New drug for schizophrenia could meet desperate need for better treatments
Schizophrenia is a debilitating mental health condition that affects around 24 million people worldwide. Patients experience hallucinations and delusions when they develop schizophrenia, with experts referring to these new thoughts and behaviors as positive symptoms. They also suffer from negative symptoms in which they lose important functions, suffering from dulled emotions, lack of purpose and social withdrawal.
Currently available drugs can control only a portion of these symptoms but, on August 8th, Karuna Therapeutics announced its completion of a phase 3 clinical trial that found a new drug called KarXT could treat both positive and negative symptoms of schizophrenia. It could mean substantial progress against a problem that has stymied scientists for decades.
A long-standing problem
Since the 1950s, antipsychotics have been used to treat schizophrenia. People who suffer from it are thought to have too much of a brain chemical called dopamine, and antipsychotics work by blocking dopamine receptors in the brain. They can be effective in treating positive symptoms but have little impact on the negative ones, which can be devastating for a patient’s quality of life, making it difficult to maintain employment and have successful relationships. About 30 percent of schizophrenia patients don't actually respond to antipsychotics at all. Current drugs can also have adverse side effects including elevated cholesterol, high blood pressure, diabetes and movements that patients cannot control.
The recent clinical trial heralds a new treatment approach. “We believe it marks an important advancement for patients given its new and completely different mechanism of action from current therapies,” says Andrew Miller, COO of Karuna.
Scientists have been looking to develop alternatives. However, “the field of drug treatment of schizophrenia is currently in the doldrums,” says Peter McKenna, a senior researcher at FIDMAG Research Foundation in Spain which specialises in mental health.
In the 2000s there was a major push to target a brain receptor for a chemical called glutamate. Evidence suggested that this receptor is abnormal in the brains of schizophrenia patients, but attempts to try glutamate failed in clinical trials.
After that, many pharmaceutical companies dropped out of the race for a more useful treatment. But some companies continued to search, such as Karuna Therapeutics, led by founder and Chief Operating Officer Andrew Miller and CEO Steve Paul. The recent clinical trial suggests their persistence has led to an important breakthrough with their drug, KarXT. “We believe it marks an important advancement for patients given its new and completely different mechanism of action from current therapies,” Miller says.
How it works
Neurotransmitters are chemical messengers that pass signals between neurons. To work effectively, neurotransmitters need a receptor to bind to. A neurotransmitter called acetylcholine seems to be especially important in schizophrenia. It interacts with sites called muscarinic receptors, which are involved in the network of nerves that calm your body after a stressful event. Post mortem studies in people with schizophrenia have shown that two muscarinic receptors in the brain, the M1 and M4 receptors, are activated at unusually low levels because they don’t receive enough signals from acetylcholine.
The M4 receptor appears to play a role in psychosis. The M1 receptor is also associated with psychosis but is primarily thought to be involved in cognition. KarXT, taken orally, works by activating both of these receptors to signal properly. It is this twofold action that seems to explain its effectiveness. “[The drug’s] design enables the preferential stimulation of these muscarinic receptors in the brain,” Miller says.
How it developed
It all started in the early 1990s when Paul was at pharmaceutical company Eli Lilly. He discovered that Xanomeline, the drug they were testing on Alzheimer's patients, had antipsychotic effects. It worked by stimulating M1 and M4 receptors, so he and his colleagues decided to test Xanomeline on schizophrenia patients, supported by research on the connection between muscarinic receptors and psychosis. They found that Xanomeline reduced both positive and negative symptoms.
Unfortunately, it also caused significant side effects. The problem was that stimulating the M1 and M4 receptors in the brain also stimulated muscarinic receptors in the body that led to severe vomiting, diarrhea and even the temporary loss of consciousness.
In the end, Eli Lilly discontinued the clinical trials for the drug, but Miller set up Karuna Therapeutics to develop a solution. “I was determined to find a way to harness the therapeutic benefit demonstrated in studies of Xanomeline, while eliminating side effects that limited its development,” Miller says.
He analysed over 7,000 possible ways of mixing Xanomeline with other agents before settling on KarXT. It combines Xanomeline with a drug called Trospium Chloride, which blocks muscarinic receptors in the body – taking care of the side effects such as vomiting – but leaves them unblocked in the brain. Paul was so excited by Miller’s progress that he joined Karuna after leaving Eli Lilly and founding two previous startups.
“It's a very important approach,” says Rick Adams, Future Leaders Fellow in the Institute of Cognitive Neuroscience and Centre for Medical Image Computing at University College London. “We are in desperate need of alternative drug targets and this target is one of the best. There are other alternative targets, but not many are as close to being successful as the muscarinic receptor drug.”
Clinical Trial
Following a successful phase 2 clinical trial in 2019, the most recent trial involved 126 patients who were given KarXT, and 126 who were given a placebo. Compared to the placebo, patients taking KarXT had a significant 9.6 point reduction in the positive and negative syndrome scale (PANSS), the standard for rating schizophrenic symptoms.
KarXT also led to statistically significant declines in positive and negative symptoms compared to the placebo. “The results suggest that KarXT could be a potentially game-changing option in the management of both positive and negative symptoms of schizophrenia,” Miller says.
Robert McCutcheon, a psychiatrist and neuroscientist at Oxford University, is optimistic about the side effects but highlights the need for more safety trials.
McKenna, the researcher at FIDMAG Foundation, agrees about the drug’s potential. “The new [phase 3] study is positive,” he says. “It is reassuring that one is not dealing with a drug that works in one trial and then inexplicably fails in the next one.”
Robert McCutcheon, a psychiatrist and neuroscientist at Oxford University, said the drug is an unprecedented step forward. “KarXT is one of the first drugs with a novel mechanism of action to show promise in clinical trials.”
Even though the drug blocks muscarine receptors in the body, some patients still suffered from adverse side effects like vomiting, dizziness and diarrhea. But in general, these effects were mild to moderate, especially compared to dopamine-blocking antipsychotics or Xanomeline on its own.
McCutcheon is optimistic about the side effects but highlights the need for more safety trials. “The trial results suggest that gastrointestinal side effects appear to be manageable,” he says. “We know, however, from previous antipsychotic drugs that the full picture regarding the extent of side effects can sometimes take longer to become apparent to clinicians and patients. Careful ongoing assessment during a longer period of treatment will therefore be important.”
The Future
The team is currently conducting three other trials to evaluate the efficacy and long-term safety of KarXT. Their goal is to receive FDA approval next year.
Karuna is also conducting trials to evaluate the effectiveness of KarXT in treating psychosis in patients suffering from Alzheimer’s.
The big hope is that they will soon be able to provide a radically different drug to help many patients with schizophrenia. “We are another step closer to potentially providing the first new class of medicine in more than 50 years to the millions of people worldwide living with schizophrenia,” says Miller.
There's no shortage of fake news going around the internet these days, but how do we become more aware as consumers of what's real and what's not?
"We are hoping to create what you might call a general 'vaccine' against fake news, rather than trying to counter each specific conspiracy or falsehood."
Researchers at the University of Cambridge may have answered just that by developing an online game designed to expose and educate participants to the tactics used by those spreading false information.
"We wanted to see if we could preemptively debunk, or 'pre-bunk', fake news by exposing people to a weak dose of the methods used to create and spread disinformation, so they have a better understanding of how they might be deceived," Dr Sander van der Linden, Director of the Cambridge Social Decision-Making Lab, said in a statement.
"This is a version of what psychologists call 'inoculation theory', with our game working like a psychological vaccination."
In February 2018, van der Linden and his coauthor, Jon Roozenbeek, helped launch the browser game, "Bad News," where players take on the role of "Disinformation and Fake News Tycoon."
They can manipulate news and social media within the game by several different methods, including deploying twitter-bots, photo-shopping evidence, creating fake accounts, and inciting conspiracy theories with the goal of attracting followers and maintaining a "credibility score" for persuasiveness.
In order to gauge the game's effectiveness, players were asked to rate the reliability of a number of real and fake news headlines and tweets both before and after playing. The data from 15,000 players was evaluated, with the results published June 25 in the journal Palgrave Communications.
The results concluded that "the perceived reliability of fake news before playing the game had reduced by an average of 21% after completing it. Yet the game made no difference to how users ranked real news."
Just 15 minutes of playing the game can have a moderate effect on people, which could play a major role on a larger scale.
Additionally, participants who "registered as most susceptible to fake news headlines at the outset benefited most from the 'inoculation,'" according to the study.
Just 15 minutes of playing the game can have a moderate effect on people, which could play a major role on a larger scale when it comes to "building a societal resistance to fake news," according to Dr. van der Linden.
"Research suggests that fake news spreads faster and deeper than the truth, so combating disinformation after-the-fact can be like fighting a losing battle," he said.
"We are hoping to create what you might call a general 'vaccine' against fake news, rather than trying to counter each specific conspiracy or falsehood," Roozenbeek added.
Van der Linden and Roozenbeek's work is an early example of the potential methods to protect people against deception by training them to be more attuned to the methods used to distribute fake news.
"I hope that the positive results give further credence to the new science of prebunking rather than only thinking about traditional debunking. On a larger level, I also hope the game and results inspire a new kind of behavioral science research where we actively engage with people and apply insights from psychological science in the public interest," van der Linden told leapsmag.
"I like the idea that the end result of a scientific theory is a real-world partnership and practical tool that organizations and people can use to guard themselves against online manipulation techniques in a novel and hopefully fun and engaging manner."
Ready to be "inoculated" against fake news? Then play the game for yourself.
What if people could just survive on sunlight like plants?
The admittedly outlandish question occurred to me after reading about how climate change will exacerbate drought, flooding, and worldwide food shortages. Many of these problems could be eliminated if human photosynthesis were possible. Had anyone ever tried it?
Extreme space travel exists at an ethically unique spot that makes human experimentation much more palatable.
I emailed Sidney Pierce, professor emeritus in the Department of Integrative Biology at the University of South Florida, who studies a type of sea slug, Elysia chlorotica, that eats photosynthetic algae, incorporating the algae's key cell structure into itself. It's still a mystery how exactly a slug can operate the part of the cell that converts sunlight into energy, which requires proteins made by genes to function, but the upshot is that the slugs can (and do) live on sunlight in-between feedings.
Pierce says he gets questions about human photosynthesis a couple of times a year, but it almost certainly wouldn't be worth it to try to develop the process in a human. "A high-metabolic rate, large animal like a human could probably not survive on photosynthesis," he wrote to me in an email. "The main reason is a lack of surface area. They would either have to grow leaves or pull a trailer covered with them."
In short: Plants have already exploited the best tricks for subsisting on photosynthesis, and unless we want to look and act like plants, we won't have much success ourselves. Not that it stopped Pierce from trying to develop human photosynthesis technology anyway: "I even tried to sell it to the Navy back in the day," he told me. "Imagine photosynthetic SEALS."
It turns out, however, that while no one is actively trying to create photosynthetic humans, scientists are considering the ways humans might need to change to adapt to future environments, either here on the rapidly changing Earth or on another planet. Rice University biologist Scott Solomon has written an entire book, Future Humans, in which he explores the environmental pressures that are likely to influence human evolution from this point forward. On Earth, Solomon says, infectious disease will remain a major driver of change. As for Mars, the big two are lower gravity and radiation, the latter of which bombards the Martian surface constantly because the planet has no magnetosphere.
Although he considers this example "pretty out there," Solomon says one possible solution to Mars' magnetic assault could leave humans not photosynthetic green, but orange, thanks to pigments called carotenoids that are responsible for the bright hues of pumpkins and carrots.
"Carotenoids protect against radiation," he says. "Usually only plants and microbes can produce carotenoids, but there's at least one kind of insect, a particular type of aphid, that somehow acquired the gene for making carotenoids from a fungus. We don't exactly know how that happened, but now they're orange... I view that as an example of, hey, maybe humans on Mars will evolve new kinds of pigmentation that will protect us from the radiation there."
We could wait for an orange human-producing genetic variation to occur naturally, or with new gene editing techniques such as CRISPR-Cas9, we could just directly give astronauts genetic advantages such as carotenoid-producing skin. This may not be as far-off as it sounds: Extreme space travel exists at an ethically unique spot that makes human experimentation much more palatable. If an astronaut already plans to subject herself to the enormous experiment of traveling to, and maybe living out her days on, a dangerous and faraway planet, do we have any obligation to provide all the protection we can?
Probably the most vocal person trying to figure out what genetic protections might help astronauts is Cornell geneticist Chris Mason. His lab has outlined a 10-phase, 500-year plan for human survival, starting with the comparatively modest goal of establishing which human genes are not amenable to change and should be marked with a "Do not disturb" sign.
To be clear, Mason is not actually modifying human beings. Instead, his lab has studied genes in radiation-resistant bacteria, such as the Deinococcus genus. They've expressed proteins called DSUP from tardigrades, tiny water bears that can survive in space, in human cells. They've looked into p53, a gene that is overexpressed in elephants and seems to protect them from cancer. They also developed a protocol to work on the NASA twin study comparing astronauts Scott Kelly, who spent a year aboard the International Space Station, and his brother Mark, who did not, to find out what effects space tends to have on genes in the first place.
In a talk he gave in December, Mason reported that 8.7 percent of Scott Kelly's genes—mostly those associated with immune function, DNA repair, and bone formation—did not return to normal after the astronaut had been home for six months. "Some of these space genes, we could engineer them, activate them, have them be hyperactive when you go to space," he said in that same talk. "When we think about having the hubris to go to a faraway planet...it seems like an almost impossible idea….but I really like people and I want us to survive for a long time, and this is the first step on the stairwell to survive out of the solar system."
What is the most important ability we could give our future selves through science?
There are others performing studies to figure out what capabilities we might bestow on the future-proof superhuman, but none of them are quite as extreme as photosynthesis (although all of them are useful). At Harvard, geneticist George Church wants to engineer cells to be resistant to viruses, such as the common cold and HIV. At Columbia, synthetic biologist Harris Wang is addressing self-sufficient humans more directly—trying to spur kidney cells to produce amino acids that are normally only available from diet.
But perhaps Future Humans author Scott Solomon has the most radical idea. I asked him a version of the classic What would be your superhero power? question: What does he see as the most important ability we could give our future selves through science?
"The empathy gene," he said. "The ability to put yourself in someone else's shoes and see the world as they see it. I think it would solve a lot of our problems."