What Do We Know About SSRI Antidepressant Withdrawal?

FLORA LICHTMAN: Hey, this is Flora Lichtman, and you’re listening to Science Friday.

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In the show, the science of SSRI withdrawal and why it continues to be a subject of hot debate among physicians and patients.

AWAIS AFTAB: So what I would say is that the available data is not methodologically strong enough that there’s a consensus in the field.

FLORA LICHTMAN: Roughly 1 in 10 Americans take antidepressants. The most common types are SSRIs, or Selective Serotonin Reuptake Inhibitors. Think Prozac, Lexapro, Zoloft.

But what happens when you stop taking them? There’s an ongoing debate among physicians and patients about the severity and prevalence of SSRI withdrawal symptoms, and discourse reached a fever pitch when HHS Secretary Kennedy compared SSRI withdrawal to heroin withdrawal. So there have been studies. But they sometimes contradict each other, and the takeaway isn’t so clear.

Joining me now to discuss the issue and dig into the data on SSRI withdrawal are my guests, Doctor Awais Aftab, clinical associate professor of psychiatry at Case Western Reserve University based in Cleveland, Ohio, and Doctor Mark Horowitz, clinical research fellow in the UK’s National Health Service and scientific co-founder of Outro Health. He’s based in London, England. I want to welcome you both to Science Friday.

MARK HOROWITZ: Thanks for having us on.

AWAIS AFTAB: Yeah thank you.

FLORA LICHTMAN: It seems like there’s a lot of disagreement about this issue about SSRI withdrawal. Is it lighting up the psychiatry community? Are researchers arguing about this in hotel ballrooms somewhere, Awais?

AWAIS AFTAB: Yeah. I would say there’s a pretty heated debate going on. And I think a fundamental problem is that we have a relative lack of good research and good data, especially about long-term outcomes. I think some of the most interesting and intense debates are happening online at the moment.

FLORA LICHTMAN: Mark, this is personal for you. This is professional for you, but it’s also personal for you. You took antidepressants for a decade. What was your experience coming off of them?

MARK HOROWITZ: I learned at medical school and in my psychiatry training the same things that Awais has been taught and other psychiatrists, that coming off antidepressants is generally fairly easy. There’s brief and mild symptoms and doesn’t cause much trouble. And that is true if you’ve been on the drugs for 8 to 12 weeks because a lot of the research that was done by drug companies looked at people who’ve been on the drugs for a few weeks.

But when I came off my antidepressants, which I tried to do for the first time about 10 years ago, I was hit by a raft of symptoms that I hadn’t expected. I had trouble sleeping. I would wake up in a complete terror, like I was being chased by a wild animal, and that would last for hours and hours of the day.

And that went on and on for week after week. In fact, it went on for months until I was forced to go back on the medication. And I should say that these symptoms were nothing like the symptoms that I had gone on antidepressants for many years beforehand as a slightly dissatisfied medical student.

And that was a real wake up call to me, that what I had learned in textbooks, from short-term studies was not reflected, at least for me, in coming off after long-term use. And I soon realized that it wasn’t an isolated experience for me but something that happened to tens if not hundreds of thousands of other people.

FLORA LICHTMAN: When I listen to this story, the thing that comes to mind is you work in this field. If this is such a common experience, why did you not about it? Where was the breakdown?

MARK HOROWITZ: Great question. In my clinical practice, working as a psychiatrist in Australia and the UK, we very seldom stopped medications that wasn’t replaced by another medication, and we very seldom followed people up. Psychiatry is very much focused on crisis. When people are in trouble, they want to do things to patch people up.

And it falls down the list of priorities, taking people off medication. So it is not a very big part of practice. In my training, I also didn’t receive any lectures on stopping medications, I should say. And that is because there is such a big focus on starting things and not such a big focus on stopping things. That’s reflected in research literature, in guidelines, clinical practice, and people’s experience.

And I did actually have a sort of series of flashbacks where I realized that many patients that I had seen were suffering from withdrawal effects, and I had misdiagnosed them with a relapse of their condition or something else, some other mental health problem because I had not been aware at the time of what was going on. So I completely understand my colleagues who don’t see these things because it is very hard to see what you haven’t been trained to see. And I have stood in their shoes, so I understand completely.

FLORA LICHTMAN: How can you tell if a patient is having withdrawal symptoms versus relapse?

MARK HOROWITZ: A few things are, one, there are distinctive symptoms in withdrawal that don’t occur in relapse. So there’s a whole host of physical symptoms– headaches, dizziness. Brain zaps is a particularly distinctive one.

FLORA LICHTMAN: What’s a brain zap?

MARK HOROWITZ: A brain zap is a sensation of a little electric shock in your head or that someone has sort of switched your brain off for a second.

The other issue, though, is that the most common withdrawal symptoms from antidepressants are psychological symptoms, things like anxiety, low mood, panic attacks, even feeling suicidal. And we know that these are withdrawal symptoms because they occur in people who stop antidepressants who are not put on them for mental health difficulties, so in people who are put on them for pain or the menopause or even in healthy volunteers. And patients will often say that. They will say, when I came off my medication, I had symptoms that I’d never had before, or they were much more severe.

The other issue is when the symptoms come on, withdrawal symptoms often come on within a few hours or days of a missed dose. Although they can also be delayed by weeks, which really confuses patients. And doctors, we think that’s because there are downstream effects that take time to reach a threshold. That can confuse people.

Response to medication is more useful in retrospect. Sometimes when medication is restarted, soon after people stop their medications, withdrawal symptoms quickly resolve. Although for some people it can take longer.

FLORA LICHTMAN: Do you see this problem as overlooked in the same way that Mark does?

AWAIS AFTAB: Yes, I agree. The problem has been overlooked. And from the very beginning, there was no systematic research around what happens when antidepressant medications are stopped, what kind of experiences people have. And to the extent that there was some awareness that withdrawal symptoms happen, they were conceptualized under the category of discontinuation syndrome or discontinuation symptoms, which was essentially a branding that was partly driven by pharmaceutical interest.

And so it created this idea that whatever is happening with stopping antidepressants, it’s a different kind of thing than withdrawal and it is milder. And it never received systematic study. And because it never received that kind of research funding and support, clinicians on the ground had very little idea of it because we didn’t have scientific data. Textbooks generally neglected it.

And also the kind of clinical culture that we have in many Western countries, there are incentives and pressures to keep the person on medication, and there is relatively less support for them to come off it. So all of that, I think, acted in coordination.

It is also the case that the question of whether a person is experiencing a return of the depression or development of a new, let’s say, anxiety condition versus withdrawal, the lines are also blurred. There are clear situations where we can say this looks like a return of depression or return of anxiety. But there’s a pretty gray area in between where a person’s prior mental illness and their vulnerability towards mental illness interacts with the fact that they have also developed a dependence on medication. And how to navigate that gray area is also tricky.

FLORA LICHTMAN: What percentage of people who are on antidepressants long term have these severe withdrawal symptoms? Do we know?

AWAIS AFTAB: Yeah. So what I would say is that the available data is not methodologically strong enough that there’s a consensus in the field. The studies that are available, they suggest a higher percentage, something around 40% to 50%, sometimes even more. But because of various considerations around how these studies were conducted, many, many people in the field remain unpersuaded or unconvinced.

MARK HOROWITZ: I have a different view to Awais. I think that’s not true, what he’s just outlined. There are very high quality studies on long-term use that I think psychiatrists like to ignore.

There are studies that are done that are double blinded, so people don’t know if they’re being taken off the drugs. They’re rated with objective instruments. It’s after being on the drugs for a year.

And they find that 2/3 of people who come off antidepressants after more than a year have withdrawal effects, and they show that these symptoms have profound impairments in terms of their functioning day to day. So I think we do have good evidence, that it is around– could be 50%. But most of these studies show about 2/3 of people have withdrawal effects.

I do agree with Awais, though, that a big part of this is how long people have been on the drugs for. And short-term users do have minor problems. Longer-term users have more major problems. And of course, in America, there are more than 25 million people who are on these drugs for more than five years, and they are in the category of people that are having more severe, more long lasting, and more disabling symptoms.

AWAIS AFTAB: One thing I want to mention is that a big element of the controversy is that there’s a mismatch between what many clinicians see in their practice and what some of the research studies around long-term use suggest. And I myself, I’ve been looking and reading the antidepressant withdrawal literature for many years now. I work in a general psychiatric setting, so I work with all kinds of patients with depression, anxiety, mood disorders who have been on antidepressants for many years.

And while I do see a small percentage of people struggling intensely with withdrawal issues, I would say the average person seems to handle the withdrawal symptoms quite well with a gentle taper that lasts a couple of weeks.

MARK HOROWITZ: One of the implications in all this is that patients are not reliable commentators of their own experience. Part of this is, look, psychiatric patients, they take antidepressants. They’re a funny bunch of people. Can we really take them seriously?

There’s a very big epistemic injustice underlying all this. But we know that one in two people in America have been offered an antidepressant at some point in their life. So this is not a very small, disturbed group of people. This is almost everybody out there.

AWAIS AFTAB: I would say another big thing is that I think, what is the exact percentage of people who have withdrawal? is an important question but also practically not the most important one. I think practically the most important thing is that people who are experiencing significant difficulties withdrawal, what needs to be done for them? How can we best handle these individuals? And also how can we prevent severe withdrawal from happening?

So I think that that’s where the focus of clinical research and scientific efforts should be, is, what is the safest way of tapering antidepressants? And what is the safest way of getting people off them?

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FLORA LICHTMAN: After the break, how do you get off SSRI antidepressants? We’ll talk about a promising approach to mitigating severe withdrawal symptoms.

MARK HOROWITZ: Patients are often told, you’re on a very small dose of a drug. You can just stop it. But the brain doesn’t care about the size of tablet you’re swallowing. It cares about the effect of that drug on the brain, on its receptors.

FLORA LICHTMAN: So you both agree that there are people who are suffering from severe withdrawal. So what is the solution for those people who are having this hellish experience?

MARK HOROWITZ: There are no randomized controlled trials yet looking at how best to take people off their drugs. But it seems from many observational studies that the slower you come off an antidepressants, the less likely it is to cause withdrawal effects in the short or long term. And people use an analogy to something like altitude sickness. The quicker you go up a mountain, the more likely you are to get into trouble because your body can’t adapt to the change in air pressure. If you go up the mountain more slowly, you’re less likely to get altitude sickness.

And the same seems to be true for coming off psychiatric drugs. Our brains and bodies get used to these drugs. If we reduce it in small amounts over time, it gives the brain and body time to adapt to the drug not being there. And that tends to reduce the risk of withdrawal effects, and that, for many patients, means coming off over months and sometimes more than a year.

And because of the particular pharmacology of the drugs, the last few milligrams are much harder to come off than the first few milligrams. And so it makes sense to go slower and slower as you get down to lower doses.

FLORA LICHTMAN: Oh, and you developed this model, this slow tapering model?

MARK HOROWITZ: Yes. So we published a paper on it. It’s called “Hyperbolic Tapering.” And I should say that many tens of thousands of patients had worked out the same thing themselves through trial and error over many decades, often without medical help.

How do we reduce our medication in a way that we can tolerate? And it was quite a Eureka moment for me when I realized that this pattern of reducing that patients had worked out exactly matches the neuroimaging of these drugs and their effect on the brain. And so I think it is a technique that tends to work, and I use it in my clinic. And there’s now research projects going on to try to define it better.

FLORA LICHTMAN: And that means I assume using liquid because you can’t split a pill down to the crumbs, right?

MARK HOROWITZ: Exactly. You’ve got to the crux of the matter, which is that the existing tablets or capsules available at pharmacies for all antidepressants have a very large effect on the brain. So patients are often told, you’re on a very small dose of a drug. You can just stop it.

But the brain doesn’t care about the size of tablet you’re swallowing. It cares about the effect of that drug on the brain, on its receptors. And so to get down that hill, you need to use, exactly like you’ve just mentioned, liquids or specially compounded tablets or capsules. And that way, people can get off that last of steep hill to get down off their drugs.

AWAIS AFTAB: I think the method of tapering that Mark is describing, the gradual hyperbolic tapering, I think it’s been a wonderful development. And at the same time, we have to recognize that we don’t have good high-quality evidence from clinical trials, especially blinded and randomized clinical trials, about the benefits of hyperbolic tapering. It’s hard to say which method is the best one for an average person who uses antidepressant medications. But I do think, for people who are having difficulty coming off them, hyperbolic tapering is at the moment the best one.

FLORA LICHTMAN: I am noticing personally, as someone who covers science, week in, week out and has done that for decades, a kind of dangerous flattening of science from all directions. And I wanted your perspective on that. Is there a way for us to better acknowledge uncertainty in science? How do we make uncertainty great again?

MARK HOROWITZ: It’s a good line. I think there is a very worrying flattening of science. It’s a way of generating new knowledge, and it’s also a kind of institution of power. And I think that dissenting voices have been quietened again and again in medicine.

One thing I wanted to point out is that this is actually a repeat story. The same thing happened with benzodiazepines. Doctors said they don’t have major withdrawal effects. It’s not everybody. We don’t think it’s physiological. It might be something about the patients. It might be relapse.

What happens is there’s a certain line. It benefits professionals. It comes from industry. And patient voices are quieted. It takes independent researchers without great funding decades to build up the evidence base to prove that something was not what it was represented to be.

And so I really think that we have to learn from past experience and be open to new ideas because otherwise we’ve learned great harm is done to patients. So I do think we need to be more open minded and not so quick to censor dissenting voices, which is happening so much now in psychiatry.

AWAIS AFTAB: Yeah. My view is that I think we have to openly acknowledge that this is an area in which there’s a lot of disagreement in the field, and there are a lot of unknowns. And the reason there is disagreement is that we lack the kind of high-quality research that can persuade people.

And so the answer, I think, is that major funding organizations, they have to make this topic a priority. They have to make research around medication harms and stopping medications a priority. And if they fund research that investigates this issue, we will have the data that resolves these unsettled questions.

FLORA LICHTMAN: I want to thank you both for taking the time to talk with me today on the show.

MARK HOROWITZ: Thanks, Flora.

AWAIS AFTAB: Yeah, thank you for covering this.

FLORA LICHTMAN: Doctor Awais Aftab, clinical associate professor of psychiatry at Case Western Reserve University in Cleveland, Ohio, and Doctor Mark Horowitz, clinical research fellow in the UK’s National Health Service and scientific co-founder of Outro Health. He’s based in London, England.

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Today’s episode was produced by Shoshannah Buxbaum. I’m Flora Lichtman. Thanks for listening.

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