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Interview with Dr. Joanna Moncrieff

Updated: Nov 11, 2022

Journalist: Timur Begaliyev

Timur Begaliyev: Welcome to SciSection! My name is Timur Begaliyev, and I am the journalist for the SciSection radio show broadcasted on CFMU 93.3 FM radio station. We are here today with Dr. Joanna Moncrieff; she's a psychiatrist studying the neuroscience of depression. Dr. Moncrieff recently published a very prominent study in the Journal of Molecular Psychiatry. Right now, the study is ranked in the top 0.001% of over 22 million other articles of the same age. The study refutes the idea that depression is just a chemical imbalance. Thank you Dr. Moncrieff for coming on today!

Dr. Joanna Moncrieff: It's a pleasure.

Timur Begaliyev: For our listeners we don't know, can you explain what the serotonin theory of depression is?

Dr. Joanna Moncrieff: Yes! The serotonin theory of depression was first put together in the 1960s. It's the idea that depression may be caused by an abnormality, most often it's thought to be a deficiency of a brain chemical known as serotonin. There are lots of chemicals in the brain, and some of them help facilitate the transmission of nervous impulses. Nervous impulses conduct the impulse from one nerve cell to another nerve cell, and serotonin is one of those chemicals that helps to transmit nervous impulses in the brain. But, serotonin is also found in other parts of the body, particularly in the gut and in blood cells. And actually, the amount in the brain is not as much as in those other parts.

Timur Begaliyev: Does your study agree or disagree with the serotonin theory of depression?

Dr. Joanna Moncrieff: The serotonin theory of depression was first coined in the 1960s, but then it was widely publicized in the 1990s by the pharmaceutical industry when they produced a range of antidepressant drugs that acted on the serotonin system. The idea was that these drugs were thought to increase levels of serotonin. Therefore, the idea was that they were rectifying this underlying serotonin deficiency. The serotonin theory was widely promoted at that time, and one of the reasons that we did the research is it was clear to me this marketing had been enormously successful and most people had come to believe depression had been proven definitively to be caused by — or at the very least associated with — low levels of serotonin. But I knew that, in actuality, the evidence was recognized as not being that strong, and some leading psychiatrists over the last 20 years have come out and said “Actually, we don't have that much evidence for the serotonin theory.” But no one had really got the evidence together! So that's what we did in our review. We got all the evidence together from the main areas of research that have looked at connections between serotonin and depression. Those areas of research include, for example, 1) areas that have looked at levels of serotonin in the blood and the urine, 2) levels of a serotonin breakdown product, metabolite, in the brain fluid,

3) research that has looked at levels of serotonin receptors, which are the proteins on the nerve cells that serotonin attaches to when it's transporting their nervous impulse responses from one cell to another. 4) We looked at research on the serotonin transporter protein that is the protein that transports serotonin out of the synapse, the gap between nerve cells, where it has its action and SSRI, selective serotonin reuptake inhibitor, drugs have their action by inhibiting this serotonin transporter protein and therefore allowing higher levels of serotonin to accumulate in the synapse. 5) And then we looked at research that has artificially induced low levels of serotonin by giving people a drink that lacks the amino acid that is the precursor substance for serotonin (that the body makes serotonin out of). And these research studies have given this drink to volunteers, and then measured whether they've become depressed after taking the drink at such a time as it's been shown, serotonin levels would be lowered. 6) And then, finally, we looked at genetic studies. There have been a lot of studies that have looked at the gene that codes for the serotonin transporter protein, and that look at whether there is an interaction between that gene and adverse life events. Basically, over all those areas of research, we did not find any convincing evidence that there were low levels of serotonin in people with depression. If anything, there were some studies that indicated there might be slightly higher levels of serotonin in people with depression. But, first of all, the results were pretty inconsistent. Secondly, most of the people in those studies were taking or had recently taken antidepressants, which probably account for the findings. So, those were the findings of our study. There were a couple of other interesting findings. One was that a very large study of plasma levels of serotonin (blood levels of serotonin) that, although they didn't correlate with depression, they were actually lower in people taking antidepressants — even when those people were taking antidepressants for reasons other than depression! And among people with depression who were not taking antidepressants, there was no difference between them and people who didn't have a diagnosis of depression. So that was interesting, and it turns out that actually there's some other research suggesting lower levels of serotonin in people who are taking long-term antidepressants.

It just adds to the fact that we are not even sure what SSRI antidepressants are doing to serotonin.

Although the theory is that they are increasing the levels, we don't really even know that, and it's possible that with long-term treatment they might be reducing serotonin levels. The other interesting thing, that we found, was from the genetic studies. Early genetic studies suggested that there might be some effect of the gene itself. Then it became difficult to replicate that finding, and people concluded that probably the gene didn't have an effect. But then one research group suggested that there might be an interaction between the gene for the serotonin transporter and having experienced adverse life events in your past. And so, there were lots of studies that looked at that and what they showed was a very strong correlation between experiencing adverse life events and subsequently experiencing depression. This confirms what we know, that as bad things happen, you do become more vulnerable to experiencing depression as we might expect. But they showed that there was, in fact, no interaction between the gene and adverse life events. And it was obvious as the studies got bigger and better, the findings on the gene itself and the gene interaction disappeared. So, that was what we found in our review.

Timur Begaliyev: So you're saying that if you are experiencing adverse life events, that doesn't impact your gene [for serotonin]?

Dr. Joanna Moncrieff: It doesn't impact the gene for serotonin, no, but the adverse life events on their own are a strong risk factor for subsequently experiencing depression or being diagnosed with depression.

Timur Begaliyev: Your study was an umbrella study. Can you explain why that is and why that might be more credible than individual clinical trials?

Dr. Joanna Moncrieff: We did something that's called an umbrella review, which is a relatively new term. An umbrella review consists of a review of reviews. So, we selected all the high-quality systematic reviews in each of the different areas of the research and looked at the results of those. We did that because looking at all the studies across all those different areas of research would be such a huge task. I don't know that any one research group could ever complete that, and so this technique of doing an umbrella review and looking at the systematic reviews in each area allowed us to take an overview of all these different areas of research. And we also did quality ratings on the reviews that we included as you would do in any sort of systematic review. An umbrella review, by the way, is a type of systematic review. We did a systematic search for systematic reviews in all the different areas of research that we looked at, and then, as you would do in any systematic review, we then selected the reviews that we included on the basis of our predefined inclusion and exclusion criteria. Then we did a quality rating of all the reviews that we included. So yeah, that was the methodology that we used.

Timur Begaliyev: How did you rate the quality of each individual study, and how did you decide which studies to include and which to not include?

Dr. Joanna Moncrieff: We used the AMSTAR quality rating scale for systematic reviews. It's a very stringent scale, so almost any review comes out as looking pretty poor on the AMSTAR rating scale. But some reviews did better than others. AMSTAR is a quality rating scale for rating systematic reviews. Like any quality rating scale for any sort of research study, it contains a number of items that you use to rate the quality of different aspects of the research. So, for example, you rate the quality of the search that was conducted, and you rate the quality of the meta-analysis that was conducted, and you rate the quality of the tests for publication bias and whether they were done or not. So that's what the AMSTAR quality rating scale is. We didn't exclude poor quality studies, but we highlighted the quality in our results. How did we decide to select studies? We basically came up with some criteria before we looked at the studies! We decided we would include any systematic review or meta analysis, or any other study that had used a large amount of data. That was because the best study, the largest and best study of the genetics, is a large individual study that has genetic samples from well over 100,000 participants and is much larger than any of the individual studies or previous systematic reviews that had been done. So we didn't want to exclude that very large and very high-quality study. There were a couple of studies, including that large database study, where we had to adapt the AMSTAR. For the database study, we used a different quality rating scale that has been designed for genetic studies in particular. Otherwise, we used fairly standard inclusion and exclusion criteria. We didn't exclude studies that included people who were taking antidepressants, partly because an awful lot of this research has included people who were taking antidepressants. And so, we thought it was important to look at that as well, even though we know that for many of these types of studies, taking antidepressants might well affect the results, and therefore might make it difficult to find out whether there's actually any underlying connection between serotonin and depression that isn't influenced by the use of antidepressants.

Timur Begaliyev: Is there any evidence that supports antidepressants? How did it get to the point that antidepressants started being prescribed?

Dr. Joanna Moncrieff: The evidence that is always cited for the use of antidepressants consists of numerous trials that have been conducted by comparing an antidepressant with a placebo substance. These are called placebo-controlled trials; pharmaceutical companies need to conduct a number of placebo-controlled trials to show that their drug is superior to a placebo in order to get a license to market their drugs. There are lots and lots of placebo-controlled trials of antidepressants, most of which have been conducted by the pharmaceutical industry. If you look across all of them, and you include the ones that were never published because their results were negative and they were buried, you will find that there is a small difference between antidepressants and placebo. Antidepressants appear to be a little bit better on depression rating scale scores than placebo tablets, but the difference is really very small. It is 2 points on the 52-point Hamilton rating scale for depression. The Hamilton Rating Scale contains a number of items that reflect different symptoms of depression, and is probably the most commonly used depression rating scale in antidepressant trials. So, the difference between antidepressants and placebo, on average, is 2 points. In fact, it is just a bit less than two points. That is what has been shown in a very large meta-analysis of placebo-controlled trials of antidepressants. Other research that has tried to work out what might be a clinically relevant difference (a clinically relevant effect on the Hamilton scale) suggests that you'd need probably in the region of seven to eight points difference before there was actually a difference that was meaningful. Certainly, you'd need a difference that was bigger than three or four points. So, it's not clear that this difference is clinically meaningful. It's not even clear that it's a genuine difference because there are various methodological factors involved in the trials that may account for this difference. For example, a placebo is used because we know that when you give people a pill and you tell them it's something that's going to make them better there is a placebo effect. People will get better just from being told that and being given that pill. But, taking an antidepressant is a different experience from taking a placebo pill. So, many people in these trials will know, or at least some people will know or will be able to guess whether they are getting the actual drug or the placebo because they experience some side effects and maybe they've taken an antidepressant before and they know what to expect. Well, maybe they just feel a bit subtly, a bit in a slightly different state, which makes them think they might be on the active drug. So, these studies are probably not fully double-blind as they're meant to be, and this small difference may possibly be accounted for by the amplified placebo effect that you get from taking the active drug, the antidepressant in these studies. And there are other ways of accounting for the effect that antidepressants might have in these trials, and this goes back to our work on serotonin. A lot of mainstream psychiatrists reacted to our work by saying “It's not important; we knew all along that serotonin wasn't involved. It's probably something similar. It's probably serotonin doing it, but in a more complex way, or it's some other biological abnormality.” They are assuming that the only way that antidepressants can work is by targeting an underlying biological mechanism of depression. But, there are other ways that antidepressants might be having effects. I mentioned earlier that SSRIs are active drugs; they're not placebos. They make people feel different. They're active drugs that affect the brain, so they change our normal mental state. They change our normal brain chemistry, and that is translated to changes in normal feelings and thoughts and behaviours. Some antidepressants have effects that are much more subtle than others, so people will take some antidepressants and won't feel terribly different. Other antidepressants that people will take, and they'll definitely know they've taken a drug. They'll feel distinctly different. One of the effects that antidepressants seem to have is that they reduce the intensity of our normal emotions. So, people often report that they feel a bit emotionally numb, and they can't experience happiness or joy anymore as well as feeling numbed to negative emotions like sadness or anxiety. Obviously, if you're taking a drug that has these effects, that is going to affect your scores on a depression rating scale that is going to ask you how intensely sad you feel and how anxious you feel. A lot of depression rating scales include symptoms of anxiety, questions about anxiety. It's also possible that antidepressants are having their effects by producing these mental alterations, and although the placebo control trials don't seem to suggest that those alterations actually make an awful lot of difference to people's ultimate outcome. Nevertheless, I think it's really important that people understand that. Understand what antidepressants are, and understand that they are drugs that change the normal state of the brain and therefore change our normal mental states. One of the changes that they produce is this numbing effect. Some of them make people feel a bit lethargic and sedated. Some of them can make people feel a bit agitated. We know that SSRIs’ in particular have a profound effect on sexual functioning that is very, very common. It occurs in most people who take them, and is probably connected with this emotional numbing effect as well. People need to be informed, in my view, that this is what antidepressants are and that this is quite plausibly how they affect how they produce their effects in antidepressant trials. As alongside these amplified placebo effects that I mentioned, and that we have many theories, but no proof, that they are working on an underlying biological mechanism of depression.

Timur Begaliyev: Is this emotional numbing effect temporary? Are there any long-term effects, like tolerance, to SSRI's?

Dr. Joanna Moncrieff: That's a really good question! The vast majority of research from antidepressants is short term. Most antidepressant trials last about 8 weeks, some last 12 weeks, a very few last six months, and a very very few last a bit longer. In reality, many people end up taking these drugs for months and for years at a time, and there really has not been any good research into how these drugs might affect you if you take them for months and years, what they might do to the brain, and whether what they do to the brain normalizes when people stop taking them. But, we do have increasing reports from people suggesting that when people stop taking them, there are changes that do not normalize. For example,

we know now that antidepressants cause physical dependence, and that's evidence that they're changing the brain and the body.

So, the brain and the body are adapting to try and counteract the effects that they're producing. Therefore, when you stop taking them, those modifications that the body has made give you the experience of withdrawal symptoms because they're not being counteracted by the drug anymore. Those withdrawal symptoms, for some people, can go on for a long time, for months, and often for years, indicating that something has changed in the brain that doesn't just normalize the minute that you stop the drug. It may take a long time to normalize; possibly it may never do so. There's also evidence that some people have persistent sexual dysfunction even after they stop taking antidepressants, and some people have persistent emotional blunting when they stop taking antidepressants. So those effects also seem to indicate that the antidepressant has changed the brain in some way that is not just temporary but is more persistent.

Timur Begaliyev: If someone is listening to this episode right now, and they are taking antidepressants, what would you tell them?

Dr. Joanna Moncrieff: I would tell them to think very carefully about what they think the drug is doing for them, what they want the drug to do for them, and what evidence they have about what it is actually doing. Then, they should make a judgment about whether it's really useful to carry on taking the drug or not. People need to take their time with this process. They need to discuss it with friends and family members. They need to discuss it with clinicians, with their doctors, and with other mental health professionals if they can. But they really need to try and work out, I think, whether they think the drug is doing something useful for them. And if they think it is, whether those useful effects outweigh the adverse effects that everyone will undoubtedly experience to some degree and from taking antidepressants. If people do decide that they don't think the drugs are really useful for them and want to try and stop taking the drugs, they need to do that very slowly and very carefully and they need to do it with support of the mental health professional. They particularly need to take it slowly and carefully when they get down to the lower doses of the drugs because lower doses have a proportionately much stronger effect than higher doses.

Timur Begaliyev: Alright, so thank you Dr. Moncrieff for coming on again! Is there any way that students can look to find out more about you?

Dr. Joanna Moncrieff: Yes, I've got a website,, which has all my blogs on it. I also blogged on the Mad in America website, and I've written several books. The first one was called the Myth of the Chemical Cure, and then I wrote The Bitterest Pills which is about antipsychotics in particular. Eecently I've just updated a book called The Straight Talking Introduction To Psychiatric Drugs.

Timur Begaliyev: OK, and so for the last question: If you wanted someone to remember three key points from this episode, what would they be?

Dr. Joanna Moncrieff: The first key point is that antidepressants are drugs that change the normal state of the brain. They are not normalizing anything! Inevitably, when you take something that changes the normal biological state, there are going to be harmful consequences. So that's the first point — we need to understand what antidepressants really are. Well, and the second point is the really important thing. The second point: There are many theories, it might be better to say speculations, about the biological basis of depression. None has been proven. We have no evidence that there is any biological abnormality in people who are diagnosed with depression. Third Point: If you are going to take drugs for depression or medication for anything, take them in as low a dose as possible for a shorter time as possible. The longer you take a drug, the more harm it can do to the body, so taking them for short periods is a good way of avoiding some of the unwanted consequences.

Timur Begaliyev: Awesome, thank you!

Dr. Joanna Moncrieff: Can I just say something about depression? I feel that I ought to say something about depression.

Timur Begaliyev: Yeah, of course!

Dr. Joanna Moncrieff: So, I think the attitude that antidepressants simply must be acting on some underlying biological mechanism of depression reveals that there is an assumption that depression is a brain disease that we can see — that it's something going wrong in the brain that causes low mood. And one day — even if we can't see what it is now — one day we'll be able to see, we'll literally be able to visualize, what it is or detect in some way what it is that's gone wrong. That is actually not our normal way of thinking about emotions, and

we've had to be coached into thinking in this way about depression. We have been coached by the Pharmaceutical industry.

How we normally think about emotions, is we think about them as feelings and experiences that occur in response to things that are happening in our lives. So, we think of depression and sadness and anxiety as emotional responses to threats, losses, and things that make us feel bad — things that we don't like. And that is, I would suggest, the appropriate level at which to explain depression — to think about what has gone wrong, and what someone's feelings are a response to, rather than looking in the brain and trying to find it in the brain. Of course, something is going on in the brain when people are depressed, but we don't actually need to know what that is to make sense of depression. We can make sense of depression already! We always could. And I would suggest

we need to go back, if you like, to that common sense understanding of depression and anxiety and other emotional states as reactions to life circumstances.

Reactions that are coloured, of course, by the personality and the history of the individual, including their genetic makeup. I think there is probably some genetic component to how we experience emotions and respond to our life circumstances. But nevertheless, what our emotions are, how we normally understand them are reactions to our current life circumstances. And that, to me, is how we need to understand them. The idea of looking for depression or anxiety in the brain is a red herring that is really not going to help us. And I think also, if we understand emotions like this, we understand intuitively that taking drugs to suppress them or modify them is probably not a good idea, and certainly not a good idea in the long term. We easily recognize that alcohol, for example, we can have a few drinks of alcohol and that changes on our pre-existing emotional state. We even have a term for it, its saying for it is “drowning your sorrows.” What we mean by that, is that the alterations produced by alcohol temporarily override your underlying feelings. I would suggest that antidepressants and other psychiatric drugs are doing exactly the same thing, and we need to understand them in that way, and we need to be just as cautious about them as we would be cautious about the idea off recommending that someone goes out and gets drunk every day in order to get rid of their sadness.

Timur Begaliyev: Yeah, I heard about something called the neuroscience bias — that neuroscience legitimizes the psychological practice to the general public. So I think that fits in at that point as well.

Dr. Joanna Moncrieff: Yes, yes.

Timur Begaliyev: Thanks for taking the time to meet with me, Dr. Moncrieff! And that's it for this week of SciSection, make sure to check our podcasts available on global platforms for our latest interviews!


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