RHR: How to Safely Approach Stopping Psychiatric Medications, with Dr. Mark Horowitz

In this episode, we discuss:

• How the body’s natural desire for homeostasis leads to increased drug tolerance and withdrawal symptoms
• The scientific and psychological differences between physical drug dependence and drug addiction
• The truth about how long antidepressant drugs stay in the system, and how long the body may take to rebound
• Whether the risk for withdrawals from antidepressants can be predicted
• How the risks of stopping antidepressant use have been underrepresented to both clinicians and patients
• What antidepressant withdrawal looks like
• Ways to distinguish antidepressant withdrawal from a reemergence of primary symptoms
• The problem with a “linear approach” to drug tapering
• How to taper off antidepressant drugs safely
• How Outro, a digital clinic operating in Canada, is empowering antidepressant users to stop their medications without withdrawal symptoms

Show notes:

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Hey, everybody. This is Chris Kresser. Welcome to another episode of Revolution Health Radio. On a recent episode, I interviewed Dr. Joanna Moncrieff, who is an expert in depression and has spent the last couple of decades debunking the myth that depression is caused by a chemical imbalance or a deficiency of serotonin, which it turns out was largely a marketing campaign created by pharmaceutical companies to sell more antidepressant drugs. She has also highlighted the overwhelming body of research suggesting that antidepressants are no more effective than placebo in the vast majority of cases. And in that interview, we talked extensively about the research supporting both of those positions, why those ideas have not taken root, and why it’s still commonly believed that depression is caused by a chemical imbalance and that antidepressants are effective on average.

At the end of that episode, I mentioned that I would soon be speaking with Dr. Mark Horowitz about how to safely taper off antidepressant drugs for people who, in conjunction with their clinician, decide that they want to do that. It turns out that this is not as easy as people are led to believe it is, and most people are not given adequate informed consent about how difficult it can be to get off of these drugs when they’re originally prescribed them. So I’m really excited to share this information with all of you because I think it’s absolutely critical for people to know about if they’re considering starting these drugs or if they’re already taking them and they’re considering getting off of them.

Dr. Mark Horowitz is an MD and PhD, and he’s a clinical research fellow in psychiatry at the National Health Service in England and an honorary clinical research fellow at University College London. He has a PhD from King’s College London [in] the neurobiology of depressant depression and antidepressant action. And he runs a clinic in the public health system, which helps people to stop antidepressants and other psychiatric drugs. He’s also a co-author on the recent Royal College of Psychiatrists guidance on stopping antidepressants, and his work informed the recent national guidelines on how to safely stop psychiatric medications. So I can’t think of a better person to speak to about this, and I think this podcast will really complement the one I did with Dr. Moncrieff recently. I would suggest listening to that one first, if you haven’t already, or at least listening to it shortly after you listen to this [episode] because it provides some important context on these topics. And I want to point out again that I realize some of the information that I covered with Dr. Moncrieff, and the information in this podcast may challenge some existing beliefs for folks who are listening, particularly if you are currently taking antidepressant drugs, or you have taken them for a long period of time. And my intention here is to offer support and informed consent again, which means just helping you understand what the research and data really say. Not what the pharmaceutical companies want us to believe, but what practicing scientists believe based on the overwhelming body of evidence that now exists on these topics. And what real, qualified clinicians, psychiatrists like Dr. Horowitz, are seeing in their work supporting people in getting off of these medications. Because it turns out that the average [general practitioner] (GP) or even an average psychiatrist is not typically informed about how to successfully taper off these drugs. And that’s usually no fault of the individuals themselves. But it’s that the organizations that publish these guidelines are not issuing the correct guidance. So the average community physician is simply not aware of how this needs to be done in order for it to be safe.

So I’m hopeful that this podcast will help spread this message both for clinicians and patients taking these medications. So, without further ado, let’s dive in.

Chris Kresser:  Dr. Mark Horowitz, it’s such a pleasure to have you on the show. Welcome.

Dr. Mark Horowitz:  Thank you very much, Chris. Thanks for having me on.

Chris Kresser:  We’re going to talk all about antidepressants, and particularly the process of tapering off of them if someone, in conjunction with their prescribing clinician, decides to get off of these medications. Before we dive into that, I always like to learn a little bit about the backstory of my guests. You are a psychiatrist, and I presume earlier on in your career and still to this day are using these medications with some patients. But at some point, obviously, you became aware of the difficulty, in some cases, of getting off of these medications and how carefully it needs to be done. I’m just curious to learn a little bit more about how you became interested in this topic and developed expertise here.

Dr. Mark Horowitz:  Sure, sure. All right. I’ll tell you how I came to this. So look, I guess I’m a neurotic Jewish person. If you’ve seen Woody Allen films, you’ll understand what my family was like. Very early on in things, I actually started using [an] antidepressant when I was 21. I was in third year medical school, and I went to see my GP, and I was put on an antidepressant. It’s part of why I ended up going into psychiatry. Like, in the cliche, I’m trying to fix myself and my family. So I was always interested in that area. I was taught about antidepressants like everyone else in medical school in my training, and I thought they were useful medications. I actually moved from my home in Australia to London to do a PhD in how antidepressants work with the idea [that] these are useful drugs, but we need to understand them better to work out if there [are] ways to make drugs more effective. I was very interested in the inflammatory theory of depression, and how antidepressants might fit into that. That’s what I did four years of research in.

The sort of turning point in things for me was at the end of my PhD. I read an academic paper about withdrawal symptoms from antidepressants, and I found that to be quite a shocking read. I had never been told about that issue with antidepressants in any of my training, any of my lectures. And I had the understanding that drugs that cause withdrawal, number one, they’re drugs that wear off over time because tolerance and withdrawal are mirror images of one another. And two, drugs that cause withdrawal, like Valium, or OxyContin, other opioids aren’t generally good for you to take long-term. So I found that quite startling, and I tried to come off the drugs myself. I was on an antidepressant then, Lexapro (escitalopram). [I had] been on the drug for 16 years at that point. And it led to the absolute worst experience of my life. I had trouble sleeping. I had panic attacks that lasted for 10 or 12 hours of the day, [and] I spent most of the day in a state of panic and terror. I took up running, and I ran 10 kilometers a day just to get a bit of relief from the whole process. And I ran until my feet bled. A few weeks into that, I thought about killing myself. None of that had been anything like what I’d gone on the drugs for. I’d gone on as a neurotic, slightly pessimistic, unhappy young man. I’d never had panic attacks with trouble sleeping, or had anything like what I experienced when I came off. So it was a very jolting experience for me.

I ended up going back on the drugs, even to a higher dose, and being too nervous to come off for a few years after that. That woke me up to what I had been told in my medical training, in my PhD, about these drugs, didn’t match the reality of them. Because a lot of the experts in my field, who I studied with in my PhD, said it was easier to stop these drugs. There were a couple of weeks of discontinuation symptoms, a euphemism put about by drug companies. It wasn’t a big deal to come off them. My experience was anything but that. And for a while, I thought it must just be me. But I soon found in online forums that there were dozens and hundreds and thousands and eventually tens of thousands of people going through a similar experience. And I guess it was that experience of finding out that these drugs were very different in reality to what I had been taught, that sent me I guess off on a bit of a journey to understand how that [came] about. What are these drugs really doing? What else had I been told that wasn’t quite accurate? And I guess that’s led to me studying how to safely stop these drugs over the last few years, and setting up a clinic in the National Health Service in England that helps people stop antidepressants and reappraising a lot of what I’ve been taught previously.

Chris Kresser:  Thanks for that background. That’s really helpful. And I imagine for your patients, and even in your writing, it’s helpful for you to have your own personal experience of this. So you know what it’s like to try to get off of these drugs. You know what it’s like when it’s done improperly, and you know what it’s like from your own experience and also your work with patients when it’s done properly.

Dr. Mark Horowitz:  Exactly, exactly. It’s a whole different story when you’re reading academic papers, as to when you’re on the receiving end of these things. So [I learned a lot] from my own experience and a lot through my current patients, as well. Exactly.

Chris Kresser:  Great. Let’s talk a little bit about why it’s difficult to get off of these drugs. You mentioned that tolerance and the difficulty in tapering off of these drugs, it’s kind of two sides of the same street. Tell us a little bit about what changes these drugs make in the brain and why that makes it difficult to and completely inadvisable to just stop them cold turkey or even to stop them over a period of one or two weeks.

Dr. Mark Horowitz:  Yeah, exactly. Great question. The principle of homeostasis is what guides our bodies and our brains, which is the drive for everything to be in the middle. So when it’s too hot outside, we sweat. When it’s too cold outside, we shiver to try to get us back into the middle. And that is the overarching principle of everything in our body. When a drug causes an abnormally high level of a chemical, our body will adapt to get back to the middle. When you take an antidepressant that increases serotonin, like a lot of them do, the body will experience that as too much serotonin. Because we now know there is no deficiency of serotonin in depressed people, what the drugs are causing is an unusually high level of serotonin. As a result, the body will become less sensitive to serotonin in the same way, as for caffeine. [With] caffeine, the body will become less sensitive to caffeine over time because it also adapts to caffeine as it does to antidepressants. And what that does, is produce tolerance to the drug. Just like caffeine wears off if you use it every day, so do antidepressants; whatever effects they have to start with become less and less as the body adapts to those, to the drug. We can see from neuroimaging of the brain that serotonin receptors in the brain will become less sensitive to serotonin in just a few weeks of using an antidepressant. Now, that produces tolerance when you’re on the drug, so the drug has less and less effect.

In America, you guys have a colorful phrase for that, “poop out.” We don’t have [that] in England. We’re much too pompous to use something like that.

Chris Kresser:  That’s crass Americans. Leave it to us.

Dr. Mark Horowitz:  Well, straight-speaking Americans, I guess. So “poop out” is a non-medical term for tolerance. Once you have tolerance to a drug, it means your brain and body is used to that drug. And when you stop it, you’ll get withdrawal symptoms. The same is true for caffeine and for other drugs like benzodiazepines, or even opioids.

Chris Kresser:  I was going to say that it’s also even true for substances that we produce endogenously like insulin, right? If you follow a Standard American Diet, which is another one of our gifts to the world, and your body is pumping out insulin too much, the cells become resistant to insulin, and that condition develops, which is, of course, a major public health issue. So, [it’s] fascinating that this can happen in both of those contexts.

Dr. Mark Horowitz:  Yes, yes. Yeah, that’s interesting. And I’ll just make one more point, which is, sometimes people mix this up with addiction. And that’s slightly different. When people say, I’m not addicted to my antidepressant. And that’s when you get withdrawal symptoms. And I think that’s become a bit of a source of confusion in this area. Because you’re right, you don’t technically get addicted to antidepressants. No one is injecting antidepressants or breaking into the neighbor’s house to get more antidepressants. There’s another term called “physical dependence,” which unfortunately has become mixed up with addiction, but it’s different. Physical dependence is what happens, if you use a drug long-term, you adapt to it as you would for caffeine, and antidepressants definitely cause physical dependence. And it doesn’t require craving a drug or compulsion, or the things that you see in addiction. But once you’re physically dependent on a drug, when you stop it, you’ll get withdrawal symptoms.

When you stop an antidepressant, your body basically misses the drug, like it will miss other things. And withdrawal symptoms will then last for as long as it takes the brain and body to get really accustomed to the drug not being there. So this is another point of confusion. People hear about withdrawal symptoms that can last months or longer. And everyone finds that a bit strange because the drug leaves your body in a few days or at most, a few weeks. So how can withdrawal symptoms last so long? And it’s because the changes to the brain, caused by being on the drug, can actually take months or years to resolve. The brain doesn’t just snap back into how it was before the drug. It takes a lot longer for things to readapt. And again, we can see that in your imaging. There are people who have been off antidepressants for months or years, and we can still see in their brains that their sensitivity to serotonin is changed, is reduced. And that’s why we think withdrawal symptoms from antidepressants can last for months or years and not just the few weeks it takes the drug to leave your system.

Chris Kresser:  Yeah, I’ve definitely seen that anecdotally in my own practice with patients. And I’m curious if this is what you’ve observed, or if the research supports this. But again, anecdotally, in my case, there seems to be a kind of direct relationship with the length of time that people have been on the drugs and the length of time that it can take to get off them or that those changes that you just mentioned persist. Is that an actual correlation that is seen in the research or that you’ve observed clinically? Or does it vary based on other factors?

Dr. Mark Horowitz:  So it’s a great question, and it’s one I spent a lot of time looking at. The data [are] not very good. We don’t have a lot of information about what the risk factors are for withdrawal symptoms. But yes, exactly what you’ve said does come out a bit, that the longer you’re on an antidepressant, number one, the more likely you are to have withdrawal symptoms. Number two, the more likely they are to be severe symptoms. And then number three, a little bit, they’re likely to last longer. And it makes sense because the longer you’re on a drug, the more your brain gets used to the drug or adapts to the drug. And it makes sense; it’s going to cause more of a disruption when you stop it. So yes, in my clinical experience, I definitely see that. The people who are on drugs for just a few weeks or months, these antidepressants, tend not to have much trouble coming off. We’ve done a little bit of research on this. We think that about a quarter or a fifth of people who were on the drugs only for a few months will have trouble. But once you’re on the drugs for more than a few years, then it becomes the majority of people [who] have trouble coming on. More like 50 percent of people.

Chris Kresser:  Wow. I find that that is almost certainly underrepresented in the mainstream media and even in mainstream medicine. Do you think that patients are getting informed consent about that when they’re originally prescribed antidepressants? Has any work been done on that topic?

Dr. Mark Horowitz:  I don’t think that any patient has ever received informed consent for antidepressants as far as I’m concerned. The double-blind randomized controlled trials of people stopping antidepressants conducted by drug companies show that 54 percent of people will have withdrawal symptoms when they stop it. A lot of those studies are short-term and again for a few weeks. The longer people are on antidepressants, the harder it is to come off. In surveys, about one in four people will have severe withdrawal symptoms. We did some surveys of patients in the National Health System in England, and we found that up to 40 percent of people were stuck on their drugs because they couldn’t come off them, although they wanted to come off them. So I don’t think anybody has been told that they may not be able to stop antidepressants if they start them because they can be so difficult to come off, that they have a one in two chance of having trouble stopping it, and a one in four chance of having serious trouble stopping it.

I think that for years, the information that’s been given to doctors and patients has underestimated the risks of these drugs in a very pronounced way. The drug companies used a pretty neat trick, which was they did studies on people who had been on antidepressants for eight weeks. And when people on antidepressants for eight weeks stop antidepressants, mostly they get mild and brief symptoms. That’s true. But most people out in America and Europe and everywhere else have not been on the drugs for eight weeks. They’ve been on them for months or years, or, in some cases, decades. So data [that are] true for people on the drugs for eight weeks when they stopped them [are] not at all relevant to people who were on the drugs for 10 years. And drug companies have put out paper after paper and in statement after statement, withdrawal symptoms, or often they call them discontinuation symptoms, a euphemism, are mostly mild and brief. And that is true if you use the drugs for eight weeks, and it’s not true at all if you use the drugs for a lot longer. So doctors and patients have been systematically misinformed about the risks of these drugs. Absolutely.

Chris Kresser:  That seems like, of course, we can’t know; we can’t get into the heads of these pharmaceutical companies. But to me, that seems like an intentional deception when they’re well aware of the fact that most people are taking these drugs for much longer periods than the eight weeks that these study periods last. And as you mentioned, even despite that, over 50 percent of patients are experiencing some symptoms [of] withdrawals, even if those are mild symptoms. This leads to another question, which is an issue not just with antidepressants and side effects, but also with many other medications. Let’s imagine a scenario where someone has depression, they go to their doctor, they are prescribed an antidepressant, they take the drug, and then they start, decide to stop taking it, and they get a bunch of symptoms of antidepressant withdrawal. I imagine that some of those symptoms, if not the majority of them, are very similar to the original symptoms of depression that they were complaining about in the first place. So I mean, that seems to make it even more difficult to study this and even more difficult for doctors to recognize that there might be an issue with these drugs.

Dr. Mark Horowitz:  Yeah, you put your finger right on the central issue, Chris, which is that withdrawal symptoms can be easily mistaken for a return of someone’s underlying issue, if you’re not well informed about what’s going on. Serotonin and the other chemicals affected by antidepressants affect almost every organ system in the body. The brain, the gut, the hormonal system, the bone marrow, everything’s affected by these drugs. When you stop them, you get symptoms that relate to all those different systems. There are two broad categories of withdrawal symptoms people get: physical symptoms and psychological symptoms. And it’s the psychological symptoms that cause the real confusion.

So just like you’ve said, withdrawal symptoms can include depressed mood, anxiety, tearfulness, crying, panic, suicidality, [and] all sorts of psychological symptoms. We know that those are withdrawal symptoms because they can occur even in people who were put on antidepressants for reasons other than mental health problems. So, for example, in studies of people who’ve been put on antidepressants for pain or for menopause, when they stop antidepressants, they can get all of those symptoms, some of which they’ve never experienced before. So we know that all of those symptoms are withdrawal effects. And exactly as you say, if you pitch up to your GP or primary care physician with these symptoms after stopping the antidepressant, often in a few seconds, they’ll tell you well, it must be your original problem coming back, your depression or your anxiety. You’d better go back on the tablets. And in fact, this shows that you need those drugs, because when you stop it, you turn into a basket case.

Chris Kresser:  Right.

Dr. Mark Horowitz:  There are a few things that can help doctors distinguish those symptoms or patients, as well, from the underlying condition. And I’ll say them briefly. Number one is withdrawal symptoms come on soon after stopping. So if you reduce or stop a drug, and a couple of days later, you feel awful and you have these symptoms, it’s much more likely to be withdrawal symptoms than your original condition coming back. Because normally, it takes weeks or months for people to develop depression or anxiety again. Number two is the presence of other symptoms. So there are lots of physical symptoms from withdrawal, things like dizziness, headache, [and] a feeling that things are not quite real, just sort of called depersonalization or derealization. There are quite specific sensory symptoms people can get, like little electric zaps in their head where they feel like their brain has been switched off for a second or little zaps gone through, which is a very distinctive symptom of withdrawal. There are gut problems, [like] diarrhea, constipation, [and] nausea, [and] some people get flu-like symptoms. So there are a whole lot of—when those symptoms come along with the anxious mood or depressed mood, it’s a clue that this is not a relapse; this is a physical condition.

Another thing to watch out for is, even if it’s mostly psychological symptoms, if these are very different from what people originally had, we should think [it’s] withdrawal. So, for example, if someone was put on an antidepressant because they were depressed and lethargic, and now when they stop an antidepressant, they’re very anxious, they’re having panic attacks, and they can’t sleep, it’s much more likely that they’ve developed quite common withdrawal symptoms, rather than coincidentally developed a new mental health disorder just at the moment they stopped an antidepressant. That’s very unlikely to happen. But withdrawal symptoms are quite likely. The last thing, more helpful in retrospect, is if they go back on an antidepressant, symptoms generally go away in a few days, whereas it would take longer if it was a mental health issue. So those things can help people distinguish between withdrawal effects and the original condition coming back. But it’s not always simple.

Chris Kresser:  That’s extremely helpful. I imagine for people listening to this, it’s going to be really valuable to have ways of distinguishing between what might be symptoms that they historically or typically experience and symptoms that are more related to tapering off of the drugs. So let’s shift gears now and talk a little bit about tapering. Before we get into the best way to do it, I’d love to hear about what you typically do see, not in your own practice, of course, or with other colleagues [who] are informed about this issue, but what would you say is sort of the default right now for tapering off of these drugs? And has that changed over the last several years as a result of your work, and your colleagues trying to shed more light on the importance of tapering off of these drugs more slowly, and in the hyperbolic way that you’re going to discuss?

Dr. Mark Horowitz:  It’s a really good question. And I can answer that question with confidence because we surveyed 1,400 patients who had come off antidepressants and asked them, what do their doctors tell them to do? So the most common approach is to stop people’s antidepressants over four weeks or eight weeks. And that normally involves telling patients to reduce their drug to a half for two weeks or four weeks, and then down to a quarter of their dose for two weeks or four weeks, and often by taking a half a dose every second day. So that’s the most common thing that people will get told by their doctors. Halve the tablet, do that for a little while, then halve the tablet and take it every second day and do that for a while, and then stop it. So that’s the most common process at the moment. I can tell you the reason why we surveyed those 1,400 people was because they had all been given that advice, they’d all had a terrible time, [and they’d] experienced horrible withdrawal symptoms. They had gone back to their doctor, who told them that if they had terrible symptoms, that must mean they need their antidepressant. They’ve experienced relapse. In fact, they may need to be on the drug lifelong; they should get back on it. And all of these patients have thought that doesn’t make any sense. Because I never had some of these symptoms before. I feel dizzy, I have a headache, [and] I’ve had electric zaps. How can this be depression? And they’ve all lost faith in their doctors, and they have instead turned to peer support websites, Facebook sites, [sites about] surviving antidepressants where they’ve gone to get more advice. And there’s now a couple [hundred thousand] people on such websites. So this is not an isolated problem. And a lot of people get into a lot of trouble this way.

Thousands of people experience drug withdrawal symptoms after stopping their antidepressant medications. In the latest episode of Revolution Health Radio, Dr. Mark Horowitz explains the biology behind physical drug dependence, the body’s natural adaptive mechanism that produces withdrawal symptoms when medications are stopped. He also explains how to safely taper off antidepressants to minimize symptoms and best support the body. #chriskresser #antidepressants #mentalhealth

Chris Kresser:  What do you see as the root of the problem here? Because I generally tend to think that most doctors are doing their best, in most cases, and genuinely want to help their patients. And I imagine you agree with that. So is it a problem with the organizations that are tasked with issuing the guidance to the physicians? Or where is this breakdown occurring?

Dr. Mark Horowitz:  Sure. So I completely agree with you. A lot of my friends are GPs and psychiatrists; [they all want] to do well for their patients. There’s no malice there at all. It simply comes down to what the guidelines are telling them to do. So I know the story a bit better in England, but I know it vaguely in America, as well. The guidelines have said the same thing for the last few years. They’ve said you can stop antidepressants over several weeks. Most withdrawal symptoms are mild and brief. So if you’re a doctor being taught that, as I was, you see people coming in, they’ve got incredibly severe symptoms of withdrawal, [and] there are some people [who] are suicidal, as I was, coming off the drug. You look in your guideline, [and] it says mild and brief symptoms of withdrawal. It can’t be this to walk into my door in hysterics. It must be something else. It must be a mental health condition coming back or something like that. And I’ve followed the guidelines, which say to stop over a few weeks. So if people are having problems, it must be about something about them, something about their mental health conditions.

So I think doctors are poorly informed. I think those guidelines, you asked [whether] things have been updated in America. The guidelines are still the same as they were 10 years ago. They say you can stop over several weeks. It has a slight clause. Some people may need longer, but it doesn’t tell you who, it doesn’t tell you how much longer or how to do it. And I think that there’s been, I don’t know; I don’t think there’s malice in the guideline committees either. I think there’s just been very little interest in this. Not many studies have been done on how to stop antidepressants. So, for example, on starting antidepressants, there’s about a thousand studies. On stopping them, there’s about a dozen, and that’s because most of the studies are sponsored by drug companies who are interested in marketing their products. They clearly have much more interest in starting than stopping these drugs. There hasn’t been attention paid to this. And that’s why I think we’ve ended up in the mess that we’re in.

Chris Kresser:  Yes, a couple of acronyms have come to mind here, which [are] FTM and WNL. FTM is “follow the money,” and WNL is “we’re not looking.” And those often go together for the reason that you just said. There’s very little financial incentive for pharmaceutical companies to sponsor studies on what happens when the drugs are stopped. There are all the incentives in the world for them to do studies on why to start the drugs. And that’s a whole other conversation, of course, but something that absolutely is, the system is set up in such a way that that kind of behavior is rewarded. So that’s a problem that we’re going to have to address at some point, which is outside of the scope of this conversation, but certainly worth noting, as you did.

Dr. Mark Horowitz:  [I] strongly agree.

Chris Kresser:  So let’s talk now about the correct way to do this. You talk about hyperbolic tapering. So tell us what that is, and maybe paint a picture of what a proper tapering process might look like for people. Let’s take a couple of hypothetical, or let’s start with a hypothetical person who’s been on these drugs for 10 years. I don’t think that’s unusual, at this point. So [for] someone who’s been on one of the [selective serotonin reuptake inhibitors] (SSRIs) for 10 years, how would you approach it with them?

Dr. Mark Horowitz:  Okay, okay, I’ll walk you through what I would do [with] the patient in my clinic [on] how to come off the drug safely. So I see a lot of people who are on drugs, as you [said], for 10 years in America. The average person, so half of the people on antidepressants in America, have been on them for more than five years, and it’s heading toward 10 years. So there’s one in four people on antidepressants in America, adults, one in four adults, and half of them have been on it for more than five years. So you’re talking about a very common person.

I won’t go through now, although I can, all the different things I talk about with people about what they think about their antidepressants, what role they think antidepressants play in their lives, what role a chemical imbalance [has], [and] how they perceive themselves. Let’s say we’ve got to the bit where they want to come off the antidepressant. I’ll walk through what I do. There are really three broad principles to coming off antidepressants. Number one is doing it slowly. So slowly, generally, means over months, and sometimes more than a year. Some people will need even longer than that. And that’s to give the brain and body enough time to adapt to there being less drug around. And that’s a lot slower than the weeks that people are normally told to do. The second thing is people need to go at a pace that they can tolerate. I’ve already done some work on what are the risk factors for withdrawal symptoms, and there’s a few things we know. There are some drugs that are worse than others, drugs like Effexor or venlafaxine, Cymbalta or duloxetine, mirtazapine, and paroxetine. They’re the drugs that cause people the most trouble, although almost any antidepressant can cause people issues. The longer you’ve been on it, the worse the trouble can be in stopping it. The higher the dose has some role. And if you’ve had a really hard time in the past coming off the drugs, that also gives you an idea about what’s going to happen when you try it again.

But it’s somewhat difficult to just look at somebody and work out how difficult the process will be. We’ve worked out a kind of risk calculator that’s a bit of an estimate to start with things. But really, the key thing is, how does someone experience a test reduction, making a small reduction, what does that do to the person? And based on that, you can modify things so that people can go at a rate they can tolerate. Some people have three children and two jobs, [and] they can’t tolerate a whole lot of withdrawal symptoms. Some people have a bit more flexibility and can go a little bit quicker, and everyone’s a bit different. And the last thing is this hyperbolic method of tapering, which is a bit of jargon that I’ll just explain. The key thing about antidepressants is they don’t affect the brain in a linear way. What they do is very small doses of antidepressants have an outsized effect on the brain. This is because when there’s not much drug around in the brain, all the receptors that the drug attaches to are open for business unsaturated. So every extra milligram of drug has a very large effect. And when all of those receptors are full of [the] drug, which is what happens at the higher doses that people use in clinical practice, every extra milligram of drug has less and less additional effects. It’s sort of like the law of diminishing returns.

So [if] a few milligrams [are] around, the effect on the brain is very steep. At high doses, it flattens out. And that produces a hyperbola, which can cast your mind back to the darkness of high school mathematics. Find a curve that goes up very steeply and flattens out like the beginning of an M, and then it goes flat at the top. And that tells us something about what happens when you reduce your dose of drug. So most doctors are using what I call a linear approach, that halve it and then halve it again is really a linear approach to reducing. And what happens is, you’re sort of walking down this curve, and to start off with, it’s very shallow. So you make a reduction at a higher dose, and it doesn’t cause people very much trouble. So going from, say, 20 milligrams, [which] is a very common dose for a lot of antidepressants, to 10 milligrams doesn’t cause people huge trouble. But when you go from 10 milligrams to 5 milligrams, you’re now in the steeper part of the curve, and it can cause a bigger change in [the] effect on the brain, which can cause more withdrawal symptoms for people. And then the final 5 milligrams is a cliff. It’s almost a straight line going down, and we’ll go from 5 milligrams to zero milligrams, which sounds like the same as going from 10 to 5, actually involves a huge change in effect on the brain. And that can cause a lot of withdrawal symptoms for people. And that’s what people tell me. The first few reductions were fine, [but] the last few milligrams were excruciating. And that’s what they’ve been told to do by their doctors. The doctors haven’t seen this relationship. That relationship that I described has only been revealed by imaging of the brain, people on antidepressants using radioactive nucleotides. And if you don’t understand that, then it doesn’t make sense why someone has no trouble going from 10 milligrams to 5 milligrams, but has huge trouble going from 5 to zero. You might think they must need the last few milligrams. But what hyperbolic tapering involves is basically following the contour of that relationship. You go slower and slower as you get down to lower doses. So when the curve becomes steep, inched down, [it’s] like climbing down a cliff very slowly.

Chris Kresser:  So does that require, I know like with benzodiazepine tapering, often it requires either a special compounding pharmacy to get those small incremental doses or even sometimes shifting from a drug with a shorter half-life to one with a longer half-life. Does that come into play with SSRIs? Does a clinician need to work with a compounding pharmacy? Or how does that work in practice?

Dr. Mark Horowitz:  Yeah, again, you’ve seen the major barrier. That’s exactly the question I was going to ask, too. So how do you do that? Because this requires going down to much smaller doses than are commonly available in the tablets at the store. There [are] two main ways to do this. One is you can get the drugs compounded, as you say, made into smaller doses. There’s actually a lot of liquid versions of these drugs available. So the manufacturers have made some of the drugs into liquid form, often to give to children or to people [who] can’t swallow, but they’re very useful to be able to make these smaller reductions. Some drugs don’t come in liquids, and people have to find other ways. There’s a couple of options. Some drugs come as beads in a capsule that can’t be turned into liquids. And people will open up capsules and count out beads in order to make small reductions. This is particularly true for Effexor and Cymbalta, and that’s a perfectly reasonable way to do things as long as you put the beads back in the other capsule so it doesn’t hurt your throat.

And then another option is a lot of these tablets can be crushed and mixed with water, which is a perfectly acceptable way to use the drugs. In England, the National Health Service explains to mothers how to crush up these tablets and make suspensions in liquids to be able to give drugs to children. So it’s a reasonable option for doctors and patients to do it. It’s an off-label use of the drugs, which means it’s not approved by the manufacturers. But a lot of the ways we use drugs in clinical practice is off-label. So the simplest option out of all those is to use a liquid made by the manufacturer, but there’s a variety of options. And that’s the way that people can make smaller doses and go down bit by bit.

Chris Kresser:  That’s helpful. I know that question comes up and will come up for people who are listening to this, both clinicians and patients. That did lead me to another question, though, which we haven’t discussed yet. And that is, are there significant variations in number one, how difficult it is to taper and number two, exactly how to taper with the different categories of antidepressants like SSRIs, [serotonin and norepinephrine reuptake inhibitors] (SNRIs), some of the older tricyclics and the different types of medications, or even the antipsychotics? I don’t know if they fit into this category. But as you know better than anyone, people are taking a variety of medications and are prescribed medications for depression from all different classes, depending on what works best for them. So yeah, is that germane to this discussion?

Dr. Mark Horowitz:  Yes. So I’ll say a few things about that. So one, yes, every individual is a bit different. As I say, probably the drug they’re on, the dose, [and] how long they’ve been taking it for, it influences things. But really, you have to individualize a tapering regime to a specific person. You can’t just take it out of a book, [like] these are the 10 doses to go on. I’m actually writing a textbook that has some suggestions, but it’s got to be modified for the person. So the best way to work it out is, are they going [at a] rate that causes them tolerable withdrawals? Everyone will probably get a few withdrawal symptoms. That’s hard to avoid completely. But it shouldn’t be so that they’re hanging on, white knuckling it, as I did when I came off very quickly. People want to be able to have a rate that [they] can tolerate. The principles are actually very similar for different classes of drugs.

So you’ve mentioned a few different subclasses of antidepressants. The approach for an SSRI, or an SNRI, or a different class of antidepressant is generally similar, because that hyperbolic curve I described is actually true for all psychiatric drugs and all of the different receptors. It comes about because of a thing called the law of mass action, which I described, which is, as you add more and more drug [to the system], more and more receptors are filled up. And the drug has less and less effect. So that relationship actually applies for all the classes of antidepressants around. And that approach of going slowly at a rate someone can tolerate, and down by smaller and smaller amounts of lower doses applies to all drugs. It actually applies to all psychiatric drugs. So antipsychotics [are] a separate class of drugs. They do tend to affect different receptors; they tend to affect dopamine, often, rather than serotonin. But the same relationship applies and the same overarching principles, also.

So I worked on a trial in England that was taking people off antipsychotics, and we used the exact same approach going at a rate they can tolerate, pausing if they have unpleasant withdrawal symptoms, waiting for them to stabilize and going down by smaller and smaller amounts of lower doses. So that also applies to benzodiazepines, to drugs like Lyrica (pregabalin), to sleeping tablets. It even applies to opioids. So I’ve done some work on all those different classes of drugs, and all of these principles are the same for all of them. Some drugs in those classes will be harder than others. So, in general, Effexor is harder than some of the other antidepressants. But the principles why. I’ll just say two more things because I realize I didn’t answer one of your questions. You [asked whether] people [should] be swapped to a longer-acting drug in order to help them come off. That’s quite useful in benzodiazepines. Valium is a drug people are often switched across to. In antidepressants, it’s a lot more troublesome, I found. I think it’s because the drugs in the benzodiazepine class are really similar to one another. And the antidepressants are not quite as similar, even ones in the same class like SSRIs. So I have found that people switching from an SSRI to Prozac (fluoxetine), which is the longest acting drug in that class, actually tend to have trouble with that more often than you would expect. So I tend not to switch people across to the longer-acting drug, although there is some rationale for that. It should be easy to come off a longer-acting drug, but I haven’t always found that that works. So, that wouldn’t be my go-to for most people.

And the second thing I wanted to say is people shouldn’t skip doses every second day. So that’s a very common way that doctors advise patients to reduce. And they’re intuiting that going down to a smaller dose is helpful. But every second day dosing tends to make the levels in people’s blood go up and down. Because most antidepressants have a half-life of 24 hours, that is half the drug is removed from the body every 24 hours. If you dose every 48 hours, it causes huge changes. And that’s not a very good way to make reductions.

Chris Kresser:  Yeah, that’s really helpful to hear about those differences. Because I have seen that with Valium; it’s often the final step in the benzo process for that reason. But it’s good to know that that’s not how it works with this class of medications. So I want to talk a little bit about one of the issues that’s come up in my clinical practice. This is not my area of expertise. And if I had a patient who is on antidepressant medications, and they want to explore getting off of them, I will, of course, refer [them] to a psychiatrist. And I often would like to refer to a psychiatrist [who’s] in their area [who] understands everything that we have discussed in the show. But frankly, I have found that to be easier said than done. And I’ve found that there aren’t a ton of GPs or even psychiatrists [who] are up to date on this, and maybe, perhaps, for the reason that you mentioned. Because the guidelines that are still issued in most countries are not educating them properly about this topic. So how do you recommend that? Imagine someone’s listening to this show, and they would like to explore getting off these drugs with their clinician, or they have already been trying to do that, and they found that it’s difficult because they’re moving too quickly, and they then have to keep going back on a drug. How would you recommend that they get support?

Dr. Mark Horowitz:  Right. So that’s a good question. It is a real dilemma, that the people that should be most qualified to help people are not knowledgeable about this area. I suggest a few things to people. The Royal College of Psychiatrists in England have put out what I consider to be pretty good guidelines about three years ago that I was involved in writing. [They were] really under a lot of pressure from the public to change the guidelines. And to their credit, they did. I sometimes get people to print out those guidelines to take to their doctor to explain what they want to do. And because it’s from an authoritative source, doctors will sometimes take that seriously. I’ve got a lot of academic papers on my website, including a paper that I wrote in the Lancet Psychiatry on why to stop antidepressants in the way that I’ve just described. Again, because it’s from the Lancet Psychiatry, doctors tend to take that seriously. Those are the kind[s] of tools that I would suggest people use to advocate for themselves to doctors.

People be aware, there [are] all sorts of websites online. Some of them have quite good advice. Some of them follow academic papers that I’ve written, or other people have written. And some of them are a bit hit-and-miss. But I think it’s important that doctors are upskilled on this. So people are not wandering through the internet to try to find out how to come off these drugs, and they can get advice from people [who] should be experts in it. And I do a lot of lecturing now. I’m invited to different places in America to give lectures to different grand rounds. So I hope this will increase in visibility, and more and more people will be aware of it.

Chris Kresser:  Yeah, I really do, too. It seems to me a glaring shortcoming that this, the whole constellation here how patients are not given informed consent to start with. So they get on these drugs with the mistaken assumption that it would be quite easy to stop them, or they might have to deal with mild, at worst mild side effects that would be temporary. That’s obviously where the problem begins, right? Because they were not able to make an informed decision in the first place. And then, as you pointed out, the very people [who] they would tend to rely on for helping them to taper off these drugs when it’s time to do that are not properly educated and not given the most recent up-to-date information from the scientific literature or experts who are doing this all day every day in the clinic with patients. So it’s deeply concerning that this is the state of affairs right now. But I hope that podcasts like this and other resources that are available online can help shed some light on the topic and give people more tools for doing this.

Along those lines, I know that you’re working on another initiative to provide this kind of support to people, which is Outro. And I believe this is a digital clinic that you’ve set up in Canada to help people safely stop antidepressants, and that this may also be coming to the [United States] later in the year. So can you tell us a little bit about that?

Dr. Mark Horowitz:  Yeah, so that’s exactly right. So you’ve said it. It’s deeply concerning, and I think that’s an understatement. I mean, I think it’s very worrying that there [are] 100 million people plus on antidepressants that most doctors don’t know how to stop. I think it’s sort of the same as there being 100 million cars without brakes on the road. People should know how to stop these drugs, when they start them. It should be a part of medical training. Starting drugs is a part of medicine, of course, and I think the other side of it should also be a part of it. I helped some Canadians to start Outro in part because I received so many emails from patients around the world, asking me to help them come off their antidepressants, because their doctors don’t know how. I sort of thought this was a bit flabbergasting, that often, they’ll get my paper and look at the email address to email me to ask someone across the world to help them because their doctors don’t know what they’re doing.

So essentially, what Outro does is what I do in my clinic in London. So I run a clinic in the public health system. Exactly as you say, I give informed consent to people. After they’ve been on the drugs for 10 years, I tell them what the actual benefits and what the risks are, and how to come off them. Then I will develop a kind of personalized regime for each patient, and monitor them and guide them through step by step as they come off and help them get through any difficulties. And we’re doing the same thing in our Outro digital clinic. It’s run by psychiatrists and nurse practitioners. And a big part of it actually is giving patients informed consent about what the drugs do and how to stop them safely. [Our goal is to] address their fears about the process. We help them organize compounded medication or liquid versions of drugs. We get them to monitor themselves. [They] can chat with a nurse; there are therapists to make the whole process safer because it can be a bumpy process, as I’ve learned firsthand. So we’re trying to make it easy to go through. The reason it’s called Outro is because there [are] lots of intros to these drugs, but very few outros to help you come off. At the moment, it’s operating in British Columbia, and in Ontario, and we are hoping that later in the year, we’ll also open in America, where I [actually] get most emails from, because it’s one of the most overly medicated countries in the world. And we hope that alongside educating doctors, that this will provide a service that patients can use, and we hope also doctors will start to learn from it and work with us so that we can scale up, help people to come off these drugs.

Chris Kresser:  Thank you so much, Dr. Horowitz, for this conversation, and thank you for the very important work that you have been doing and continue to do on this subject. I know you’ve already helped so many people come off of these drugs safely, and I hope that this interview will reach many people. As you said, these are very commonly prescribed medications. They’re drugs that people are taking for years, if not decades, on average, and there’s very little support right now out there for people who are taking these medications. So I’m looking forward to this conversation getting out there and people, and Outro becoming available in the United States so that people can get the assistance they need when they get off these drugs.

Dr. Mark Horowitz:  Thanks. Thanks, Chris. Thanks for having me.

Chris Kresser:  Okay, everybody, thanks for listening. Keep sending your questions to ChrisKresser.com/podcastquestion. And as another reminder, I recorded a previous podcast with Dr. Joanna Moncrieff about the myth of the chemical imbalance theory and the idea that low serotonin levels cause depression. And we also talked about a large body of evidence, which suggests that antidepressants are not effective in most cases, according to the gold standard research that we have on this topic.

So I hope you listen to that podcast, as well, if you didn’t get that already, because it provides a lot of important context and foundational understanding for this show. So thanks again, Dr. Horowitz, and thanks, everybody, for listening.

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