New drug for schizophrenia could meet desperate need for better treatments

New drug for schizophrenia could meet desperate need for better treatments

The field of treating schizophrenia with drugs has been stuck in a long drought but, this month, a late-stage clinical trial found a new drug called KarXT could treat a range of symptoms.

Adobe Stock

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.

Sarah Philip
Sarah Philip is a London-based freelance journalist who writes about science, film and TV. You can follow her on Twitter @sarahph1lip.
Is there a robot nanny in your child's future?

Some researchers argue that active, playful engagement with a "robot nanny" for a few hours a day is better than several hours in front of a TV or with an iPad.

Andy Kelly

From ROBOTS AND THE PEOPLE WHO LOVE THEM: Holding on to Our Humanity in an Age of Social Robots by Eve Herold. Copyright © 2024 by the author and reprinted by permission of St. Martin’s Publishing Group.

Could the use of robots take some of the workload off teachers, add engagement among students, and ultimately invigorate learning by taking it to a new level that is more consonant with the everyday experiences of young people? Do robots have the potential to become full-fledged educators and further push human teachers out of the profession? The preponderance of opinion on this subject is that, just as AI and medical technology are not going to eliminate doctors, robot teachers will never replace human teachers. Rather, they will change the job of teaching.

Keep Reading Keep Reading
Eve Herold
Eve Herold is an award-winning science writer and consultant in the scientific and medical nonprofit space. A longtime communications and policy executive for scientific organizations, she currently serves as Director of Policy Research and Education for the Healthspan Action Coalition. She has written extensively about issues at the crossroads of science and society, including regenerative medicine, aging and longevity, medical implants, transhumanism, robotics and AI, and bioethical issues in leading-edge medicine. Her books include Stem Cell Wars and Beyond Human, and her latest book, Robots and the People Who Love Them, will be released in January 2024. Her work has appeared in Vice, Medium, The Washington Post and the Boston Globe, among others. She’s a frequent contributor to Leaps.org and is the recipient of the 2019 Arlene Eisenberg Award from the American Society of Journalists and Authors.
Fetuses can save their mothers' lives

Stem cells from a fetus can travel to the heart and regenerate the muscle, essentially saving a mother’s life.

Adobe Stock

Story by Big Think

In rare cases, a woman’s heart can start to fail in the months before or after giving birth. The all-important muscle weakens as its chambers enlarge, reducing the amount of blood pumped with each beat. Peripartum cardiomyopathy can threaten the lives of both mother and child. Viral illness, nutritional deficiency, the bodily stress of pregnancy, or an abnormal immune response could all play a role, but the causes aren’t concretely known.

Keep Reading Keep Reading
Ross Pomeroy
Steven Ross Pomeroy is the editor of RealClearScience. As a writer, Ross believes that his greatest assets are his insatiable curiosity and his ceaseless love for learning. Follow him on Twitter