The symptoms of the condition are split into three categories: positive symptoms, such as hallucinations or delusions; negative symptoms, such as social withdrawal or an inability to show emotion; and cognitive symptoms, which include disturbances in working memory and executive functioning. Current medications do little to treat the latter two. And for many, they don’t help at all: An estimated 30 percent of patients are considered treatment-resistant. For another chunk, the drugs only work partially. 

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.”