RHR: Reviewing the Evidence on the Serotonin Theory of Depression, with Dr. Joanna Moncrieff

In this episode, we discuss:

• The origins of the chemical imbalance theory of depression and whether there is scientific evidence to support this theory
• How human bias has perpetuated the myth of the serotonin theory and the use of tricyclic drugs to treat depression
• Our approach to understanding and treating depression prior to the chemical imbalance theory and how this theory has altered approaches to depression in the mental health profession
• Why the pharmaceutical industry sought to override the dominant conceptualization of depression
• Whether we can say that there is a true biological basis to depression
• What happens to people with and without depression when levels of neurotransmitters in the brain are altered in clinical trials and the role of the placebo effect in antidepressant drug trials
• The long-term negative effects of selective serotonin reuptake inhibitors (SSRIs) on the human body, particularly in adolescence

Show notes:

• “The ‘Chemical Imbalance’ Myth” by Chris Kresser
• “The serotonin theory of depression: a systematic umbrella review of the evidence” by Joanna Moncrieff, Ruth E. Cooper, Tom Stockmann, Simone Amendola, Michael P. Hengartner, and Mark A. Horowitz 
• Blaming the Brain: The Truth About Drugs and Mental Health by Elliot Valenstein
• “Placebo Response of Non-Pharmacological and Pharmacological Trials in Major Depression: A Systematic Review and Meta-Analysis” by André Russowsky Brunoni, Mariana Lopes, Ted J. Kaptchuk, and Felipe Fregni
• Dr. Joanna Moncrieff’s website
• Follow Dr. Moncrieff on Twitter
• Learn more about the Adapt Naturals Core Plus bundle or take our quiz to see which individual products best suit your needs
• If you’d like to ask a question for Chris to answer in a future episode, submit it here
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• Get your free LMNT Recharge Sample Pack when you purchase any LMNT product at Kresser.co/lmnt
• Visit Paleovalley.com/Chris and use the code KRESSER15 to get 15% off your order

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Hey, everybody, Chris Kresser here. Way back in 2008, I wrote an article called “The ‘Chemical Imbalance’ Myth,” which challenged the dominant idea that depression is caused by a chemical imbalance in the brain and changes in serotonin levels. As you can imagine, it was a pretty controversial article. It probably received more comments than just about anything else I’ve ever written, along with quite a lot of hate mail and pretty strong attacks, despite the fact that the article was very well-referenced and included many links to peer-reviewed evidence.

And since then, that theory has only fallen apart further, most recently with a landmark paper that was published by Dr. Joanna Moncrieff and colleagues. It was a review of meta-analyses that had been published on this topic, and it just systematically debunked the idea that depression is caused by a chemical imbalance and changes in serotonin levels. That’s the topic of this show. I’m really excited to welcome Dr. Joanna Moncrieff as my guest. She [is] a professor of critical and social psychiatry at University College, London, works as a consultant psychiatrist in the [National Health Service] (NHS), and has been researching and writing about the overuse and misrepresentation of psychiatric drugs, and about the history, politics, and philosophy of psychiatry for many, many years.

I first came across her work in the early 2000s, which is what led to me writing that series of articles starting around 2007 or 2008. Since then, I have followed her work for all of that time and continue to be just blown away by how persistent this myth is in the complete absence of evidence to support it. I just want to warn listeners that this episode could be provocative if you’re currently taking an antidepressant. And if this is news to you, that this theory of chemical imbalance is not supported by the evidence, I just want to gently invite you to listen to this with an open mind, to not take it personally, [and] to understand that there are forces at work, namely pharmaceutical companies that have invested tens, if not hundreds, of millions or even billions, of dollars in perpetuating this hypothesis. That’s even a generous term to use, a hypothesis. It’s really more of a marketing campaign that has been used to sell more antidepressant drugs. And, again, this could be disturbing. I want to give you fair warning. But I also hope that you can listen to it and take in some of the information because ultimately, I believe it’s incredibly empowering to learn that depression is not some permanent thing that we can’t change [or] some flaw in our brain that can only be addressed by taking a psychiatric drug, [but rather] that we actually have quite a bit of agency over our own mental health and the ability to make progress without taking these drugs, in many cases.

I realize that’s a longer intro than normal, but this is, I think, a very important episode. I really enjoyed this conversation with Dr. Moncrieff, and I have the deepest respect for her work and her persistence in the face of great opposition. Not opposition to the science, which nobody really seems to be able to challenge, but just to the general idea. Because as Upton Sinclair once said, “It is difficult to get a man to understand something when his salary depends on his not understanding it.” And I think that’s largely what’s going on here with this particular theory. There is just too much money invested in perpetuating it. Also, probably lots of careers and reputations, on top of that. My hope is that as Dr. Moncrieff and others who are publishing very, very detailed and complete analyses that debunk this theory, over time, the public perception will shift. That’s my hope. And I hope that this podcast can play some small role in that happening. So, without further ado, let’s dive in.

Chris Kresser:  Dr. Joanna Moncrieff, thank you for being here. It’s such a pleasure to have you on the show.

Joanna Moncrieff:  Thank you for having me. Looking forward to our conversation.

Chris Kresser:  So yes, I’ve been really looking forward to this. Because as we were chatting before the recording started, I’ve followed your work for at least 15 years. I’ve been writing about the chemical imbalance theory of depression since then over those many years and [reading the work of] other researchers like Dr. Elliot Valenstein. And I think I’d like to just start with the history here. How did this idea that depression is caused by a chemical imbalance and particularly serotonin depletion, or serotonin imbalance get started in the first place? Because it became widespread, and pretty much anyone you would ask on the street would say that that’s what causes depression. But how did this even start?

Joanna Moncrieff:  That’s a good question. So it [started] in the medical community; it [started] in the 1960s when certain drugs start[ed] to be proposed to have antidepressant properties. And people [were] starting to think, oh, maybe depression might have a chemical basis. So they start[ed] to speculate about how these different drugs that [they were] using might be affecting people’s moods. And first of all, the focus [was] on noradrenaline and actually, for many years, the main focus was on noradrenaline. That was thought to be the key brain chemical involved in mood. But serotonin was also proposed to be important in the 1960s. And that idea [was] picked up in the 1980s when the SSRIs start[ed] to come onto the market.

Now, the other thing to say is that the medical profession, particularly psychiatrists, [were] keen on the idea of depression having a biological basis all the way through from the 1960s onward. But the pharmaceutical industry [was] not interested in antidepressants, or depression, until the 1980s. Because before that, they [were] busy making a lot of money selling vast, vast quantities of benzodiazepines. Those [were] the big sellers in the 1970s. And very large numbers of Americans and Europeans were taking benzodiazepines at that time. And then, in the 1980s, there [was] a real crisis concerning benzodiazepines. It [became] apparent that they [were] in fact addictive, even though [they had] been marketed as being a non-addictive alternative to barbiturates. And it [became] apparent that [they’d] been doled out like sweets to people who [had] social and circumstantial problems. So they start[ed] to get really bad press, it [became] very difficult to market a drug for anxiety, and the pharmaceutical industry [switched] to depression. And they also realize[d] when they [did] that, when they start[ed] to launch these new SSRI antidepressants, like Prozac, of course, is the first one or the first one that [became] successful launched in 1987. And because the scandal about the benzodiazepine situation [was] still in the air at that time, they realize[d] that they [had] to sell these drugs with a different sort of story.

Now benzodiazepines were quite clearly drugs that alter someone’s normal mental state. They’re mind-altering substances. And they basically replace people’s underlying feelings with a drug-induced state. And that was clearly apparent to everyone. Because the benzodiazepines had gotten such bad press, that had brought the whole process of giving people drugs to essentially numb their emotions and numb them and distract them from their social problems, into disrepute. It had brought that whole activity a bad name. So the pharmaceutical industry, I believe, realized that they had to tell a different story. And that’s when the pharmaceutical industry really got behind the idea of depression being a chemical imbalance and started to very widely promote that idea.

Chris Kresser:  That makes a lot of sense to me knowing the history of the pharmaceutical industry and other drugs that they’ve been involved with, with similar marketing-based introductions. But let me ask two questions as a follow-up, and we can tackle the first one to begin with and then move on to the second one. I assume this wasn’t just pulled out of thin air. That there was at least some early evidence or some, even if it was later proven to be false or incomplete, that led them in the direction of this chemical imbalance theory. You mentioned early on in the ‘50s, there was some, I believe there was a bacteriologist named Albert Zeller, who founded a drug that was the first monoamine oxidase inhibitor, and there were some other sort[s] of indications that these changes in chemicals in the brain were at least possibly contributing to depression. So did they just take a little bit of evidence that existed, even though it was fragmentary and incomplete, and blow that up? Or was there more going on at that point that justified that approach?

Joanna Moncrieff:  So really, this idea comes from the fact that certain drugs were noticed to alter mood. There was never really any convincing evidence independent from the drug effects that there were abnormalities in brain chemicals, either serotonin or noradrenaline or anything else. So it really was an assumption. There was an assumption made that if you’re able to change mood by giving a chemical, therefore, depression and mood states must have a biological origin. So that’s really what happens. And the evidence that chemicals change mood, of course, can be interpreted in different ways, as I suggested for the benzodiazepines. So the early drugs, the first drugs that were thought of as being antidepressants were drugs that were being used for the treatment of tuberculosis in the old mental asylums. And if you look at the early papers on those drugs, they are clearly stimulant type substances with a profile that is similar to amphetamines. And people recognized that at the time. The early papers [said] these drugs are very like amphetamines. They keep people up, but they make people psychotic. Then later papers start[ed] to talk about the drugs differently. And those stimulant effects appear[ed] in the small print at the end as a side effect, rather than an effect of the drug. So of course, these drugs were making people happy; they were making people energetic and alert because they were stimulants. So that’s how they affected mood.

Then other drugs come along that are called antidepressants that don’t have stimulant effects. The tricyclic drugs actually had sedative effects. And I think probably what’s happening there is you’re seeing a placebo effect affecting both patients but also observers, also affecting the clinicians. This was a period where people were very enthusiastic about finding drugs for the treatment of mental disorders, and could easily convince themselves that they had a drug that was effective and that they were noticing some beneficial effects in people. The first paper about the first tricyclic antidepressant, imipramine, for example, describes it as curing impotence during sexual deviation, as defined at the time. It’s now recognized that imipramine causes impotence if it does anything to sexual function. So that was a very odd observation and almost certainly not down to the imipramine. And I think that just shows you how enthusiastic people were about these drugs and how that colored their perceptions of what they were doing.

Chris Kresser:  Yeah, it seems to me that this is a human bias overall. We prefer to know rather than to not know, and I think this is particularly prevalent in medicine. There’s a quote I came across, I think it was from Elliot Valenstein in his book. He said, “A theory that is wrong [is] considered preferable to admitting our ignorance.” It seems like that had something to do with it. We didn’t know what caused depression. It was affecting a lot of people. We didn’t have a clear solution or treatment. And as soon as there was something that seemed like it could be a theory that would lead to particularly pharmaceutical treatment, that it was off to the races after that.

Joanna Moncrieff:  Yeah, I slightly dispute that. I think we did have a theory of depression; we just didn’t have a biological theory of depression. There was, the old [Diagnostic and Statistical Manual of Mental Disorders] (DSM) defines depression, it defines all mental disorders as reactions to circumstances, to life circumstances. They’re all called depression. It’s a depressive reaction formation. They were regarded in a different way than we regard mental health problems today. And ordinary people, I think, have always held the view that emotional states like depression consist of a reaction to circumstances. Obviously, with individual differences, the way that individuals react to their circumstances is colored by their upbringing, by their history, and to some extent by their genetic makeup. So it’s not that biology is completely irrelevant. But it’s not causing the emotion in the immediate term in the sense that biological theories of depression want to suggest that it is.

And this came out to me when I was looking at the material from the Defeat Depression campaign, which was a depression awareness campaign run in the U.K., in the early 1990s, partly funded by the pharmaceutical industry, particularly Eli Lilly, the makers of Prozac. And the people who were running that campaign commissioned a survey before they got the campaign running. And the survey uncovered that most people believe[d] that depression was caused by unemployment, marriage breakdown, [or] poverty. That was people’s view of depression. They did not feel that it was caused by a chemical imbalance or a brain problem. And that view was a view that that campaign and the pharmaceutical industry deliberately set out to change and to override, so that they could instill in people views that would be conducive to them taking antidepressants.

Chris Kresser:  That’s so fascinating. I want to come back to other potential biological contributors to depression later in the conversation that have been more recently studied and get your take on those. But I want to continue this conversation because that’s the main focus of this interview. So we’ve established that there was never really solid evidence to support the chemical imbalance theory of depression. Now I want to ask you about evidence that [directly] contradicts that theory. And maybe I can just ask you a few questions, and you can tell me if these are true or false. So does reducing levels of norepinephrine, serotonin, or dopamine produce depression in humans?

Joanna Moncrieff:  So I’ll answer your question in a minute. But first of all, I’ll say it’s very difficult to prove a negative.

Chris Kresser:  Okay.

Joanna Moncrieff:  So I don’t think it’s the case that we have evidence that depression is definitely not a biological condition, and we probably never will have that evidence. Because you’d have to have massive, massive studies for every area, to be quite sure that it’s been disproved. What I think we can say confidently is that we have not proved that there is a biological basis to depression, and that was what people have been led to believe. So can you cause depression by reducing levels of brain chemicals in people who don’t have depression to begin with? And the answer is no.

For example, looking at serotonin, there have been several studies [that] have used an experimental mixture of amino acids, which lack the amino acid that serotonin is made out of called tryptophan. And if you give people this mixture of amino acids without the tryptophan, in order to make proteins, the body has to use up all the tryptophan that’s available already. Therefore, there’s not much available tryptophan to make serotonin and to cross into the brain to make serotonin in the brain. It’s probably not a perfect procedure. It’s probably doing other things, as well, to be honest. But it does reliably reduce tryptophan levels. And it’s thought to reduce serotonin levels. Anyway, that has been compared with giving people a drink of amino acids containing tryptophan. And basically, there’s no evidence that that produces depression in people who don’t have depression to begin with.

There are some studies that show that it might make people’s depression worse, or bring on a temporary recurrence of symptoms in people who have had prior depression. But there are a number of problems with that. The first is that the number of people and those studies is very small. The ones that have been looked at in a meta-analysis, no one’s done a recent meta-analysis. And the only studies that we found of that sort that had been done recently actually didn’t show any effect in people with a history of depression. And then the other consideration is that these people have been exposed to or [are] very likely to have been exposed to antidepressant drugs, which we know interfere with the serotonin system in some way and therefore may confound the results of those experiments. So basically, from what are called “tryptophan depletion studies,” there is no evidence that reducing serotonin produces depression.

Chris Kresser:  What about the flip side of that? Do drugs that raise serotonin and norepinephrine, like amphetamines or cocaine, alleviate depression reliably?

Joanna Moncrieff:  That’s a good question. I think people don’t realize actually how little we really know about what drugs do. So, SSRIs are meant to increase levels of serotonin. But actually, we found some evidence, and it turns out, there is quite a lot of evidence out there, that certainly in the long term, they probably reduce levels of serotonin. And they may well, some of them at least, have effects on other neurochemicals that haven’t really been very well researched or understood. Now, amphetamine is a drug that affects numerous brain chemicals, and we’re not sure which ones are the key chemicals. But probably, its main effects are produced by its effect on noradrenaline, which is associated with arousal. And probably, to some extent, dopamine, as well, which is also associated with arousal. But it also does seem to increase levels of serotonin.

Does amphetamine relieve depression? Well, amphetamine makes people feel good as other stimulants do, as cocaine does, while people are taking it. Does that mean it’s curing depression? In my view, no. It has the same effect [on] anyone, whether you’ve got depression or not. It has effects in animals, behavioral effects in animals that are consistent with its effects in humans. But if you give it to people with depression, there are some studies that show that amphetamine is an effective antidepressant, that it reduces depression rating scale scores better than a placebo, or as well as other antidepressants. Which shouldn’t surprise us given what we know about its profile of effect.

Chris Kresser:  Right. The question, though, as you point out, is, is that a valid ongoing treatment for depression, considering the whole range of effects, side effects, etc.? On a related note, I don’t know that there’s ever been a great explanation for why antidepressant drugs like SSRIs take so long to produce an elevation of mood. From my understanding, and please correct me if I’m wrong, they produce their maximum elevation of serotonin in only a day or two and noradrenaline or norepinephrine, but it often takes several weeks for people to experience a full effect. Is that also an argument against the chemical imbalance theory, in your mind? Or is there some other explanation for why that is?

Joanna Moncrieff:  So let’s come on to what antidepressants do. In my view, antidepressants do not have worthwhile effects on depression. If you look at placebo-controlled trials of antidepressants, the difference between an antidepressant and a placebo is miniscule. It’s really, really small. It’s two points on the 53- or 54-point, commonly used Hamilton rating scale of depression.

Psychiatrist Dr. Moncrieff’s new meta-analysis review confirms that the chemical imbalance theory of depression is a myth—one that was intentionally created by the pharmaceutical industry to sell medications to the masses. How has this theory, widespread in our modern society, affected our bodies and our mental health? Join me on the latest episode of Revolution Health Radio to find out. #chriskresser #depression #mentalhealth

Chris Kresser:  And if I can just interject, is that, Joanna, for mild, moderate, and severe depression? Or are there differences across the intensity of depression?

Joanna Moncrieff:  Some studies seem to find slightly higher differences in people with severe depression. But some studies don’t. I would say the jury’s still out on that, and the average average difference is very small. Moreover, I think there are other explanations other than the pharmacological effects of the drug that may account for those differences, particularly the fact that people often know whether they’re taking the antidepressant or the placebo, especially if they’ve taken antidepressants before, which many people in these trials have done.

Chris Kresser:  So they’re not truly blinded.

Joanna Moncrieff:  So they’re not truly blinded. They’re meant to be double-blind trials, but they’re not. And we know that the expectations that people have about what they’re getting, about whether they’re getting the drug or the placebo, have a very profound impact on the outcome of a study. So there’s a very interesting study that compared sertraline, an SSRI antidepressant, with St. John’s wort, and a placebo. Now, in this study, people couldn’t guess what they were on. And this was a negative study; there was no difference between the two drugs and the placebo. But when you asked people to guess what they were taking, the people who thought they were taking either St. John’s wort or sertraline did much better than people on the placebo. And the difference is around five to eight points difference. Much bigger than the normal difference you would see between a drug and a placebo in a randomized controlled trial. So what that says to me is that we know there are some studies where people can guess correctly what they’re taking. And if they can guess, you’re going to see this expectation effect influence the outcome of the study as if it were a true outcome of a true drug effect.

So my view is that, sorry, to come back to your question. So my view is that antidepressants actually are no better than placebo. And that the reason why we have this idea that antidepressants take two weeks to work is that placebo takes two weeks to work. It takes two weeks for people’s hope, the hope that people have and the good feeling people have from having been listened to and feeling that something’s been done, and something’s going to help them to translate into an actual improvement in mood. And also, I think it takes two weeks for people to, often to get out of the situation they’re in, that has made them depressed. Not everyone, of course. For everyone, it takes much longer. For many people, it takes much longer. But for some people, two weeks is an amount of time where actually they can stand back; they can think, okay, maybe I was feeling awful because of this, and I could do this about it. So that’s why I think we have that two-week effect that’s so often quoted.

Chris Kresser:  Right. It’s got nothing to do with brain chemicals and how long they’re taking to increase or anything like that. That’s how long it takes for the treatment effect that’s caused by placebo, to actually happen. Two things here. First, I completely agree and would say that I think the average person is not well informed about the extent to which placebo plays a role in, certainly, in antidepressant research, but just in research in general. And this has been a fascination of mine for many years. And I’ve written a lot about this, too. Ted Kaptchuk, for example, who’s now at Harvard, but started his career as an acupuncturist, [had a] very interesting career trajectory, and then ended up studying the effects of placebo in antidepressant medications in many other contexts, as well. But I remember a paper he published in 2009 in PLOS One, which found that the extent of placebo response is large, regardless of the intervention, and is mostly associated with the study population and size so that the greater the study population size, the greater the placebo effect, I think. What would you say? Because what happens from whenever I write articles about this, and I do want to be sensitive to people who are listening, as well, I get sometimes vitriolic hate mail from individuals who insist that they have been helped by antidepressants, who know, beyond a shadow of a doubt in their bones, that it was the medication and not a placebo effect that helped them, and [who] take great offense to the suggestion that the drug didn’t have an effect and depression is not biological. Because their interpretation of that often, I think, is that means depression is my fault, that there’s something wrong with me, that I’m to blame for what’s going on; this is all on my shoulders, and if only I was a better person, or could live my life better, then I would not be depressed. And that story is pretty heavy for most people to take on and not preferable to the idea that depression is caused by a chemical imbalance that medication could fix. I imagine you’ve encountered this, as well, whether from patients or other researchers or professionals in the field. So I’m just curious how you approach that, how you respond to that.

Joanna Moncrieff:  Yeah, yeah. That’s a really good point. I mean, the first point I’d like to make is, it seems to me, I’m not trying to say that people are gullible. When people are really depressed and really distressed and hopeless, it is not at all surprising that being offered something that they are told might help them gives them hope and therefore helps them. So I’m really not trying to say that people are gullible. I think it’s a very normal human response. So that’s one point to make. The second point is, I’m not trying to stop people [from] taking antidepressants. But I am trying to make sure that people are informed, and that they are not misinformed and misled. And it is a fact that people have been misled into believing that there is a proven chemical abnormality in the brain. And that is not a fact. Nothing of the sort has been proven. The evidence is completely inconsistent and very weak. But the trouble is, of course, that because of this campaign that we were talking about earlier that was started by the pharmaceutical industry with the support of the medical profession, many people have been persuaded that that is the case, and have come to develop an identity that that they have something wrong with their brain, and that they need a drug or some other physical intervention to put that right.

So of course, it’s very challenging when someone comes along and says, actually, that identity is not founded on fact; it’s not founded on evidence. Of course, that is very challenging. But on the other hand, it’s not a good thing to have a brain problem. And being told that actually your brain is normal and your emotional responses are normal is a good thing in the long run. It may be difficult to absorb because you’ve been persuaded to adopt this identity that’s been sold to you. But actually, it is a good thing to know that there’s nothing wrong with your brain. And yes, it does give us some responsibility for our moods. But that is also a good thing because the flip side of having some responsibility is that there is something that we can do to help ourselves recover. We do have some agency.

And I also think we all have emotional difficulties from time to time, and some more than others. As I said, there are individual differences, and there are some people for lots of different reasons, but often commonly because of terrible things that have happened to them in their past lives, [who] struggle with their emotions more than others. And people like that deserve sympathy and support. It’s not blame, not you’re responsible; get on with it. We’re washing our hands [of] you. People deserve support. I don’t think that people have to have a biological problem or a brain chemical problem in order to merit support from health or social services to get through a difficult time.

Chris Kresser:  Right. And what may be an unintended or intended, I’m not sure, effect of this chemical imbalance theory is that they may be less likely to get that support than they would be otherwise, if depression was looked at in a more holistic frame. In other words, if everyone has just bought into the theory that it’s [a] chemical imbalance, and someone goes to the doctor complaining of depression, chances are, they’re just going to be prescribed an antidepressant, and there’s not going to be a referral to a psychologist or another mental healthcare provider or psychiatrist. Even if they do go to the psychiatrist, nowadays, that has largely become a pharmacological interaction, where it’s just a question of what drug is going to be prescribed. Many psychiatrists are not doing psychotherapy or providing that kind of support anymore, largely because of this. This notion has taken such a deep hold in our culture.

Joanna Moncrieff:  Yes, I think you’re right. Certainly, in the U.K., a lot of people do get therapy. We do now have therapy service on the National Health Service that is offered to everyone. But certainly, in the past, the option of offering people an antidepressant, I think, has made it less likely that people will get other sorts of help. I also think this whole concept, this whole idea that depression is a biological brain-based problem, actually means that doctors, psychologists, [and] everyone who’s trying to help people with their problems are not really necessarily listening to the problem. Because what they’re doing is saying, “Oh, you’re someone with depression.” They’re dealing with a label, rather than with an individual with a unique set of problems. And that’s, in my view, how we need to help people with depression. We need to see them as unique people who have their own unique set of problems that they need support with, and it will be different for each individual. So this idea that there is such a thing as depression that has a single sort of treatment or a single collection of treatments is nonsensical to begin with.

Chris Kresser:  I think that’s such an important point. And going back to what you said before about how, yes, when you take this information in, it can be difficult at first because it challenges an idea that you may have had. And that actually, that idea, at least at first glance, may in some way make things easier. At least, if someone is interpreting depression as being their fault, it removes that blame from their shoulders. So there is a way that I could see that makes it easier. And I’m just speaking personally as someone who’s suffered from depression in my life, so I know what it feels like, and I’ve been through this myself. So I’m not at all lacking in empathy for people who struggle with depression because I’ve been through some pretty dark places, personally. But I’ve also experienced the difference in interpreting that depression as something that is transitory, or at least potentially transitory, that is not a fundamental characteristic of who I am, that doesn’t define me, like you said. That isn’t a problem in my brain that is only fixable by taking a pharmaceutical drug. And one of the things that actually really empowered me was your work and the work of other people [who] debunked this theory. And anger was actually something that helped me get through this. Anger at pharmaceutical companies for perpetuating this story and then realizing that I was a victim of that marketing push, basically. That I took on this whole idea of what caused depression. And for me, it was short lived because I got exposed to your work and the work of others, disabused me of that myth. But I think that anger can be actually a powerful motivating force in that situation where people realize that they’ve been willfully taken advantage of in order to be a profit center for these pharmaceutical companies [that] want to sell more drugs.

And there’s very little accountability for those companies for things like this, which is a whole other conversation. We won’t go down that road. But it seems to me that awareness is key. It’s the starting point to a different way of dealing with depression, whatever that might be for each individual. But without awareness, you can’t even take that next step.

Joanna Moncrieff:  Yeah, absolutely. I mean, I’ve met several people in the same sort of situation since the publication of the serotonin paper, and had many people contact me saying exactly what you’re saying and really feeling very disturbed and very angry about what had happened.

Chris Kresser:  Yeah, so that’s a good segue to the next question. What is the reaction? When I read your paper, my first thought was, oh, boy. I hope Joanna’s doing okay. What has the response been like from your peers in your field and just the public at large? What’s it been like since you published that paper?

Joanna Moncrieff:  So the response from my peers, from the psychiatric profession, has been, basically, to try and shut down the debate and to divert it, and to do anything to stop people questioning the benefits of antidepressants, and to stop people questioning the idea that they work by targeting some sort of biological abnormality. So the tactic has been, oh, yeah, of course, we all knew that the serotonin theory was wrong. But it’s more complicated than that. It’s more complicated. Of course, serotonin is involved in some way, and so is this and so is glutamate, and so is dopamine, and so is neuroinflammation. And just to throw everything at it, to give the impression that there is good research that depression has a biological basis. And I think most crucially, to say, don’t worry about antidepressants. Carry on, regardless. This doesn’t change anything. So that’s been the reaction.

Chris Kresser:  Wow, that’s incredibly disappointing, I’m sure for you much more than me. But even for me as a bystander, it’s wild to me that as professionals who are trying to learn as much as we can about how to support our patients and make progress. I mean, I understand intellectually, why there would be so much resistance. When you invest deeply in a theory, and you become identified with that as a clinician, and it’s defined the way that you’ve treated patients perhaps for five, 10, 20, 30 years, I get on a human level that that can be hard to pivot from because then what do you? Have I been wrong for all these years? And what am I going to do? And it’s still very disappointing that that is the response to what I view is pretty much incontrovertible evidence that you presented in that paper, and that they’re not actually challenging the evidence. They’re just, like you said, diverting, and obfuscating rather than actually critiquing the arguments you made in the paper.

Joanna Moncrieff:  I think it’s extremely disappointing. And I am also feeling very angry because I do feel that actually, there are people in the profession who do not want the public to actually have access to the facts and don’t want the public to be able to appreciate the debate and discussion that exists around antidepressants. Yeah, I think the bottom line is that they really, really don’t want people to, well, first of all, to question the idea that depression is at [the] root a biological problem. And secondly, to understand antidepressants in the way that we used to understand benzodiazepines. To understand them as an emotion number, something that just changes anyone’s mental state. Because people naturally would question whether that’s a good idea. And when you start talking about drugs, if you acknowledge that these drugs are not correcting a chemical imbalance, but they are drugs, they’re not placebo tablets, you have to acknowledge that actually they’re creating a chemical imbalance. They’re actually changing our normal brain chemistry. And I think the professions really don’t want people to hear that statement. Because people will then rightly worry about what changing your normal brain chemistry might do to you, to your brain, particularly if you keep taking these drugs that are causing these changes, day in, day out for months and years on end.

And we do have some evidence that long-term use of antidepressants can do some really harmful and damaging things to the brain. Thankfully, not in everyone. [I’m] not saying this is a universal experience, but they can. They can cause really severe and difficult withdrawal symptoms, and they can cause sexual dysfunction, which in some people appears to persist after people have stopped taking the medication.

Chris Kresser:  I would love to talk about that (crosstalk).

Joanna Moncrieff:  Sorry, yeah.

Chris Kresser:  Yeah, along with specific populations, like teenagers, which I’m particularly concerned about. And before we do that, I just want to ask one more question that I get a lot when I read about this topic, which is this: Okay, so maybe antidepressants don’t work by addressing chemical imbalance or serotonin, shifting serotonin levels. Maybe they have pleiotropic effects, like statin drugs, for example, have. When it was revealed that there might be some issues with the statins working, even when cholesterol levels aren’t changing as much as you would think they are, they have these other pleiotropic effects, which, for people who are listening, are effects that are different than maybe the primary effect that was intended with the drug. I know you’ve kind of already answered this question when you explained that antidepressants don’t work better than placebo on the global level. But what would you say to this argument, or this idea that antidepressants might help some people because of a pleiotropic effect?

Joanna Moncrieff:  So since we published the serotonin theory, there seems to be more and more emphasis on other possible biological theories of what antidepressants might be doing. And one of the popular ones, which also ties into the use of psychedelics that are becoming very fashionable now, is the idea that they stimulate neurogenesis and that there’s some deficiency of neurogenesis in depression. There is no evidence [of] this. There are some mostly animal studies showing [a] possible increase in markers of neurogenesis. But there are many explanations for that. And one explanation is that if you damage the brain, the brain naturally produces neurogenesis to compensate for the damage. So actually, finding indicators of neurogenesis is not necessarily a good thing; it might indicate that the drugs are damaging the brain. But actually, the majority of evidence comes from studies looking at the size of the hippocampus, and some studies suggest that the hippocampus is reduced in people with depression. Some studies don’t. None of these studies have effectively ruled out drug treatment as a possible cause. And that’s basically what the evidence comes down to.

I think calling this a “theory” is actually doing it more respect and justice than it deserves. It’s a speculation along with many other speculations, which has much weaker evidence than there was for the serotonin theory. And that didn’t stack up. And the evidence for all these theories is very unlikely to stack up. And in a way, the people putting these theories forward, I think many of them probably know that, and they don’t care. They just know that if they put something out there, then they can keep on convincing people that depression is biological and that they need to take a drug to deal with it. And that’s the main function of the theory. Not actually really to explain anything. Or at least anyway that, even if that’s not what you intend, that is certainly the effect of putting all these ideas out there.

Chris Kresser:  If one were cynical, one could say it’s more of a marketing campaign, the legitimate scientific theory that’s based [on] published peer-reviewed evidence. Let’s talk a little bit about some of the possible long-term negative effects of SSRIs. I at least want to spend a few minutes on this because as you pointed out, a lot of people are under the mistaken impression that these drugs are completely safe. They’ve been used for decades; every doctor in every practice prescribes them. So how could it be possible that they would have serious long-term side effects and risk? And if you could address the general population, and then any specific populations that are of particular concern like teenagers, that would be great.

Joanna Moncrieff:  Yeah, yeah. So antidepressants have a range of side effects or adverse effects like any drug. And immediately speaking, they’re probably less impairing to take than some other drugs prescribed for mental health problems, such as antipsychotics, which are more immediately noticeable, slow you down, and have lots of function-impairing effects. And modern antidepressants, like SSRIs, at least, produce less of that sort of effect. But nevertheless, they do have immediate effects. And one of the very well-recognized immediate effects they have is sexual dysfunction. And they interfere with sexual function in almost every way that you could think of. They cause impotence, delayed ejaculation, and reduce[d] genital sensitivity. And this seems to probably correlate with their ability to cause emotional blunting, as well. So they are drugs that reduce sensitivity both physically and emotionally. And it’s well recognized that they have these sexual effects in a very large proportion of people who take them; 60 percent, it says in a few studies. And the SSRIs are the particular culprits here. Other antidepressants have less impact on sexual functioning, although they do have some, most of them. So we recognize that they have these effects in the short-term. And what has been coming out over the last few years is that in some people, these effects do not go away when [they] stop taking the drug, and seem to go on for years, in some cases. [They] possibly [are] getting better gradually over the years, but we just don’t know. We don’t have enough long-term follow-up evidence. So obviously, this is a real worry with lots of young people and teenagers taking these drugs. And I suspect that very, very few doctors are telling people about this. I think very few doctors are actually aware of it. And I think that’s partly because there does seem to be in the medical literature an inclination to publish all these rosy figures and lots of studies about the benefits of drugs and a much greater reluctance to publish anything that shows negative effects of drugs, or to fund research that looks at negative effects of drugs. So often, these effects start with, we only find out about them sometimes years down the line when people start reporting them.

And, as well as the sexual side effects, I mentioned earlier that it is now well recognized again, that antidepressants cause withdrawal effects. And in many people, these will not be problematic, but in some people, they are problematic, and really can make it very difficult to come off the drugs. And in some people, these effects, even when they’ve come off the drugs and even when they’ve come off the drugs quite slowly in some cases, these effects can go on for months and sometimes years. And I think both of these things just highlight that the brain is a very delicate organ, and we really should not have been messing around with it with drugs, whose long-term effects we have not properly tested. And people really need to know this information. They need to be very, very careful before they take drugs that change the normal state of our brain chemistry and the normal state of our brain functioning.

Chris Kresser:  Would you argue that that’s particularly true for the developing brain in teenagers and that that population is even more susceptible to these impacts?

Joanna Moncrieff:  Absolutely. I don’t know whether we have evidence about antidepressant side effects in young people, but we certainly have evidence on antipsychotics. [S]ide effects [of antipsychotics] in young people are more common and more severe. So absolutely, it’s a real worry with the developing brain. And I think there’s also a psychological issue with giving antidepressants to people who are still maturing emotionally. I’ve talked about how they are emotionally blocking, and therefore, maybe block the emotions that we need to go through in order to learn to manage ourselves and manage our emotions. And also, I think it just gives, particularly when you’re giving them to children, a really dangerous message that there’s something wrong with you, you’re flawed, you’re biologically flawed, and you need to take something.

Chris Kresser:  Yes. So this has been just incredibly illuminating. I’m so grateful for you spending your time with us. And I want to finish, and I’m sure you would agree with me, by just mentioning that if you’re listening to this, you’re taking antidepressant drugs, and you’re now questioning whether that’s a good idea, please don’t stop them immediately on your own without consulting with your physician or prescribing clinician, whoever is doing that. There are some risks to doing that cold turkey. And as you know, Dr. Moncrieff, I’m going to have Dr. Mark Horowitz on as a guest in a few weeks. [He] is an expert in how to safely taper off of these these drugs, which is another thing, incidentally, that I found very low in awareness about in the general medical community, and that patients are often not given informed consent about how difficult it might be to get off the drugs and how long it might actually take to do that safely, and how to even get proper guidance for how to do that. So I hope that with the interview with Dr. Horowitz, we can shed further light on that. But in the meantime, please, please don’t make any decisions without consulting your healthcare provider. Is there anything you would like to add about that?

Joanna Moncrieff:  Yes, just that for people who’ve been on antidepressants for any length of time, greater than a few months, really, you need to be very careful about reducing them, and make sure you reduce them very slowly so that you don’t end up with severe withdrawal symptoms.

Chris Kresser:  Are you working on anything else right now? And I imagine you might need a little break after that paper that you just published. But any other lines of investigation or areas that you’re focusing on now?

Joanna Moncrieff:  I’m involved in various projects, looking in more detail at withdrawal effects and whether they’re more severe in people who’ve been on medication for longer and that sort of thing, what might help people get off them more easily. And I’m also trying to write a book about the whole experience of having published this paper because, as I (inaudible), I feel so shocked and angry about the response to it.

Chris Kresser:  Yeah. Well, for what it’s worth, on a personal level, I want to thank you because I personally benefited from your work in helping to debunk some of the myths around what causes depression. And I can speak for the thousands of patients I’ve treated over the last 15 years who have benefited from that. And then I think also the hundreds of thousands, if not millions, of people who listen to this podcast and read the blog that have directly benefited from your work. So if that’s any consolation, we are very grateful for you persisting over so many years against a lot of opposition and, as you pointed out, not a welcoming and solicitous reception to this work. It’s very important and valuable, and I genuinely want to thank you for it.

Joanna Moncrieff:  Thank you, Chris. And thank you for trying to get the message out there to more people because I think that’s so important. So yeah, thank you for helping me do that.

Chris Kresser:  And thanks, everybody, for listening to the show. Keep sending your questions in to ChrisKresser.com/podcastquestion, and we’ll see you next time.

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