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.
As countries around the world combat the coronavirus outbreak, governments that already operated sophisticated surveillance programs are ramping up the tracking of their citizens.
"The potential for invasions of privacy, abuse, and stigmatization is enormous."
Countries like China, South Korea, Israel, Singapore and others are closely monitoring citizens to track the spread of the virus and prevent further infections, and policymakers in the United States have proposed similar steps. These shifts in policy have civil liberties defenders alarmed, as history has shown increases in surveillance tend to stick around after an emergency is over.
In China, where the virus originated and surveillance is already ubiquitous, the government has taken measures like having people scan a QR code and answer questions about their health and travel history to enter their apartment building. The country has also increased the tracking of cell phones, encouraged citizens to report people who appear to be sick, utilized surveillance drones, and developed facial recognition that can identify someone even if they're wearing a mask.
In Israel, the government has begun tracking people's cell phones without a court order under a program that was initially meant to counter terrorism. Singapore has also been closely tracking people's movements using cell phone data. In South Korea, the government has been monitoring citizens' credit card and cell phone data and has heavily utilized facial recognition to combat the spread of the coronavirus.
Here at home, the United States government and state governments have been using cell phone data to determine where people are congregating. White House senior adviser Jared Kushner's task force to combat the coronavirus outbreak has proposed using cell phone data to track coronavirus patients. Cities around the nation are also using surveillance drones to maintain social distancing orders. Companies like Apple and Google that work closely with the federal government are currently developing systems to track Americans' cell phones.
All of this might sound acceptable if you're worried about containing the outbreak and getting back to normal life, but as we saw when the Patriot Act was passed in 2001 in the wake of the 9/11 terrorist attacks, expansions of the surveillance state can persist long after the emergency that seemed to justify them.
Jay Stanley, senior policy analyst with the ACLU Speech, Privacy, and Technology Project, says that this public health emergency requires bold action, but he worries that actions may be taken that will infringe on our privacy rights.
"This is an extraordinary crisis that justifies things that would not be justified in ordinary times, but we, of course, worry that any such things would be made permanent," Stanley says.
Stanley notes that the 9/11 situation was different from this current situation because we still face the threat of terrorism today, and we always will. The Patriot Act was a response to that threat, even if it was an extreme response. With this pandemic, it's quite possible we won't face something like this again for some time.
"We know that for the last seven or eight decades, we haven't seen a microbe this dangerous become a pandemic, and it's reasonable to expect it's not going to be happening for a while afterward," Stanley says. "We do know that when a vaccine is produced and is produced widely enough, the COVID crisis will be over. This does, unlike 9/11, have a definitive ending."
The ACLU released a white paper last week outlining the problems with using location data from cell phones and how policymakers should proceed when they discuss the usage of surveillance to combat the outbreak.
"Location data contains an enormously invasive and personal set of information about each of us, with the potential to reveal such things as people's social, sexual, religious, and political associations," they wrote. "The potential for invasions of privacy, abuse, and stigmatization is enormous. Any uses of such data should be temporary, restricted to public health agencies and purposes, and should make the greatest possible use of available techniques that allow for privacy and anonymity to be protected, even as the data is used."
"The first thing you need to combat pervasive surveillance is to know that it's occurring."
Sara Collins, policy counsel at the digital rights organization Public Knowledge, says that one of the problems with the current administration is that there's not much transparency, so she worries surveillance could be increased without the public realizing it.
"You'll often see the White House come out with something—that they're going to take this action or an agency just says they're going to take this action—and there's no congressional authorization," Collins says. "There's no regulation. There's nothing there for the public discourse."
Collins says it's almost impossible to protect against infringements on people's privacy rights if you don't actually know what kind of surveillance is being done and at what scale.
"I think that's very concerning when there's no accountability and no way to understand what's actually happening," Collins says. "The first thing you need to combat pervasive surveillance is to know that it's occurring."
We should also be worried about corporate surveillance, Collins says, because the tech companies that keep track of our data work closely with the government and do not have a good track record when it comes to protecting people's privacy. She suspects these companies could use the coronavirus outbreak to defend the kind of data collection they've been engaging in for years.
Collins stresses that any increase in surveillance should be transparent and short-lived, and that there should be a limit on how long people's data can be kept. Otherwise, she says, we're risking an indefinite infringement on privacy rights. Her organization will be keeping tabs as the crisis progresses.
It's not that we shouldn't avail ourselves of modern technology to fight the pandemic. Indeed, once lockdown restrictions are gradually lifted, public health officials must increase their ability to isolate new cases and trace, test, and quarantine contacts.
But tracking the entire populace "Big Brother"-style is not the ideal way out of the crisis. Last week, for instance, a group of policy experts -- including former FDA Commissioner Scott Gottlieb -- published recommendations for how to achieve containment. They emphasized the need for widespread diagnostic and serologic testing as well as rapid case-based interventions, among other measures -- and they, too, were wary of pervasive measures to follow citizens.
The group wrote: "Improved capacity [for timely contact tracing] will be most effective if coordinated with health care providers, health systems, and health plans and supported by timely electronic data sharing. Cell phone-based apps recording proximity events between individuals are unlikely to have adequate discriminating ability or adoption to achieve public health utility, while introducing serious privacy, security, and logistical concerns."
The bottom line: Any broad increases in surveillance should be carefully considered before we go along with them out of fear. The Founders knew that privacy is integral to freedom; that's why they wrote the Fourth Amendment to protect it, and that right shouldn't be thrown away because we're in an emergency. Once you lose a right, you don't tend to get it back.
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.