Charles Raison, MD, on Examining the Long-Term Use of Antidepressants

Psych Congress Steering Committee member Charles Raison, MD, recently spoke with The Sun magazine about depression, diagnosing the disorder, and treatments for it, including antidepressants, psychedelics, and nonpharmacological approaches.

In this video, Dr. Raison discusses some of the issues covered in the article with fellow Psych Congress Steering Committee member Andrew Penn, RN, MS, NP, CNS, APRN-BC. In particular, they examine the long-term use of antidepressants and explore alternative treatment options.

Additional Resource:

Conover S. "Parting the Clouds." The Sun. Feburary 2021. Accessed March 8, 2021.


Andrew Penn:  Hello, I'm Andrew Penn, and I'm here today with my colleague on the Psych Congress and Sana Symposium Steering Committee, Dr. Chuck Raison. Dr. Raison, thanks for joining us.

Dr. Raison: Hey, how're you doing, Andrew?

Penn: I'm good. I've been reading this article that you were interviewed for in The Sun magazine, which is, of course, not a psychiatry journal. It's always refreshing to read something that doesn't have statistics peppered throughout it.

You were sharing your ideas in very long form about depression. One of the things that came up in this article, I've heard you talk about this at conferences, around the role of antidepressants.

When I was trained in 15, going on 20 years ago now, the conventional wisdom was if somebody has had multiple episodes of depression, if you get them well on an antidepressant, you keep them on that antidepressant—probably for life. What I'm hearing you say in this article is you're questioning the wisdom of that. Could you say more about that?

Dr. Raison: This was a shock-a-roo for me, man. Like you, I was trained exactly the same way and I was a huge proponent of antidepressants for what ails you. That probably everybody would be better just to take these things forever. I really, I think in the '90s, was very close to that position.

It was our good buddy, Rakesh Jain, who also is a significant member of various steering committees with Psych Congress who disabused me of that notion. This is now probably 8 or 9 years ago. He said, "Chuck, do you know about tardive dysphoria?" I said, "I have no idea what you're talking about." I owe it to him when he began to look at, if you look, there's a lot of data out there that suggests that this chronic antidepressant use, at least, may come at a price.

It may be that some people will do best overall in their life if they stay on an antidepressant forever, but there's problems with it. Maybe we can touch upon a little bit of that.

The idea that people are best served by staying on antidepressants comes largely from studies where they all have the same design. Which is, you take people, you get them well on antidepressant, and then you watch them for a while, while they're well on the antidepressant.

Then they flip a coin, and then, blindly, you either get a 50 percent chance of staying on the antidepressant or you roll over to the placebo. If you do that, what you see is the people that roll over to the placebo completely crash and burn. They crash and burn pretty quickly. If you look across studies, on average, probably 70 percent of people are depressed again within a year.

Penn: So that's the argument for staying on it.

Dr. Raison: That's right. That's right. Except that there are studies…my favorite is a study that was done by a guy named Matt Keller, who's a really interesting evolutionary psychologist.

They had a cool idea. They got a whole bunch of data on modern antidepressants from the FDA. They said, "We're going to look at people who had a response to the placebo arm versus people who had a response to the antidepressant arm."

Most of these studies are six weeks in length or 8 weeks. At the end, they take you off whatever you are on, and we're going to ask this very simple question. Are you more likely to stay well if you respond to a placebo and it stopped, or if you respond to an antidepressant and it stopped?

The data were very clear that you do much better with a placebo. You're way, way more likely to crash again if you get an antidepressant. The more potent the antidepressant was at the serotonin reuptake site, the faster you crash. So, Paxil was especially heinous in that regard.

Then naturalistic data showing that if you look across these large cohort studies—and of course, causality is always more complex here—but being on antidepressants longer, it's actually associated with a worse outcome.

You could say, "Maybe people with the worse outcome are more likely to stay on an antidepressant." But at the very least, it's not doing what it needs to do in the real world to show this real clear signal that, "Man this is the way forward."

In contrast, let's say, you get type 1 diabetes and you want to look at everybody who takes insulin versus everybody that said, "I'm not going to take insulin." You would find that the people that took insulin lived a lot longer than the people who never wanted to take insulin because they'd all be dead.

It's very clear that that is an intervention that, while not without costs, provides a clear benefit. That does not exist in the world of antidepressants.

The other piece of the data is that, in the real world, the best studies from the real world, like STAR*D, suggested something like 75 or 80 percent of people who do have a remission acutely will lose it within a year.

So this idea that 6 weeks of an antidepressant in a study, therefore, establishes these agents are maintenance agents is probably flawed logic. The logic was, if you're taking it at 6 weeks, just keep taking it. But people lose the effect. The data don't work so well. How long you have to take an antidepressant before you've bought the ticket and have to take the ride is a really interesting question. Larger studies to date, though, suggest the longer you take an antidepressant, the more likely you are to have withdrawal problems and relapse when you stop it.

Penn: Should we have an exit strategy when we start an antidepressant? Like we're starting to do now more with benzodiazepines if we're going to prescribe them, where you say...I tell my students, "Think about it like prednisone. You give a prescribed taper, you have an off‑ramp." Should we do that with antidepressants?

Dr. Raison: If you look at the data, I think that that is increasingly... I think in 5, 10 years with standard antidepressants, that is what we're going to be saying. Yeah, we probably need an off‑ramp. What that off‑ramp is, there just aren't data for that.

The other thing it speaks to, and I'm a medicine doc, if you came and saw me, I'd give you an antidepressant, despite what I'm saying, oddly, but it speaks to the fact that psychotherapy should be the first intervention for depression.

Because there are very credible data that psychotherapy has a much longer maintenance effect after it's stopped than antidepressants do. This large, large study from a guy named Steve Holland's showing that.

Now, if you want to get into stuff that's strange, though, there was a recently published paper where they looked at whether adding psychotherapy to an antidepressant would enhance the short‑term effect. No doubt, it did.

This is a group of people where half of them just had an antidepressant, half of them an antidepressant and psychotherapy.

 Then they basically randomized people, they took all the people that went into remission and they randomized them, but either stayed on the antidepressant or go off the antidepressant. Remember, there's data showing that if you just get psychotherapy without an antidepressant, you get this prolonged benefit where you're less likely to relapse.

In the study where the antidepressant was paired with the psychotherapy, nothing. The psychotherapy showed no protection at all. Which to me raises this interesting question about, medicines tend to dull down everything, whereas psychotherapy often works when people feel their problems and deal with them.

Penn: Let me ask you this. What else should we be doing instead in addition to psychotherapy? What else do you think would be effective here?

I do a lot of research into the role of, say, psilocybin‑assisted treatment. Why would that have this acutely antidepressant effect in a way that maintains well after the drug has gone? What's happening there?

Dr. Raison: We don't know. We think, if you look at the data, what is it that predicts long‑term, say, antidepressant responses to a psychedelic like psilocybin? All the studies suggest that it’s the quality of the conscious experience that happens during the dosing session.

People that have a mystical experience where they feel that life has a deeper meaning than they realized before, or they feel more connected with something bigger than themselves, or they face their problems and have an emotional breakthrough, or they have this real sense, they gain key insights, heartfelt insights, all those things were associated with long‑term antidepressant response.

I'm hoping that psychedelics do turn out to be like a year of psychotherapy in a day like some people say. Because if that turns out to be true, then many people will get this protracted benefit that is sort of the same thing you see with psychotherapy. Where there's a consistent change with how they see and feel about the world. I've got worries about psychedelics, too, though.

Penn: Before we go there, hold on one second because most people think of psychedelics as these happy summer love kind of drugs to go dancing on or something.

In psychotherapy, sometimes, the treatment itself is really difficult. It can be emotionally arduous. People feel emotionally challenged by these experiences. They can cry, they can have deep grief. Why would that be antidepressant? Because you say something really interesting in the article. You pretty much talk about how people will change their story about their lives and that that gives them a greater sense of happiness.

But there's almost a sense that wellness and happiness are not necessarily the same thing. And that you almost need to be a little bit unhappy sometimes, perhaps episodically, in order to actually be well. Because this thing that you're talking about the antidepressants, where maybe you don't feel sadness but you don't feel much of anything, hasn’t really seemed to work either.

Dr. Raison: Yes. I have become obsessed with that idea. It's not exactly rocket science. The reason we get unhappy very often is because the world is telling us things that we need to stop and listen to. Or our insides are telling us things. The way we're doing things isn't working.

There's a lot of evidence that depressive type phenomenon evolved as a signal that you need to change what you're doing. They also give life a certain type of reality. Life is difficult. Finding a way to own and cope with that difficulty is probably the highest form of well-being.

It's not easy to achieve, though. The problem is it's easier said than done, but I do think that there's a deep truth in that. You're right. We know from studies now that depressed people have really, really difficult experiences, like, "I don't ever want to do that again."

But the difficulty, when it works, they feel like they faced down something or they feel like they're able to either overcome it or accept it. It comes in different flavors. You're right. It's that numbing down, it's that turning down of all volume that antidepressants tend to do, especially serotonin antidepressants.

This probably has got something to do with why long-term they've really become problematic. I'm consulting on a patient right now, a woman who has chronic anxiety and episodic depression and she's on an agent that's doing great with her anxiety, but she's having more and more physical symptoms.

Smart woman. She interprets it as, "It's been run out of my brain and into my body. I can't consciously feel anxious, but I'm tense in my body." I think it's kind of a metaphor. These agents, they don't solve your problems. They just make them go lay down on the corner or take a nap for a while.

Penn: When you were saying about this confrontation with your challenges, I think about that line, was it from Zorba the Greek? The whole catastrophe. Life, the whole catastrophe, taking all of it and not numbing yourself to certain aspects.

I want to be careful not to make that sound as if people who are seeking help for depression are unwilling. Many times, they struggle to a degree where they feel nothing other than pain. I'm always wary of narratives that romanticize psychological distress. That's a pitfall.

Dr. Raison: Absolutely man. Full disclosure, like a good psychiatrist, I've struggled with my depression. I am a remarkable responder to regular old antidepressants.

Part of my interest in this is because of my own experience of, "Problem? What problem?" Watching, in my own life, the limitations, the value of that. Jeez, if you've got to pay your bills and you're feeling crappy and you can't work.

But there's no free lunch. This is why I've gotten so interested in these other...we all study things we're interested in, that we've experienced ourselves. I'm not a big responder to many of the things I study, sadly for me, but I'm hugely interested. Because I do think that, at the end of the day, there are two ways to deal with depression. One way is just to turn down emotionality. Sometimes, that's what it takes. In fact, maybe that's often what it takes.

But I believe that there is this other way, which has to do with actually an intensification of emotion, including grief, but in a certain way where it generates a softness and gratitude as opposed to this, "If I'm depressed, I'm such a loser. I'm a failure. Look, I'm not as good as so and so. I'm overwhelmed." That is antithetical.

There's another place that has sadness to it that has a very, very different stance and an engendering of thankfulness. Helping us find our way to that space is the optimal way to treat depression. I don't know how to do it, but I believe that that's true. That's why I'm so interested in these other modalities because they seem to push further in that direction.

Penn: I'm thinking, I've got this puppy dog at home and he likes to bite me. Not aggressively but playfully, but he's got sharp teeth. If you pull your hand out, you tear up your hand.

The way you get it out is you actually push your hand into its mouth and that pops open. Then you can be free. It's very counterintuitive to go into something that is more painful, transiently, but then you're free of it.

Dr. Raison: Yes. Or conversely, that one way to win a tug of war is to drop the rope. The other's you're going to get pulling and pulling. That's another way we often talk about. "You don't trust him, let him go." Sometimes it's like you got to, "Yes."

Yours is exactly right. It interesting, this sounds like a non sequitur, but we've done this work with heat, with hypothermia. We heat people, put them in a machine, we heat them up really, really hot. Then a lot of people get this prolonged antidepressant response. Interestingly, the people that come into the box with a higher body temperature already get the bigger response.

It's exactly the same thing. That the body temperature is elevated because these circuits that are connected to mood aren't working optimally. Instead of just making everything easy, pulling them off, you actually put your hand into the dog's mouth.

You push them with more heat and the system sensitizes and opens up, what we call adaptive stressors. There is a future in mental health treatment of trying to explore where these adaptive stressor type treatments might be able to be added to what we're doing.

Penn: You and I could talk all day about this but our viewers may not be as interested as us. Let's go ahead and stop there. I want to thank you for joining me today and talking about this fantastic...

Dr. Raison: Good interview. Thank you, Andrew.

Penn: Thanks, Chuck. Bye.

Dr. Raison: OK. Sure, man. Bye.