Karuna Therapeutics and Bristol Myers Squibb are winners of the 2025 Gizmodo Science Fair for their research and development of Cobenfy (xanomeline-trospium), the first truly novel medication for schizophrenia seen in 50 years. The question Can we find another way to tackle schizophrenia and other psychiatric disorders and do it without the heavy side effects of modern drugs? The results Last fall, the Food and Drug Administration approved Cobenfy (a twice-daily pill) for schizophrenia. In the pivotal clinical trials that secured its approval, people on the drug experienced a significant reduction in their symptoms compared to placebo, including “positive” symptoms like hallucinations. It was also safely tolerated, with fewer people experiencing the adverse effects common to other antipsychotics, such as weight gain. Why they did it For Andrew Miller, lead inventor of Cobenfy and founder of Karuna Therapeutics, Cobenfy’s approval was the culmination of an effort that first began over 15 years ago (Bristol Myers Squibb completed its acquisition of Karuna in 2024). Nearly every schizophrenia drug today works by targeting the neurotransmitter dopamine in our brain (some schizophrenia symptoms are linked to too much dopamine in certain brain regions, while others are linked to insufficient dopamine elsewhere). But Cobenfy takes a different approach. The first half of Cobenfy, xanomeline, targets the neurotransmitter acetylcholine through activating two specific receptors in the brain (muscarinic acetylcholine receptors 1 and 3). Earlier research in the 1990s suggested that xanomeline could potentially alleviate symptoms common to schizophrenia and other forms of psychosis. Unfortunately, those same studies also showed the drug could cause serious adverse side effects by activating these receptors elsewhere in the body, particularly the gut. “Fifteen years ago, I started talking to researchers in schizophrenia, asking questions like, ‘Where’s the emerging science? What’s interesting?’ And one of the ideas that I kept coming back to was this muscarinic idea. But there was this challenge. There was some evidence that suggests it works, but we can’t overcome these side effect considerations,” Miller told Gizmodo. Miller and his team’s innovation was to combine xanomeline with a second existing drug, trospium chloride, that would largely block its activity everywhere except the brain. The net result allows xanomeline to work as intended in the brain while not affecting the rest of the body. It still took plenty of work to find the right drugs to pair up, though. Miller notes that when his team first tried to identify the optimal muscarinic agonist and antagonist to mix together, they came up with 7,410 potential combinations. Why they’re a winner An estimated 1% of the U.S. population is currently affected by schizophrenia. Many are unable to work full-time jobs or live independently, often due to their uncontrolled symptoms. About a third of people with schizophrenia simply don’t respond to the dopamine-based antipsychotics available today; others are unable to tolerate the disruptive side effects of these drugs, including weight gain and sexual dysfunction, for very long. So Cobenfy may offer these patients a genuinely promising alternative treatment. “The name of the company, pre-BMS, was Karuna, which is a Sanskrit word. The single-word translation in English, or at least the closest word, would be ‘compassion.’ But it’s really about taking action to relieve the suffering of others. That was our goal and our motivation in doing it,” Miller said. More than just that, Cobenfy could potentially be the first of many to come. Scientists are hopeful that we’ll be able to develop other drugs that can safely activate muscarinic receptors in the brain, and some of these drugs could turn out to be more effective or have other advantages compared to Cobenfy. Muscarinic-based drugs, like other antipsychotics, may also have uses beyond treating schizophrenia. “There’s been a huge need from the beginning to target drugs that don’t directly go to that particular dopamine infrastructure in the brain,” Rishi Kakar, psychiatrist and one of the lead investigators in the EMERGENT clinical trials that secured Cobenfy’s FDA approval, told Gizmodo. “So I think that’s what is the most exciting part about it—that there is a completely different way of now attacking schizophrenia.” What’s next Bristol Myers Squibb did suffer a setback earlier this April when its Arise trial failed to show that Cobenfy performed better than placebo in treating schizophrenia when used in combination with other antipsychotics (though it was potentially better, the difference wasn’t statistically significant). But the company is pushing ahead with several trials testing Cobenfy for other indications, including treating agitation, psychosis, and cognitive impairment in people with Alzheimer’s disease, as well as bipolar disorder. Though Miller took some time to rest following Cobenfy’s approval, he has since become chairman of the board of directors at Progentos Therapeutics, a biotech company aiming to develop treatments for multiple sclerosis and similar conditions. The team Miller estimates that thousands of people have played a role in getting Cobenfy to the public, including the 250 employees involved in Karuna’s research and development at the time of the drug’s approval. “It’s an amazingly complex process, and I don’t think I really knew or appreciated that until I directly went through it—just the amount of different technical disciplines and expertise needed. And then there’s the international aspect of what it means to develop a drug and do studies in other countries and to deal with other regulatory bodies besides the FDA,” Miller said. “Developing a new drug is such a process of attrition, and unfortunately the vast, vast majority of them don’t make it. So it was certainly a huge privilege and a great experience to be a part of one that did.” Click here to see all of the winners of the 2025 Gizmodo Science Fair.