Antidepressants

Hi, I'm Wendy Zogman, and you're listening to Do You Let Me Be His Science Versus. This is the show where we get facts against pharmaceuticals. Today, we're tackling one of the biggest mental health questions of the decade. Do antidepressants really work?

Now, if you're feeling depressed or you just want to talk to someone in the US, you can call the National Suicide Prevention Lifeline at 1-800-273-8255. That number will be on our website, along with other resources. Currently, I'm on Trasadone. Prozac.

Final vaccine. Well-view trend, it's a telephone. You probably aren't. That's a pro.

We are well-intrally living in the age of antidepressants. Only one in every 10 Americans over the age of 12 take antidepressant medication. That's according to the Centers for Disease Control. And over the last two decades, the number of Americans on the meds has jumped nearly 400%.

But it's not just Americans who are having these pills. Globally, the number of people on antidepressants has increased over the decade. Since the late 1980s, these pills have been considered a major breakthrough in the treatment of depression. But in 2008, a study came out that cracked the industry wide open.

It said that antidepressants work about as well as a sugar pill. And because of that, there is little reason to give these pills to most people suffering from depression. Headlines came out screaming, antidepressants don't work, and immediate frenzy began. For millions of patients struggling with depression putting their faith in medications to feel better, this won't come as happy use.

The fight is about antidepressants for the medical community is at war. And the war reaches on today with academics continuing to pump out papers and books with titles like Ordinarily Well, The Case for Antidepressants. And then those on the other side calling antidepressants the emperors new drugs. Meanwhile, patients are left in the middle, not knowing whether they should take the drugs or not.

So, today we are going to wade through the studies and the counter studies to find out, do the drugs work. When it comes to antidepressants, there are lots of prescriptions. But then, there's science. Before we get into the debate about the drugs, let's talk about depression.

The National Institute of Mental Health describes it as a serious mood disorder that lasts for two weeks or more. The serious mood disorder can manifest in many, many different ways. So, to give you a tiny sense of what it feels like to have depression, we spoke to a group of people that are willing to spill their guts out to a microphone. New office.

The way that I often describe depression is it's not really an emotional thing, it's more of a lack of emotion. The suicide didn't even make sense because there was no pleasure in the darkness either. It was just zero. Better really short temperature, we have patient and that's not typical.

I was having difficulty sleeping, eating. I had like alpers of rent crying. I couldn't see the future being better than the present was. Oh my god, that's like the worst feeling ever.

Do I want to die? Do I want to die? Do I want to die? Like, it's very hard.

Depression can feel like an attack on the inside. The people we spoke to said that something small could set off a cascade of internal abuse that hijacks the entire day or even the entire week. It's an intense experience that can hold you prisoner, they said. So, could a pill really be the key to escaping that internal prison?

There are several different types of antidepressants on the market, and many of them boost levels of particular chemicals in your brain that are known to help regulate your mood. Now, some drugs, for example, will pump up levels of serotonin, while newer drugs give your brain access to more serotonin, as well as another chemical called norepinephrine. On the website of one of the country's best selling antidepressants, it says, quote, experts believe that depression results when certain chemicals in the brain are out of balance, in court. So, an injection of these certain chemicals should be making people happy.

But what if the chemicals in these drugs aren't actually doing anything? There's an intriguing body of research that suggests the power of these drugs doesn't come from any chemical inside the medication, but rather than the power of placebo. The idea of placebo is basically that your thoughts can change your biology. So, with depression, you could be taking a pill that is actually just a sugar pill, but if you believe it's the real medicine, then you'll feel better, just because you expect to.

And a placebo effect can change how we respond to all kinds of things, from pain-relief to hypnosis, to the treatment of urinal bowel syndrome, and it's this thing that Irving Kirsch, psychologist and researcher, has devoted his career to. And he's the one that did that study in 2008 on antidepressants, the study that sparked this whole debate over whether these drugs work or not. My name is Irving Kirsch, I'm the associate director of the program in placebo studies at Harvard Medical School, and my favorite color is, believe it or not, black. Maybe I like black and red, the anarchist colors.

Interesting for a man who's run a tear down the way we treat people with depression. Now Irving has studied the placebo effect in all sorts of things. But in the 1990s, he started to get curious about the placebo effect in people with depression, because he thought that depression would be exactly the kind of condition that would have a big placebo effect. One reason for that is that a core feature of depression is hopelessness, a sense of hopelessness.

One of the things they're hopeless about is ever getting better. And so now they've got a new kind of drug coming out that hasn't been tested against being tested in this new clinical trial. Maybe that will work. That's something that makes it still a sense of hope.

Irving went about studying antidepressants by getting clinical trials data from the Food and Drug Administration. These are the guys that approve whether drugs are allowed to be on the market. Because the thing is that the placebo effect is such a powerful effect that to get a drug approved by the FDA, drug companies have to consider it in their trials. Typically, what drug companies will do is they'll get a group of people, they'll give them a particular drug that they're testing, and they'll get another group of people and they'll put them on a placebo.

Then the company pretty much has to show that the drug worked better than a placebo. But here's the thing, drug companies don't have to publish all of their studies. So they can pick and choose what they release to make their drugs better than perhaps they are. Now, this is currently changing.

But at the time that all of the antidepressants on the market were approved, that was the system. So Irving did some detective work, got all of a day on the published and the unpublished stuff. And what did he find? The surprising thing that we found was that people got better when they were taking the drug, but they also got better when they were taking the placebo.

And the difference between the response to the placebo and the response to the act of drug was much smaller than one would expect from a treatment that had been heralded as constituting a revolution in the treatment of depression. Dehum, this discovery was a real breakthrough. Something that could change the way that depressed people are treated. But many of his colleagues didn't feel that way.

The reaction was of many people, this can't be true. Of course anti-depressants work. Then came even more research suggesting that Irving was onto something. Around the same time, as Irving's 2008 paper came out, scientists were discovering that the claim that the drug companies were making about people with depression needing to boost certain chemicals in their brain wasn't right.

In fact, it turned out that people with depression weren't necessarily low on certain chemicals, and didn't mean them to be topped up. Now there are other theories about how these drugs work. The truth is, we still don't know what these drugs are doing. So could it really be all placebo?

Irving published more and more papers in 2012, 2014, and 2015, all finding that antidepressants really aren't that much better than a dummy pill. But doctors keep writing prescriptions for antidepressants. Irving says it's because they too are being fooled by the placebo effect. And he says there is a rich history of mistaking placebo for effective medicine.

That's why for so many centuries, bloodletting was thought to be an effective treatment. You have to go back and you'll see the kinds of treatments that they use successfully in the history of medicine included things like frog sperm and feathers and fur and spiders that were given as treatments that people would ingest and if it didn't kill them, it might make them better. And that's part of the history of placebo effect. How do they get the frog sperm?

I have no idea. It's a good question. Now to be fair, the psychiatrist that we spoke to said, yeah, we get it. We know that not everyone who was depressed should be given these pills.

And lots of psychiatrists, in fact, won't prescribe drugs for some of their depressed patients. The National Institute for Health and Care Excellence are leaving health agency in the UK, specifically it says that people with mild depression usually shouldn't be offered antidepressants. They suggest other things like therapy. But Irving and his research are taking this debate one step further and saying that antidepressants are essentially frog sperm and that no one, not even those who are suicidal, should be on the meds.

Not even the very most depressed patients. No one shows that much difference between drug and placebo, not even close. Irving doesn't see patients anymore. But at the time his research started coming out, he did.

And he was so confident in his findings that he changed the way he treated his patients. When I started seeing the data, I stopped referring. Clients I was seeing for antidepressant medication. So even if he's right, and antidepressants are all placebo, who cares?

What's the problem with giving people sugar pills if they don't make them feel well? If they can get out of bed and go to work? Who cares? What's doing that?

Just give the people their frogs sperm. Well, not so fast, says Irving. There's something else to consider here. The frogs.

No, there's nothing else to consider here. Lots of something else's. These drugs have many side effects. I started to realize that I was always able to come in and sabotage.

It's like really sleepy all the time. Yeah, it's like last week. I gained a lot of weight at one point. Like I was like three steps behind my actual body.

I had lots of sex drive and again, from the beginning, I had a shockingly low libido. It affects your sexually. Stuff down there does not work. Come on, you're on it.

A 2014 analysis of a bunch of studies found that on average, around 30 to 50% of adults treated with antidepressants and some kind of sexual problem from taking their meds. There are also rare but noted side effects, like having heart problems or being at an increased risk of gastrointestinal bleeding. And Irving says that this list is even longer. He points out that drug companies don't always publish their side effects.

A 2014 study backed that up. It looked at more than 100 trials of antidepressants and anti-psychotics and compared the numbers of side effects in the published and unpublished documents. On average, the drug companies left out more than 40% of the side effects from their published studies. Bottom line, Irving says that the risks of antidepressants are just too high.

And the benefit is just too small. Continuing to tout antidepressants as a first line treatment, given data that placebo's work almost as well, and that antidepressants have the greatest risks in terms of side effects and health risks, to tout that as a first line treatment is irresponsible and doing harm to depressed people. But while Irving made a confident in his work, it is by no means scientific consensus. There are a lot of doctors and researchers out there who disagree with him.

Strongly. I want to talk a little bit about what he just told you. Because I think the case for antidepressant as placebo is a house built of fantasy breaks. Dr Peter Kramer is one of the loudest critics of Irving's work.

That was him at a debate with Irving earlier this year. Peter is a psychiatrist and professor emeritus at Brown University. He's written books on the benefits of antidepressants. And to give you a sense of how much Irving and Peter disagree on the importance of antidepressants, Peter's first book was called Listening to Prozac.

I'm ahead of it. And Irving wrote a paper soon afterwards called Listening to Prozac, but hearing placebo. Yikes. Peter has been treating patients with depression since the late 1970s.

And he remembers the world before antidepressant drugs were widely prescribed. You saw people who were seriously depressed at a level you just don't see that often today. There were people who looked like a juror etching or a blue carry Picasso painting. I mean, thin, a rack with pain, wringing their hands, repeating depressive phrases.

And in those days it was treated with psychotherapy. Peter believes that the age of antidepressants that we're leaving today isn't driven by powerful placebo, but rather by doctors like him seeing how powerful these drugs really are. You know, you give these medicines to people, they start feeling substantially better within weeks. I think when doctors saw how well these medicines were often they were impressed and adopted them wholeheartedly.

And the thing is that Peter relies on a raft of studies to back up his belief that antidepressants are better than dummy pills. Studies like a 2008 analysis of 74 clinical trials looking at the published and unpublished data and found that the drugs were, quote, shown to be superior to placebo, end quote. Well, there's just a host of evidence that any depressants do outperform placebo. And, you know, I think the debunking case is just bad science.

So what is going on here? And how can everyone have their own studies to back up the exact opposite conclusion, especially when you get this? They are all using clinical trial data that they got from the FDA. How can they get the exact opposite answer?

Is it magic? No. Madness. No.

It's because of this. Hamilton. We'll explain after the break. Welcome back.

We've just introduced you to two professors with very, very different ideas about antidepressants. They both have studies to back up the claims that they are right. What magic are they using to get their results? No magic.

Except for the magic of statistics. It all has to do with the tool that you use to crunch the numbers and see whether a drug works. So children, snuggle up and let me tell you a tale of how depression drugs get on the market and how scientists use the same data to make their own arguments. It all starts when you measure how sick someone is.

You have to do this in clinical trials and then you can see whether someone improves or not after they've taken a pill or after their popular SIBO. Now, while doctors can check your blood pressure for hypertension or do a test to see if you've had an infection, researchers are yet to find an objective test for depression. So to figure out if someone has improved after taking antidepressants, they have to ask all these questions about how you're feeling and then they tally up the points and then they use those results to rank their patient symptoms on a scale to see just how depressed they were before and after taking the drugs. And there are a few different scales that you can use for depression, but one of the most popular is called the Hamilton Scale.

Yes, the Hamilton Scale. And it's been used for more than 50 years. This survey includes questions like, do you think that life is not worth living? And if you do, you get one point on the same scale.

But here's another question on the same scale. Do you have heavy feelings in your abdomen? Like, maybe feeling constipated? If you do, you get one point.

Have you lost your appetite? Do you feel like people have let you down? Do you get gas, do you have mild headaches? Do you feel restless at night?

If you do, for each one, you get one point on the Hamilton Scale. Those with the higher points have the more severe depression. Lower scores mean milder depression. Now, in a drug trial, researchers will take the patient's scores at the beginning and end of a trial, looking to say what's changed.

And are we specifically looking for the difference between how people's scores changed if they were put on placebo and how people's scores changed if they were put on the drugs? The goal here is for researchers to see if there is a significant difference between the effects of placebo and the effects of the drugs. And this, this is important. Because it's where Irving, Dr.

placebo, and where Peter, Dr. Prozac diverge. I didn't want to be Dr. Prozac.

Okay, so it's here where Dr. Prozac diverge. You see, like we said before, it's all about how you crunch the numbers. There's statistical significance, which is what Peter points to to help make his case that antidepressants work.

It's been the goal standard of measuring drug effectiveness for decades. For all drugs, not antidepressants. And statistical significance measures are whether the results of your clinical trial were not due to random chance. That is, they weren't just a fluke.

But there is also something called clinical significance, which is a higher bar to jump. And this is what Irving, Dr. placebo, uses. And this is a test that's supposed to accurately reflect the patient's experience.

That is whether the patient's feel like the drug is actually working. So when Irving says... Even with the most severely depressed, you don't get a meaningful difference. What he really means is this.

There's a statistically significant difference between drug and placebo. But it's not a clinically meaningful difference. So statistical significance, this is what we will call the low bar. Because it's simply asking whether the difference bound between the placebo and the drug was not due to random chance.

And clinical significance, that's the high bar. Do people feel better on the drugs? So this is what the debate is all about. And it's why it's such a hot media topic, because it's all about statistics.

So now that we're all together on this one, low bar, high bar, let me tell you a little bit more about the high bar. The high bar was determined by a leading public health body in the UK. And it requires that people taking the antidepressants improve by at least three points. On the Hamilton scale compared to those on placebo.

It's worth pointing out that Irving is not alone in wanting to use the high bar. Even beyond depression research, in many areas of medicine, there has been a long push to use higher benchmarks and statistical significance. Now, in theory, it's a great idea to use a high bar to judge a drug's effectiveness. Right?

To show that the changes you see are going to be important to the patient? But there are real questions about whether the scale used to set this bar, the Hamilton scale can actually do that. Remember those questions on the Hamilton scale? We're saying you have a heavy abdomen, we'll get you the same amount of points it's feeling like life is not worth living.

Or to Peter, that's just wrong. And it can make placebos look more effective in clinical trials than they really are. People in the placebo arm of the trial may do better in terms of their constipation or sleep without really doing better in their court depression. Plus, antidepressants can actually increase your score on the scale because they have side effects that actually cause sleep disruption and headaches, making someone's depression on the Hamilton scale look worse, even while the drugs actually might be helping their depression.

And Peter isn't the only one that has a problem with Irving's high bar. But 2008 paper called it, quote, down right arbitrary end quote. And on that, here's another thing you have to know about Dr. placebo, Irving.

His studies actually find that people with extremely severe depression do jump his high bar on the drugs. But get this, that three point difference between drug and placebo needed to clear the high bar, that's not good enough for him anymore. Now we have found out that even that would be an overly liberal and overly lenient criterion and you would need a seven point change in order for somebody to be rated by their clinician as minimally improved. That should be something just to get any benefit, at least the minimal improvement.

But while Irving keeps moving the bar, the arguments from antidepressant proponents also run into trouble. Because if the scale is broken and we can't properly measure depression, then a lot of clinical trials that show that the drugs work, the ones that rely on that low bar, they're wrong too. Because here's the thing, they also use the Hamilton scales. And there are other scales that you can use that focus on things like whether you can hold down a job or they try to look at your overall quality of life.

But the thing is, these scales don't consistently show that the drugs are that much better than placebo either. And let's just say, we don't know how to accurately measure whether someone's depression is getting better. And that's not all we don't know. Like we said in the first half of the show, we don't know exactly what these drugs do in the brain.

Plus, a lot of this debate about placebo versus antidepressants is based off short-term studies. Many antidepressant clinical trials only go for six or eight weeks. So we don't have much research on what these drugs are doing in the long term. Or what placebo does in the long term.

How depression works in the brain. Helen Mayberg is a professor of neurology and psychiatry at Emory University. She studies brain scans of highly depressed people. And she thinks about all the unknowns in quite a beautiful way.

It's like an orchestra. Within a brain area, you know, all the violins have to play together. They have to be synchronized properly with a bassoon and the basses and the flutes. You know, we can come up with all kinds of clever metaphors about brain choreography.

But at the end of the day, what is the system that emotional pain can lock you down to not even get away? Oh, no one knows. So the issue is it's a mystery. Given all of these mysteries and unknowns here, Helen says a drug that clears the low bar, statistical significance, might actually be important.

It might just be enough of a lift for some people. How can anyone judge statistically what's a meaningful, clinical change? It's like if you're trying to get up the side of a mountain and the placebo gets you part of the way, but it's that extra kick that gets you over the ledge from the active drug. One doesn't want to discount that needed extra boost.

And I think that until we really have a way to quantify what that extra part is, I'll still take getting over the ledge if I need the extra help together. Still though, the fact that this whole debate is about a little lift kind of tells you that on average, the drugs are that great. The problem is, is that our drugs aren't as good as we want, which doesn't mean that they're worthless. And this was something that we heard from a few doctors.

Gregory Simon is a clinical psychiatrist and chair of the Scientific Advisory Board of the Depression and Bipolar Alliance. Whew, what a title. I don't think anyone, at least anyone who practices much or pays much attention would say that the current generation of anti-depressant drugs is remarkably effective or terribly successful. His clinical work has given him a chance to see these drugs work in practice.

And he says that, yeah, it's been a bit of a bummer. That's quite disappointing. You know, they are modestly effective, highly variable in their effects from person to person, and lots of them have side effects, and that's not a very good situation. I would certainly, in my clinical practice, I may do with what I have.

So I certainly prescribe those medicines, and I've seen them help a lot of people. But would I wish for something better? Absolutely. That high variability that Gregory is talking about might be explained by the fact that different people responded to anti-depressant drugs in different ways.

The results from drug trials are an average. So people who might be responding really well versus people that might be responding really poorly, just get washed out in a mix. Helen Mayberg, who talked about the August-round people's minds, is researching these different responses. Her work using brain scans is showing that there does seem to be different types of brains that need different types of treatment.

We will learn along the way that when we start to get people to treatment, that matches their brain type. Then we'll be able to see that if you get drug and you should have gotten drug, because that is the treatment needed. And even though this is the live research question, who should get the drugs, Helen says it's an important part of the equation. I don't think that anyone can deny that there is a placebo response with any depressants.

The question becomes is that because there is an effect above the placebo, is that difference worth it at the individual patient? Helen regularly sees people with severe depression as part of her research, says that because you don't know how different brains are going to react, it's worth giving the drugs the benefit of the doubt. And Gregory, who treats patients with depression, agrees. But I think, oh, he doesn't say patients anymore.

Your studies and your words are very strong about antidepressants not being effective. And then when you've imagined someone with a patient running in front of them, and there's nothing that's working in their suicidal. Then you might reach for attention, certainly, to reach for anything. I don't know what I would do at this point.

I'm glad I'm not in that position when the talk goes out to the suffering. And it's hard when you haven't found anything else to not look for something that might work. So when it comes to science versus antidepressants, do they stack up? Do the drugs work better than a placebo?

Well, it depends. If you use the most scientifically accepted standard to statistical significance, then yes, they do. But if you raise the bar to try to see a clinical significance, then the most part, they don't. But there are problems with this high bar, because the way that we measure depression is kind of crude, and it doesn't take in all the nuances of the disease.

Either way, you count it though, and this is important. For people with very severe depression, the drugs help more than placebo. But given the unknowns here, Dr. Helen Mayberg and other doctors that we spoke to do hope that patients will try to get all of the treatment that they can.

If you can get better on placebo, that's great, because that means your brain has a capacity to repair itself. But if someone does make a sugar pill and continues to do badly, I would certainly hope that the fear of side effects wouldn't start people from actually entertaining the idea that an actual any depressive medication or other treatment might be in their best interest. The thing is, when it comes to depression, sometimes you need to try a few things to find out what works. Because at the moment, the science isn't good enough to say whether the pills will or won't work for you.

For now though, what we can say is there is no evidence that frog sperm is useful. That's science versus antidepressants. And by the way, this is our last episode of the season. But don't worry, we'll be back in the spring of 2017 in the U.S.

We'll also be occasionally sending out interesting little tidbits so keep your ears open and hang around up the ads to hear some of our favorite moments that didn't make it into this season of science versus. Sometimes you need to kill your darlings. Not you guys, we love you guys. This episode has been produced by Heather Rogers, Diane Wu, and Shruti Rivendren, asking your producer is Caitlin Sorey, edited by Anne Rose Strassa and Caitlin Kenny, that's checking by Michelle Harris.

A big thanks to Carly Schwartz for sharing her story with us, and to all the New Yorkers who are happy to share their very personal stories with a complete stranger holding a microphone. That's why we love New York. Sound design and music production by Matthew Voll, mixed by Martin Peralta and Bobby Lorde, music written by Martin Peralta and Bobby Lorde. You can always keep in touch on Twitter, we're at Science versus at Science VS or on Facebook.

Yes, we are on the faces. We are also doing our very first live show in Toronto, all the hot dogs podcast festival on November 19th. So go to Toronto, have a visit to Toronto. Sorry, I meant Toronto, you don't pronounce the tea.

Learning, thanks to everyone who helped get our new season of Science VS off the ground. The engineering team at Gimlet, Alex Bloomberg, Caitlin Kenny, Austin Mitchell, and Rose Strassa. A big thanks to Leopold Rogers and the whole Rogers clan, Emily Big Family, Bessori Fam, Joseph LaVell Wilson, and all of the women family, the original Science VS Back Checkers, we couldn't have thought of you without you. People can come up with a bat, they can't live with a tomahawk with a car, with a pointy stick.

Tomahawk with your second one? I'll just have to watch that. No bugs, right. No bugs, right.

I was like, you're going to send me some like, no, I'm a journalist. I'm going to look at the bodies, we need bugs, right? It's like, oh. They fling themselves out of the maggot mask, like a flying ping, and then the alicorn, yeah, there's their pinging out.

The idea that I kind of Hollywood style thrusting into the vagina was going to give you sexual pleasure, and how the thrusting was going to give you more. Hey, Mommy, you didn't even quite have a seat, you're always in for anal, like you've got so many curves, and I don't have any brakes on my car, it's a cute one. What is your name? My name is Heather, what's your name?

Mia. You're becoming more and more convinced that Joe is in love with you. And just in case, can you just tell people they're not in love with Joe? You're not in love with Joe, you don't even know who Joe is.

Just say how his boyfriend's name is Joe. You're in love with Joe. You're in love with Joe. I mean, he's got him in the next time.