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- [00:07]
Blake
Yeah. So I remember distinctly during the pandemic, I was 31 years old, and my mental health at that time, it was really at an all time low. My life was just unraveling.
- [00:18]
Thomas Goetz
This is Blake. He lives in Long Beach, California. And a few years ago, he began to struggle with depression.
- [00:25]
Blake
I was broke. My car. Car broke down. I remember running out of gas one day and I was stuck on the side of the road. And I didn't even have enough money in my checking account to cover it because I had so much debt from, like, getting taken advantage of in crypto and all of that. It was just one thing piling on top of another. And I was just having panic attacks like crazy. I wasn't sleeping for days on end. My girlfriend was terrified. I wasn't in a good place. I was suicidal. I did not want to be in this world. I finally just got to the point where I had nothing to lose. And I just reached out to a doctor who referred me to a psychiatrist. The psychiatrist had me fill out paperwork where I would list my mood per question. So it would be something like, how do you feel about going to work every day? Very satisfied or very dissatisfied? There's a scale. So just various questions like that. And I was noticing as I was filling this out, every question I was asked, I was checking off very dissatisfied for pretty much all of them. And it kind of hit me like a bolt of lightning because I had all these years of untreated trauma and chronic stress. I guess I was essentially trying to drive a car with an empty gas tank. It really just didn't matter how hard I pushed. I just wasn't going anywhere. And he recommended Zoloft.
- [02:01]
Thomas Goetz
I'm Thomas Goetz, and this is Drug Story. Today's Drug Story is about Zoloft, an antidepressant that's also known as Sertraline. Sertraline is the most widely prescribed antidepressant in the United States. About 8 million Americans take it to manage their depression, if they're lucky. Most of those 8 million people have an experience like Blake did. They take a survey, measure the problem, get a prescription.
- [02:29]
Blake
And once I started seeing those changes, it was like someone had turned on the lights in a dim room or something. I went from being weighed down by a constant state of fog and anxiety to waking up with more hope and excitement. Tasks that felt very difficult just became a lot more manageable, and they were even enjoyable. I had more confidence. I started having dreams again, like ambitions and these beliefs that I could actually achieve what I put my mind to instead of just always being pessimistic and thinking of, nah, like, I'm not good enough to do this, I'm not good enough to do that. And just all these negative thoughts that would just consume my head were just starting to slowly dissipate. And so it's been really transformative.
- [03:33]
Thomas Goetz
Depression is the most common mental health issue in the United States and worldwide. It's estimated that one of every five Americans struggles with their mental health. They may try therapy, they may try an app, but many of these people wind up taking medications to help them, most commonly a type of antidepressant called an ssri. You've probably heard of these drugs by their brand names, Prozac, Lexapro, Paxil, and the drug we're talking about in this episode, Zoloft. These drugs are also often prescribed for anxiety. But today we're mostly going to talk about their use to treat depression. SSRI stands for selective serotonin reuptake inhibitor. That describes what the drug does in the brain, but it doesn't exactly explain how the drug actually works, or rather why it works, because it turns out that we don't really know why these drugs work or for a lot of people, why they don't work. Most people have to try two or three or even four different antidepressants before they find one that helps them, which is why the questionnaire that Blake took was so important. Depression is something happening in our brain, but there's no blood test, there's no MRI or CT scan that can detect it, at least not yet. So the best we can do is ask some questions, ask people who are struggling to describe or characterize what they're experiencing. These surveys are the best way we have today to get a peek at what's going on inside, because depression, like a lot of things involved with mental health, is invisible. All these questions and all this trial and error can be a messy and frustrating process. So in this episode of Drug Story, we're going to jump into that mess. We're going to learn why drugs like Zoloft are probably better than nothing, but also by no means a perfect answer. And we're going to explore how we might get better at matching the right treatment for the right person at the right time. That's all coming up on Drug Story. And I should say right up front, if you are feeling depressed or in crisis, there are people ready right now to help you. Just dial 988. That's the 988 lifeline. Counselors are there waiting to talk, ready to help, you can call or text right now.
- [05:59]
Brandon Marshall
9882010 at the peak of my career, I signed one of the biggest deals and I thought that money and things would change my life. But I was so wrong. A couple months later I'm at McLean Hospital and if I had 988, it probably got me to a healthier state faster. So if anyone's out there that's in a crisis that may need help, text, call 988 or if you want to chat 988lifeline.org Brandon Marshall Peace
- [06:33]
Thomas Goetz
Drug Story
- [06:33]
GoodRx Representative
is sponsored by GoodRx.
- [06:36]
Thomas Goetz
Every prescription has a story, and for
- [06:38]
GoodRx Representative
many patients, affordability is a defining chapter. CodRx makes it easier to find lower prices on prescriptions from GLP1s to flu meds, so cost isn't a barrier to care. Trusted by nearly 30 million Americans and over 1 million healthcare professionals each year, GoodRx offers savings at more than 70,000 pharmacies nationwide, helping people start and stay on on the therapies that keep them healthy. To start saving, go to goodrx.com that's goodrx.com GoodRx is not insurance
- [07:14]
Thomas Goetz
welcome back to Drug Story. Each episode has three parts the diagnosis, the prescription, and side effects. This is part one, the diagnosis, where we look at the disease behind the drug and how that condition emerged in modern days. In this episode, we're talking about depression, or what is known today clinically as major depressive disorder, or mdd. Depression goes back as far as humanity itself. It has had many names over the centuries, often known as melancholy, a word that comes from the Greek word for black bile. An excess of black bile secreted by the spleen was long believed to be the cause of depression. Unfortunately, it's a lot more complicated than that. Depression has been described in many ways by many people. Abraham Lincoln probably suffered from depression, as did Winston Churchill and Georgia o'. Keeffe. Even Sigmund Freud likely had depression. He self medicated with cocaine. Maybe the most succinct description comes from an 1802 poem by Samuel Taylor Coleridge. A grief without a pang, void, dark and drear, a drowsy, stifled, unimpassioned grief which finds no natural outlet or relief in word or sigh or tear. The phrase a depression of spirit emerged in the 18th century, and by the mid-19th century, the word depression was being used to describe a state of diminished emotional or mental capacity. In the 20th century, as psychoanalysis and psychiatry emerged, depression began to be recognized as a true psychiatric condition, a disorder. But even as depression was recognized as a distinct problem, it was still very hard to understand what was going on and still very little to be done about it. Like so much of mental illness, depression has also carried a lot of stigma. Sigmund Freud considered depression the result of guilt and. And self loathing. It was, as the cliche goes, all in the head. That myth meant there has been a lot of shame and embarrassment and fear surrounding depression. So much so that for decades, for centuries, many people took pains to hide their struggles from others. In certain societies and in certain times, it could in fact be very dangerous to be depressed with the threat of ostracization or institutionalization or worse. But in the 1930s, more clinical, more medical understanding of mental health started to emerge with the idea that depression and other forms of mental illness, like paranoia or schizophrenia, they could be measured and diagnosed. But there was no blood test, no X ray that could peer inside someone's head and discern what was going on. So the only alternative was to ask. The first effective questionnaire for depression was the Minnesota Multiphasic personality inventory, or MMPI. This was first published in 1943. The test was developed by two scientists at the University of Minnesota, Stark Hathaway and J.C. mcKinley. These were two serious, meticulous researchers. The MMPI was their attempt to systematize various forms of mental illness. They crafted a process to map out personalities and states of mental health. The MMPI wasn't a questionnaire per se. It was a series of 504 statements that someone would answer true or false. The statements were mostly benign. I wake up fresh and rested most mornings. I think I would like the work of a librarian. There seems to be a lump in my throat much of the time. My table manners are not quite as good at home as when I am out in company. But some of the statements hinted at something darker. I brood a great deal often. I can't understand why I have been so cross and grouchy. I cry easily. I believe I am being plotted against. Hathaway and McKinley gave the test to hundreds of visitors at the University of Minnesota Hospital where they both worked. They called these the Minnesota Normals. Everyday Minnesotans, often farmers or laborers of Scandinavian or German heritage, almost all white. Their answers would create a yardstick for what was considered normal or healthy. They also gave the test to patients at the hospital with known mental health. Paranoia, depression, hysteria. Yes, in those days, there was something called hysteria. It's been debunked NOW. Hathaway and McKinley matched the way these patients answered the MMPI questions with their diagnosis, so that these test takers created patterns that mapped to certain personality types and mental states. The test was fairly routine, but it took a long time to answer all 504 questions, at least an hour or two. In the end, all those questions created a lot of data that seemed to open the door to what was going on inside. The magic of the MMPI was not in any one of those true false statements, but in their combination and how. Different answers revealed different personality types, different scores could reveal not only a condition, but also its severity. Very quickly, the MMPI became the most widely used tool for diagnosing mental health and including depression. The U.S. army soon adopted it as a way to screen draftees by personality and aptitude. The Catholic church gave it to new seminarians to make sure they were fit for the priesthood. Airlines gave it to pilot applicants. Police and fire departments asked recruits to take the test. And psychiatrists and psychologists used the MMPI as a standard part of patient intake. Within a few years, it was translated into Spanish, French, Canadian, French, Chinese, and Japanese. The MMPI has been revised several times, but it is still used today. Now that depression could be measured, it could also be diagnosed. And it turned out that a good many people were depressed. In 1950, somewhere about 5% of Americans qualified as having depression. That number would grow over time. The condition became better understood and more people seemed to feel depressed, perhaps in part as a result of this modern life. Today, depression is often called a disease of civilization or a disease of modernity. It's one of a handful of conditions like anxiety or obesity or type 2 diabetes that modern life just seems to make worse. Lack of sleep, poor eating habits, social isolation, lack of exercise, lack of purpose. Each of these have been associated with higher rates of depression. And each of these problems has become widespread in modern America and have all increased in recent decades. Indeed, a review of MMPI results from the development of the test in 1938-2007 showed a six fold increase in people scoring as depressed. But even if the MMPI made it easier to see depression, there was still the matter of how to treat it. In those early days of the 1940s and 50s, there just wasn't a lot that medicine could do for people with depression.
- [14:56]
1954 National Association for Mental Health Radio Drama Narrator
You have a broken leg, you go to a hospital to have it set, you have a bad stomach ache, your doctor treats it for you. You have an infection again, your doctor treats you with antibiotics. But what do you do when you have a mental breakdown or you're on the verge of a mental breakdown? Hold on now. Wait a minute. How many people have mental breakdowns? One person in every four families is a possibility for a mental breakdown. How many people you figure in a family? Four people. You mean one person in every 16? That's right. One person in every 16. Everywhere in the United States, on every street, in every town.
- [15:32]
Thomas Goetz
Aw, nah.
- [15:33]
1954 National Association for Mental Health Radio Drama Narrator
Who you kidding? No one. But you're kidding yourself if you think mental sickness happens only to fictional characters in books and in the movies. You're kidding yourself if you think mental sickness happens only to big names you read about in your newspapers. You mean it can happen to anybody? Anybody you live with, the very people you live with in your own community, on your own street, even in your own home.
- [15:55]
Thomas Goetz
That's from a 1954 radio drama from the national association for Mental Health. So what was there to treat depression then? Well, not much actually. There was therapy, mostly psychotherapy. There was also electroconvulsive therapy or electric shock therapy. That was made famous in One Flew over the Cuckoo's Nest. Despite the gruesome image of it, electric shock therapy did work for many people. It's still used today. Sometimes. Some people were prescribed tranquilizers like benzodiazepines. Others were prescribed amphetamines. Both kinds of drugs carried significant risks for side effects, not least of them addiction and the risk of overdose. It wasn't until 1960 when one of the first drugs to call itself an antidepressant emerged. Phenelzine, which was sold under the brand name Nardyl. Unlike amphetamines, which might create a burst of euphoria but didn't change the underlying depression fence, Bennelzine did change brain chemistry and it appeared to actually alleviate depression. But the drug caused a lot of side effects, including suicidal thoughts in some patients. It was especially risky to use with certain common foods. So drug companies continued to scour for other solutions. In the 1960s, a new theory emerged that depression was related to low amounts of the neurotransmitter serotonin in the brain. Serotonin is a chemical that occurs naturally. It's associated with learning, sleep, appetite, and also feelings of well being and happiness. It turned out that people who had committed suicide often had low rates of serotonin in their brains. This and other experiments led to what was called the serotonin hypothesis, that when the brain didn't produce enough serotonin, the result was depression. That theory led scientists at Eli Lilly and other pharmaceutical companies to to try to find a compound that increased the amount of serotonin in the brain. They started with of all things, Benadryl. That common antihistamine, Benadryl was known to have some antidepressant properties, but it also caused drowsiness and other side effects. So the researchers began to see if they could tease out compounds that increased serotonin in the brain without those side effects. Again, that's what SSRI stands for, Serotonin Specific Reuptake Inhibitor. The drug inhibits serotonin from being absorbed. That's uptake. The theory goes, there is more serotonin floating around in the brain, and that makes us feel better. Eventually, the Lilly scientists narrowed in on a chemical called fluoxetine and they began human experiments. The drug didn't help everyone, but it did seem to work much better than other drugs out there, and the side effects were much less. The development of fluoxetine took a long time, mostly because it was a totally different kind of drug. And it wasn't clear how it worked. So the FDA required Lilly to do a lot of clinical trials, including three studies that compared fluoxetine against a placebo to be sure it was better than nothing. In 1987, after 16 years, luoxetine was approved by the FDA. And soon everyone would be talking about it using the brand name that Eli Lilly chose for the drug, Prozac. It's hard to overstate how big a deal Prozac was at the time when it was first approved, Prozac was intended for severe depression, which was considered to be a fairly rare condition. But soon, the idea of who the drug could help began to change. Many people not classified as severely depressed were still struggling. Maybe Prozac could help them. It probably couldn't hurt. And it was also easy to prescribe Prozac, since any MD, not just psychiatrists, could write the prescription. Within five years of approval, 5 million Americans were taking Prozac. It was the biggest psychiatric drug in history. It was a cultural phenomenon, with COVID stories in Newsweek and New York magazine and best selling books like Listening to Prozac and Prozac Nation. But there was still a stigma around the drug and around mental illness in general. So in 1988, just a year after Prozac hit the market, the National Institute of Mental Health began a new campaign aimed to educate more people that they might have depression and that there was something they could do about it.
- [20:26]
Interviewer
With us to tell us more about depression is Dr. Frederick Goodwin, scientific director of the National Institute of mental health. Dr. Goodwin, what are you hoping to achieve as a result of this campaign?
- [20:40]
Dr. Frederick Goodwin
Well, we have found that there are a large number of the 10 million patients who have been diagnosed with our surveys who have not sought treatment within even the last year. That is to say, over over half of the patients who suffer from depression, which was so nicely described on your piece, don't seek treatment. And we found in looking into why this is, that they have attitudes that really do describe a sense that it's something they should be able to take care of themselves. It's a weakness of character. We also found that people in the public in general are much more willing to take medication for a headache or a backache than they are indeed for something much more serious than depression.
- [21:18]
Interviewer
And so this campaign is aimed at changing societal attitudes as well as the attitudes of people who may be suffering from depression.
- [21:28]
Dr. Frederick Goodwin
Yes. And it requires across the board that as we have to change attitudes of the public, we also have to change attitudes of various health care providers.
- [21:37]
Thomas Goetz
That campaign worked, as did other efforts to change the perception of depression. It also helped that science developed many easier ways to measure depression. Surveys that are just as valid, but a lot faster than taking that entire 500 question MMPI survey. There's the Hamd survey, which was first developed in the 1960s and revised many times since. It has about 20 questions takes about 20 minutes. In the 1990s, the pharmaceutical company Pfizer developed the PHQ9 survey, which is just nine questions. There's even a two question test, the PHQ2, that does a pretty good job measuring depression. The PHQ2 asks just two things. Over the last two weeks, how often have you been bothered by any of the following problems? One, little interest or pleasure in doing things, and two, feeling down, depressed or hopeless. That first question measures something called anhedonia, which is defined as the inability to experience pleasure or joy. All of these things made it a lot easier to tell if something was wrong. And the new drug made it easier to do something about it. In the ten years after Prozac came on the market, the number of Americans being treated for depression tripled. That's not because there were three times as many depressed people. It's probably more that people came out of the shadows and ask for help. And then, as often happens after a big breakthrough drug appears, more SSRIs were approved by the FDA and were available for a prescription. There was Citalopram, known as Celexa, and Sertraline, known as Zoloft. The SSRI revolution was a whole new paradigm for treating depression. In 1998, more than 100 million prescriptions were written for antidepressants in the United States. And most of those were written not by psychiatrists, but by general practitioners, primary care doctors. But it turns out there was a lot about these drugs that science didn't know or was even wrong about. In fact, almost everything people thought about how SSRIs worked, well, it was just wrong. Even today, we still don't know how these drugs work or who they will work for. We'll explain all that after the break. But first, here's a commercial that ran for Zoloft in 2001. To be clear, this is not a paid advertisement on Drugstore. It's an old commercial that helps us tell this story. Here it is.
- [24:12]
Zoloft Commercial Narrator
You know, when you feel the weight of sadness, you may feel exhausted, hopeless and anxious. Whatever you do, you feel lonely and don't enjoy the things you once loved. Things just don't feel like they used to. These are some symptoms of depression, a serious medical condition affecting over 20 million Americans. While the cause is unknown, depression may be related to an imbalance of natural chemicals between nerve cells in the brain. Prescription Zoloft works to correct this imbalance. You just shouldn't have to feel this way anymore. Only your doctor can diagnose depression. Zoloft is not for everyone. People taking maois or Pemazide shouldn't take Zoloft. Side effects may include dry mouth, insomnia, sexual side effects, diarrhea, nausea and sleepiness. Zoloft is not habit forming. Talk to your doctor about Zoloft, the number one prescribed brand of its kind, Zoloft. When you know more about what's wrong, you can help make it right.
- [25:14]
Thomas Goetz
Welcome back. This is Part two, the Prescription, where we talk about the development of the drug, in this case, Zoloft or Sertraline. So that commercial for Zoloft that you just heard, when it first ran back in 2001, it was considered a breakthrough ad. What you couldn't see was the images because you're listening, not watching. So I'll describe it to you. Unlike many drug ads, there aren't any people in the ad. They're just these animated blobs, but blobs with faces that kind of look depressed. Until, of course, they take the Zoloft and then they kind of bounce up and they are now happy blobs. The reason this ad was such a big deal was that for many people watching it, it was the first time their experience with depression had been captured and expressed so well. The ad offered a simple explanation for depression, that it is a chemical imbalance in our brains that changed how people thought about depression. Maybe it wasn't all in our heads. Maybe it actually was a chemical problem, a biological problem, a medical problem, not just a mental problem. It was real. And Zoloft, and by extension, other SSRIs. These drugs changed our brain chemistry and fixed the balance. This ad put that idea into words and images in a way that really hadn't been expressed previously. It gave people a blameless explanation. And it validated an experience that many people had but had a hard time expressing for themselves. It made depression not someone's fault or failure or weakness, and more of a disease that could be treated. But. And this is a big but, but it seems that it isn't factor that simple. The serotonin hypothesis, this idea that there's a chemical imbalance and our brains just need to boost serotonin levels, that turns out to be somewhat misguided. For one thing, sometimes people with normal levels of serotonin in their brain are depressed, sometimes severely depressed, and the opposite, too. Sometimes people with lower levels of serotonin show no signs of depression. For another thing, SSRIs don't even work that way. Yes, they boost serotonin levels in the brain. That is measurable. And it happens pretty much right away when you start an SSRI like Prozac or Zoloft. But that doesn't mean you get better right away. In fact, people taking these drugs don't feel the positive effects for several weeks, sometimes even a month or two. So it's not just a matter of fixing the balance. Instead, what researchers think is going on, and this is just another hypothesis, is that various regions of the brain aren't connecting as they should, and that serotonin can help repair those pathways and connections. That's a very simple explanation, but it basically means it's more complicated than we thought. But even if we don't know why the drug works well, at least it works right? Well, that's true, but only for some people. Here's the thing. Most people expect a lot out of medicine. We go to the doctor, we get a prescription, and we think that drug is the answer. It's going to solve our problems, it'll cure our ills. But that doesn't always happen. In fact, there's a lot of variability in how people respond to different drugs. For many people, a prescribed drug just won't have the intended effect in our body that it may have had in those clinical trials. That's the difference between efficacy and effectiveness.
- [28:59]
Dr. Aaron Carroll
I think people imagine that all you need to understand to, like, take care of people Is, does the drug work or not? Does the procedure work or not? Write a prescription? Everything is solved. But there are huge differences between what we might call efficacy and, like, how something works in a trial or in perfect conditions and effectiveness, which is how well does it work in the real world.
- [29:23]
Thomas Goetz
This is Dr. Aaron Carroll, a physician and health researcher. Today, Dr. Carol is CEO of Academy Health, a health research organization that tries to measure what happens in the real world of medicine.
- [29:36]
Dr. Aaron Carroll
It may be that we have a drug, but if you can't get in to see the doctor, it's not going to work for you. If you. If you can't drive to the pharmacy, it's not gonna work for you. If you can't manage your life in such a way that you can take it on time and regularly, it's not going to work for you. If it costs too much, it's not gonna. I mean, all of these things come into play and are probably as important, if not more important than so much of the things that we consider healthcare, but they don't get talked about all the time and they don't get studied.
- [30:07]
Thomas Goetz
Dr. Carol is really good at explaining complicated things in medicine. And what we know and don't know about depression and antidepressants is very complicated, which to me makes it fascinating. Again, what's going on in there? One of the reasons I wanted to talk with Dr. Carol was because a few years ago in 2018, he wrote a column in the New York Times about the fuzzy evidence around SSRIs like Sertraline, and how there were concerns around whether they really did work better than a placebo. Did an SSRI help people more than a sugar pill, a fake pill? The evidence is, well, unclear. It's complicated. And then he wrote about them again More recently in 2023, when he shared his own personal experience again in the New York Times.
- [30:54]
Dr. Aaron Carroll
This is one of those very strange situations where even I think what I wrote in 2018, in my personal experience, have been very different. So if you captured Aaron in 2018 and brought him back, I think I would have said, like, look, there really is not a lot of great evidence that say that SSRIs work and work incredibly well for the vast majority of people. The studies where they do work, it's usually in people with pretty severe depression, but at least moderate to severe depression. And it's really short term in the sense that the studies last a couple months, and that's where we see benefit. But there are so many people in the United States, let alone the world, that Use these chronically and for mild to moderate depression. For that, we don't really have a lot of great evidence. And I would have said, yeah, I think there's probably way too many people on these drugs, given the evidence that does exist. But if you fast forward to Aaron of today, I had during the pandemic a pretty bad panic attack and actually passed out and fell down a mountain and needed to be airlifted to a hospital. And that was finally when my doctor, who's also a friend, was like, maybe you want to try, you know, an ssri. And I finally gave in and I have found enormous benefit.
- [32:12]
Thomas Goetz
Dr. Carroll knows he is lucky. He tried Sertraline and it pretty much worked. He feels better. He struggles less. For a lot of people, though, taking that first antidepressant is just one step on a long road of trial and error. Back in 2008, the results of a huge study by the National Institute of Mental Health were released. The study was called STAR D. And I'm not even going to tell you what that stands for. Okay, actually, I will. Sequenced treatment alternatives to relieve depression. The STAR D trial was an attempt to grapple with this annoying fact about antidepressants like Zoloft. They didn't work as well in the real world as they did in clinical trials. So the STARD experiment tried to imitate the real world, the trial and error of finding a drug that actually works for someone. Here's how it they recruited 3,000 people with clinical depression. They were not taking a drug. Then they randomly started different groups of patients on different antidepressants. After 12 weeks, if someone wasn't responding to the drug, they weren't feeling better. They switched them to a different drug, again randomly. If that one didn't work after 12 weeks, they tried another. And if that didn't work, they tried one last drug, four tries at most. The good news was that by the end of the study, about 70% of patients had found something that worked for them. But only half had found that drug on the first or even second try. Many needed to try three or even four drugs before they found the one that worked. And no drug really worked better than any other. There was no clear winner. Each drug worked best for different people. The stardee study changed how people think about depression and how doctors might treat. Wasn't a perfect study. There may be some placebo effect at work here. People knew they were taking a drug after all. Just the idea that they were getting treatment. Well, that may have made some people feel better. But the study showed that for many people, at least half the trial and error is just going to be part of the process. And since this is depression, we're talking about that struggle, that frustration can make it even harder to deal with the depression. But the study also showed that for people who stuck it out and kept trying to, most of them would find something that worked. By 2000, antidepressants were the best selling category of drugs of any sort in the United States. Fully 10% of the U.S. population was using an antidepressant. Today, a staggering 29% of Americans have used an antidepressant at some point. That's more than one in four people. And Sertraline, Zoloft, that's the most prescribed antidepressant of all. Even though there's still not a lot of clarity about what to try first, Dr. Carol explains.
- [35:08]
Dr. Aaron Carroll
When there are many, many options, who knows? It's really dependent on what your doctor was trained, what they're thinking, perhaps what you're thinking, what insurance will cover. And so it's not thoughtful in the sense of like, let's figure out the best thing for this person. It's a mixture of external constraints put on you by the healthcare system and personal preference, usually of the person prescribing it, that just basically rolling dice.
- [35:36]
Thomas Goetz
Coming up, we look at how we could get better about knowing what works for whom. And we dig into the brave new world of treating depression. But first, here's another commercial from the vaults. This one a 2009 ad for a drug that's not an SSRI. It's called Abilify. I'm taking an antidepressant, but it feels
- [35:57]
Interviewer
like I need some more help.
- [35:59]
Abilify Commercial Narrator
Approximately two out of three people being treated for depression still have unresolved symptoms. If your antidepressant alone isn't enough, talk to your doctor. One option he may consider is adding Abilify. Abilify is approved to treat depression in adults when added to an antidepressant. Learn more about Abilify. Call your doctor if your depression worsens.
- [36:22]
Thomas Goetz
Welcome back to Drug Story. This is part three. Side effects. So we've learned how depression is Everywhere and how SSRIs can be life changers for some and a struggle for others. And we've learned that the experiments that convinced the FDA to approve SSRIs in the 1980s and 1990s randomized clinical trials. But they didn't reflect real life circumstances where things can get a lot more messy sometimes. As that ad for abilify makes clear, SSRIs didn't work as they were supposed to. But here we are. Today, many, many people are taking antidepressants. More than 13% of American adults, nearly 20% of adult women are taking an antidepressant. That's according to a survey from the cdc, the Centers for Disease Control and Prevention. That is a lot of people. More than 33 million Americans, in fact. Which raises a what are the side effects, the consequences of diagnosing so many people with depression and then giving them drugs that kinda sorta work for some people, but not everyone. Can't medicine figure out how to make this less messy? Let's say first that surely one positive consequence has been to reduce the stigma around depression. Today, depression is broadly recognized as a condition that people should seek help for and that can be treated. That's without a doubt a good thing. For people struggling with depression, there is hope and there are ways to get better. But what are the best ways to get better? What works best and for whom? After all, here we are almost 40 years since Prozac first came out and many tens of millions of people, hundreds of millions surely have taken SSRIs. And millions more have taken other drugs like Abilify, the drug we just heard a commercial for which is one of those so called atypical antidepressants. For some people, other drugs work better, better than SSRIs. Why can't we learn from all this experience? Well, for a few reasons, it turns out. First, the data isn't really captured. Your medical records just aren't good enough as a source of evidence. And your doctor may make notes in a very different way than mine. So it's pretty much impossible to use those records as a data set to compare treatments and outcomes. And nobody else is tracking what's happening with people who are in the real world, let alone comparing the results against each other in a statistically valid way. That is called comparative effectiveness research. And, well, let's, let's just have Dr. Aaron Carroll explain this.
- [39:10]
Dr. Aaron Carroll
What we really would want in an ideal world is putting all these things up against each other and seeing which works best, or trying to figure out, like, which works best for which people. That is, again, expensive. And there's no industry that's going to do that. I mean, if I make a drug, I'm a drug company, I want to pay for all the research that's going to prove my drug works once it gets approved. However, I have no interest in trying to do research that shows something's better. So we have to rely on public funding to do that comparative effectiveness research and very, very little of that public funding is directed towards that because once things are approved, we usually wash our hands and we're out. But that's what we need in the real world to be like, which one would work best for me? We don't know. Or which of these works best, period. We don't know because we don't really do a lot of head to head to head trials.
- [39:57]
Thomas Goetz
In an ideal world, this research would include all the many ways to treat depression, including SSRIs, but also all the other medications. Some of these drugs are well known. Cymbalta, Fexor. There's also Wellbutrin, Trazodone, Trintillex. There are also drugs like ketamine. So lots and lots of drugs to try. There are also many non drug treatments. There's transcranial magnetic stimulation, where someone wears a cap that sends electromagnetic pulses into the brain. It works really well for some people, especially people for whom drugs don't work. And there's always therapy, of course, which can be highly effective, especially a kind of therapy called cognitive behavioral therapy. And then there's just good old fashioned exercise.
- [40:43]
Dr. Aaron Carroll
There's like almost nothing in the world as good as exercise. I mean, it's a wonder drug.
- [40:49]
Thomas Goetz
Somewhat surprisingly, it has been shown to be hugely beneficial for depression.
- [40:53]
Dr. Aaron Carroll
It does so many positive things and other than the time constraint, there's almost no harm. I have no problem recommending exercise to everyone who can possibly do it. You may get a benefit with mental health and if you do, that's Grady. But if you don't get a benefit, you're gonna still get a huge number of other benef benefits which have been proven again and again. So exercise, do it. The other things you mentioned, however, there are some real harms. I mean, ketamine is a big drug. That's not a try it. It's, you know, let's see what happens. It needs to be very tightly managed and watched and you can overdose. And so I would not start with that necessarily. I would also not start with a lot of other drugs which have potential harms and have not been studied in terms of benefits. Because what we don't want to do is give someone a preponderance of harm. And when we know that there are harms and benefits are not known, there's a very high likelihood of doing bad. And so that's when you really want to study because it's like you want to make sure in the studies that the benefits outweigh the harms.
- [41:59]
Thomas Goetz
The standard Operating procedure still boils down to a lot of trial and error. Try something, see if it works, try something else until hopefully people start feeling better. I should add that there's also a lot of enthusiasm these days that artificial intelligence can help speed up the process. Maybe AI could be better than doctors, even psychiatrists, at matching a patient's symptoms and concerns and needs with a therapy that is more likely to work. There are a lot of companies exploring this. Here's hoping that they do find a process that helps people get help faster. If this is all, well, sort of unsatisfying. That's just the reality of science and medical science in particular. Medicine is a method of working our way towards an effective solution. It takes a long time, it is
- [42:50]
Dr. Aaron Carroll
a slow crawl, and I think everyone wants to find the magic tweet or TikTok, which solves everything. And it's like, that's never going to happen. It's going to be a slog. Getting to truth is just like a slow. We take wrong turns and we got to come back. Every time I heard someone say, like, follow the science, a little part of me died. Because the idea that science is this very clear arrow that everyone can look at and see the same thing is like, that is not how science works at all.
- [43:19]
Thomas Goetz
Yeah, well, how does science work?
- [43:22]
Dr. Aaron Carroll
I think we keep trying to ask questions and then answer them, and each one should adjust the arrow a little bit. But lots of different things push the arrow in different directions. And it, it depends also, like, what the question is you're asking, which is not the same for everyone. And so it's gray. There's a lot of gray. And more often than not, we could say, look, there are a variety of options. They have trade offs.
- [43:48]
Thomas Goetz
That's hard to hear in these days of instant gratification, but it's true. We expect a lot out of medicine. We want fixes and solutions and cures. But few things are ever that simple, that effective. What we do have, well, most of the drugs at the pharmacy can help. They're often better than nothing, but they're never a sure thing. Sorry if that's disappointing, but it's true. That's real life. It's messy. That's it for today's drug story. For an annotated list of our sources for this episode, visit Drugstore co Drug story was created, written and hosted by me, Thomas Goetz. Molly Warner is our research director. From reasonable Volume. Rachel Swaby produced and sound designed this episode with assistance from Audrey Ngo. Elise Hu was the editor. Mark Bush is Our engineer Drug Story was produced with support from the University of California, Berkeley School of Public Health. Special thanks to Claudia Williams and Michael Liu. Thanks also to Dr. Aaron Carroll at Academy Health and Blake Matthew who has a great YouTube channel. Channel is called It's Blake Matthew. Drug Story is an independent production. If you'd like to support our work, contact us at Drugstore Co. You can also subscribe to our substack there and be notified when new episodes come out. And if you liked this episode, help us spread the word. Rate us on Apple or Spotify. There are so, so many drug stories to tell. Moxifloxacin, pancuronium, xylometazylene. Come on, you want to hear about these things. Next up on Drug Story, a look at the phenomenal rise of testosterone replacement therapy with millions of men proudly taking hormones. Is TRT the cure to low T and all else that ails the American male? We shall see. Thank you for listening. Listening to this episode of Drug Story may increase your desire to take a 500 question question survey caused wistful nostalgia about the 1990s and deepen your appreciation for medical research organizations like Academy Health. We advise you to get lots of exercise, step out of the house more often and get a dog.