Since a schizophrenia drug, the first in decades with an innovative mechanism of action, gained US FDA regulatory approval in September 2024, some researchers have proclaimed a new era for psychiatric medicine. About half a dozen similar drugs — for schizophrenia, Alzheimer’s disease and other conditions involving the brain — are in various stages of development, most in early-stage clinical trials. However, the success of these medicines is not a given. In mid-November 2024, a trial of a highly anticipated schizophrenia drug reported disappointing results.
For decades, schizophrenia drugs worked in essentially the same way. They blunted the activity of dopamine, a chemical involved in the disorder’s hallmark symptoms, such as hallucinations and delusions. The new kid on the block is KarXT, sold as Cobenfy. It targets muscarinic receptors and leads to antipsychotic and cognitive benefits. “I don’t think I’ve ever seen this much buzz and excitement over a new approach in psychiatry in my career,” says Jeffrey Conn, a Pharmacologist at Vanderbilt University in Nashville, Tennessee.
KarXT’s success in winning US regulatory approval has revived interest in muscarinic drugs. “Drug discovery is coming back to psychiatry,” says Arthur Christopoulos, a Molecular Pharmacologist at Monash University in Melbourne, Australia, who was involved in the development of KarXT.
However, developing new medicines is a hard, long road. On 11 November, Abbvie, a pharmaceutical company in North Chicago, Illinois, announced that its muscarinic drug for schizophrenia, called emraclidine, had failed to outperform a placebo. What this means for other muscarinic drugs in development remains to be seen, Christopoulos says. “It is still early days.”
New psychiatric drugs
KarXT’s road to development wasn’t smooth, either. Xanomeline, one of the active components of the drug, was developed in the 1990s and shown to reduce psychotic symptoms in people with Alzheimer’s disease. However, in a clinical trial, many participants who received the drug stopped taking it owing to nausea, vomiting, and other side effects. Muscarinic receptors are present throughout the brain and body so drugs that target them can have broad effects. The drug was shelved, along with others under development at the time. “Almost everyone decided that muscarinic agonists were probably an impossible feat to accomplish,” says Conn, who was one of the scientific Co-Founders of the company behind KarXT.
In 2009, Karuna Therapeutics, based in Boston, Massachusetts, combined xanomeline with another compound, trospium, which blocks muscarinic receptors but cannot cross into the brain, preventing unwanted side effects in the body. The combination became known as KarXT. In clinical trials, people with schizophrenia taking the combined drug experienced antipsychotic and cognitive benefits, with milder side effects than for xanomeline on its own.
Mode of action
Xanomeline acts mostly on two of the five muscarinic receptors: the M1 and M4 receptors. Animal studies suggest that the M4 receptor is most strongly associated with antipsychotic effects, whereas the M1 receptors is linked to cognition.
REFERENCE: Nature; 21 NOV 2024; Diana Kwon