A new schizophrenia drug revives the previously investigated drug xanomeline. Historically, physicians used xanomeline to treat Alzheimer’s disease until its removal from the market in 1998 because of gastrointestinal side effects. The investigation into its use for schizophrenia ceased for the same reason. However, an experimental drug, KarXT, combines xanomeline and trospium and takes a novel approach to treatment while reducing side effects and improving quality of life.

The Old Approach

Traditional pharmaceuticals for schizophrenia target dopamine in the brain. However, dopamine is an essential neurotransmitter for controlling motor function and plays poorly understood, nuanced roles in cognition, emotion, and social interaction. Long-term side effects of dopaminergic medications include weight gain and movement disorders. Metabolic dysfunction corresponds to premature death by increasing the risks of heart disease, high cholesterol, and Type 2 diabetes in patients. Movement disorders such as dyskinesia are often irreversible and result in motor tics, uncontrolled movements, and tremors.

The New Approach

The combination of xanomeline and trospium targets muscarinic receptors associated with acetylcholine, the same receptors targeted by drugs like atropine, used to increase heart rate in emergency medicine, and nicotine. These receptors affect the sympathetic and parasympathetic nervous systems, holistically impacting the human body. These drugs in combination target both the peripheral and central nervous systems, resulting in downstream changes to dopamine and serotonin. When trialed on its own, xanomeline produced severe, intolerable side effects common to anticholinergic medications such as constipation, dry mouth, and nausea that resulted in its discontinued use in 1998. Now, combined with Trospium, early trials reduced these side effects to more tolerable levels.

If approved, KarXT will be the first of its kind in a class of new antipsychotic medications. While still in the approval process, early clinical trials show promising results. Additionally, KarXT offers the promise of removing weight gain side effects and dyskinesia. Both are common reasons for patients to discontinue treatment against medical advice.

Results So Far

Trial results show promise with significant improvement in patients with schizophrenia by week 2 of treatment, and continuous improvement at one year, with symptoms of schizophrenia reduced from severe to mild. Participants showed an absence of metabolic side effects, though pre-existing dyskinesia remained. Patients experienced side effects of dry mouth, nausea, and constipation at tolerable levels.

KarXT is in phase 3 clinical trials with its FDA approval decision to be made on September 26, 2024. Overall, KarXT offers potential new hope in the treatment of schizophrenia and reduces or eliminates all common causes for medication discontinuation.