Short Wave - A Brand New Kind of Schizophrenia Treatment

Episode Date: October 23, 2024

For the past 70 years, schizophrenia treatments all targeted the same chemical: dopamine. While that works for some, it causes brutal side effects for others. An antipsychotic drug approved last month by the FDA changes that. It triggers muscarinic receptors instead of dopamine receptors. The drug is the result of a chance scientific finding ... from a study that wasn't even focused on schizophrenia. Host Emily Kwong and NPR pharmaceutical correspondent Sydney Lupkin dive into where the drug originated, how it works and what it might shift for people with schizophrenia.Read more of Sydney's reporting.Curious about other drug treatments in the news? Email us at [e-mail] and we might cover your topic on a future episode! See pcm.adswizz.com for information about our collection and use of personal data for sponsorship and to manage your podcast sponsorship preferences.NPR Privacy Policy

You're listening to Shortwave from NPR. Hey, shortwavers, Emily Kwong here with NPR's pharmaceutical correspondent, Sydney Lufkin. Hey. And Sydney, your job means you report on a lot of different drugs and medicines, right? Right. I talked to a lot of experts. For this story, however, the most important person that I spoke to was just a regular person who told me about her experience with a certain kind of medication. Tiffany is a librarian in Oklahoma. She has a master's degree, a husband.

Four cats, a dog, a hamster, and a shrimp in an aquarium. She also has schizophrenia, a mental illness in which people have delusions, hallucinations, and other symptoms. No medication has ever touched my delusions. Those are my main symptom, and they are with me from the beginning to the end. They're all the time. She's had delusions of thinking she's not human, thinking cameras are always watching her, stuff like that. When I have an episode, it's just all ramped up so that I'm thinking about it all the time, racing thoughts, can't think about anything else, can't stay present in the real world. So for her privacy, plus the fact that schizophrenia has a lot of stigma attached, she's asked us to only use her first name.

Yeah. Tiffany told me that when she was first put on an antipsychotic drug as a teenager in the 90s, she felt like a zombie. And she remembers looking back at a video from that time and thinking about how she just didn't recognize. herself. It was my birthday and I was opening presents. Everyone was happy and I'm just sitting there like, there's nothing going on. Like I'm staring at a blank wall. And so I lied. And I told everyone I was better. Wow. Okay. Yeah. That sounds really tough. And teenagehood's already difficult. Right. So what did she end up doing? She stopped taking the drug. She was basically like, this isn't worth it. And she stuck it out for years until she experienced another psychotic episode. And

the full-blown delusions and hallucinations came back. How old was she at the time? She was actually in her 30s at the time. She knew it was time to try medication again, but some of the side effects were brutal. Common antipsychotic drugs can cause weight gain and increase the risk of diabetes, which is a really crummy tradeoff. No kidding. Back to Tiffany.

One drug gave her a movement disorder, like she couldn't stop pacing. I was pacing in my office for eight hours a day, and it is exactly three and a half steps. turn three and a half steps, turn, three and a half steps. It was a nightmare. And for a lot of people with schizophrenia, it's the same. They're just trying pills and gritting their teeth through side effects until they find something that works. Tiffany calls it the meds game.

And what works for one person may not work for another one. I mean, this disease has been known about. I would have expected medication to be better at this point. Like, why isn't there a better option? Okay, so we have to go back in time a little bit here. The first antipsychotic drug was introduced in the 1950s, and it acted on the same chemical that helps the brain communicate with the rest of the body, dopamine. The dopamine hypothesis proposed that schizophrenia is associated with excessive dopamine neurotransmission. So too much dopamine activity.

This is Dr. Anne Shin. She's a psychiatrist who directs clinical research on schizophrenia and bipolar disorder at McLean Hospital near Boston. And she says dopamine is the neurotransmitter usually associated. with reward and learning, but it actually has a lot of functions, and that's why it has a lot of side effects. Well, 70 years later, all the medicines are still riffs on the same concept. They target dopamine and have a bunch of side effects. Wow. And then a new drug came along.

So today on the show, how a chance scientific finding led to the first new kind of schizophrenia drug in 70 years. You're listening to Shortwave. The Science Podcast from NPR. Okay, Sydney, I am curious, where did this new drug come from? What is it called? What's its story? So like a lot of medical discoveries, this new drug, Comenfi, which is made by Bristol-Myers Squibb and got FDA approval last month, kind of happened by accident.

In 1997, researchers in the U.S. and Canada were conducting clinical trials on a potential medication for Alzheimer's disease. Alzheimer's. the brain disease that causes memory loss? Yeah. And they weren't looking at schizophrenia at all. This drug acted on a part of the nervous system called the muscarinic receptors, which got their name because they respond to muscarin, a chemical found in some mushrooms.

And by chance, when researchers looked at their study results, they saw that patients had fewer episodes of psychosis while taking the drug. Who knew? Something other than a drug that directly acted on dopamine could reduce psychosis. All right. So cue all the muscarinic. Psychosis drugs, right? Not quite. There was a major problem. Humans have muscarinic receptors all through their bodies. And the same drug that activated those receptors in the brain also ended up

triggering receptors in the gastrointestinal tract. So more like cue the diarrhea, nausea, vomiting, etc. Okay. Yeah. That sounds not so great. It's not good. So patients, especially because in Alzheimer's they're older, could not tolerate it. And so the company, Eli Lilly in this case, shelved the drug. But one guy, Andrew Miller saw the results of the study and was like, there's something here. I became really interested in schizophrenia and through that work became really interested in the idea of targeting musketic receptors because here was serendipitous clinical finding that suggested potential efficacy, which is really hard to come by in psychiatry. So he latched onto that detail. Yeah, he's the CEO of Karuna Therapeutics, which was acquired by pharmaceutical heavyweight Bristol-Meyer Squibb for $14 billion with a B earlier this year. year. So they've got a drug that works, but Andrew and his team still had this problem, major

gastrointestinal side effects. And to solve it, they decided to add a second medicine, one already used for overactive bladder, to shut down the muscarinic receptors triggering those symptoms. That second medicine can't cross the blood-brain barrier, you know, this layer of cells that act like a bouncer and only let some stuff into the VIP club that is your brain. So the two drugs work in tandem to shut down the muscarinic receptors in the body while allowing them to do their thing in the brain. Okay, I get it. So the first drug does its job addressing the psychosis. The second drug keeps everything calm down below. Exactly. Here's Dr. Ann Shin again. Basically, Karuna kind of did this brilliant thing of putting it all together in a combination drug.

And again, she's talking about Miller's company, which was acquired so it doesn't really exist anymore. So I'm just wondering, does Andrew, the guy who invented this drug, have any personal connection to schizophrenia that, like, motivated him to do this? You know, kind of. He told me that at one point, his grandmother was hospitalized after experiencing delusions in Alzheimer's disease. And she thought someone was in the house. And she fell and she hurt herself. So her doctors wanted to put her on an antipsychotic drug to keep those delusions at bay. And his mom called him to talk about the drug options available. I remember having this phone conversation with my mother,

where she explaining, you know, this is what the doctor said we should do, sitting there feeling like, well, this makes sense. But knowing in the back of my mind that there's a box warning for increased mortality, increased cerebral vascular events, heavy sedative effects, so we have this treatment. So my grandmother's quality of life was going to be substantially less than it was before. But there simply wasn't any other option. I mean, this is the reality of kind of where we're at with psychiatric drugs.

Like, some of them work, but there's these side effects that are significant. And he at least is trying to develop something different, but just didn't have this in time for her. Right. It's like kind of bittersweet. And even now, Kobenfi hasn't been approved for Alzheimer's patients experiencing psychosis. But that could happen in the future. This is so interesting. So, Sinu said the FDA approved this drug, Kobenfi. when can patients like Tiffany from the beginning of the story, when can she try it?

Right. So it was approved and it's available as of October. So now it has a list price, though, of $1,850 a month. That's a lot. Yeah. I mean, it is also in line with other schizophrenia treatments, but insurance coverage can be really tricky. If it's like a lot of the other new medications, insurance is generally going to mandate that people try at least two generic medicines first. before they will pay for it. That was Dr. Jacob Ballin, an associate professor of psychiatry at Stanford University. He says he has a lot of patients and their parents who are excited about a potential new treatment option. Ballin is also working on an ongoing study of how Cobenfi fits in with existing drugs and whether they can maybe be used together. While the new medicine isn't for everyone, it could help patients who've had trouble with existing treatments or for whom nothing has worked. Okay. I have to ask you this, are there any downsides to this new drug?

Yeah, so the FDA based its approval on double-blind placebo-controlled studies. That means some patients received co-benefi and others got a placebo, but neither the patients nor the clinicians knew which was which until the study was over. But the study only lasted five weeks, and that's prompted some experts to point out that questions remain about the drug's long-term safety and efficacy. Studies also haven't compared it head to head with one of the existing antipsychotic drugs, like the dopamine ones, to say for sure that it is more effective. Common side effects with co-benthe include nausea, constipation, and rapid heartbeat. All good to know.

Tiffany, our girl, what is she thinking about all this? She's interested in trying the drug down the road. Okay. Every time I have an episode, you know, I lose bits of myself and bits of functionality. And that's not fair to my husband. And I hate it. So if I could have something that would help me have a little bit more initiative, that would be wonderful. Unlike previous drugs, which only tackled the so-called positive symptoms of schizophrenia,

like hallucinations and delusions, co-benefi has been shown to decrease the so-called negative symptoms, such as apathy and lack of motivation. In our conversation, I asked her what she would want to hear on the radio from someone with schizophrenia like her, because, you know, with the stigma around this, it's not every day you get to. to hear from people who have it. And I want to end on that note. She has some advice for people with schizophrenia who are still searching for the right treatment. Keep trying. I mean, it's really hard to go on and off medications. But when you find the right one, it makes a huge difference, night and day. Yeah, she and all people with schizophrenia, they deserve that relief. Well, Sydney,

thank you so much for bringing me this reporting. Thank you for having me. For more stories like this, check out our episodes on OCD and Fear and Anxiety. We'll link those stories in our show notes. Plus, review and follow us wherever you get your podcasts. It really helps more people find our show. This episode was produced by Hannah Chin and edited by our showrunner Rebecca Ramirez. The facts were checked by Tyler Jones. The audio engineer was Maggie Luthor.

Beth Donovan is our senior director and Colin Campbell is our senior vice president of podcasting strategy. I'm Emily Kwong. Thank you for listening to Shortwave, the side. Science Podcast from NPR.