis, you know, we had lots of other so I think that's, that's one of the things that's happening. And, and, and maybe also, you know, all this publicity about mental health, it has lowered the bar to so that lower levels of distress are now being labeled as mental health problems or psychiatric problems, which would not previously have crossed the bar. And I think it's, you know, it's difficult to say, each, each age, each generation has has different, stressful, difficult circumstances to deal with, don't they? I mean, I grew up when the Cold War was, was, you know, looming over us, and everyone was terrified of the nuclear catastrophe. Now we've got, you know, climate change, and, and all the worrying consequences of that, that people are growing up with. As well, as, you know, I would say, probably a more competitive environment than than we had a few decades ago. But on the other hand, maybe more, you know, maybe more opportunities, in some ways. So I, I think it's very difficult to say whether life has actually got more depressing for people or not. There are always there are always challenges in life. And there certainly are challenges about about our modern age.

Nick Jikomes 1:08:23

Yeah, so I mean, independent of that, you know, whether people are becoming more depressed in general, or just, you know, changing our language and our diagnostic criteria. One thing that also facet fascinates me about depression and antidepressant use is the demographic differences that you see here. So, in particular, you know, there's a chart that I've seen circulate a lot that I believe came from the New York Times, but but you can see this data in multiple locations. And that's basically across the board in any age and sex cohort, you look at antidepressant use has increased over time. But there's one demographic that like stands out pretty strongly from all the all the rest, and that's basically middle aged white women. They're prescribed antidepressants far and above other age, and race and sex demographics. So what do we know anything about what's going on there and why certain demographics of people are using antidepressants at a much higher rate than other demographics.

Joanna Moncrieff 1:09:20

So, middle aged white women have been the main users of barbiturates of benzodiazepines are now of antidepressants. They are fast becoming the main users of stimulants for which are prescribed for adult ADHD. In fact, they were the main users of stimulants going back to when they were prescribed for depression and neurosis back in the 1950s. So that that group of people seems to be the group of people that present to their doctors with mental health problems with distress with anxiety with depression, whatever they want. however it is currently labeled. And why that is is a good question. Yeah, I mean, I'm just,

Nick Jikomes 1:10:12

we don't we don't know why. But this is not an antidepressant specific phenomenon. This is a demographic that that shows this pattern across history for other types of drugs as well. Yes, yes,

Joanna Moncrieff 1:10:22

you can see this. And if you look back at old advertisements, they're all aimed at the same demographic, but it's it's so sorry. No worries. Hello. Hi, I'm just doing a podcast man. Yes, we'll do Yep. Okay, bye.

Nick Jikomes 1:10:45

So anyways, you look historically in advertisements for these various classes of drugs have often tended to target this demographic specifically, yes,

Joanna Moncrieff 1:10:53

you say that you see the same. You see the same sort of woman portrayed in adverts going back to the 1940s. As are portrayed in adverts today. It's quite extraordinary. I have some pictures that I sometimes sort of put side by side to show people how similar

Nick Jikomes 1:11:09

and I guess there's a chicken and egg problem here. Are, is this demographic using more of these drugs? Because they're being targeted? Or are they being targeted? Because this demographic is for whatever reason, more likely to want to or need such types of treatment?

Joanna Moncrieff 1:11:24

Yes, I'm sure it's a bit of both. And, yeah, what why, why it is particularly middle aged women. Seek help of this sort. I'm not an expert on but there is some, you know, work in psychology suggesting that men are more likely to externalize their distress, to become angry or maybe to go to the pub and drink. Whereas women often internalize it. And, you know, therefore, think of themselves as being ill and needing needing a fix from from the doctor and medical fix.

Nick Jikomes 1:12:00

So another phenomenon that I would love to chat with you about is sort of the impact of technology and social media, on mental health and mental illness, generally speaking, and I don't just mean like, how is social media affecting all of us in terms of our mental health, what I specifically mean is, the phenomenon that I and many others have observed, it's quite clear that you can see out there is that social media has enabled people with certain psychiatric conditions, whether it's major depression, or schizophrenia, or bipolar disorder, or autism, or whatever, to sort of document and advertise their journey with whatever that ailment is. So for example, you might go into YouTube, or Instagram or whatever. And there are YouTube channels with very large followings. And the entire channel is about say, one woman's battle with bipolar disorder, and documenting, you know, her ups and downs and what drugs she's using and how they're making her feel, and this and that, and the other. And you can look at that from two sides. I think, on the one hand, you could say, well, this is positive, it's enabling people with ailments to connect with other people who have a similar experience, no matter where they are on the globe, it's enabling them to get, you know, positive reinforcement and affirmation from people to help them overcome their ailment. And it's, you know, it's giving them it's giving them an outlet, so that they're not just sort of negatively ruminating on whatever they may be suffering from. On the other hand, it strikes me that there may be are some perverse incentive incentives that get set up here, because now you've got situations where people are getting positive reinforcement, and even making considerable sums of money, basically, for having an ailment and, you know, it's not difficult to imagine that, you know, the ailment that comes to be positively associated by that person, and and that the sort of positive reinforcement they're getting, for documenting and advertising, what they're going through, is actually setting them up to want to perpetuate that. So do you have any thoughts on how social media and the ability to connect with people in that way for people with like, serious mental illness is actually affecting their ability to to get better?

Joanna Moncrieff 1:14:10

Yeah, I think that's a good point. But going back, I'm, I'm really concerned about this phenomena, because I don't think that people fully understand the nature of the labels, mental health labels that we use, they are simply labels and I yeah, I don't think people understand that. They are often said to be diagnoses. Now in physical medicine, a diagnosis generally means that you have or even if you're thinking about, you know, car mechanics, a diagnosis generally means that you found the cause that you've looked inside the body and you found the cause. While we were talking earlier about the evidence on serotonin, we have not found the cause of depression or indeed any other mental health problem in the brain. And what a term like depression or anxiety or ADHD, or even schizophrenia, what all these terms mean is they are just referring to a collection of behaviors and problems that as people express them, they are no more than that. And, and I think that using these labels actually makes it more difficult for people to really pinpoint the problems that they really are having, because they latch on to a label. And then they start to see their problems through the lens of that label. And everyone is an individual, and in my experience, everyone with depression is completely different and has a completely different set of problems. And, yeah, there's some commonalities, but often not many. So, so I think, I think it and I find this also, when I'm practicing with my patients, when people are very convinced that they have a particular disorder, it's often really quite difficult to work out exactly what their problems are, and what they need help with. Because they've just, they've just come to see themselves in terms of this label. And often, what that means to people is, well, I've got this label, therefore, I need this drug. And, and obviously, I, you know, I, I think that that the benefits of drugs are not not non existent, but they're pretty limited. So I think it's very important to work out exactly what problems people are having, so that you can then work out whether taking a drug is worthwhile, but also what are the things you might be able to do to help someone with, so that so that's my, my main problem with with social media is this, that it's really making people fixate on labels. And, and people don't understand that these are just labels, they think it's the same as if they, you know, as if they had a diagnosis of, of, you know, liver cirrhosis, or lung cancer or

Nick Jikomes 1:17:05

more of the screen? Yeah, I think what you're saying is, yes, a lot of our social media technology has enabled people to form an identity around what seems to be concrete, the label is concrete, right? There's a word like depression or bipolar. But what you're saying is, you know, even though there's many people with depression, and there's going to be some common net commonality, there is a very heterogeneous diagnosis, or thing to have. And the variation between people who associate with that label is going to be immense. And yet, they're almost in some cases, taking it on as a very sort of particular and concrete identity and becoming attached to it potentially in maladaptive ways.

Joanna Moncrieff 1:17:43

Yes, absolutely. And, you know, we have to remember that these, the, you know, these these labels, all in are implying, if you see them as diagnostic, medical, diagnostic labels, they're all implying that there's something wrong with your brain. And, you know, it seems to me that it's a very damaging message for people to be absorbing and, and absorbing, sometimes so enthusiastically, that they have a damaged brain because we, we have no evidence that there's anything wrong with with these people's with people's brains, people who are diagnosed with, with mental health problems. And, and I really worry that, you know, if people have the idea that there's something wrong with their brain, that they will limit themselves and you know, that that might severely sort of influence their life choices in ways that, yeah, might might mean, they don't live us full a life as they could potentially have.

Nick Jikomes 1:18:41

So, you know, given what you've studied throughout your entire career, given the recent paper you put out, calling into question, the idea that serotonin causes depression, and therefore the SSRIs are the best, or at least a very good type of treatment. Where do you see things going in terms of depression treatment in the coming years? Do you think the prescription rates or SSRIs will start to plateau and go down? Are you enthusiastic about any other avenues of treatment? Where do you see things going for depression treatment in the coming years?

Joanna Moncrieff 1:19:16

Well, I I would have predicted that prescribing of antidepressants would have gone down 10 or 15 years ago, because there was already a push them to market drugs for adult ADHD and drugs for bipolar disorder. But but they haven't they've kept on the rates of antidepressant use have kept on going up. We've just got increases in these other use of these other drugs as well now, so I won't predict that antidepressant use will go down, but I will predict that use of other drugs for depression will will go up it's already happening with ketamine psychedelic drugs are being widely marketed for use for depression nowadays. And as I said, there's some opioid opioid drugs in development and one I think, just actually been launched. The psychedelics are interesting because initially, they started off being investigated in conjunction with psychotherapy, as psychoactive drugs. So the idea was that people would take one of these drugs would have a, a trip, psychedelic experience, and then they would, and that this might enable them to get some insights that would help them manage their depression. So it was actually, although it was using a drug, it was actually quite a psychological model of trying to help people. And, and the process of psychotherapy would assist people to develop these insights that they might have. What worries me is that what we've seen with ketamine is that the Psychotherapy is too expensive, it gets cut out. And also it's not really not really very good, doesn't make much commercial sense to market, something that you're only going to use once or twice. So increasingly, ketamine has just been presented like an antidepressant, it's something that you have, not necessarily every day, but you have regularly for long periods. And I'm worried that that's also what will happen with psychedelics. And indeed, it is starting to happen in the way that they're presented. They're more and more being presented now as something that is targeting an underlying abnormality, not not a chemical imbalance, particularly, but this idea that they're helping to regenerate nervous connections that are deficient in some way.

Nick Jikomes 1:21:33

Yeah, I mean, one of the, one of the most exciting things about the psychedelics to me has been that, you know, the, the major exciting results have tended to be with one or a small number of macro doses, fairly large doses, where you have this psychological psychedelic experience in conjunction with psychotherapy. And you're seeing very remarkable effects, in many cases with just the therapy plus one or two of these doses. At the same time, when I'm observing evolve out and out in the marketplace of ideas, and the literal marketplace of items, is this notion of microdosing. And, you know, again, it just gets back to this notion of taking something recurrently because that is where the business motives lie.

Joanna Moncrieff 1:22:16

Yes, absolutely. Absolutely. I think that's right. And that and that, that worries me and I also just, you know, it's just so dishonest. We, we don't, you know, it's pure speculation, all this stuff about neural connections. The psychological model, at least is honest, it's telling you you're taking a psychoactive drug, you know, potentially really powerful psychiatric side psychoactive drug. I mean, I, you know, I'm not necessarily convinced that that's useful for everyone. But there may be some people who who find some, you get some help from it, but at least that's honest, at least that's presenting it honestly. And this micro dosing is just slipping into the the old story, it's probably you've got a problem with your brain, this drug is going to fix it, therefore, you must take it forever.

Nick Jikomes 1:23:03

Well, Joanna, I want to thank you for your time, we've covered a lot of interesting ground, do you want to summarize? You know, just just summarize for people, anything that you want to reiterate, maybe mentioned the name of the paper that you recently published that was making getting a lot of attention or point people to where they can find your work or anything that you think is worth pointing them to?

Joanna Moncrieff 1:23:22

Yes, yes. So the paper was published in a journal called molecular psych psychiatry. And there's been lots of blogs written about it, me and my, one of my co authors wrote a couple of articles in the conversation, which describe it, describe the research as well. And what I'd like to say about it is so so the paper shows that there is no evidence to support the serotonin theory of depression, the idea that depression is caused by low serotonin. Now, this is important for the use of antidepressants because they have been justified on this basis. This is they were first launched, in conjunction with this idea that this is what they were doing. And if we, if we don't have evidence that antidepressants are working in this way, on an underlying mechanism that generates depression, we have to think about them in a different way. We have to think about them, as psychoactive drugs that far from reversing an underlying abnormality are actually creating an abnormal brain state of the brain, they're actually changing normal brain chemistry, and therefore they produce mental changes and behavioral changes. And people need to I think that people need to look at antidepressants and all the other drugs that are prescribed for mental health problems in this way they need there's no dispute about the fact that these are psychoactive drugs that they're drug They do have mind altering effects of one sort or another. But it's just not highlighted. They're not presented to people like that. Because there's this either explicit story about the chemical imbalance or underlying assumption that, that it's something like that is what's going on. And something like that is what is important. But if you look at drugs, that these drugs as drugs that change our normal mental states by changing our normal brain chemistry, then you can easily see that they will produce changes in in, you know, anxiety or depression or other symptoms of mental of psychological problems. But those changes may not necessarily be worthwhile, because they certainly won't be they won't be long lasting. They're not going to persist when you stop taking the drugs. And we know that taking a drug like that on a daily basis may have negative consequences in the long term.

Nick Jikomes 1:26:06

Well, once again, thank you for your time and hope to talk to you again in the near future. Okay, thank you.

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