Daniel Knoepflmacher, MD (Host): Welcome to On the Mind, the official podcast of the Weill Cornell Medicine Department of Psychiatry. I'm your host, Dr. Daniel Knoepflmacher. In each episode, I speak with experts in various aspects of psychiatry, psychotherapy, research, and other important topics on the mind.

Today, we'll be discussing SSRIs or selective serotonergic reuptake inhibitors and the related medications in that class of antidepressants. They are among the most commonly prescribed medications in the US, along with blood pressure and cholesterol-lowering drugs. It's estimated that one out of six American adults takes an antidepressant, with over 330 million prescriptions filled per year.

While they were first introduced almost four decades ago, in the past few years, there's been a significant increase in controversy about them, some of which has been fed by statements coming from the federal government.

During his Senate confirmation, Health and Human Services or HHS Secretary Robert F. Kennedy, Jr. said that he knew people, including members of his family, that had a much worse time getting off of SSRIs than they have getting off of heroin. Less than a month later, President Trump signed an executive order that established the president's Make America Healthy Commission. It specifically stated that a goal would be to assess the threat posed by the prescription of SSRIs.

In May of 2026, the Make America Healthy Again, or MAHA Initiative, hosted a Mental Health and Overmedicalization Summit in DC. Secretary Kennedy spoke along with officials from other federal health-related agencies and several figures have spoken out publicly as part of organized movements against antidepressants, including several patients who shared firsthand stories about their difficulties tapering off of these medications.

Several leading medical advocacy and legislative groups pushed back against HHS and the MAHA Initiative's campaign against SSRIs. A group of 14 federal lawmakers sent a letter opposing official efforts to promote mass deprescribing, warning that it would undermine trust in public health, confuse patients, and insert ideology into personal medical decisions made between patients and their doctors.

As we record this today, it's unclear what federal directives about antidepressants may be coming down the pike or whether there will be specific executive orders issued as there has been for vaccines and Tylenol.

Today, our goal will be to ground our discussion in facts as we wade directly into this controversy. We'll examine what's been said, provide evidence-based information about antidepressants and the conditions they treat, and explore why these medications are receiving so much scrutiny. I'm joined by two friends of this podcast, both of whom have been guests here before. They each bring tremendous knowledge and years of experience related to this topic. Dr. Richard Friedman is a professor of psychiatry here at Weill Cornell, director of our psychopharmacology clinic, and a prolific writer who just wrote a piece for The Atlantic that I highly recommend called "The Real Antidepressant Crisis." Dr. James Kocsis is also an esteemed professor of psychiatry here and led many influential clinical research studies on the treatment of depression and other mood disorders.

Richard, Jim, thank you both for joining me today. This is a topic that's regularly misconstrued in public discourse and in the media, so I'm really happy to have the two of you here to sort through this with me.

So, let's jump right in. To begin, I want to clarify what we're talking about, because the terms antidepressant and SSRI are often used interchangeably. While SSRIs are antidepressant medications, they're also, of course, used to treat many other conditions, and not all antidepressants are SSRIs. So, can you explain what an SSRI is, how it works, and how these medications are similar and distinct from other antidepressants?

Richard Friedman, MD: Sure, Daniel. And it's a pleasure to be with you and also to be with my wonderful colleague, Jim Kocsis, from whom I've learned so much over the years. So up until very recently, most antidepressant classes worked by increasing the signaling or the amount of neurotransmitters in the brain, and those neurotransmitters are what we call the monoamines, popularly known as serotonin, dopamine, and norepinephrine, and they do it to varying degrees.

But the SSRIs were new in the sense that they selectively targeted one particular neurotransmitter, and that is serotonin, whereas the older drugs were nonspecific and would increase the activity of one or more monoamines. So, what was different about the SSRIs was that it was selective just for serotonin. And serotonin is important in regulating mood as are dopamine and norepinephrine, but it's selective. And we think that it works initially by starting a cascade of events that starts with an increase in the activity of serotonin in the brain, and then there's a whole cascade of events that result in improvement in depressive symptoms.

Daniel Knoepflmacher, MD: Thank you, Richard. That's a great clear explanation of how these medications work and what they are. I want to turn, of course, to the controversy about these medications. So, many groups that are critical of psychiatry, several of which have become linked to the MAHA movement from which RFK Jr. Emerged as a leader, they paint a picture of the over-medicalization of normal human struggles, and they often describe medications as either ineffective or harmful or both. And Richard, you talked about this in your Atlantic article, and you actually, you pointed out that there's a grain of truth in these claims that antidepressants are over-prescribed, for what we would call everyday worries. Tell us more about that grain of truth.

Richard Friedman, MD: Right. So, I mean, I know that both Jim and I have seen patients who are prescribed antidepressants who don't actually have the illness called depression. They have unhappiness, they have stress in their lives, and they're sad or they're unhappy, but that's not the same as depression. And so, if you have everyday unhappiness and you take an antidepressant, of course, all that will happen is you will get side effects, but it's not going to make you happier.

So, what's critical to understand is that these drugs require that you have an illness called depression and that you have the right target for the treatment, because it would be akin to giving people who have an everyday cold, which is a virus, an antibiotic. And if you did that, you would see the antibiotic would look and appear to be ineffective because it's an inappropriate use of the drug.

James Kocsis, MD: So, let me jump in and make a couple of comments about this topic of the so-called over-medicalization in the use of SSRIs. First of all, let's be clear upfront that 75% of SSRI prescriptions are made by non-psychiatrists. They're made by primary care physicians. They're made by nurse practitioners.

Only about 25% of SSRI prescriptions are actually written by psychiatrists. So, that leads to the issue that perhaps these non-psychiatrists may not be so well-trained in the diagnosis of depression and the appropriate use or prescription of antidepressant medications. So, that may lead to some of what Richard has just alluded to, that they may be over-prescribed for what is called everyday worries stress, and so on.

But there's another side of this coin. Psychoepidemiological studies have discovered that many patients with the diagnosis of depression are not treated. So, you know, there's also a problem of under-prescription, because many people with major depression never come to the attention of a psychiatrist and, you know, never end up getting proper treatment. So, I think, on both sides of this, there can be some issues of under-prescribing and some issues of over-prescribing.

Richard Friedman, MD: I think that the real crisis, the one that's the best documented in the country, is about one in three people with depression receive no treatment at all, whether it's an antidepressant or it's psychotherapy. And there's no question about that. That's been replicated several times. Whereas the claim that there's wild over-prescribing of antidepressants has very little support. It's anecdotal in nature. It's driven by speculation, but not by research findings. And we can get into that a little bit, but that's a misrepresentation of the reality on the ground, I think.

Daniel Knoepflmacher, MD: Can you guys get a little bit into that research? I mean, Jim, you talked about the psychoepidemiology on the side of under-prescribing for people who have depression, but what about the misprescribing for everyday worries? Have there been studies of that?

James Kocsis, MD: Yeah. I mean, I actually looked into this. I did a literature search on over-prescribing. there are no studies that support the over-prescription of antidepressants. The idea comes from certain influencers. There are people who claim it's an anecdotal claim that antidepressants are over-prescribed for everyday worries. But there is absolutely no epidemiologic or research support for that idea.

Richard Friedman, MD: Yes, exactly. There was a study which some people allude to, which was done by a colleague at Columbia. I think it was 2014, it was a study that looked at health records of more than a million patients, mainly treated in medical settings, and they found that about 30% or 40% of antidepressant prescriptions were written without a documented psychiatric diagnosis, and then leapt to the conclusion that there was rampant overuse of antidepressants.

But that finding really doesn't prove that at all. We know that antidepressants are legitimately prescribed for lots of other reasons, including pain, quitting smoking, insomnia, and they're also very effective in treating anxiety.

So Daniel, you said in the very beginning something like one in six, about 17% of Americans take an antidepressant, which sounds like a lot. But if you actually add up from all the epidemiologic evidence that we have, the psychiatric burden in this country, not just depression, but PTSD, other anxiety disorders for which antidepressants, SSRIs in particular, are appropriate. There really is very poor evidence that these drugs are over-prescribed. If anything, they're under-prescribed.

Daniel Knoepflmacher, MD: Well, you talked a little bit, Richard, in the beginning about the history of development of SSRIs and how there were prior medications, one medication, that existed before, one class of medication were the tricyclics, which as you said, were less selective. But one piece of that is that there were more side effects potentially with those medications and also more risk in terms of safety in certain respects.

So, one of the big things about SSRIs was that they were fairly tolerable as medications go. Yet what's really become a focus of a lot of this anti-SSRI movement is that they are prescribed a lot and then they're not easy to get off of. In fact, I mean, I quoted this statement about the SSRIs being more addictive than heroin that Kennedy made live in Congress and it was recorded. And understandably, this statement in the press coverage was identified as grossly inaccurate. But it is part of the public discourse that is out there about these medications. So, this idea that antidepressants are addictive. Could you guys comment on this?

James Kocsis, MD: Yeah, sure. So, I mean, from a technical standpoint, SSRIs are not addictive. You do not develop tolerance. You do not need to keep increasing the dose. And when you stop an SSRI, you may have some discontinuation symptoms, but they are in no way similar to the so-called withdrawal that you get when you come off of opiates or when you come off of alcohol or when you come off of sedative hypnotic drugs. So, I think it's important to distinguish between the withdrawal symptoms of addictive substances and the discontinuation symptoms that may occur when people come off of SSRIs.

Let me tell you what those are. The common discontinuation symptoms are a little bit like having a bit of a cold or a flu. You can get headache, you can get lethargy, you can get dizziness, you can get what is called brain zaps. But these are usually most often mild and most often transient. They only last for a few days.

There's a small number of people who seem to have a lot of trouble with discontinuation symptoms, and the discontinuation symptoms can last for quite a long time. And in those cases, you know, we have to do some special work in terms of slow tapering or substituting an antidepressant that has a long half-life that makes it easier for them to come off of antidepressants. But I think, you know, the whole idea of calling the discontinuation symptoms, withdrawal symptoms is pejorative, and it makes the people on SSRIs look like they're addicts, which is not true.

Richard Friedman, MD: And I would also add one thing to this, which is that I think that the description of SSRIs as addictive drugs reveals something else that the public is worried about with these, which is the notion that people are dependent on a drug to stay well. And this is hard for some people to accept. But for us, the idea that, let's say, antidepressants, which help people with depression get better, these drugs also help them stay well and prevent recurrences of depression.

And in the sense that, in other areas of medicine, it's widely accepted and understood that you stay on, let's say, your blood pressure medicine to keep your blood pressure normal, or you stay on your statin to keep your cholesterol and LDL levels in desirable range. And in a sense, so you're dependent on that medicine for a good health outcome. In a similar way, you're dependent on antidepressants if you have chronic depression, which many, many people with depression do, in order to stay well. That kind of dependence is healthy. We want to encourage that. And I think that's one of the things that scares people, because the brain is considered different than the rest of the body. It's a special organ. It's the place where your sense of self resides. And I think there's a lot of anxiety about tampering and taking medicines that affect the brain, and it's special.

Daniel Knoepflmacher, MD: I want to talk more about the discontinuation and deprescribing later, because there's a lot to discuss there. But I'm going to go on with some of the statements that were made and want to hear your responses to them.

So, another statement from HHS Secretary Kennedy was connecting SSRIs to youth violence. I believe this came out in a statement right after a school shooting, I think in Minnesota. And these were linkages to SSRIs and these school shooters. What's the data showing? I mean, this is something that certainly people are paying attention to. So when it comes to school shootings and other episodes of violence in adolescence, what is in the data when it comes to potential SSRI linkage to adolescent violence?

James Kocsis, MD: Well, you know, Columbia University actually has a mass murder database. I don't know if you're familiar with that. But the mass murder database shows that 4% of mass murderers are on antidepressant medications. Obviously, 4% is a lot lower than the rate of being on antidepressant medications in the general population.

So, there really is no link, either statistically or causally, between being on antidepressant medications and being a school shooter or a mass murderer. If anything, the data suggests that more mass murderers should be on antidepressants because, as we know, they are often suicidal. I mean, that's often part of the mass murder scenario, is that they take other people out and then they take themselves out. Some of them are probably depressed, and they should be on antidepressant medications, and they're not. Expert opinion on this matter also has been expressed by medical societies that there is no causal link between being on either antidepressant medications or SSRIs and being a mass murderer.

Daniel Knoepflmacher, MD: One piece that's linked to this is the—you talked about suicidality, Jim. I mean, it's violence against others, but also there is a black box warning about a potential increase in suicidal ideation in adolescents with SSRIs. This has been often looked at by this anti-SSRI movement as fodder for that, but there's actually quite a bit of controversy even about that black box warning. Any comments about that piece?

Richard Friedman, MD: So, the black box warning came about when the FDA looked at all clinical trials of antidepressants. And basically, what they found was a very small increase in suicidal feeling and thinking, but only in young people, and it was transient, and it was about 1.5% of people taking antidepressants compared to those who were on placebo.

And the risks occurred only in young people. They were transient. And this you have to compare to the actual risk of suicide behavior and actual completed suicide in depression. People are much more worried about the medicine. But I think what's important for listeners to understand is that depression itself, when it's not treated, is associated with a risk of suicide in the range of 2% to 9%, depending upon the severity of depression.

So, depression itself is a very serious disease. It's got a lot of morbidity and mortality associated with it. The treatments have an extremely low risk and are dwarfed by the risks of the disease itself.

Daniel Knoepflmacher, MD: Yeah. And I'll mention that, when some of these statements came out of HHS about the threat of SSRIs and linkage to violence and to suicide, one of the groups that made a public statement was the American Foundation for Suicide Prevention, and they shared extensive evidence of how SSRIs reduce depression and suicidality, just as you're describing, Richard, and they warned that poorly supervised discontinuation of these medications actually would increase risk for relapse and significant suicide risk. So, this is the national foundation focused on suicide making specific statements to that effect.

Richard Friedman, MD: Right. And a very large meta-analysis found that, in the FDA, database, this effect only occurred in young people up to the age of sixteen or seventeen. And in all other groups, there was either no effect or there was a protective effect in all the clinical trials. Take home message is depression itself has a high risk of mortality from suicide. Untreated depression is the thing that really should worry Americans. The treatments are safe and effective.

James Kocsis, MD: Just remember, Daniel, what we just said, that only 4% of mass murderers are on antidepressants. So, it's the 96% who are not on antidepressants who probably have more of a risk of suicide

Daniel Knoepflmacher, MD: Yeah. Yeah. Well, I'm going to turn to another area of controversy with a specific group. In July of 2025, the FDA convened a panel on antidepressants in pregnancy. And in that panel, there was discussion of a new black box warning for pregnant women. The New York Times reported that experts in reproductive psychiatry and in maternal mental health watched the panel, and this is a quote from The New York Times. They described it as, "Unbalanced, favoring prominent critics of antidepressants over those who treat severely ill patients."

As we've talked about on prior episodes of this podcast, because we've, we focused on the topic of reproductive psychiatry, the decision about antidepressant treatment during pregnancy should be evaluated carefully because there is a significant risk from untreated illness, just as you were talking about when it comes to adolescents or other groups.

And in this case, with treatment, it can present a real reduction of that risk, because there's often a higher risk for untreated depression in this population than any risk that could come from antidepressants. And this is something that is very well-studied. So, how do you both counsel your patients on SSRIs when they're considering pregnancy?

Richard Friedman, MD: I tell them first that, in aggregate, the best datas show that SSRIs are safe to use in pregnancy, that they're associated with an increase in risk to the fetus. And so, if there's a significant risk of depression, and many of my patients who have severe depression there is, then it's safe to remain on antidepressants.

The phenomenon of postpartum depression is an extremely serious problem, both for the mother and for the newborn. So, I tell people that the best evidence is that it's safe to remain on antidepressants. A lot of women may want to avoid antidepressants, just not wanting to take medication during pregnancy, which one can understand. But if the risk of depression is high, they are safe to take.

James Kocsis, MD: I'm mystified about why they would be considering a black box warning for antidepressants in pregnancy. All experts that I'm aware of, I refer to the head of women's psychiatry in our department, Alison Hermann. I refer to the American College of Obstetrics and Gynecology. I refer to the Society for Maternal and Fetal Medicine. They all endorse the safety of SSRIs during pregnancy. All the evidence that we have is that SSRIs are safe during pregnancy. We have a lot of knowledge about the risks of being depressed during pregnancy. So, I'm not even sure why they were considering a black box warning.

Daniel Knoepflmacher, MD: Well, I think it's in line with a certain movement here that is looking at these medications as problematic in a wholesale way without some of the nuance that we're discussing, because I would argue that this is pretty similar to what happened with discussions about Tylenol during pregnancy, with discussions about vaccines and other things that have been coming up in this context at this time.

I'm curious though to think about SSRIs in this context. You alluded to this a bit earlier, Richard, in talking about what people's fears are, but why are we so focused, or why are they so focused on SSRIs and they're being put under so much scrutiny when they're, you know, as commonly prescribed as statins and anti-hypertensive medications, and people don't seem to get as agitated about taking those medications?

Richard Friedman, MD: Well, I think part of the reason is that the target of these drugs is the brain, and people are very anxious about taking medications that they fear will somehow change them and change their character and alter them in some ways that may be irreversible. And I always tell my patients that I understand this risk—this concern, not risk—that all these effects that antidepressants have are reversible. Side effects are reversible, therapeutic effects are reversible. You can lose them when you stop the medicine. But I think there's a special concern that people have about taking medicines that will alter them, their brain, and therefore the risk somehow they will be changed in some way that's different than, let's say, if they take a pain medicine or they take an antihypertensive. They don't have the same concern.

But I just wanted to go back to one thing which had to do with the nature of evidence. We were talking about, you know, the use of these drugs in pregnancy, why all of a sudden this concern. I think a lot of people don't really understand the difference between anecdotes, stories that they hear, you know, in social media or from influencers, and what we would consider to be reasonable, solid evidence.

And I think that if you hear stories that abounds in the popular press or you see them, you know, on social media, one thing that people don't really consider is how common is it that these occurrences really happen? So, you hear about something, and it's very dramatic. Four or five cases of a bad outcome in people taking an antidepressant. But nobody says to themselves four cases, but out of a total number of how many millions of people who were exposed?" Right? So, there's a difference between anecdotes, which are important stories to know about, and actual solid scientific evidence, and they are not the same thing.

James Kocsis, MD: Can I just amplify, one thing on what Richard just said? And that is there are quite a few anti-psychiatry groups. And I think probably RFK Jr. has been influenced by some of these groups. There's a group called Mind Freedom. There's a group called Survivors of Psychiatry. There's a group called Surviving Antidepressants. And some of them have numbers like 10,000 members or 23,000 members. But remember, there are 55 million people in the United States who are on antidepressants. So, divide 10,000 by 55 million, and that'll tell you the percentage of people on antidepressants who belong to these anti-psychiatry groups. But Ido think that they have had an outweighed influence on the MAHA movement.

Daniel Knoepflmacher, MD: Absolutely. And I think those numbers, while obviously those thousands compared to the millions, that's a much smaller number, the amplification of these messages is very important to consider right now. And I think to Richard's point, there is something about psychiatry specifically. By the way, there's mistrust of medicine and science too. So, it's not just psychiatry.

But I do think that there's something about our identity, our sense of personhood, and our minds being impacted by medications as people feel it, that that feels particularly scary. I think there's also a piece of stigma that this has to do with mental illness and there's not a comfort in accepting mental health problems in general, and there's a linkage to that as well.

I do wonder, though, in our age of polarization, do we need to be careful and really try to understand why there's 23,000 people signed up with this group and think, first of all, we have to present the evidence, which is what we're trying to do today. We have to be clear as communicators to the public to make them understand what the data shows and what the difference is between anecdotes and real substantial evidence.

But do we also want to address some of these concerns directly? And maybe are there questions we should be asking? Are there problems that we have as a field when it comes to how we talk about these medications, to how we prescribe them, to how we de-prescribe them? I'm just wondering what you guys think about potential areas where we could do better.

James Kocsis, MD: Well, I think that we should acknowledge that there is a small number of people who have a lot of difficulty, discontinuing antidepressant medication. And we should focus on education on proper methods for deprescribing in those rare instances.

Richard Friedman, MD: Right. And I would also add that we could do a better job of explaining to the public what the actual benefits are and that they're specific, these drugs, in this case, antidepressants, are not to treat everyday unhappiness. They're to treat a serious problem called depression, major depression, which is as real a biological and medical illness as hypertension or elevated cholesterol. And if we don't do that, then people have an inflated sense of the power of these drugs to make them feel happy, and they're not happy pills. If you don't have depression, they will just give you side effects. They will not make you feel good.

Daniel Knoepflmacher, MD: Yes. There needs to be clear discussion of how these benefit people with depression, real depression, and as you said earlier, also anxiety and some other conditions such as OCD, where these really actually have—we'll maybe touch on this later, but even stronger effect sizes than even with depression.

Richard Friedman, MD: Right. And I think we should be very forceful in explaining why the views of some anti-psychiatry influencers to communicate to the public, I think in a way that does disservice to the public, that all they need to do is exercise the right way and eat the right foods, and they'll be perfectly fine, and they can stop taking all their medicines, not just antidepressants, but medicines in general is a misguided notion that doesn't really take into account that there are illnesses that have an underlying biology, and that sometimes people need to take medicine, whether it's for blood pressure or cholesterol or depression in order to get better. And that there should be no stigma in doing so. It's a sign of strength to get the right kind of help when you need it.

Daniel Knoepflmacher, MD (Host): I want to go back to one thing that you mentioned, Jim, was the deprescribing, and especially when it comes to this small but important group of people who are exquisitely sensitive to the discontinuation of these medications. And they understandably have had difficult experiences and I think felt perhaps misunderstood, and that's driving some of the patient accounts that are part of these groups that are against SSRIs.

So, one of the recommendations that's featured in discussions of deprescribing is something called hyperbolic tapering. And this approach, just to explain what it is, it avoids reducing the medication by the fixed amounts of the existing doses. So instead of going from 20 milligrams to 15 milligrams to 10 milligrams, et cetera, you would decrease it at a fixed percentage of whatever that current dose is with little, fractional amounts, something like go down by, let's say, 10% each month.

And the theory behind this is that brain receptor occupancy of the medication, is more sensitive at the end of a taper because at that point, it's dropping, more precipitously with these smaller reductions. And there was a study in Lancet that used PET scan data to show this dose receptor occupancy relationship that is hyperbolic when the doses are tapered below a therapeutic minimum.

Now, this is illustrating something that's a mechanism. It's showing it on a molecular level in PET scans or, you know, on a PET scan level, but showing what's happening in terms of receptor occupancy. It's not really something that's been studied clinically, so whatever's happening in the people's brains with PET scans, that doesn't necessarily correlate with any side effects or experiences at that point.

So, I'm curious what you both know about this approach, by the way, being promoted as part of these government panels, and what you understand of this aspect of this deprescribing movement.

Richard Friedman, MD: I would say that for the vast majority of people in whom I deprescribe and taper them off antidepressants when we have made the decision that they may no longer be necessary, most people don't have a serious problem stopping medicine. I think it's a very small percent of people. But if you accept that that's true, and I do, and there are some people that have a very hard time stopping, either you can go down so slowly that the runway is long, like going down in an airplane. You know, if you try to go down from 36,000 feet to ground in five seconds, everyone will be sick. Some people are extremely sensitive, and so you have to have a very, very long taper, whether it's hyperbolic.

Obviously, if you're starting at a very low level, when you drop from the tiniest dose to zero, that's 100% reduction. It's always going to be hard at the very end, so you just do it very, very slowly. Or alternatively, one option is to switch over to a very long-acting SSRI like fluoxetine. Prozac has a very long half-life where it's much easier to do this, because it's like turning off the key in a large, heavy truck. It keeps going.

James Kocsis, MD: So, I would just add that I don't know how many hundreds of depressed patients I've treated in my career, and I don't know how many hundreds of patients I've tapered off antidepressants in my career, but I've never had one of these super problems. I mean, every patient that I've had, I've been able to successfully—if we agreed that they needed to come off or wanted to come off antidepressants—we always succeeded using the methods that Richard just described.

Daniel Knoepflmacher, MD: That's a really important point, Jim. I mean, I think all three of us—I certainly haven't had as many hundreds, as you have, Jim, in the many years you've been a psychiatrist. But even in my time, all three of us have had patients where it was clear that they were much more sensitive. And as we were taking them off medications, we had to listen and collaborate with them and find the right rate of tapering to make sure that they didn't experience any untoward effects as they were getting off the medication.

Alternatively, I'll ask you both if you had this experience, I've also had the experience with patients who've come in after, let's say, they're been on a medication for a certain amount of time, we're not meeting as frequently. And they say, "Oh, by the way, about five weeks ago, I just stopped. I went from 150 milligrams to zero." And said, "Oh my gosh," or, you know, "Did you experience..." "No, no, I didn't feel any difference. I don't think I need to be on the medication anymore." And so, you have people at the other end of the bell curve who actually seem particularly not sensitive to these potential side effects aswell.

James Kocsis, MD: Yeah, absolutely. I've had the same experience as you, and it just shows that, you know, many people can come off without having any discontinuation symptoms at all.

Richard Friedman, MD: Right. And I would add that it's, it's good to consider that there are many other problems that people have when they stop antidepressants that are preexisting problems. And so, when they stop their antidepressant, you can get the resumption of preexisting problems that have nothing to do with the antidepressant. So, it's important to just keep in the back of your mind that when you hear stories, extreme stories of very difficult times that people have had stopping antidepressants, there are other factors, medical, psychological factors that may be going on in the background that are misattributed to the stopping of the antidepressant.

Because from our experience, collective experience, we just have very, very rarely seen serious problems stopping antidepressants. And it's not just the three of us. I have many, many colleagues, and they scratch their heads and say the same thing.

Daniel Knoepflmacher, MD: You know, I think this gets to some wider rhetoric that this idea of over-medicalization and the brush that's being painted, the roller of paint that's being painted on how these medications are being prescribed, is that it's completely like a pill mill. Like, "Oh, you say you're sad, take pill, increase pill, get off pill, or don't get off pill forever," that there's this almost robotic, kind of depersonalized way of practicing. When in fact all three of us are describing patient-centered care, where every individual needs to be understood as distinct, and you need to be talking to them and understanding them and adjusting accordingly.

And I actually think that is a failure on our field, perhaps, of not getting that message out enough, that really we need to be countering this by saying, "No, this is the kind of patient-centered care," which is a term that they're saying we need more of that, and we're saying, "No, that's actually what we're practicing and that you're trying to destroy by using no nuance and misconstruing this." That's a message that I think psychiatrists need to be conveying to the world. Thinking though about antidepressants specifically, Jim, I can't resist but to ask you a question given all the work that you did over many years researching, depression and bipolar disorder, and you did some influential research that involved antidepressants. Can you just give us a little, I guess, overview of some of the most important findings that came out of your research when it comes specifically to antidepressants?

James Kocsis, MD: Sure. And by the way, Richard Friedman was a co-investigator in many of these studies that I'm going to talk about. We focused on large studies, multi-site studies, primarily of people who had chronic depression. And we were studying long-term efficacy. So, what we did was we treated literally hundreds of patients with antidepressant medications.

And after about six months of treatment, we took the people who had responded favorably, the responders, and we randomized them so that half of them would be slowly tapered onto placebo, and the other half would be continued on their antidepressant medication, and we would follow them for the next one or two years.

And two things that we found out was, number one, that with slow de-prescribing, slow tapering, we had very little difficulty with discontinuation symptoms. That's in the placebo patients. And the other thing that we found out was that with continued antidepressant medications, we saw very few relapses. In the placebo group, the people who came off antidepressants, about 50% or 60% of them relapsed over the one to two-year period and needed to be restarted on antidepressant medication. So, what does that mean?

What that means is that about at least 30% or 40% of people can come off their antidepressants, don't need to be on them, and may stay off them at least until they may have another episode later in their life. But there's a large group, 50% or more, who every time they discontinue antidepressant medications, they get sick again. They become depressed again. And those people need to be on antidepressant medications long term, maybe for the rest of their lives. They are not addicts. They are not bad people. They have an illness, a chronic illness analogous to diabetes, analogous to hypertension, analogous to high cholesterol, that requires them to be on a medication. And if they discontinue their medication, they get sick again. So, that's basically the main gist of what we found in these studies.

Daniel Knoepflmacher, MD: I didn't know that Richard, you collaborated on that. Sorry, I would've brought your name up as well. Well, one thing that comes up in the rhetoric from those who are critical of antidepressants is mentioning the serotonin hypothesis of depression. And I think this was something maybe in the early era of the introduction of SSRIs, there was a lot of talk about these medications are addressing a serotonin imbalance in the brain.

And even as Richard you described, that's not how we talk about it today. We talk about it as there being a cascade effect from increasing serotonin through SSRIs, not that just an increased level of serotonin is a direct treatment of the depression, that there's this complex cascade effect.

So I was just curious, since you guys were involved early on in research and have more memory of this than I would, if you could say a bit about the serotonin theory of depression and how it developed and how it's shifted over the years.

Richard Friedman, MD: Sure. So, serotonin we know is important in modulating and maintaining mood, but not in the, in the simple serotonin deficiency model. And there's a lot of evidence both in humans and in animals for the role that serotonin plays in mood. One of the strongest pieces of evidence in humans that's interesting is, you know, if let's say you've done well and you have depression and you respond to Prozac, an SSRI, and I go ahead and I deplete you of serotonin, and there's a way to do that experimentally, I can actually bring about depression by lowering serotonin.

But interestingly, when people take antidepressants and they get better, they very often don't feel better right away. There's a lag time of a couple of weeks. And we know that serotonin levels rise pretty quickly within hours or days in humans and in animals. So if the serotonin hypothesis were literally true, you should feel better almost immediately, but you don't.

And one of the things that we're realizing is that the cascade eventually ends up in changes in synaptic plasticity, meaning how neurons connect to each other and how they increase their connectivity after weeks of being on antidepressants. And one substance that gets increased in response to chronic exposure to antidepressants is a substance called BDNF, brain-derived neurotrophic factor, which is kind of like a brain fertilizer.

So in many ways, antidepressants are neuroprotective. They are enhancing the growth and connection of neurons. And depression, especially depressions that are brought about by stress, do the opposite. They decrease BDNF and they decrease the connection between neurons. So in a sense, even though it's not just serotonin, serotonin's the first step in initiating the cascade, we now think it has to do with remodeling of circuits in the brain and the connection between neurons that helps people, you know, get out of depression and feel better.

James Kocsis, MD: I can add a number of things. First of all, there are effective antidepressants that have nothing to do with serotonin. Probably one of the most commonly prescribed is Wellbutrin, bupropion, which works on neurotransmitters called norepinephrine and dopamine, but has virtually no effect on serotonin.

So, we know that there are people whose brains probably have problems with other neurotransmitters besides serotonin and that includes norepinephrine and dopamine. But there are also other newer antidepressants. One example would be ketamine or esketamine that don't seem to have anything to do with monoaminergic neurotransmitters at all.

So in other words, what I'm saying is that the biology of depression is heterogeneous, that serotonin is relevant for some people, but not all people. And there are a number of other neurotransmitters that are probably relevant for different people with different kinds of depression. And that's one of the reasons why we're very interested in developing newer antidepressants with novel mechanisms of action that have nothing to do with serotonin.

Daniel Knoepflmacher, MD: And as we've talked about, we need to look at SSRIs in all of their applications, because they're very effective for anxiety. One really great example is in the treatment of premenstrual dysphoric disorder, where they have extremely high effect sizes, much higher than for depression, and they actually work immediately. So, you don't even have to take it every day of the month. You could take it during the period where the PMDD symptoms are emerging. So, that's got to be a completely different mechanism.

And again, I think this gets to nuance and scientific complexities that are not being considered when there's a broad brush stroke saying that these medications are deleterious or damaging, because there's a lot of different uses and benefits that don't just live within depression.

One thing that's underlying all of the anti-SSRI rhetoric is a general sentiment that these medications are actually ineffective at treating depression. And critics argue they're only slightly more effective than placebo, and that exercise or psychotherapy or lifestyle changes are effective alternatives, and obviously would have fewer negative side effects.

But we do know that, and you guys have studied this, that these medications can be effective, and I know each of us has witnessed their benefits directly for patients. So, what is the nuanced overview of how effective SSRIs and other antidepressants are for treating depression, and where does placebo effect fit into all of this?

James Kocsis, MD: So, there is no doubt that, in clinical trials of antidepressant medications, there are often high placebo response rates, and that makes it difficult to show that the active drug, the antidepressant medication, is actually more effective than placebo. And in many instances, it ends up being something like, you know, 60% of patients respond to active drug and 40% of patients respond to placebo.

And if you think about that, it makes it seem like, well, antidepressants are not that much better than placebo. So, the question is: Why do 40% of patients respond to placebo? First of all, we all know that depression is a relapsing and remitting illness, so some people just get better as part of the natural history of the illness during the clinical trial.

The other thing is that many clinical trials rely on what is called symptomatic volunteers. In other words, we advertise in the newspapers for people with depression to answer, you know, an advertisement and volunteer for a clinical trial. And in those cases, some of these people, we've found out actually more or less make up the story about their depressive symptoms, and their job is to have enough depressive symptoms to get into the clinical trial.

And their job during the clinical trial is to get better, whether they're on active drug or whether they're on placebo. And obviously, that inflates the placebo response rate. So, you know, there are a number of issues that make it difficult to actually establish the efficacy of antidepressant medications.

Some of the things that can be done to remedy that problem is to stop using symptomatic volunteers and use real patients, you know, real inpatients. The older antidepressant medications like the tricyclic antidepressants were very effective, but all of the studies were done on depressed inpatients where, you know, there was a very low placebo response rate. I'll stop with that and let Richard amplify.

Richard Friedman, MD: That's so clear, Jim. I would also add that if you study patients who have severe depression, as Jim said, patients who were in the inpatient hospital, there's no question they have a disease. But when you're dealing with more mildly ill patients who are being treated as outpatients, who answer advertisements, you have a combination of people who have everyday unhappiness, and there are some people who have major depression, but the symptoms are mild.

And we know that the milder the depression, the higher the placebo response rate. So, the difference between the drug and placebo gets smaller as depressive severity goes down. And the other thing about modern clinical trials is people spend a lot of time in the study around study personnel who are asking them a lot of questions.

And so, the placebo is not exactly a placebo anymore because you're getting a lot of questionnaires, they have a lot of attention. There is a psychosocial support aspect to modern clinical trials, even in the placebo arm, where you get a lot of TLC from study personnel. So, it's not like you go in and you see a computer, the drawer opens up, and you get your pill. You're spending time getting a lot of questions thrown at you. And that has an effect.

Daniel Knoepflmacher, MD: I'm wondering, as we've talked about all of the ways in which this has been misrepresented or misconstrued or oversimplified, what do you both fear is going to be the impact of all of this in potential policies that could come from it?

James Kocsis, MD: What we fear will be the impact of discouraging people from being on antidepressant medications. What I fear is that people will suffer and that people will die. And people will suffer because their depression relapses, and that's not a happy thing. That's not a pleasant thing to experience. And obviously, as we've discussed, you know, one of the symptoms of being depressed is developing suicidal ideation and suicidal activity. So, there's the risk that by discouraging people from being on antidepressant medications, we will cause a certain number of suicides. So, I think, you know, those are big things to fear.

Daniel Knoepflmacher, MD: Well, you've both written about this. Richard, you wrote the article in The Atlantic, and Jim, you sent a letter to Psychiatric News, which is a publication that's sent to all of the psychiatrists in the APA commenting on this.

James Kocsis, MD: By the way, that was published this week.

Daniel Knoepflmacher, MD: Oh, okay. Yeah. Yeah. Those psychiatrists who are listening, if you look at Psychiatric News, you can see Jim's letter there. You guys are coming on this podcast and talking about this, and that's, I hope, an important step as well. But what do you think, just individually and as a field, psychiatry needs to do to help people get an accurate understanding of these medications and really try to foster trust in the treatments that we're providing?

Richard Friedman, MD: Well, one major role I feel that we have as psychiatrists is as educators, first of our patients, and for those who feel able to and are willing to do it, to contribute to the public dialogue and to provide balanced true information about the benefits of treatments, whether it's antidepressants or psychotherapy.

You know, we're not always so good in the field about telling the public about what we do. And my experience is, having written for the public for many years, if we don't talk about what we do and we don't talk about the science, others do it for us, and often in ways that are misrepresented in exactly the ways we've been talking about today, and distorted and also discouraging people who would benefit from actually having treatment in the first place.

James Kocsis, MD: We live in an age of social media. And bad news gets a lot more attention than good news, right? So, that's one of the things that we're contending with is these anti-psychiatry groups that talk about the evils or the bad news about antidepressants. That's much more interesting and exciting. It's like the New York Post versus The New York Times, right? That's the fight we're fighting.

Daniel Knoepflmacher, MD (Host): Well, I think we need to keep fighting the fight. And it's part of why I do this podcast and, you know, it's why I'm just thrilled that the two of you came on to help those who are listening understand the nuance of this. And yes, we've got to continue getting the word out as a field, as individuals, those of us who are comfortable doing it. Not sure that any of us are quite influencer material, but maybe at least we can find other ways to get the word out, even if it isn't negative, and talk about the positive impact of all of this.

Richard Friedman, MD: there's no reason why, you know, you can't have an educated, informed influencer who happens to know something about what they're talking about.

It's just as Jim said, I mean, it's the virality of social media that's the problem, where, you know, anybody with an opinion has enormous audience. As in the past, they could speak to one or two people and influence them, now they have hundreds of thousands, if not millions.

James Kocsis, MD: I believe that Richard Friedman is an influencer and has a very significant impact. And, Daniel, thank you very much for doing these On the Mind podcasts.

Richard Friedman, MD: Yes.

Daniel Knoepflmacher, MD: Well, you guys both have influenced me tremendously as mentors and as colleagues. So, I'm just grateful that you both took the time to come here and talk about this thorny issue, but really got to the heart of it in a way that I hope has been very engaging for those who listen. So, thank you both for taking the time and joining me today.

Richard Friedman, MD: It was my pleasure.

James Kocsis, MD: Yes. Thank you very much, Daniel. It's been a pleasure working with you again.

Daniel Knoepflmacher, MD: Yes. This is again for both of you, so I'm really grateful. And I also want to thank all who listened to this episode of On the Mind, the podcast of the Weill Cornell Medicine Department of Psychiatry. Our podcast is available on many major audio streaming platforms. That includes Spotify, Apple Podcasts, YouTube, and others. If you like what you heard today, please give us a rating. I can't say this enough. The more we get ratings, the more it helps people learn about us. So, please give us a rating. You can even write a review if you want. And subscribe so you can stay up to date with all of our latest episodes. And tell your friends. We'll be back again next month with another episode. Until then, wishing you good health in body and mind.

kids health promo: Every parent wants what's best for their children. But in the age of the internet, it can be difficult to navigate what is actually fact-based or pure speculation. Cut through the noise with Kids Health Cast, featuring Weill Cornell Medicine's expert physicians and researchers discussing a wide range of health topics, providing information on the latest medical science.

Finally, a podcast to help you make informed choices for your family's health and wellness. Subscribe wherever you listen to podcasts. Also, don't forget to rate us five stars.