Charpentier hadn’t intended to spark a revolution; he was actually trying to make a better antihistamine. But by tweaking an existing drug called promazine, he ended up making a new compound called chlorpromazine. The drug was passed on to a surgeon by the name of Henri Laborit, who was on the hunt for a more effective anesthetic. He noticed it produced a calming effect in his patients, and in 1952 Laborit convinced colleagues at a military hospital in Paris to give the drug to a 24-year-old man suffering from psychosis. Twenty days of treatment later, the man was ready “to resume normal life.” Despite no one being sure how the drug worked, its popularity exploded across the United States and Europe as a treatment for psychosis, birthing antipsychotics as they’re known today. Around the same time, it was found that drugs used to increase the release of the neurotransmitter dopamine, like amphetamines, can lead to the onset of psychotic symptoms. Researchers eventually discovered that drugs like chlorpromazine might work by dampening the transmission of dopamine. Fiddling with dopamine levels became the cornerstone of schizophrenia treatment, laying the foundation for the dopamine hypothesis of schizophrenia—the theory that a dysregulated dopamine system causes the condition’s symptoms. Since this rush of discoveries in the middle of the 20th century, the field hasn’t progressed much. The dopamine focus has led to antipsychotics becoming the classic treatment for schizophrenia. The drugs currently on the market do achieve a degree of relief for many people living with the condition, but they have a poor effect for some patients, zero effect for others, and are notorious for triggering unwanted and sometimes overwhelming side effects. Frustratingly, the antipsychotic that works best against schizophrenia’s symptoms—clozapine, which emerged in the late 1980s—can have the nastiest unwanted effects, including weight gain, diabetes, and excessive sleepiness. “It doesn’t work in everybody, but it’s about as effective and amazing as drugs get,” says Ragy Girgis, associate professor of clinical psychiatry at Columbia University. Overall, the weak efficacy and notorious side effects of the currently available drugs mean a big percentage of people with schizophrenia simply stop taking their medication. But a new drug is bringing hope to the field. Xanomeline-trospium, or KarXT, has a novel way of diminishing dopamine transmission that’s showing promise at reducing symptoms while also limiting side effects. “The field has been waiting for something like this for far too long,” says Sameer Jauhar, a psychiatrist in London and a lecturer in affective disorders and psychosis at King’s College London. “I think it’s a breakthrough,” says Christoph U. Correll, professor of psychiatry at Hofstra University in New York. “For 70 years, we’ve been waiting for a new mechanism of action.” While dopamine seems to be a key player, exactly what triggers schizophrenia, which affects about about 24 million people worldwide, remains elusive. But the need for better treatments is clear. The condition is one of the leading causes of disability worldwide: One in 20 people with schizophrenia takes their own life, about 80 percent leave employment, and it cuts its affected peoples’ lives short by one to two decades. For the past 30 or so years, researchers have made their way through scores of drugs that target neurotransmitters other than dopamine to see if those do any better. While many showed promise in animal trials, all eventually flopped with a dull thud. A 2019 review looked at 250 studies testing other targets, dating back to the 1970s. All failed as soon as they were tried in patients. KarXT returns the focus to the dopamine system—but manipulates it in a newfangled way. The drug targets part of the brain called the muscarinic acetylcholine system using the compound xanomeline, which stimulates parts of the surface of neurons—called M1 and M4 receptors—to reduce dopamine transmission. Xanomeline had long been known for its efficacy in alleviating psychotic symptoms, but it also carried some unwanted side effects, such as nausea and vomiting. But now biotech company Karuna Therapeutics says it has solved this bug by adding in the drug trospium, which helps control common side effects xanomeline produces when given on its own. In August 2022, the topline results of a Phase 3 trial of about 250 people reported that the drug significantly reduced the severity of schizophrenia symptoms. At the end of the trial, participants were evaluated using the Positive and Negative Syndrome Scale, or PANSS, a widely used assessment in which schizophrenia patients rate the severity of 30 symptoms on a scale of 1 to 7, giving their condition an overall score. The trial reported a 9.6-point reduction in the overall score for those taking the drug compared to a placebo after five weeks—and KarXT showed promise for treating positive as well as negative symptoms. Perhaps most importantly, the drug wasn’t associated with the classic side effects of traditional antipsychotics. Karuna Therapeutics plans to submit the drug to the US Food and Drug Administration in the middle of this year, according to president and CEO Bill Meury. While there’s reason for optimism, it’s still a little early for all-out celebration in the field. “We’re gonna need a longer-term follow-up, we’re gonna need clinical real-world studies,” says Jauhar. And Correll would like to see the drug tested in patients with treatment-resistant schizophrenia. Nevertheless, for a disease that is often disabling, with an estimated 50 percent of patients who are given medication not taking it as prescribed, this drug’s encouraging trial results are worthy of excitement, says Jauhar. “We just need to subject it to the same rigor that we subject other things to, and not get too excited.”
