(Mis)Diagnosis: Bipolar Disorder
48:41 Share

This message comes from NPR sponsor Rosetta Stone, an expert in language learning for 30 years. Right now, NPR listeners can get Rosetta Stone's lifetime membership to 25 different languages for 50% off. Learn more at rosettastone.com slash NPR. This is The Pulse, stories about the people and places at the heart of health and science. I'm Maiken Scott.

On the surface, Abigail Kafka's life seems pretty nice and fairly ordinary. I'm 45 years old and I live on the outskirts of Berlin with my husband, our books and a bunch of houseplants. Abigail is a writer. During the week, I usually load my laptop onto my bike and ride along the river to work. After work, I go to the gym. Then I ride home and cook dinner. We watch I Love Lucy,

Oh boy, does this look good. Mmm, it is good. Sundays, we often go for a walk in the woods and make tacos. But there's a very different life Abigail used to lead, a backstory that she's kept hidden away. I used to avoid talking about my past. As far as I was concerned, my life started in 2014, just like my LinkedIn profile.

But the backstory resurfaced when Abigail started therapy during the pandemic. She opened up to her therapist about her past and about the things she'd been through. When I finished, she paused. She put her pen to her lips. Then she said, that's not normal. It's not what anyone expects to hear from a therapist. So it caught me by surprise. It's not? I asked her. She looked at me and said, no.

And that journey back made her question a diagnosis that she had gotten decades earlier, which had completely upended her life. Bipolar disorder.

It's estimated that between 5 and 10 million Americans have bipolar disorder. But how much do we really know about this common and life-altering mental health condition? On this episode, diagnosing mental illness and what happens when mental health experts get it wrong. Later on, we'll hear about a test that's long been used to evaluate the effectiveness of antidepressants, but this test has come under criticism.

To get started, let's hear more from Abigail Kafka and her quest to investigate a big part of her past. I wanted to check in with someone who was around when I was 19 and a student at Columbia University. So I called up my friend Robert. He's known me my entire life. Okay, now I'm recording.

We were hanging out together in New York in 1999. I remember that you were young and smart and ambitious and adventurous. Freshman year was rough. I was lonely. I got mono. So I took a leave of absence. I tried going back to school in the spring, but things only got worse. I was taking classes and working as a waitress. I was a terrible waitress.

Then I had a bad breakup with someone I was seeing. And one afternoon in my dorm room, I hurt myself. It was spontaneous, but on purpose. And it wasn't potentially fatal, but it was serious enough that I got scared and called Robert.

And I remember saying, you can't be screwing around. I must have hung up because I had to call 911. Robert met me in the emergency room. And after a couple of hours, I was discharged into his care. It felt like it was going to be okay. It didn't feel dangerous. Two or three days later, my parents flew me home to San Diego to see a psychiatrist. He wrote me a prescription for Celexa, a common antidepressant.

Once I was back at school, I had some bad side effects from the medication, which really freaked me out. I reported this to the psychologist at my university, and he told me to go to New York Hospital. Just to get stabilized, he said. When I arrived there, I was locked in a yellow padded room. I was terrified and angry. But when I protested, they injected me with an antipsychotic. I woke up in a hospital bed. It was totally surreal.

Later on, I was transferred to a ward on the ninth floor in a wheelchair. Robert came to visit me there. I remember like just these lights with a green tint, like on a different planet. I remember worrying, not really understanding the depth of your condition. I ended up staying there for about two weeks. Then my dad checked me out of the hospital and took me back home.

I was so zonked out on medications that I wasn't fully aware of what was happening. In the span of three or four weeks, I had been locked in an institution, kicked out of school, and completely uprooted from my life as an independent adult. All of these decisions were being made for me. I wasn't even really aware that they were being made. My dad sent me to a new psychiatrist, who gave me a new label. Bipolar.

Bipolar, he said, is the reason I acted out. It explained everything. Suddenly, I was a patient with a serious mental illness. And this is what I would be for the next 15 years of my life. This story isn't about those 15 years. They were both horrifying and boring. I saw many, many doctors. I was on more psychiatric medications than I could count.

I remember I was dating someone at the time. They thought it was so cute that whenever I saw them, I was trembling with emotion. I never told them it was the lithium.

But more than the side effects like tremors and weight gain, I was constantly getting fired from jobs for reasons I didn't understand. We just think you're overqualified for this position. Unfortunately, we don't have any room for you on this schedule. In this economy, we need someone who puts everything into this business. We have decided to let you go. I would make friends and we would start hanging out, going to the beach, trading clothes, and then it would all suddenly stop with no explanation.

For years, I couldn't go to the grocery store or out to eat. I spent endless days, weeks, months alone, unable to leave my one-room apartment, sometimes smoking and watching reality TV on my laptop, sometimes just listening to the ceiling fan whir and click above me. Eventually, I was designated disabled by the state of California.

I felt like everyone understood something about how to live in the world that I just couldn't grasp.

But there was one doctor during that whole 15-year stretch who helped me see a way out of my life as a patient. My name is Jeremy Flegel. I am a psychiatrist currently living in Bend, Oregon. I used to live in San Diego where you and I met. I started seeing Dr. Flegel in 2007, about eight years into my treatment for bipolar disorder. My life was a mess, but a quiet mess.

I hadn't had any kind of crisis or episode for years at that point. I asked him what he remembers about meeting me. I have a very good picture of, you know, the office, of the room, where you were sitting. I remember you chose the chair sort of in the corner. I wondered what he thought about the bipolar diagnosis I'd come in with. I remember...

Having this thought when this diagnosis was made by these people who I think were good and been doing their job for a really long time, that, hey, this must be what it is. He also remembered that I came to him on a bunch of medications that I wasn't sure I wanted to take. Like the entire umbrella of our conversation was, how do I live my life as I want to live it without pharmaceuticals? And both of us

trying to figure out if we're brave enough to do that together. And here's the thing. Eventually, I was. It took me seven years. But in April 2014, I took my last pill. Can I ask what it's like remembering that? I feel that that's probably the most myself I was since I got the diagnosis. Makes me really happy to hear that, by the way. Thank you.

Thank you. And this is the part my therapist in Berlin said is not normal. I haven't been on medication for over 10 years. In 10 years, I haven't had any mental health crises. My therapist said people with bipolar disorder don't just get off their medications and live a normal life. So as I was hearing this, I was thinking, wait, what? What does that mean?

Do I have some sort of superpower? Or did I waste 15 years of my life for nothing? It was so jarring that I couldn't even grasp the other possibility, probably the obvious one, that maybe those doctors my dad sent me to were wrong, that maybe I didn't have bipolar disorder. I couldn't sort this all out during the therapy session. But afterward, I started thinking about it, wondering, why was I diagnosed as bipolar?

What made my doctor so sure about that? And how much of those harrowing 15 years of treatment boiled down to that one label? I wanted answers. And since I'm a writer, I decided to go about this the best way I can, by writing about it, and maybe rewriting my own history. I reached out to Justin Cramon, a reporter and producer, to help me investigate and tell this story. So the first thing I did was to contact a doctor named Mark Rago.

He teaches psychiatry at Yale Medical School and was a practicing psychiatrist for 25 years. We found an article where he argues that over-diagnosis of bipolar is a big issue in the U.S. Justin and I asked if he'd answer some questions about my bipolar diagnosis. I started by telling him my history about the crisis I'd had in college and the bad reaction to the medication. So none of that says you're bipolar, right?

I told him about getting off all the medications. Have you been medication-free and living your life since then? I've been medication-free since 2014. If you are bipolar and you go off your medicine, you are going to relapse within months. I was amazed by how absolutely he made this statement. But there was more. When I was in practice, I just had a stream of people coming to me saying,

diagnosed with bipolar disorder with no evidence to support it. He explained, "Bipolar disorder is characterized by an alternating pattern of depression and mania. Mania is the key component. Not sleeping for days, having racing thoughts, being highly active. People feel on top of the world. But it gets dangerous. The elevated moods make you do irrational and destructive things.

They're not living normal lives. Over the past 30 years, medical professionals have more than doubled their billed visits for patients diagnosed with bipolar disorder. Mark cited studies showing a 40-fold increase in kids diagnosed with bipolar disorder around the year 2000.

Abigail was diagnosed in 1999. When you see bipolar disorder checked on a patient history form, what percentage chance are you thinking this is correct? Less than 10%. Wow. Mark says the reasons for the increase in bipolar diagnoses are complex. But the gist is that in the late 90s, there was both a trendiness and vagueness to the bipolar diagnosis. Like,

It seemed to fit a lot of patients who'd been difficult to treat. And these new drugs, known as second-generation antipsychotics, were just hitting the market. They were billed as safe and effective treatments for bipolar disorder, along with a host of other psychiatric problems. It follows you wherever you go. It's a cloud of depression. And although you've been on an antidepressant for at least six weeks, you're frustrated that your depressive symptoms are still with you.

And so bipolar, some argue, became a kind of go-to diagnosis for anyone who is depressed but hard to treat, like a kid who acted out at school or someone going through a bad breakup. Once you have a diagnosis, it biases everyone who sees it. I've seen people, you know, they get dragged into the system.

Their life becomes being a patient, and they never quite get better because they're not receiving the proper treatment. After talking to Mark, I spent a lot of hours interviewing experts on this issue at some of the most influential bipolar research centers in the U.S. And the story gets more complicated and contentious from here. Not all the doctors I spoke to agree with Mark's analysis.

And we'll get to that. But talking to Mark Rago did finally confirm to me that I was misdiagnosed with bipolar disorder, that the doctors were wrong, and their mistake caused me a lot of damage. It wasted a lot of my life, my 20s and half my 30s. I felt hurt and angry at my parents, especially my dad, who sent me to those doctors. I had always trusted him to help me get the best care available. We've never talked about it before.

I need him to hear my take on all of this. I'm getting ready for the interview with my dad tonight, and I'm nervous. I think my dad just really wants to be so supportive and helpful, but I think it might get intense. I don't know. I don't know what to expect. My name is John Kafka. I am 74 years old. My dad is actually also a doctor, a pediatrician, so he has some background in psychiatric diagnoses.

But I wasn't sure how much he remembered about my own history and diagnosis. So I decided to start at the beginning. What was I like when I was younger? Spirited, smart. You always stood up for yourself. You just didn't seem like a fearful or anxious kid. Do you have any memories of me struggling with my mental health before I went away to college? No. I mean, it might have been there and I might have just overlooked it.

So what was it like for you when you got the news that I was in an emergency room? I probably at first was a little bit in denial about how serious the situation was. I was worried and terrified, and I felt like a failure as a parent. I want to talk a little bit about the doctors you took me to in San Diego. What was your sense of the treatment that I was getting at that time? You know, looking back on it, it was probably not as good as it should have been.

But I was sending you to the same group of doctors that I had been sending my patients to for years, that I was obligated by insurance to send my patients to. And it would have been hard for me to acknowledge that you weren't getting the best care. Neither one of us remembered any manic episodes. But my dad also noticed that I wasn't getting better.

Still, I kept seeing the same doctors and trying the same kinds of medications. And this is really what I was holding against him. He didn't ask enough questions at the time. It's just that what I've kind of come to realize is that I am not and never was bipolar. And I wasn't able to get treatment for the issues that I was really struggling with. And it took years of my life.

And I'm really sad and pissed about it. I mean, that's terrible. But, you know, I'm not going to defend my choice. You know, we can't use a 2024 perspective to look at something two decades ago. So if I screwed up, I'm sorry. But looking back on it, I think I was in good faith taking you to experienced and well-trained psychiatrists.

Some of these other experts have told me that they think my case was particularly bad in terms of the length of time that I spent unnecessarily medicated. Well, I guess to the extent that my actions resulted in that, I would certainly be regretful about that as well. I was doing my best. There really wasn't much more to say after that, so we moved on to a happier time. In 2015, about a year after I had gotten off the medications...

my dad and I went out for dinner to our favorite wood-fired pizza place, where we sat on the patio and shared a bottle of wine. My dad told me he was relieved that he doesn't have to worry about me anymore. Do you remember that evening and that conversation? Yes. How did I look? You looked like my daughter. I decided to end the conversation there, at the one place where we could agree. But later that night, after the interview with my dad, in bed with my husband, Philip,

I wondered if I should have said more. I keep thinking of things I wish I had asked and said to my dad. What is it you wish you had asked? Like, I wish I had pointed out that the initial idea to send me back to New York alone with a bottle of SSRIs was idiotic.

And I wish I had sort of prodded him a little more when he made this declaration that he was sending me to the same doctors that he sent his own patients. So I think you can still ask him that another time. I think you did a good job, so I wouldn't punish yourself. I mean, Justin told me, you know, I'm supposed to think of a through line, as he calls it. But right now, the only through line I can think of is...

I lost years of my life. Because you're angry, I think, which is understandable. And also, it's not going to change because this has happened. He's right. This has happened. It's not going to change. I kept thinking about his words over the following days and weeks. I kept asking myself, what can I change? What can I do?

During that time, Justin checked in to ask me some of the questions he thought people might ask when they hear my story. I sort of hate to ask, and you can just not answer if you don't want to, but I want to give you an opportunity to. These were the hard questions, the ones he'd been saving, like... Does all of this still affect you now, like, day to day? Well, you know, if I feel energized and happy, I automatically think...

Am I a healthy amount of happy? I just don't trust my emotions. I don't have bipolar. That's more clear to me now than it ever was. But it's almost like I'm afraid of a relapse of this illness that I know I don't have. It's been a few weeks since you spoke to your dad. And I'm kind of wondering how you're feeling now about the role your parents played in all of this.

Well, I've watched enough Real Housewives to know that any apology that includes the words if and but isn't a real, genuine apology. Ultimately... That's where you garnered that? Yeah, that's where I learned that. And ultimately, it's not the apology I want or need, but...

Also, you know, there were times in my past when I'm pretty sure I would have been homeless and hungry or even dead without the support of my parents. Not everyone has a dad who brings them frozen yogurt in a mental hospital, you know? How much do you blame the medications for your feelings and the circumstances of your life during this 15-year period?

It's not like I was happy before I took the medications. I was miserable, but I was still functioning. I attributed that to the medications, but also to the circumstances that the diagnosis put me in, which was the feeling that I'm ill. And that really affected the way I viewed myself and my capabilities. What's the reason you didn't seek out a second opinion for yourself? Hmm.

I believed them. I had no reason not to, you know. I didn't know that I could or should seek out a second opinion. I am the child and grandchild of doctors, and I was indoctrinated to think that doctors are right.

And at the same time, you know, the fact is I saw a lot of different therapists and psychiatrists. So to me, it was just constantly confirmed that this diagnosis was correct because none of these doctors that I was seeing were questioning the diagnosis. And this is one of the reasons I decided to finally revisit my past.

It became clear to me when doing research for this piece that misdiagnosis of bipolar is a real issue in the U.S. This was true in the late 90s and aughts when I was diagnosed. And it's still true today.

So who knows how many people are sitting alone on their sofas with their ceiling fans, watching TV, trapped in this situation, or needing medications or something else that they aren't getting because no one has taken the time to really understand what they're going through. Which is why I wanted to tell this story. Because I want other people to ask the questions I didn't ask.

I want other people to advocate for themselves, not to throw away their medications, but to start a conversation. In a way, I'm making this piece for the person that I was when I was 19. That was Abigail Kafka. She is a writer and she's working on a memoir. Justin Craymon produced that story. Sound design by Bowen Wong.

Coming up, how common are misdiagnoses with bipolar disorder? There is a lot of disagreement over this. Overall, I do think that bipolar disorder is overdiagnosed. I would guess underdiagnosed. It's the same for every psychiatric diagnosis, and that's not overdiagnosis, that's a disagreement. That's next on The Pulse.

This message comes from Midi Health. Women in midlife face a healthcare desert, but Midi is here to fill the gap, offering expert care for perimenopause and menopause covered by insurance. Hot flashes, insomnia, brain fog, weight gain, and moodiness don't have to be accepted as just another part of aging. Midi clinicians understand how these symptoms can connect to menopause and prescribe a wide range of solutions. Book your visit today at joinmidi.com. That's joinmidi.com.

This message comes from Charles Schwab. When is the right time to sell a stock? What is the best way to steer your portfolio through an unsteady market? Financial decisions can be tricky. Financial Decoder is an original podcast from Charles Schwab. Host Mark Riepe, head of the Schwab Center for Financial Research, offers practical solutions to help overcome cognitive and emotional biases that may affect our investing decisions.

Listen at schwab.com slash financial decoder or wherever you get your podcasts.

This message comes from Rinse. These days, you can do a lot from your phone. Book a vacation, buy and trade stocks, but you can also make your dirty laundry disappear and then reappear washed and folded with Rinse. Schedule a pickup with the Rinse app, and before you know it, your clothes are back, folded, and ready to wear. They even do dry cleaning. Sign up now and get $20 off your first order at Rinse.com. That's R-I-N-S-E dot com.

This is The Pulse. I'm Maiken Scott. We just heard Abigail Kafka's story. She's a writer who was diagnosed with bipolar disorder when she was in her 20s. Abigail spent years on medication, not able to really work or have a life, until she slowly got off her medications under the guidance of her doctor.

Now she believes that her diagnosis was wrong, that she didn't have bipolar disorder. Some of the experts she talked to say misdiagnosis is common and bipolar disorder is overdiagnosed. But there is a lot of disagreement over this. Justin Cramon, who reported the story with Abigail, interviewed several psychiatrists to better understand the diagnosis and its history. And he's here now to talk more about what he's learned.

I talked to researchers and clinicians at some of the leading bipolar centers in the U.S. Right now, the gold standard for diagnosing bipolar is the Diagnostic and Statistical Manual of Mental Disorders, the DSM-5. So you basically see if the patient's responses fit the criteria and symptoms laid out in this book, the DSM-5. Okay, that sounds fairly straightforward. Yeah.

Yeah, but it doesn't always shake out that way. One big thing to be aware of is that bipolar research got a lot more complicated in 1994.

A new edition of the DSM came out that year, and it created this new subcategory of bipolar disorder, type 2. So classic bipolar, what's now called bipolar 1, has depression alternating with these manic episodes where people are acting really out of character, have a very inflated sense of self-importance. They make massive moves. They can destroy careers, romances, lives, finances, etc.

But one of the features of bipolar II is a milder form of mania called hypomania. It doesn't last as long and it isn't as destructive. So hypo with an O meaning below, the mania is not as visible. And to me, that also sounds like it could be really tricky to see it, to diagnose it.

Add to that that people don't usually seek treatment when they're manic. Like they're feeling good. They come in when they're depressed, when they're feeling bad, which means the diagnosis is historical. Like it looks back on a past state. With hypomania, you're basically trying to figure out if someone felt a little too good, like manic good, ever in their past for a brief period of time. And you can see where it starts to get just difficult to judge.

The story brings up this explosion of bipolar diagnoses in the late 90s. Is that because of the addition of the type 2 diagnosis? So that doesn't completely account for this, what really was an explosion in bipolar diagnoses in the late 1990s. In the second half of the 90s, there was this perfect storm of factors that led to the rise in bipolar diagnoses.

First, there was some research about how mood disorders, which include bipolar, were underdiagnosed in U.S. hospitals. And that led to these questionnaires being developed to flag patients who had bipolar, to say basically this is a good candidate to look into further for this disorder. But these questionnaires that were developed, which you can fill out in like 10 or 15 minutes,

started to be used not as screeners, but as definitive diagnostic tools, which is not how they're intended. And Abigail told me she filled out like a lot of these over the 15-year period where she carried the bipolar diagnosis. Then came the use of second-generation antipsychotics. These medications were developed in the 1980s, but began to be used to treat bipolar in the mid-1990s.

The thought and the marketing thrust was that they could supplement or even replace antidepressants for a lot of the illnesses where antidepressants weren't working. And so bipolar seemed somewhat easy to diagnose with the questionnaires, fairly easy to treat with the drugs. And the sense was that even if the diagnosis was a little off, well, the drugs fixed that too.

There was just this excitement, like if you went to medical conferences at that time, I was told, around the whole area of bipolar, that this could solve a lot of problems, streamline care, and make it less expensive. So that does make it sound like bipolar is overdiagnosed. Is that what you walked away with? That's where I wanted to be really careful in researching this story. All the circumstantial evidence is there.

It's a big claim to say that millions of Americans are misdiagnosed with a life-changing, and by the way, very expensive illness. Some people say that there's a clear line from drug companies pushing new antipsychotics to overdiagnosis.

You have doctors like Mark Rago in Abigail's story who do believe there's a huge problem of bipolar overdiagnosis that persists in this country. And here's Claudia Baldassano, a psychiatry professor who directs UPenn's bipolar outpatient program. Overall, I do think that bipolar disorder is overdiagnosed.

especially in the setting of crisis centers, inpatient hospitalizations, especially when there is a comorbid substance abuse. In the crisis center, I would say that probably about a third of

of patients who come with a diagnosis of bipolar disorder actually have it based on my own diagnosis. So two-thirds, I believe, do not have bipolar disorder. In my faculty practice, the misdiagnosis is at the level of about half from what I see at the crisis center. But still, clearly there is overdiagnosis in this setting.

Wow. So that's a lot of people. Is there any research on this to quantify these numbers? So psychiatrist Dr. Mark Zimmerman at Rhode Island Hospital published a paper a while back that also claimed to show overdiagnosis of bipolar disorder since the late 1990s.

But I think it's really important to point out that in the sample of doctors I spoke to, there were an equal number who felt, even with the explosion of bipolar diagnosis in the 90s, that the disorder may still be underdiagnosed, that there are just so many people who have it.

Here's David Miklowitz, a psychiatry professor at UCLA Semmel Institute. I would guess underdiagnosed. It's one of the more high reliable diagnoses in the DSM.

A lot of experts believe the accuracy of bipolar diagnosis is no different or even better than many other psychiatric diagnoses. Nasir Ghami directs the mood disorders program at Tufts Medical Center, and he really took issue with the contention that bipolar is overdiagnosed. Do you think it's different for MDD? Do you think it's different for generalized anxiety disorder? It's the same for every psychiatric diagnosis, and that's not overdiagnosis, that's a disagreement.

So where do we go from here? What do we do with this information?

Well, first, I think we often talk about bipolar like it's a yes or no thing, like it's a binary choice. You have it or you don't. And it's just helpful to understand that there's a huge gray area. It's so complicated to diagnose, especially bipolar 2. And there are many cases where it doesn't seem the proper care has been taken either to diagnose or to withhold diagnosis.

And then from a patient standpoint, several doctors told me that stories like Abigail's are the ones that are not getting told. Like we see the cost of underdiagnosing because people hurt themselves or become unhoused. But we rarely talk about the cost of overdiagnosing and overmedicating, what that does to people's lives in the long term, which looks really different, right? But it can cause real suffering also, right?

And it's like a diagnosis that sometimes is made in 20 minutes or 30 minutes in crisis settings is like tying a knot in someone's life. And it can take years or decades to untangle that knot. But at the same time, this is where I want to be really safe talking about this. I don't want the takeaway to be throw out your medications.

Bipolar is real. It's clearly dangerous when untreated. What we wanted to do was make a story that empowers patients and doctors to ask questions, that acknowledges uncertainty and encourages people to get second opinions when they're not sure. Thank you, Justin. Thanks so much, Maiken. Thank you.

Justin Craymon is a reporter and producer. You're listening to The Pulse. I'm Maiken Scott. You can find us wherever you get your podcasts. Also, subscribe to our newsletter to stay in touch with us and to find out what's happening on the show. To sign up, go to whyy.org slash The Pulse Newsletter.

Coming up, a common test to evaluate antidepressants is drawing criticism. You can't put a mouse on a psychiatrist's couch and ask it how it's feeling. That's next on The Pulse. This message comes from EarthX. To advance the latest sustainability solutions, EarthX 2025 returns to Dallas, Texas.

One planet and one mission. EarthX hosts for five days of innovation and connection, including Oceans and the Blue Economy, the Future of Energy, the Circular Economy, Conservation Texas Style, and the Sustainability Investment and Business Innovation Summit. EarthX 2025, April 21st through the 25th. Register at earthx.org.

This message comes from Progressive Insurance. Fiscally responsible. Financial geniuses. Monetary magicians. These are things people say about drivers who switch their car insurance to Progressive and save hundreds. Visit Progressive.com to see if you could save. Progressive Casualty Insurance Company and Affiliates. Potential savings will vary. Not available in all states or situations.

This message comes from NPR sponsor, 1Password. Protect your digital life with 1Password. If you're tired of family members constantly texting you for the passwords to streaming services, 1Password lets you securely share or remove access to logins.

Access from any device, anytime. 1Password lets you securely switch between iPhone, Android, Mac, and PC with convenient features like autofill for quick sign-ins. Right now, get a free two-week trial for you and your family at 1Password.com slash NPR.

This is The Pulse. I'm Maiken Scott. Many people who have serious depression do not respond to the available medications, or they only experience partial relief of their symptoms. And the development of new drug treatment options has been slow.

Testing new medications is challenging. The early research is done in animals, usually with mice. There's a standard test that's been used since the 1970s to see if an antidepressant could work. It was used in the development of well-known drugs like Prozac and Zoloft. But researchers are challenging whether it's actually a good indication of a drug's effectiveness. Alan Yu has more.

Testing mice for depression is challenging. You can't put a mouse on a psychiatrist's couch and ask it how it's feeling. Sarah Bailey is a pharmacologist at the University of Bath in the UK. She's been studying how the brain responds to stress for many years. Her research involves antidepressants that target opioid receptors in the brain. The most common antidepressants target serotonin.

Much of Sarah's work involves doing an experiment called the forced swim test. Researchers put mice in a tank of water that's about 77 degrees Fahrenheit for a few minutes.

It's within the range used in public swimming pools and that's to minimize the risk of hypothermia to the animals. A researcher will observe the mice the entire time. In my experience using the full swim test, no mouse or rat has ever drowned. These mice are naturally buoyant. When they're immobile, they float. The mice can float, but they also do not like being in the water. They swim around and try to get out.

This test came out of other research in the 1970s, where scientists put rats in a maze for learning experiments. They found that some rats would just give up after a while. They found that the same is true of mice in a cylinder filled with water. Eventually, the mice give up. They stop swimming and just float. But if they give mice an antidepressant before this test, the mice swim for longer.

And so the thinking is that if a new unknown drug makes a mouse swim for longer, then that drug could potentially act like an antidepressant. Sarah says the mice recover quickly from the test.

After about six minutes, the researchers take the mice out, dry them off and put them in a cage on a warm mat. They show normal mouse behaviours in the cage. You know, they're exploring, they're grooming, they're looking around.

And after about 10 minutes, they're returned to their home cage with their cage mates. Sarah says she does other tests as well. But right now, there is nothing like the forced swim test. It remains the most well-validated test of antidepressant efficacy. And as yet...

there are no alternatives to using the full swim test. When she says well-validated, she means that when a new drug makes mice swim for longer during this test, scientists can be sure this means it is acting like the antidepressants that they already know and understand. Despite this, some scientists have moved away from using this test in recent years, like neuroscientist Scott Russo.

He's at the Icahn School of Medicine at Mount Sinai in New York. He used to use this test a lot to study stress and depression. But he started phasing it out about eight years ago. There hasn't been a huge loss in the type of knowledge that we gain from not performing the forced swim test anymore. It was never really clear how relevant it was to human depression anymore.

And its ability to identify new potential antidepressants is incredibly limiting. He says one of the problems is that the forced swim test actually works a little too quickly after a mouse gets an antidepressant.

If you give a human an antidepressant, it can take weeks before the drug starts working. The forced swim test and the behavioral response to antidepressants is a much shorter timescale and on the order of, say, hours to minutes. And we just know that's not how humans respond to antidepressants. He says it's not clear if a mouse in a forced swim test is really a good analog for human depression.

Another problem with the test, he says, is that it limits the ability to identify new antidepressants. Meaning, what if there are new drugs that can treat depression, but do not work like the antidepressants that we already know about? The false SWIM test, he argues, could rule those drugs out.

For instance, ketamine is a drug that can treat depression, but works on different systems in the brain than other antidepressants. Now, as the field of drug discovery starts to pivot away from new monoamine-based therapies to other drug targets, for example, like glutamate in the case of ketamine or serotonin receptors not targeted by standard antidepressants like in terms of psychedelics,

He argues it's not clear if the false SWIM test will help discover new drugs that could work like ketamine. He's not the only researcher moving away from this test. Broadly speaking, government agencies cited concerns over the impact to animals and how useful the test is for research.

Two years ago, Australia's National Health and Medical Research Council said they will no longer fund most research using the forced swim test. The National Institute of Mental Health in the US discourages researchers from using it. The UK government said they will look at research proposals that use this test more closely to see if there are other ways to do the work.

Katherine Herman welcomes these moves. She's a veterinarian at the Center for Alternatives to Animal Testing at the Johns Hopkins Bloomberg School of Public Health.

Three years ago, she worked on a paper that found researchers studying major depressive disorder in humans rarely cite research done using the forced swim test. Obviously, if something is translatable, if it's useful for the clinic, clinicians would cite that in their papers.

So that's a big red flag regarding the usefulness of this animal research for human drug development for major depressive disorder. So if the forced swim test is on its way out, what are researchers doing instead?

Neuroscientist Scott Russo says since his lab stopped using the forced swim test, they have used tests that can be done in both humans and mice. One example, train a mouse to press a button to get a reward. Whether that rewarding stimuli be a peanut butter cup,

or another social mouse to interact with. And when you chronically stress mice, they don't perform that task as well as unstressed healthy mice. And he can do the same test when he moves on to human subjects. Instead of peanut butter cups as a reward, he uses money.

The idea behind this is that if you can do similar tests in both humans and mice, then whatever he discovers will be more likely to transfer over. Pharmacologist Marco Bortolato at the University of Florida has proposed an alternative called the "sinking platform test".

He says one of the problems with the forced swim test is that the mice fear they will drown, so there could be a lot going on besides depression. He tries to climb out and he can't, so there is fear, there is anxiety. There are many additional components that we consider as potential confounds. The forced swim test is like a big hammer that could be hitting several things at once.

He suggests a more targeted approach, where researchers test for a specific part of depression. He wants to test for persistence, or how often a mouse will try to do something without the fear of dying. With this new test, the mouse will be in a tank of water, but there are platforms it can climb onto to escape. The platform might sink.

And then as soon as it syncs, there is going to be another platform that emerges. So in essence, the animal learns that this escape strategy, if you will, can sometimes occasionally fail. The mouse learns this for a few days. Then the mouse does this with a different setup. This time, all the platforms will sync.

The test is how many platforms do the mouse climb onto before it gives up. They stay in the tank, they swim, they do other things, but they do not show any more interest in climbing these platforms. And so what we found is that an animal that has undergone chronic stress definitely tries to climb fewer platforms during the test.

And animals that have been treated with antidepressants, on the other hand, tend to engage with many more platforms, tend to climb many more platforms. Marco explains that with this test, it is no longer a one-time life or death situation from the mouse's point of view. The mouse knows what is going to happen, so that takes away the shock and fear of drowning.

He says he has tested this with two kinds of antidepressants, which is a promising start. But there will be years of experimenting before the sinking platform test or any other test can become the new standard. I asked pharmacologist Sarah Bailey, the researcher who is still doing the forced swim test, what she thinks of this alternative. She says she'll need to see more data about this test.

But she also says the forced swim test is one single six-minute test that the mice can recover from, whereas this requires days of training. So is there really better for the mice? She says that's the problem when I asked her to imagine doing her research without the forced swim test. So we'd probably end up using more animals in tests that are less well-validated...

That story was reported by Alan Yu.

That's our show for this week. The Pulse is a production of WHYY in Philadelphia, made possible with support from our founding sponsor, the Sutherland Family, and the Commonwealth Fund. You can follow us wherever you get your podcasts. Our health and science reporters are Alan Yu and Liz Tang. Our intern is Christina Brown. Charlie Kyer is our engineer. Our producers are Nicole Curry and Lindsay Lazarski.

I'm Maiken Scott. Thank you for listening. This message comes from NPR sponsor Allianz Travel Insurance. Is this the year you finally plan those trips to Paris, Prague, and Milan? Learn how an all-trips plan can protect your trips all year at AllianzTravelInsurance.com.

Support for NPR and the following message come from Bowlin Branch. Change your sleep with the softness of Bowlin Branch's 100% organic cotton sheets. Feel the difference with 15% off your first set of sheets at bowlinbranch.com with code NPR. Exclusions apply. See site for details.

Support for this podcast and the following message come from Indeed. You just realized your business needed to hire someone yesterday. Indeed's Sponsored Jobs helps you stand out. According to Indeed data, sponsored jobs posted directly on Indeed have 45% more applications than non-sponsored jobs.

Speed up your hiring right now with Indeed and get a $75 sponsored job credit to get your jobs more visibility at indeed.com slash NPR. Terms and conditions apply. Hiring. Indeed is all you need.