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.
Tapping into the Power of the Placebo Effect
When Wayne Jonas was in medical school 40 years ago, doctors would write out a prescription for placebos, spelling it out backwards in capital letters, O-B-E-C-A-L-P. The pharmacist would fill the prescription with a sugar pill, recalls Jonas, now director of integrative health programs at the Samueli Foundation. It fulfilled the patient's desire for the doctor to do something when perhaps no drug could help, and the sugar pills did no harm.
Today, that deception is seen as unethical. But time and time again, studies have shown that placebos can have real benefits. Now, researchers are trying to untangle the mysteries of placebo effect in an effort to better treat patients.
The use of placebos took off in the post-WWII period, when randomized controlled clinical trials became the gold standard for medical research. One group in a study would be treated with a placebo, a supposedly inert pill or procedure that would not affect normal healing and recovery, while another group in the study would receive an "active" component, most commonly a pill under investigation. Presumably, the group receiving the active treatment would have a better response and the difference from the placebo group would represent the efficacy of the drug being tested. That was the basis for drug approval by the U.S. Food and Drug Administration.
"Placebo responses were marginalized," says Ted Kaptchuk, director of the Program in Placebo Studies & Therapeutic Encounters at Harvard Medical School. "Doctors were taught they have to overcome it when they were thinking about using an effective drug."
But that began to change around the turn of the 21st century. The National Institutes of Health held a series of meetings to set a research agenda and fund studies to answer some basic questions, led by Jonas who was in charge of the office of alternative medicine at the time. "People spontaneously get better all the time," says Kaptchuk. The crucial question was, is the placebo effect real? Is it more than just spontaneous healing?
Brain mechanisms
A turning point came in 2001 in a paper in Science that showed physical evidence of the placebo effect. It used positron emission tomography (PET) scans to measure release patterns of dopamine — a chemical messenger involved in how we feel pleasure — in the brains of patients with Parkinson's disease. Surprisingly, the placebo activated the same patterns that were activated by Parkinson's drugs, such as levodopa. It proved the placebo effect was real; now the search was on to better understand and control it.
A key part of the effect can be the beliefs, expectations, context, and "rituals" of the encounter between doctor and patient. Belief by the doctor and patient that the treatment would work, and the formalized practices of administering the treatment can all contribute to a positive outcome.
Conditioning can be another important component in generating a response, as Pavlov demonstrated more than a century ago in his experiments with dogs. They were trained with a bell prior to feeding such that they would begin to salivate in anticipation at the sound of a bell even with no food present.
Translating that to humans, studies with pain medications and sleeping aids showed that patients who had a positive response with a certain dose of those medications could have the same response if the doses was reduced and a dummy pill substituted, even to the point where there was no longer any active ingredient.
Researchers think placebo treatments can work particularly well in helping people deal with pain and psychological disorders.
Those types of studies troubled Kaptchuk because they often relied on deception; patients weren't told they were receiving a placebo, or at best there was a possibility that they might be randomized to receive a placebo. He believed the placebo effect could work even if patients were told upfront that they were going to receive a placebo. More than a dozen so call "open-label placebo" studies across numerous medical conditions, by Kaptchuk and others, have shown that you don't have to lie to patients for a placebo to work.
Jonas likes to tell the story of a patient who used methotrexate, a potent immunosuppressant, to control her rheumatoid arthritis. She was planning a long trip and didn't want to be bothered with the injections and monitoring required in using the drug, So she began to drink a powerful herbal extract of anise, a licorice flavor that she hated, prior to each injection. She reduced the amount of methotrexate over a period of months and finally stopped, but continued to drink the anise. That process had conditioned her body "to alter her immune function and her autoimmunity" as if she were taking the drug, much like Pavlov's dogs had been trained. She has not taken methotrexate for more than a year.
An intriguing paper published in May 2021 found that mild, non-invasive electric stimulation to the brain could not only boost the placebo effect on pain but also reduce the "nocebo" effect — when patients report a negative effect to a sham treatment. While the work is very preliminary, it may open the door to directly manipulating these responses.
Researchers think placebo treatments can work particularly well in helping people deal with pain and psychological disorders, areas where drugs often are of little help. Still, placebos aren't a cure and only a portion of patients experience a placebo effect.
Nocebo
If medicine were a soap opera, the nocebo would be the evil twin of the placebo. It's what happens when patients have adverse side effects because of the expectation that they will. It's commonly seem when patients claims to experience pain or gastric distress that can occur with a drug even when they've received a placebo. The side effects were either imagined or caused by something else.
"Up to 97% of reported pharmaceutical side effects are not caused by the drug itself but rather by nocebo effects and symptom misattribution," according to one 2019 paper.
One way to reduce a nocebo response is to simply not tell patients that specific side effects might occur. An example is a liver biopsy, in which a large-gauge needle is used to extract a tissue sample for examination. Those told ahead of time that they might experience some pain were more likely to report pain and greater pain than those who weren't offered this information.
Interestingly, a nocebo response plays out in the hippocampus, a part of the brain that is never activated in a placebo response. "I think what we are dealing with with nocebo is anxiety," says Kaptchuk, but he acknowledges that others disagree.
Distraction may be another way to minimize the nocebo effect. Pediatricians are using virtual reality (VR) to engage children and distract them during routine procedures such as blood draws and changing wound dressings, and burn patients of all ages have found relief with specially created VRs.
Treatment response
Jonas argues that what we commonly call the placebo effect is misnamed and leading us astray. "The fact is people heal and that inherent healing capacity is both powerful and influenced by mental, social, and contextual factors that are embedded in every medical encounter since the idea of treatment began," he wrote in a 2019 article in the journal Frontiers in Psychiatry. "Our understanding of healing and ability to enhance it will be accelerated if we stop using the term 'placebo response' and call it what it is—the meaning response, and its special application in medicine called the healing response."
He cites evidence that "only 15% to 20% of the healing of an individual or a population comes from health care. The rest—nearly 80%—comes from other factors rarely addressed in the health care system: behavioral and lifestyle choices that people make in their daily life."
To better align treatments and maximize their effectiveness, Jonas has created HOPE (Healing Oriented Practices & Environments) Note, "a patient-guided process designed to identify the patient's values and goals in their life and for healing." Essentially, it seeks to make clear to both doctor and patient what the patient's goals are in seeking treatment. In an extreme example of terminal cancer, some patients may choose to extend life despite the often brutal treatments, while others might prefer to optimize quality of life in the remaining time that they have. It builds on practices already taught in medical schools. Jonas believes doctors and patients can use tools like these to maximize the treatment response and achieve better outcomes.
Much of the medical profession has been resistant to these approaches. Part of that is simply tradition and limited data on their effectiveness, but another very real factor is the billing process for how they are reimbursed. Jonas says a new medical billing code added this year gives doctors another way to be compensated for the extra time and effort that a more holistic approach to medicine may initially require. Other moves away from fee-for-service payments to bundling and payment for outcomes, and the integrated care provided by the Veterans Affairs, Kaiser Permanente and other groups offer longer term hope for the future of approaches that might enhance the healing response.
This article was first published by Leaps.org on July 7, 2021.
New tech helps people of all ages stay social
In March, Sonja Bauman, 39, used an online platform called Papa, which offers “family on demand,” to meet Mariela Florez, an 83-year-old retiree. Despite living with her adult children, Florez was bored and lonely when they left for work, and her recoveries from a stroke and broken hip were going slowly. That's when Bauman began visiting twice per week. They take walks, strengthening Florez’s hip, and play games like Connect Four for mental stimulation. “It’s very important for me so I don’t feel lonely all day long,” said Florez. Her memories, blurred by the stroke, are gradually returning.
Papa is one of a growing number of tech approaches that are bringing together people of all ages. In addition to platforms like Papa that connect people in real life, other startups use virtual reality and video, with some of them focusing especially on deepening social connections between the generations — relationships that support the health of older and younger people alike. “I enjoy seeing Mariela as much as she enjoys seeing me,” Bauman said.
Connecting in real life
Telehealth expert Andrew Parker founded Papa in 2017 to improve the health outcomes of older adults and families. Seniors can meet people — some their grandkids’ age — for healthy activities, while working parents find retirees to watch their children. These “Papa Pals” are provided as a benefit through Medicare, Medicaid and some employer health plans.
In 2020, Papa connected Bauman, the 39-year-old Floridian, with another woman in her mid-70s who lives alone and has very limited mobility. Bauman began driving her to doctor’s appointments and helping her with chores around the house. “When I’m not there, she doesn’t leave her apartment,” said Bauman. The two have gone to the gym together, and they walk slowly through the neighborhood, chatting so it feels less like exercise.
Parker was driven to start Papa by the problem of social isolation among seniors, exacerbated by the pandemic, but he believes users of all ages can benefit. “Many of our Pals feel more comfortable opening up with older members than their same-aged friends,” he said.
Other platforms aim for similar, in-person connections. Generation Tech unites teens with seniors for technology training. And Mon Ami, which provides case management software for aging and disability service providers, has an app that connects isolated older people with college-age volunteers.
Making new connections through video
Several new sites match you with strangers for real-time video chatting on various topics, such as finding common ground on political issues. Other video platforms focus on intergenerational connections.
S. Jay Olshansky, a gerontology professor at the University of Illinois-Chicago, recalls the first time he saw Hyunseung Lee, an 11-year-old from Seoul, through his computer screen. The kid was shy, but Olshansky, 67, encouraged him to ask questions. “Turns out, he was thirsting for this kind of interaction.”
They’d connected through Eldera, a platform that pairs mentors age 60 and up with mentees, using an algorithm, for video conversations. “The time and wisdom of older adults is the most important natural resource we can give future generations,” said Dana Griffin, Eldera's CEO. “Connecting through a screen is the opposite of social media.”
In weekly meetings, Olshansky noticed Lee’s unique interest in math. “There’s something special in you,” Olshansky told him. “How do we bring it to the surface?” He suggested Lee write a book on his favorite subject, and the preteen ran with it, cranking out 70 pages in two weeks. Lee has published his love letter to theorems on Amazon.
Hyunseung Lee, age 11, of Korea, and U.S. college professor Jay Olshanksy, 67, discuss math, strategy and Hyunsung's budding career as a book author during their video chats through a platform called Eldera. (Photo by Dana Palmer/Eldera)
Lee’s parents told Olshansky that their son has become more assertive — a recurring theme, Griffin said. “Confidence is the number one thing parents tell us about.” Since Eldera’s inception last year, the number of mentors has grown exponentially. Even so, Griffin said the waitlist for mentors typically numbers 200 kids.
Another site, Big and Mini, hosts video interactions between seniors and young adults; about 10,000 active users have joined since 2019, said co-founder Aditi Merchant.
Users often bring the benefits of their video interactions to their real-world relationships. Olshansky views Lee as an older version of his grandkids. “Eldera teaches me how to interact with them.” Lee, high on confidence, began instructing his classmates in math. Griffin noted that a group of Eldera mentors in Memphis, who met initially on Eldera, now take walks together in-person to trade ideas for helping each other’s Eldera kids solve problems in their schools and communities.
“We’ve evolved into a community for older adults who want to give back to the world,” said Griffin. Other new tools for connection take the form of virtual reality apps.
Connecting in virtual reality
During pandemic isolation, record numbers of people bought devices for virtual and augmented reality. Such gadgets can convince you that you’re hanging out with friends, even if they’re in another hemisphere. Lifelike simulations from miles away could be especially useful for meaningful interactions between people of different generations, since they’re often geographically segregated.
VR’s benefits require further study, but users report less social isolation and depression, according to MIT research. The immersive, 3-D experience is more compelling than FaceTime or Zoom. “It’s like the difference between a phone call and video call,” said Rick Robinson, Vice President of AARP’s Innovation Labs.
“When VR is designed right, the medium disappears,” said Jeremy Bailenson of Stanford.
Dana Pierce, a 56-year-old government employee in Indiana, got Meta's VR headset in May, 2021, thinking she’d enjoy it more than a new laptop. After many virtual group tours of exotic destinations, she has no regrets. Her adventures occur on Alcove, an app made by Robinson’s Innovation Labs. He co-created it with VR-company Rendever and sought input from people over age 50 to tailor it to their interests. “I’m an introvert,” said Pierce. “I’ve been more socially active since getting my headset than I am in real life.”
Tagging along with her to places like Paris are avatars representing real people around the world. She’s gotten to know VR users in their 70s, 80s and 90s, as well as younger people and some her own age. One is a new friend she plays chess with in relaxing nature settings. Another is her oldest son. He lives 90 minutes away but, earlier this year, Pierce welcomed him and his girlfriend to her virtual house on Alcove. They chatted in the living room decorated with family photos uploaded by Pierce. Then they took out a boat to go VR fishing — because why not — until 2 a.m.
“When VR is designed right, the medium disappears,” said Jeremy Bailenson, a communications professor who directs Stanford’s Virtual Human Interaction Lab. He’s teaching a class of 175 students entirely in VR. After months of covid isolation, the first time the class met, “there was a big catharsis. It really feels like you’re in a big crowd.” Like-minded people meet in VR for events such as comedy shows and creative writing meetups, while the Swedish pop group ABBA has performed this year as digital versions of themselves (“ABBA-tars”) during a virtual concert tour.
Karen Fingerman, a psychologist and director of the Texas Aging and Longevity Center at the University of Texas-Austin, supports the idea of VR for social connection, though she added that some people need it more than others. Hospitals and assisted-living facilities are using products such as Penumbra’s REAL I-Series and MyndVR to bring VR excursions to isolated patients and seniors. “If you’re in a bed or facility, this gives you something to talk about,” said Gita Barry, Penumbra’s executive vice president.
Pierce uses it on most days. She may see another adult son, who lives with her, less often as a result. But VR helps her manage real-world stressors, more than escaping them. After a long workday, she visits her back porch on Alcove, which overlooks a pond. “It’s my little retreat,” she said. “VR improves my mood. It’s added a lot to my life.”
Some seniors are using more than one technology. Olshansky and Lee discuss strategy while playing Internet chess. And Olshansky recently began using VR. He sees his sister, who lives far away, in a virtual beach house. “It’d be a great way to interact with Hyunseung,” he said. “I should get him a headset.”
A version of this article first appeared in The Washington Post on December 3, 2021.