In 1993, Florey Professor Brian Dean discovered that M1 and M4 muscarinic receptors, which are integral to the brain’s cholinergic system, were lower in some people with schizophrenia; such changes would affect their ability to interact with others and their cognition which are symptoms of the disorder.
“At that time no drug treatment was effective in reversing these two symptoms of the disorder,” Professor Dean says.
His discovery opened up new treatment possibilities for drugs targeting cholinergic defects in people with schizophrenia.
“Existing schizophrenia medications haven’t really changed since the 1950s. Many people with the disorder are non-responsive and many experience unpleasant side effects such as weight gain, dizziness and sleepiness. I really hoped my discovery could lead to a drug that was effective without side effects to put people off taking it.”
Pharmaceutical company Eli Lilly developed the drug xanomeline that, as suggested by Professor Dean’s research, activated muscarinic M1 and M4 receptors.
While the treatment lessened the positive, negative and cognitive symptoms of schizophrenia in a group of treatment-resistant people, it caused unacceptable side effects. Trials were stopped and Eli Lilly ceased work on xanomeline.
Next, Karuna Therapeutics pursued a treatment combining xanomeline with trospium, a drug to counter xanomeline’s side-effects. Patients in a one-year trial of the resulting KarXT experienced significant and consistent improvement in symptoms and the drug favorably impacted their weight and long-term metabolic profiles.
Professor Dean says KarXT looks set to get US Food and Drug Administration approval in late 2024. Once that happens, other countries are likely follow suit, he says.
“KarXT is a whole new approach to treating schizophrenia,” Professor Dean says.
“This 30-year journey, from the discovery of deficits in the cholinergic system in schizophrenia, to a treatment, shows how basic research like ours at the Florey is critical to the development of new drugs for brain disorders.”
Media contact
Kathryn Powley, Media and Communications Manager
[email protected] | 0456 666 271