E114 - Do Psychiatric Drugs Work? (with Professor David Taylor)

Professor David Taylor is Director of Pharmacy and Pathology at the Maudsley Hospital and Professor of Psychopharmacology at KCL. David is the Editor-in-Chief of the journal Therapeutic Advances in Psychopharmacology. Professor Taylor has been the lead author of the Maudsley Prescribing Guidelines since their inception in 1993. David has also authored over 375 clinical papers in journals such as the Lancet, BMJ, JAMA Psychiatry, British Journal of Psychiatry and Journal of Clinical Psychiatry. 

Today we discuss:

 - What the science says about the effectiveness of anti-depressants.

- Evidence based principles for prescribing anti-depressants safely. 

- Common side effects and withdrawal symptoms. 

- Do anti-depressants work via so called "emotional numbing" effects?

- The use of anti-depressants for other conditions such as OCD and PTSD. 

- Emerging treatments for depression such as ketamine and psilocybin. 

- New treatments for psychosis such as KarXT (Cobenfy). 

Interviewed by Dr. Alex Curmi. Dr. Alex is a consultant psychiatrist and a UKCP registered psychotherapist in-training.

If you would like to invite Alex to speak at your organisation please email alexcurmitherapy@gmail.com with "Speaking Enquiry" in the subject line.

Alex is not currently taking on new psychotherapy clients, if you are interested in working with Alex for focused behaviour change coaching , you can email - alexcurmitherapy@gmail.com with "Coaching" in the subject line.

Give feedback here - thinkingmindpodcast@gmail.com - 
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Transcript

[00:00:00] Welcome back. If you've been following the podcast in recent weeks or months, you probably know that one of the topics we frequently discuss is that of the potential benefits and drawbacks when it comes to treating mental health conditions with medication. And that can include conditions like depression, anxiety, OCD, trauma, psychosis, bipolar disorder.

We've had guests on like Mark Horowitz. Joanna Moncrief, Richard Bentall, among others. With us to help us continue this conversation today is Professor of Psychopharmacology, David Taylor. And to be frank, I can think of no better guest to help us answer these questions. David is the Director of Pharmacy and Pathology at the Maudsley Hospital and a Professor of Psychopharmacology at King's College London.

He's the Editor in Chief of the Journal of Therapeutic Advances in Psychopharmacology. He has been the lead author of the Maudsley Prescribing Guidelines since their inception in 1993, which has since sold 300, [00:01:00] 000 copies in 14 editions and 12 languages. Indeed, if you're a psychiatrist and you've had to answer a problem about medication, the chances are at some point you've looked at the Maudsley Prescribing Guidelines.

David has also authored over 375 clinical papers. in journals such as the Lancet, the BMJ, JAMA Psychiatry, the British Journal of Psychiatry, and the Journal of Clinical Psychiatry. Today we discuss how antidepressants are coming under increasing scrutiny, both from the general public and the culture, but also certain clinicians, and to what extent that scrutiny is valid.

What the research says as to how effective antidepressants are. What are the really common side effects. The withdrawal effects of antidepressants. The relevance of Joanna Moncrief's 2021 meta analysis about the serotonin hypothesis of depression. We examine the claim that SSRI antidepressants merely work by emotional numbing.

We talk about the effectiveness of antidepressants in other [00:02:00] conditions like OCD, post traumatic stress disorder and anxiety disorders. We also discuss the effectiveness of newer drugs like psilocybin and ketamine for depression. And lastly, we go on to discuss antipsychotics, medications that help us treat conditions like schizophrenia, bipolar, and the new drug, CAR XT, that's currently being researched, and which may shed more light on how and why psychosis might arise in the individual.

The first half of this conversation, where we talk about antidepressants, depression, anxiety, OCD, I think that's an important conversation if you're training in mental health, but also if you're considering taking an antidepressant, if you have taken an antidepressant or if you have a friend or family member who might be taking one of these drugs.

The second half of the conversation is a little bit more technical and is a deep dive into antipsychotic medicine. And you might get more from that if you're actually working in the field of mental health. But if you're interested in psychosis, And what might be happening in the [00:03:00] brain in psychosis, you will probably find that valuable to listen to as well.

This is the Thinking Minds podcast, a podcast all about psychiatry, psychotherapy, self development, and related topics. If you like it, do share it with a friend, give us a rating, leave a comment or review on the channel you're listening on. Thanks very much for listening. And now here's today's conversation with Professor David Taylor.

David, thank you so much for joining me. Thank you for having me. One thing we've been talking about quite a lot on the podcast is antidepressants. It feels like antidepressants are coming under a lot more scrutiny nowadays by the general public, by the culture, but even by some clinicians like Joanna Moncrief, Mark Horowitz, who I've talked to on the podcast.

And even after releasing those podcasts, I got some emails from clinicians, psychiatrists, who they themselves are rethinking antidepressants. So it seems like there's a lot more scrutiny on these drugs. Do you [00:04:00] think that scrutiny is warranted? Is it appropriate? Do you think that's backed up by the science or not?

What are your thoughts on this? Well, I think that the first thing to say and to recognize is that depression is a pretty horrendous condition. It's something I have experience of myself. And when it strikes, you kind of feel like you need some kind of emergency treatment. Such is the, the unpleasant nature and unpleasant isn't a word that really covers the, the suffering that one goes through with depression.

So I think it's important to recognize that depression needs an urgent treatment and it needs an effective treatment. And perhaps that is reflected in the fact that Many prescribers are quite willing prescribers of antidepressants because they, for obvious reasons, want to relieve suffering [00:05:00] in their patients.

I think we are in a period where we are reconsidering the extent of the use of antidepressants. And this is part of a normal cycle, I think, where drugs are introduced. They're often Their benefits are often overemphasized, shall we say, and their adverse consequences under emphasized. And then, after they've been used clinically for years or even decades, there's a kind of reversal of that, and their limitations are better recognized, both in terms of a more limited than originally anticipated or measured efficacy, and a wider adverse effect profile.

So I know that there's a debate at the moment about, I suppose there are two things, one, whether or not there is a chemical imbalance in depression that, that antidepressants put right. And [00:06:00] second, that the question is to whether antidepressants work or not. I think the first one really is, is a question that doesn't really need answering in as much as it's not very common these days for ascribers to say to people, Oh, you've got a chemical imbalance.

Let's fix it with this here chemical. It's, it's, it's much more often recognized that depression is a consequence of things that happen to you in your life and your genetic predisposition to conditions like depression and anxiety. And, and, you know, everything's chemicals in the end, everything's atoms and protons and electrons.

So, whatever depression is, it is something to do with chemicals, ultimately. But that's not to say that we necessarily have to say that there is, quote, an imbalance in these chemicals. The question that really needs answering is Do these, do these things work? My [00:07:00] understanding, and I think that I've got a good reason for that.

My understanding is that antidepressants do work. And I base that on the results of clinical trials. And in particular, the overall results of clinical trials. So, if you look at antidepressants compared with placebo, You will find some trials where the antidepressant performs better than placebo and some trials where the antidepressant performs no better than placebo, that is that they're equal, but no trials at all where placebo is better than antidepressants.

So, you know, if we think about that in terms of, say, football, if, if we have matches between Liverpool and my team, Leicester City, and Leicester City either win or [00:08:00] draw, and Liverpool never win, then we could conclude that Leicester City are a better team than Liverpool, because Liverpool never win, and I think we can do that with Entity Presence, because There are no studies that I'm aware of, and if there are some, there are very few of them, where placebo beats an active treatment.

So, we have this body of evidence, and it kind of gets around the problem of, of the nature of clinical trials, which shows that antidepressants, on balance, are effective. They may not be hugely effective, but again, you, you have to think about the, the way in which results of trials are reported in as much as we often are given a, a score change.

So we'll have these scales where people get a score of how bad their depression is and their depression score will go down by X number of points. And that's [00:09:00] the, that's the outcome that we're often presented with. That, that isn't an outcome that. is likely to apply to very many people because it's an average of people who've had no response, people who've got worse, and people who've got better.

And if you look at people who get better, then their, their, their actual change in symptoms is, is much greater than the average because the average includes the people who didn't get better or got worse and, and who got worse. So that's a rather long answer. But the conclusion is that it's difficult to argue against antidepressants being effective.

Perhaps if I could add one more thing, and that is that one of the criticisms of the clinical trials is that they are not double blind. That is to say that the people in the trials and the people assessing the effects of the medication might know that they're on an active treatment. And that is quite often the case, but not always the case.

And it's not the case with [00:10:00] a antidepressant called agomelatine, which effectively has no more side effects or no different side effects from placebo. So you can't tell that you're not, or are taking an active treatment or placebo. And the agomelatine studies are identical in outcome to antidepressants in general, in that.

About half of them, the agamalatine beats placebo, and then the other half, agamalatine and placebo are equal. Uh, again, no, no studies where placebo is better than agamalatine. So, there's another bit of evidence to suggest that antidepressants are truly effective. Because even when you can't tell that you're, you're taking or not taking something, they, they still seem to be better.

And when I talked to, I mean, interesting difference between you and Joanna in that respect, because when I talked to Joanna about her serotonin meta analysis that [00:11:00] would disprove the so called serotonin hypothesis of depression, she felt that that result then immediately perhaps invalidates or Uh, puts on the heavy scrutiny whether or not we should be prescribing those drugs at all.

And you're taking the view I can hear that perhaps we don't understand how these drugs work, but here's all this evidence showing that it does work. One of the other things I think both Joanna and Mark Horowitz raised was that they felt that perhaps the benefit of uh, antidepressants was primarily due to the emotional numbing phenomenon.

Now this phenomenon is interesting because it was never, when I was in my training, it was never taught to us as a potential side effect of antidepressants, and I must say it is something that's reported quite often to me anecdotally, I mean, I would say very often, uh, by, by patients who have been on antidepressants that they feel there's been, that there was this kind of emotional numbing effect, which could be helpful, but ultimately [00:12:00] often causes them to stop taking it.

What, what would you say to that, to that view that it's the emotional numbing that's beneficial? Is there any evidence for that? Or is it an open scientific question that still needs to be researched? Yeah, I'll take your first bit first, which is the, the, the, the taking one thing going on to another, which is if there is no chemical imbalance, if there's no shortage of serotonin in depression, then the antidepressants don't work.

I think that's a leap too far. My title is professor of psychopharmacology. So you might think that I spend all day thinking about receptors and transporters and reuptake inhibition, but I don't, I'm much more interested in, in much broader outcomes. And I don't need to know how antidepressants work. I need to know whether or not they work and whether or not their benefits outweigh the negative aspects of their use.

And which is worth pointing out that happens a lot in medicine where it's not fully understand understood how a [00:13:00] treatment works, but we know that it works. and that on balance it's safe, potential risks and side effects, but so it's not unique to psychiatry. The, your second question was about emotional numbing.

It's a difficult phenomenon to, to, to describe, I think, but I suppose most listeners will, will have an idea of what emotional numbing means. I suppose it's a limitation in the degree to which you can feel happy or sad. It's not. But that phenomenon is not something that's easily measured. As you say, lots of people report that that's how they feel on antidepressants.

And I suppose with antidepressants, whatever people say they feel is correct, because they are the people feeling it. I would, I would point people towards some of the other effects of antidepressants, which are not to do with that aspect of their action. So for example, if, if we look at the nature of insomnia and [00:14:00] depression, we often think about it in terms of early, middle and late.

So early is not getting to sleep. Middle is waking up in the middle of the night and late is waking up early in the morning and not getting back to sleep again. Each of those seems to be made better by antidepressants, whatever their mode of action. And that seems to me, To be something separate from the emotional part of depression, it's more of a physical manifestation of the condition itself, which seems to be improved.

In fact, I'm understating it definitely is improved to a greater extent with antidepressants than it is with placebo. So I don't, I wouldn't wish to deny people's experience of emotional numbing. I, you know, people have mentioned that to me over the years. As you say, it might be a good thing for some people, not for others, but there are other aspects of depression which are effectively treated by antidepressants, which suggests that they have a [00:15:00] broader antidepressant action.

Yeah, and I would also want to point out that I have also on the other hand heard. anecdotal evidence from patients who say, for example, anhedonia also improves. Anhedonia being the loss of ability to feel pleasure at normal stimuli. So for example, seeing a sunrise or listening to a song that you like.

And patients have told me that being treated with antidepressants has led them to regain that ability to, to feel pleasure from things, which of course is a very important symptom of depression. And one of the, one of the greatest tests, I think, for somebody working in, in pretty much any area of medicine is to try to think about how you would have a member of your family treated.

And this is a question that has arisen with me and people in my family in regard to antidepressants. And It does give one a slightly different perspective. I suspect I might be more ready to [00:16:00] recommend antidepressants for somebody who isn't a relative of mine than who is. I'm not entirely sure why. But the thing I would say to all people is that the antidepressant has to be worth taking.

You have to derive a benefit from it, otherwise it really isn't worth taking, because there are downsides to taking antidepressants that, that we'll probably come on to, that need to be balanced by the good side, there needs to be some benefit, and that benefit has to be greater than all of the negative aspects put together.

So what are the biggest negatives or potential negatives that someone should be aware of before taking something like an antidepressant? I will come to that question, because I want to answer it. One thing I wanted to make sure I did say is that the idea that antidepressants take a long time to start working is a myth.

If you look at the pattern of response in people who [00:17:00] do respond to antidepressants, then they do most of their improving in the first week of treatment. In the second week of treatment, they do their second best bit of improving and so on and so on. So the Most rapid rate of improvement is early on, and the slowest rate of improvement is late on.

For the most part, if somebody hasn't had any response by, say, three weeks, then that medicine at that dose is very unlikely to work at all, no matter how long you give it. So this is, this is important to know because this means that we can use antidepressants to see if we can recover in that period. And if we don't recover in that period, then we can, in some cases, increase the dose or change the, the, the medication.

And examine whether or not it's working over another three weeks. We don't have to spend six [00:18:00] weeks, uh, eight weeks, 12 weeks waiting for something to happen because if, if nothing happens by three weeks, it's very probably never going to show any, any improvement. Yes. And following on from that, would you also recommend that even if an antidepressant is established to work in an individual that they should have very regular check ins, be that with their psychiatrist or their GP, to have that pros and cons assessment, like, is this medication still working?

Are there new side effects? And I only raise this because I very commonly see patients prescribed antidepressants, typically by the GP, on it for five to ten years, during which period no one has asked them, you know, is this working or not? And they just kind of remain. on it for no particular reason. This is something I've discussed with Mark Horowitz, who's a great pal of mine.

And we, we kind of came to the conclusion that where antidepressants are going to be used, we ought to be using them [00:19:00] rather more like antibiotics. That is that we, we use them as a targeted time limited treatment for a specific condition. And that means that we, we treat depression with an effective antidepressant for as short a time as possible, bearing in mind that there is evidence that if you stop too early, then a recurrence of depression is more likely.

The data are a little bit murky, but that seems to be the case that if you, if you're on an effective antidepressant, you need to stay on it for probably six months. And then slowly, uh, come off it in order to get the maximum benefit from it. Um, uh, uh, it's come into my mind that I haven't answered your question about adverse effects.

Right. In my mind, I divide antidepressant adverse effects into the ones you get at the beginning and the ones that carry on. throughout the time that you take them. So acute and chronic, [00:20:00] if you like. Acute effects are different from chronic effects. So the acute effects are usually with SSRIs like floxetine or citalopram, citalopram will be nausea.

Uh, sometimes you might see what we call agitation, that bit of increase in energy or difficulty. getting to sleep. Those things, nausea, insomnia, agitation, they tend to wear off over the first couple of weeks. I, I, I like to say to people when they start against depressants, you be the judge of how you take this.

Start with, you know, maybe half the dose, see how you feel on that. Go, go up to the full dose. If you get, if you start to feel a bit nauseous, then perhaps miss a day, start again so that the patient is in control of the. The initiation of the, the antidepressant, a lot of people will stop taking antidepressants very early on because they're not given the, the power, so to speak, [00:21:00] to, to adjust their dosage until they get used to it.

So actually on the dosing in the beginning can be a good thing. Yes. Yes. It allows you time to get used to the adverse effects should they occur. And enables you to get on an effective dose so that you can see whether it's going to work or not. I suspect the biggest problem is, is that of sexual side effects or adverse effects.

Particularly a loss of interest in sex and lowered libido. And also there's a decrease in the ability to achieve orgasm in both men and women. which is actually used therapeutically. So there's a medication on the market in some countries, which is effectively an SSRI, which is used for premature ejaculation in men.

So these are side effects that don't tend to lessen over time. And there's even a suggestion that they might continue after the antidepressant has stopped being taken. [00:22:00] Alongside those more obvious long term adverse effects are some things that you can only detect if you look at whole populations of people taking antidepressants.

So one of those is an increased risk of, of bleeding, and by that I mean a stomach bleed or even a brain bleed. There's a slightly increased risk of those things in people taking SSRI antidepressants, particularly in people who also take. Drugs like warfarin or other blood thinners like doax or people who are on anti inflammatory, non steroidal drugs.

Those combinations seem to give rise to a slightly increased risk of bleeding, but bleeding is a very unimportant and a dangerous adverse effect. So a slight increase in that is worth thinking about. And, of course, we should talk about withdrawal effects and you co authored the Maudsley Deep Ascribing Guidelines with Mark as well.

[00:23:00] Am I right in saying you've had some personal experience of having withdrawal side effects from antidepressants? Yes, some time ago now, a couple of decades ago, and it was rather a shock to me. You know, I work in the business, so to speak, and, you know, this is my daily life is, is, is Drugs used in mental health conditions, and I knew about antidepressants.

I knew they had withdrawal symptoms, and when I stopped taking a venom vaccine, I was, I was beyond surprised, really. I was shocked at the, not only the severity, but the variety of withdrawal symptoms that I got. And I, it occurred to me then that we weren't, we weren't helping people by diminishing the nature and severity of these withdrawal reactions.

So at the time we were saying to people that withdrawal reactions were [00:24:00] mild to moderate and short lived. They absolutely weren't with me mild or moderate. They were, they were Pretty horrendous. And what did you experience? I had very poor sleep. I, when I did sleep, I had the most kaleidoscopically vivid dreams.

I had sudden mood changes. I felt like I had the flu. I had almost constant electrical shock sensations in my limbs and my head. I felt so dizzy that I could barely stand up at times. So, all of these things, all at the same time, was, was a pretty unpleasant experience, and it lasted several weeks, even though I was trying slowly to reduce the dose.

Um, as I said at the beginning, this is 20 odd years ago, so we know much more about how to stop these medications now, and you can, you can probably stop them without, Getting those symptoms or at least having them [00:25:00] in only in a mild form. And that's another aspect of this that we've learned really from people who've had to stop taking antidepressants that there is a way to stop them if you want to avoid withdrawal symptoms.

And the principles of that are to go extremely slowly, much slower than is typically recommended. Is that right? How, what are the basic principles of coming off these drugs? Well, principle number one is that. It's individual to the patient. So some people can stop antidepressants fairly quickly over a matter of weeks.

Some people. Maybe a few months, some people a year or more. It depends on, on the patient, the medication, how long they've been taking it, the dose. But it, it, the, the speed of the withdrawal needs to be dictated by the patient who's experiencing the process themselves. So the idea is that we go slowly and We call it hyperbolic tapering, but [00:26:00] I've been told by somebody more skilled in math than me that that hyperbolic is the wrong term to use.

But the, the, the key feature of it is that, is that you decrease the dose by a fixed proportion of the previous dose. So let's say 50%, which would be the absolute maximum you would reduce. So you would go from 20 to 10 to five to 2. 5 to 1. 25. to 6. 2 0. 625 and then stop. So this is a, this, this hyperbolic tapering gives rise to a linear reduction in the activity of the drug over time.

Yes. And Mark explained to us really nicely on the podcast, how you want to reduce like that because it's actually reflects. the way that drugs occupy receptors in a slightly counterintuitive fashion that you wouldn't accept. A tiny amount of drug can occupy almost all of the receptor and therefore even at a tiny, a [00:27:00] tiny, what seemingly tiny reduction can cause a huge loss of engagement of that drug in the receptor.

And So far, you know, as, as these new ideas about reducing antidepressants are emerging, has there been much resistance? Do you think from the psychiatric community in the UK? Perhaps not, but have you encountered any resistance? Well, you can see this play out on social media platforms like Twitter or X.

There are, there are people who ardently believe that antidepressants don't really work and that they are dangerous placebos. There are people. At the other end of the spectrum, who believe that antidepressants are very valuable drugs and are largely innocuous. I, I suppose I fit somewhere in between those in that I recognize that depression is a condition that, that needs urgent and effective treatment and that antidepressants can be that treatment for some people.

But [00:28:00] at the same time, I recognize that there are negative aspects to the use of antidepressants, not least the The fact that they don't work for everybody, but also that they have long term adverse effects. And if you take them long term, there is a risk of withdrawal. And I think in long term use, it's probably true to say that everybody gets some kind of withdrawal reaction.

If they were to stop antidepressants. The severity of it and the duration of the withdrawal symptoms would, would be different between different people. But I think it would probably, we'd probably, if we looked hard enough, we'd probably find it in everybody. And that's one of the debate, the debate that goes, that goes on and continues today.

The debate about what proportion of people get symptoms, what proportion of people get severe symptoms. Last year, there was a Lancet [00:29:00] psychiatry paper, which suggested that only. 3 percent of people stopping antidepressants got severe withdrawal symptoms, and only 15 percent got them in total, but there were, um, problems with that.

Analysis, which I'm sure, um, mark and Joanna, uh, probably spoke about, uh, when they were, uh, on the podcast. They didn't actually, so if you ha, if you, so it's be good to hear your point of view. I think you can see how wide did the mark the, the paper was by its conclusions. They concluded that tapering didn't make any difference to withdrawal reactions that the duration of treatment didn't make any difference to the likelihood of withdrawal reactions.

And that the dose didn't make any difference to the likelihood of withdrawal reactions. Now all those things are pretty much things that we know. Not to be true with probably with 100 percent certainty. So when when the conclusion of a paper goes against [00:30:00] what we know, we have to look very carefully at it.

And there were a number of problems with the paper. Probably the main difficulty. I had with it was that they chose studies which simply simply simply categorized people as having withdrawal symptoms or not having withdrawal symptoms, and they excluded anything, any study which had used a rating scale to.

examine how severe people's withdrawal symptoms were. So in doing so, they probably excluded the most useful studies because those were the studies that had actually bothered to use a measure to look at the extent to which people suffered withdrawal symptoms rather than just whether or not they did.

Alongside that, they They seemed, in many of the papers, not to have directly asked patients about withdrawal effects, [00:31:00] but waited in a number of cases for patients to report to them that they had had withdrawal effects, which isn't, isn't really a way you would design a study that was serious about discovering whether people had withdrawal effects when they stopped antidepressants, simply waiting until somebody told you that they'd got some symptoms, which of course they'd have to recognize as withdrawal effects.

being withdrawal symptoms, probably without any knowledge of what they might be. The other problem was that the duration of the treatment varied from a matter of a few days. So I think at least one study was in pre, premenstrual syndrome, where only a few days treatment were given. Clearly, you know, withdrawal symptoms are not going to occur in that duration of treatment.

And very few of the studies were, were very long term, extending over in many months or years. And one of the issues Mark raised is that he worries [00:32:00] about the extent to which, um, pharmaceutical companies funding these studies may cause them in subtle ways to be altered in order to show results that might favor outcomes, which would be beneficial for them.

I don't know if the study you just mentioned falls under that category, if it was funded by a pharmaceutical company, but. In general, is this an issue that you worry about? Well, that very same paper, the Lancet Psychiatry paper, examined whether or not manufacturer sponsorship made any difference to outcomes, and they claimed that it didn't.

I think that the way that the pharmaceutical industry works to make its medicines look better than they actually are, they're quite subtle methods. So rather than skew studies so that they find a particular outcome. The, some pharmaceutical manufacturers are more likely to do pretty reasonable studies, [00:33:00] but, but not to publicize or to publish those studies that, that don't show their, their medicines in a good light.

So they don't publish negative findings, essentially. Yeah. Yeah. So that's, that's called publication bias, but that kind of takes us back to What I was saying at the beginning, there are registers of trials, so you can go back and find all the trials that were registered as being about to take place, and you can go back and look at what happened to those studies, and then you can include them in an overall analysis.

I've done this myself with a few antidepressants. And what you find is that the studies that don't see the light of day, or at least don't get published in journals, are the negative ones. And the ones that do, they're generally the positive ones. But, when you add them all together, there is still an effect for the antidepressant over placebo.

And also, [00:34:00] as I mentioned before, placebo pretty much never beats active treatment. Right, okay. Maybe one more point on antidepressants before we move on. You mentioned that, of course, sometimes, I mean, I like the idea you mentioned of thinking of thinking of them as antibiotics, like a more short term intervention.

And that's certainly fits with my clinical experience. You mentioned sometimes we can treat for too little that that's if someone comes off antidepressants prematurely, perhaps they can relapse. How easy is it to distinguish between a relapse of depression versus withdrawal effects of antidepressants?

Antidepressants. Is the distinction quite clear? Or again, is this an open scientific question that requires more research? Do you think I think that I think they're quite easy to distinguish? They're quite easy to tell apart. But I do think that the presence of withdrawal symptoms muddies the waters when we look at [00:35:00] the long term benefits of antidepressants.

So to take My first point, electric shock sensations and overwhelming dizziness are not symptoms of depression. They're not usually the symptoms that you go to your doctor with and the doctor says, Oh, you've got depression. They are symptoms that emerge when you stop taking antidepressants. So if you have electric shock sensations, you've definitely got withdrawal symptoms.

If you, you might also have a low mood and you might also have insomnia, and that may or may not be withdrawal symptoms or.

I suspect in most cases, it is part of a syndrome of withdrawal symptoms and that these, these symptoms go away or can be reduced or mitigated by this slow hyperbolic tapering in, in clinical trials. It's pretty clear now that if you take [00:36:00] two groups of people, allow one group to stay on an antidepressant.

and you get the other group to stop taking an antidepressant, then the group who stops taking the antidepressant will get withdrawal symptoms, unless you're very, very careful about it. And those withdrawal symptoms will register on the scales that are used to measure the severity of one's depression.

And this means that when, when we stop antidepressants in clinical trials, and we report that X percentage of people relaxed, what we're saying is X percentage of people met a threshold score. on a depression rating scale, which may have been caused by a return of the depression, but might also have been caused by the emergence of withdrawal symptoms.

We can't say which. So there's still there's some clear daylight between the two, but also some gray area that needs to be taken into [00:37:00] account. Yes. And you can have both, you can have both withdrawal symptoms and a return of the depression or anxiety. Yes. Are there any, um, new drugs on the horizon, uh, for the treatment of depression, which you're interested in?

Some that might show a newer mechanism of action, like we will discuss about antipsychotics later, or we could talk about. psychedelics like psilocybin or ketamine that are they markedly better at potentially treating depression than SSRIs, more conventional antidepressants? Markedly better? Possibly. I don't think that the answer to that question is definitely.

So psilocybin and ketamine are drugs which seemingly have a different way of acting. They're not part of the, the paradigm of, of, of inhibiting. Nerve cells taking up of serotonin, they seem to work in [00:38:00] different ways. Again, we're not entirely sure exactly how they work and they seem to work more quickly than antidepressants.

And by that, I mean in a matter of hours rather than a matter of days or weeks. So they have a much more prompt effect. I think the jury is still out on both of them. It's worth bearing in mind that a lot of the time new, new drugs seem to be. and advance. They seem to be better than what we already have, but the more we look into it, the less that becomes the case.

That's the cycle you mentioned at the beginning. Yes, and I think we're seeing it with both ketamine and psilocybin now that as more trials get done, as bigger trials get done, as better trials get done, the superiority of psilocybin and or ketamine over standard antidepressants is reducing. Although There is a possibility [00:39:00] that they do represent better treatments.

From my, the point of view of my own experience, a better treatment for depression would be one that acted as quickly as possible. So a good analogy would be somebody with a, with a broken femur. You wouldn't want to give them pain relief that would kick in after a week. You'd want it to kick in after a few.

Uh, seconds or minutes, and the same is true, I think, of depression, that the quicker you can gain relief from depression, the better it is. It sounds like an obvious thing to say, but I think people who perhaps haven't experienced depression might not have a sense of the urgency that people feel for it to be taken away from them, even, you know, that it's such an unpleasant, painful experience.

So in that respect, ketamine and psilocybin. probably offer an advance over current treatment. I think that's a very important point, which [00:40:00] obvious as it may be has never been brought up. I've never heard about it. So I think very important point to mention. And also, particularly when it comes to psilocybin.

What makes me think this may be something new may represent a paradigm shift is, of course, with psilocybin. You're pairing a biological intervention, the drug, with a psychological intervention. And often, the patient's first person experience is that they're having some sort of psychological change. And there's an idea that psilocybin may be helping to promote introspection, psychological flexibility, psychological growth.

in a way that we know is helpful for depression when we look at, for example, cognitive behavior therapy and how that helps people think more flexibly and therefore be less likely to fall into bouts of depression. So that's quite an interesting move forward as well, I think. Yes, for some reason, the fact that hasn't been mentioned yet comes to mind.

And that is that we talk about [00:41:00] treating depression with, with, with chemicals. And it's worth remembering that Depression arises because of people's genetic predisposition to it, but also because of their experiences in life, and some of those experiences are, are current experiences and, you know, very few drugs will treat the depression that's associated with, with it.

abject poverty, for example, you're asking too much of a, of a medicine to, to, to treat that really. So we should never forget the, the, the situation in which the person with depression resides, if you like, and, and how. how likely something is to work, given, you know, their situation, the, uh, the way they have to live their lives.

Absolutely. I think it would be also worth mentioning, talking about the use of antidepressants in other conditions besides depression like [00:42:00] OCD, post traumatic stress disorder, PTSD. How, are there noticeable differences between the, what the research shows for the efficacy of these drugs in OCD, PTSD, as opposed to depression.

Yeah, I think probably it's best to think about the use of antidepressants in depression. And then a second category is, is everything else. These are what might have been called years ago, neurotic disorders. So generalized anxiety disorder, disorder, phobias, post traumatic stress disorder. Obsessive compulsive disorder.

If we group those all together as not depression, they, antidepressants are different in those other conditions, generally speaking because they take a little bit longer to work and in many of those conditions you need a somewhat higher dose than you do in depression. It does vary a little, a little bit between conditions, but generally speaking, [00:43:00] the same observations apply in those non depression conditions as they do in depression.

That antidepressants are generally effective and the placebo never or very rarely beats an active treatment. Right. Okay. Some of these things that, you know, the, the, the symptoms are. easier to quantify in terms of their severity. So, so obsessions and compulsions are probably a more tangible thing to measure in respect to their severity than is depression itself.

Uh, which reminds me of another thing that I should say to listeners. And that is that one of the problems we have in psychiatry is that we don't, we can't measure something concrete like blood pressure or. blood glucose, we, we have to make an estimate of the severity of somebody's condition by asking them questions and then scoring them on a chart, which is, which is prone to its own biases [00:44:00] and, and sensitivities and lack of sensitivity.

Yes. And obviously, as with depression, when you're treating these conditions, like OCD, PTSD, anxiety with medications, the evidence would show that it's most effective when it's paired with some sort of psychological intervention and probably also realistically taking into account, as you say, the person's social circumstances and doing your best to ameliorate those problems as well.

Yes. And I suppose You know, treatment continues for as long as it's required based on the success of, of, of psychological treatments that run alongside the, the drug treatment and the, the, you know, positive changes in the, in the patient's situation. Yeah, absolutely. It can be hard to tease apart what's happening exactly there.

I'd like to talk a little bit about antipsychotic medications. So for listeners, when we're talking about psychosis, we're of course talking about things like [00:45:00] hallucinations, hearing voices, unusual beliefs, what we might call delusional beliefs, paranoia, things like that. I think most psychiatrists would generally feel, I suspect, more comfortable talking about more comfortable relying on the efficacy of antipsychotics than antidepressants.

It seems to be a little bit less controversial and generally psychiatrists find that more often than not antipsychotics actually do work in relieving a very, very, you know, difficult, intense, stressful mental condition. Um, but that being said, sometimes they don't. So sometimes patients are treatment resistant and there still seems to be quite a lot of mystery about what could be the biological mechanisms.

underlying a mental state like psychosis. And again, people like Joanna Moncrief would say actually there is no evidence for a biological mechanism. There's at least one new antipsychotic emerging, CAR XT. Um, could [00:46:00] you talk a little bit about what makes CAR XT different and what does the research tell us about it so far?

Well, before we get into CAR XT, which is called carbenfee now, this was rather Uh, annoying when these drugs change their name, we need to go back to the, to the early 1950s because this is, this is where the psycho pharmacological era starts, and it pretty much starts in 1952 with a report that a drug used for TB, isoniazid, was making everybody on the TB wards, um, not depressed or rather happy.

And this was a revelation to a kind of psychoanalytical dominated field in psychiatry. That's giving somebody a chemical could alter their mood. And more or less at the same time that this was going on, some French [00:47:00] psychiatrist had borrowed from a cardiovascular surgeon some chlorpromazine that That the surgeon had been using as a premedication agent and they'd given it to their people with psychosis, what we would call schizophrenia and bipolar disorder, and found that it made people rather calm and also reduced their hallucinations, their auditory hallucinations, reduced the, the The extent to which they heard voices, it reduced their, their disordered thoughts.

So these things were discovered accidentally, which I suppose is, is, is can be considered a negative thing because we've then spent the, you know, next 60 years trying to work out what it is that these things do that, that makes them work. But the positive side of this is that the effects of isoniazid, later iperoniazid, uh, later Imipramine, which was developed, [00:48:00] um, from both of these lines of inquiry, the effect of those things was so obvious that you could, you could see it with the naked eye.

You didn't need any clever trials. If you gave it to people with depression, they got better. Likewise, the antipsychotics, if you give it to people with psychosis, their psychosis went away for the most part in most people. So the effect was, was so obvious that you didn't need a trial to show it. And this is what happened in the 1950s, that they.

Various compounds were developed with kind of barn door, uh, obvious level effects on patients who had hitherto shown no response to anything at all, really. If we look at the line of inquiry with antipsychotics, we found chlorpromazine was effective. We've made other drugs like chlorpromazine. They were effective.

Paul Jensen developed from, of all things, pethidine, haloperidol, which was also antipsychotic. And then, in the [00:49:00] mid 60s, after the discovery of dopamine and dopamine receptors, it was found that these drugs were blocking dopamine receptors. So from that came the dopamine theory of psychosis or schizophrenia, which simply puts is that in people with psychosis, there's too much dopamine.

And the way we treat it is do we, is, is that we block the action of dopamine with dopamine blockers or dopamine antagonists, uh, which are antipsychotics. And we've been living with that line of inquiry for, uh, 60 plus years now. A few years ago, a drug was introduced called Pemovansirin, which is a drug which is effective in psychosis that we see in Parkinson's disease, and it's effective without affecting dopamine, which is peculiar because it's thought that the psychosis that we see in Parkinson's disease is actually caused by [00:50:00] the dopaminergic drugs, the dopamine stimulating drugs that we give people to treat their Parkinson's.

So, that was probably the first sign that you could treat psychosis with something other than a dopamine blocker. And then, seemingly, out of nowhere, came CarXT or Cobenfe, which is a combination of two drugs, Xenomaline and Trospium. Now, Xenomaline has been about for quite a while. It's a, it's a stimulating drug.

It stimulates receptors rather than blocks them, and it doesn't affect Dopamine, or at least directly, it stimulates cholinergic, so called muscarinic receptors. And it was initially examined as a treatment for dementia, and there were some trials in the 90s, the 1990s. Which showed that it had a small effect in, um, [00:51:00] improving cognitive function in people with dementia, had a rather larger effect, uh, in respect to treating psychosis in people with dementia, but, uh, that it was almost, um, completely intolerable to patients because it, it, it, it caused a variety of adverse effects, including fainting in, in a substantial proportion of patients.

So, so normally as a possible treatment was pretty much abandoned until somebody had the bright idea of blocking the effects of zanomaline outside the brain and allowing it just to work inside the brain. And that's what letrospium is for. That's a, uh, a drug which blocks cholinergic or muscarinic receptors outside the brain.

So zanomaline It's actually, it's blocked outside the brain, so it doesn't cause so many side effects. But it's effect is not, in the brain, is not impeded by trospium, which can't itself get into the brain. [00:52:00] So now we have a treatment, at least in the United States, where it's been licensed, which doesn't directly affect dopamine.

Now, I was interested to see some of the marketing literature for Cobenfe, because it seems we're so wedded to this idea that Dopamine blockade must be important somewhere in, in psychosis that the marketing literature says that the, the, the zanomalene is muscarinic cholinergic agonist activity eventually leads to a reduction in dopamine output.

So they're kind of saying it works in a different way, but it works in the same way, which I'm a little confused by and it also seems to be. an assumption, uh, too far, if you like. And perhaps I can fall back on my usual position, is that I don't really care how it works as long as it does work. And it does seem to work.

One of the ways we, we measure or tell people how well something works is by, [00:53:00] by citing its effect size, and a big effect size would be about 1. A medium effect size would be about 0. 6 and a small effect size would be about 0. 3. So antidepressants have an effect size of about 0. 3. If you take into account all of the trials that have ever been done with antidepressants, the effect size is probably less than 0.

3, closer to 0. 2. The effect size of Cobenfi is 0. 6. So it's at least double the size of the effect of antidepressants. Static antipsychotics too have an effect size of about 4. So it seems to be bigger than that. Now we could get very excited about this because it's, on the face of it, it seems that Cobenfi is going to be more effective than antidepressants.

standard anti psychotics, but it hasn't yet been compared with a standard anti psychotic. So all we have at the moment is a couple [00:54:00] of trials where it's been compared with placebo, and there are two possible explanations for its large effect size, either Cobenfi is more effective than, than the drugs we're used to, or in the trials that were done, placebo was much, much less effective than it is in other studies because the effect size, uh, calculation is done by looking at the difference between the placebo effect.

and the antipsychotic effect. So, the jury's still out on that. People are very, very hopeful that, that it, it will represent a, a step forward in treatment. It's probably worth saying that we do have another drug which has some of the properties of, of cobenzepine, that's clozapine. You can see with clozapine that it's a a drug which stimulates muscarin receptors because it causes [00:55:00] hypersalivation and salivation is controlled by acetylcholine.

And the more cholinergic action you have, the more muscarinic agonism, the more saliva is produced. And that's a key side effect of clozapine. And now it seems might be a key therapeutic effect of that drug. So it might also help us solve the mystery, which has been around, I suppose, since the 90s, when clozapine was introduced, which is why the hell is clozapine?

so effective in these treatment resistant cases. Yes. Yeah. It might, it may well do that. I suspect the clozapine does a two or three things that are important and this might be one of them, but it would add some weight to the, to the idea that clozapine works via this method, because I'm not sure that any other drugs have that muscarinic agonist, these M4 agonist activity.

that you see with COSIPE. And I also wonder, is it still possible that conditions like psychosis, bipolar disorder, which [00:56:00] can of course present in subtly different but important ways, could we still be dealing with groups of conditions that have different, uh, underlying biological mechanisms and therefore are amenable to different kinds of drugs, like some drugs, some conditions more amenable to dopamine blockade?

Uh, like with Olanzapine, say, and some more amenable to Muscarinic Blockade, like with Clozapine or Car XT. You could claim with good support, I think, that we've made up these conditions, that we've, we've drawn together a constellation of symptoms, and we've said that this constellation is condition A, and another constellation is condition B, and then we have fudges, so we have schizophrenia and we have bipolar disorder, but where we have people that have got symptoms of both schizophrenia and bipolar disorder, we call it schizoaffective disorder.

So with their constructs based on symptom outcome clinical outcome. Yeah, which which [00:57:00] may not be related to the Biological basis for the condition. Yeah, just like comparing it to physical health medicine One person could have a cough. Another person could have a cough. One person could have tuberculosis The other person could have kovat 19 and in mental health.

We're just dealing with the cough. We're dealing with the more superficial manifestation and the, unfortunately, biggest problem in mental health, I tell a lot of my patients, is the etiology remains quite mysterious. Yes, and just because we say to somebody you have this condition, you know, they need to understand that we've invented this condition.

It isn't something that necessarily exists. It may well exist as a particular pathology or biological basis, but we don't know that. The cough idea, you know, I think Chest infection, which is often given as a diagnosis, is a very good example because chest infection could be tuberculosis, could be empyema, could be pleurisy, could be pneumonia, there's so many [00:58:00] different things that are chest infections that are radically different in nature and their biological basis and that's a very good parallel, I think, for conditions in psychiatry.

Even if you, you can, you can 2 diabetes, say, philosophically. Is that a pancreatic problem? Like, your pancreas not producing enough insulin? Or is that a problem of eating a diet for 30 that causes your pancreas to overproduce insulin? Because it's never thought of as the latter. It's always thought of as the former.

It's a pancreatic problem, but more and more understanding actually it's a problem of of diet and, and lifestyle. And in fact can be reversed even if you change your lifestyle sufficiently. Um, are there, are you excited about any potential novel methodologies? that we can use actually to reveal some of these mysteries, like, for example, psychiatric genetics to help us tailor our, um, treatments more towards the individual, or perhaps the use of artificial intelligence [00:59:00] to help us with the computational challenges of obtaining and sorting through all of this data.

I mean, I don't know much about artificial intelligence. I, I've tried a few of the free AI apps and I've asked them questions about things that I think I know about and they're giving me fairly rudimentary answers at the moment. Maybe I'm not asking the right question. I have been told that it does really depend on how you ask the question, what words you use.

But clearly this is going to be something that will develop in respect to its ability to, to answer complex questions. And I imagine would help us in, in any. number of ways. I'm aware, to go on to the second subject, which is genetics, that we have had Uh, a promise of, uh, a step forward in, in, in treatments and in therapy and understanding before that came [01:00:00] with the Human Genome Project and, and the, the promise that we, the medicine would be personalized by the genetic revolution.

That really hasn't happened. There, there are a few areas of medicine where genetics play, play a major part. So some cancer treatments, for example, but not many. Not many others. I think things are coming along reasonably well in mental health. There's a couple of studies looking at response to risperidone and aripiprazole to antipsychotics, looking at the enzymes that are responsible for metabolizing those.

And you can predict, not with certainty, but with a good probability, responders and non responders with that test. My own work has been in the field of clozapine genetics. And I've, I've developed with a colleague in Spain, a geneticist in Spain, [01:01:00] a method which can predict the rate of metabolism of clozapine by looking at genetic variance within an individual, which was shown to be the most accurate predictor of clozapine dose that will be required.

So. If that could be used more, I think it would be helpful to make clozapine use safer. We've also just published a study where we used genetic testing to identify people with what's called benign ethnic neutropenia, which is really just a tendency to have a low neutrophil count in one's blood. It's called benign because it doesn't have any adverse consequences.

An ethnic neutropenia implies that it occurs only in people with certain ethnicities, but it actually is not bound by ethnicity. It's more a familial condition, which is, it's passed down from generation to generation. But what we found, what we showed in that study is that if you, if you look for the, [01:02:00] the genetic variant that's responsible for.

Benign Ethnic Neutropenia in people on clozapine, you will find an awful lot of people with undiagnosed Benign Ethnic Neutropenia, which makes non use of the test when it's available, rather inexplicable because Benign Ethnic Neutropenia is a condition where the neutrophils can fall and clozapine would then have to be stopped.

And when clozapine is stopped in people, they usually relapse very badly. So do you think we should be, we should stop, um, taking this into account and continue prescribing the clozapine regardless of the neutrophil count? Yeah. And in fact, I've, I've I've experience of several instances where that has exactly been the case.

So, a couple of weeks ago, a patient presented having been on Clozapine for, I think, five or six years. They suddenly had a low neutrophil count. We did the genetic test that showed that they [01:03:00] had benign ethic neutropenia, which meant that their low neutrophil count was, in fact, normal for them. That's the key point about banana neutropenia, that there are a group of people who generally have lower neutrophil counts than people, for example, of European ancestry.

So we were able to continue with that patient. And I've experienced lots of others, uh, in similar situations. If you look at people on the The Clozapine non recharge database, most of those have got, uh, undiagnosed bananas that you should be near. Right. Okay. Yeah, that makes a lot of sense. So hopefully more and more as we answer some of these questions, we'll be able to streamline these drugs, make them safer, uh, and allow us obviously to discontinue a pretreatment when appropriate, but also continue it when it should be continued.

Absolutely. We're out of time, but David, when we were trying to find guests who could help us answer these questions about the different psychiatric drugs, [01:04:00] we couldn't think of a better guest than yourself. Thank you so much for coming on and spending some time with us and helping us answer these very difficult questions with us today.

Thank you. It's been an absolute pleasure.