Short Wave - Depression And Alzheimer's Treatments At A Crossroads

Episode Date: November 10, 2022

Researchers are launching a make-or-break study to test the conventional wisdom about what causes Alzheimer's disease. And in a recent small study, the antidepressant effects of ketamine lasted longer when an intravenous dose was followed with computer games featuring smiling faces or words aimed at boosting self-esteem. As science correspondent Jon Hamilton heads to the Society for Neuroscience's annual meeting, he talks to Aaron Scott about his most recent reporting on depression and Alzheimer's, and previews what he'll be talking to researchers about at the meeting.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 there, folks, Aaron Scott, here with NPR Science Desk Brain Guy, Mr. John Hamilton. Hello, John. Hey. Thank you for stopping by. I hear you've got a lot going on this week. Oh, I do, Aaron. This is a super busy week for me because on Saturday I will be heading to San Diego for the Neuroscience 2020 meeting.

It's an annual conference run by the Society for NPR. neuroscience and is really big. Imagine a small city filled with brain scientists. Sounds deliciously cerebral. Total nerd fest. And I mean, these are my people. And this year, I am hoping to talk with some of these scientists about brain disorders that are common, but not that well understood. So let me just mention a couple of them that I've been reporting on recently. Alzheimer's and depression. With Alzheimer's, the question is whether most efforts to treat the disease, in the past couple of decades, have been based on an idea that is just wrong. And that idea is approaching its day of Rackenet. Wow. Okay. That's maybe exciting, maybe intimidating.

And then there's something a bit more uplifting. It has to do with ketamine. A lot of people know this as a mind-altering party drug, also perhaps as an anesthetic. And in the past few years, it has become a really important treatment for severe depression that doesn't respond to other drugs. It's also the first really new type of depression treatment to come along in decades. I talked to some scientists who say they've been able to make the antidepressant effects of ketamine last a lot longer, using these super upbeat computer games. Today on the show, then, we are going to listen to some of John's recent reporting and then talk about what he's looking forward to at the big brain meeting in San Diego. You're listening to Shortwave, the Daily Science podcast from NPR. Okay, John, so first up,

Alzheimer's. Yeah, this is a story I did about something known as the amyloid hypothesis. It's an idea that has dominated the field of Alzheimer's since the 1980s, even though some scientists have always had doubts about it. So now some researchers are launching this study that is designed to show once and for all whether the hypothesis is right. When Alois Alzheimer first described the condition more than a century ago, he noted that patient's brains contain distinctive plaques. Then in the 1980s, scientists showed that these plaques were made of a sticky substance called beta amyloid. And ever since, most efforts to treat Alzheimer's have focused on getting rid of the sticky substance. Dr. Randall Bateman of Washington University in St. Louis says that still makes sense. We have 30 years of solid data, thousands of studies that all say this is sufficient to cause Alzheimer's. And yet, a growing number of drugs that reduce amyloid have failed to slow down the disease. For example, Baitman and a team of researchers gave the drug Gantanaramab to people with a gene that causes Alzheimer's in middle age.

He says an analysis of the drug's effects offered mixed results. What we found in that analysis was that it had reversed the amyloid plaques in their brains, some of them, to near normal levels. We did not have evidence of a thinking memory benefit. Even so, Baitman thinks it's too soon to abandon the amyloid hypothesis. He says Gantanaramab seemed to delay several brain changes associated with Alzheimer's, and in September, a preliminary report suggested the drug lachanamab actually did slow down the loss of memory and thinking. So Bateman thinks anti-ameloid drugs can still work. Penicillin, a great breakthrough, failed its first two clinical trials.

Fortunately, people didn't say, oh, the antibiotic theory is a bad idea, and we should give up on it. Bateman says anti-ameloid drugs may have failed so far because they've been given to people who already had plaques in their brains. At that point, he says, it may not be possible to stop the process that leads to the destruction of brain cells. So Bateman is banking on a study that will start treatment much earlier. My prediction is it will work, and it'll work fantastically if we can really prevent the plaques from starting and taking off and those downstream changes from going. My prediction is these people will never get Alzheimer's. If prevention fails, though, Bateman says it could mark the end of an era. Many of us think of that as the ultimate test of the amylate hypothesis, that if that doesn't work, nothing will work.

The primary prevention trial will be run by Bateman's colleague, Dr. Eric McDade. McDade says it's based on the idea that when amyloid begins to build up in the brain, it initiates a cascade of adverse events. These include the appearance of toxic tangles inside neurons, the loss of connections between neurons, inflammation, and ultimately brain cell death. What we're actually trying to do is to prevent that amyloid pathology from developing in the first place. McDade says that will mean starting treatment long before symptoms appear. At the point of somebody having symptoms, we know now that they probably have had amyloid in their brain for one to two decades. Like the earlier study, this one will give cantanaramab to people from families with gene mutations

that often cause them to get Alzheimer's symptoms before age 50. But McDade says this time, the team will begin treating people as young as 18. The earliest they can come in is 25 years before we anticipate they would start to develop symptoms. And so for most of these families, that actually puts them in their mid-20s where we're going to start this trial. The study will enroll about 160 people, which is small for a drug study. But because the scientists know the genetic background of each participant, they can predict, when a person would be expected to develop amyloid plaques. McDade says that means the team can focus on other markers of the disease,

like tangles and cell damage. If we prevent amyloid pathology from developing and these other markers continue to develop and unfold, this would be one of the best ways to say, rather conclusively, listen, amyloid is really not what we should be targeting. The study plans to enroll its first patients by the end of the year. Wow, John, so this sounds like it really, could be a paradigm shift. Are there other promising avenues that research scientists are pursuing?

There are. Some scientists are focusing on another hallmark of Alzheimer's, and that is these toxic, tangled fibers that build up inside of neurons. There are several experimental drugs being tested that are designed to treat Alzheimer's by removing these fibers. Another approach is to reduce the inflammation you see in the brains of people who have Alzheimer's. Scientists are looking to see whether anti-inflammatory drugs might help keep brain cells alive. And then there's this idea that you might be able to protect brain cells with drugs that improve the cell's metabolism. So the chemical changes inside that allow a cell to make energy and then get rid of waste products. Interesting. I look forward to more your reporting on this, but we are going to switch gears for a completely different kind of story. It sounds like there's been some really promising development with the drug ketamine for severe depression.

Let's listen to your reporting on this. An intravenous dose of ketamine can relieve depression in hours and often rescues patients who haven't responded to other drugs. But Rebecca Price, a psychologist at the University of Pittsburgh, says the effects tend to wear off after a week or two. And then returning for infusions over and over to keep that relief going can end up being really burdensome. and costly and just isn't accessible to all patients. So Price and a team of researchers wanted to find a way to make ketamine's antidepressant effects last longer. They decided to focus on one particular symptom. Low self-esteem and even quite severe self-loathing is quite typical to see in the context

of depression. The team drew on research suggesting that ketamine temporarily causes certain brain areas to enter a state in which they form lots of new connections. Price says during this period, the brain seems to be more receptive to learning and change. So we tried to use that window of opportunity just after ketamine to strengthen associations specifically between the idea of me, myself, and positive information and attributes. The team did a study of 154 people, including a group that played special computer games for several days after they received an infusion of ketamine. Some of these games involved words, and Price says every time the word I appeared, it was followed by a positive term.

Good, lovable, sweet, worthy, etc. Price says other games used images. For example, participants were asked to click on a photo as soon as it flashed on one area of the screen. But every time they click on their own photo, what appears right afterwards in that same location as a smiling face. Price says the games had a surprisingly powerful effect, which the team described in the American Journal of Psychiatry.

By doing these really simple computer exercises for just four days after the infusion and then nothing further. We could extend the antidepressant effect of one infusion of ketamine for at least a month, and it's looking like it was actually closer to three months. If those results hold up, the approach could make ketamine treatment much more affordable. Dr. Sanjay Matthew is a professor of psychiatry at Baylor College of Medicine and a co-author of the study. He says right now insurance rarely covers the treatment.

ketamine infusions can cost anywhere from $300 to $800 or even higher. So that's obviously a huge challenge for many patients and the biggest reason we can't send more patients to ketamine. And Matthew says that because therapists are in such short supply, mental health centers would welcome a computerized addition to ketamine therapy. It could be disseminated widely in clinics that don't have resources to be able to engage, in any number of psychotherapies that work on self-esteem and beliefs about oneself. Matthew says even the busiest clinic has time for a smile or two.

We love a clinic full of smiles. Thank you, John, for bringing us these updates. So you are packing your bag for the big neuroscience meeting. What are some of the topics you're going to be talking to folks about there? Well, in addition to depression and dementia, there's some of the topics you're going to be talking to folks about there. some stuff about using psychoactive drugs like psilocybin to treat mood disorders. There is a lot of stuff being presented about sleep. And there's going to be some stuff about how COVID-19 actually changes the brain. Wow. Excellent. Excellent. Well, we shall look forward to talking to you about it all when you get back.

All righty. The radio stories were edited by Omina Khan. Our episode was edited, produced, and fact-checked by Giselle Grayson, our amazing senior supervising editor who can obviously do it all. Brendan Crump is our podcast coordinator, Beth Donovan is senior director, and Anya Grumman is the senior vice president of programming. I wanted to take a minute here to talk about Shortwave Plus. Shortwave Plus subscribers help make shows like this one possible, and they also get to listen to all our episodes without any sponsor breaks. To find out more, go to plus.mpr.mpr.org slash shortwave. And to everyone who's already subscribed, thank you. Thank you, thank you.

I'm Aaron Scott. Thanks for listening to Shortwave, the Daily Science Podcasts from NPR.