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Novel Schizophrenia Treatments

CE / CME

Strategic Steps in Schizophrenia: Mastering Modern Muscarinic Management

Psychologists: 0.50 APA CE Credit

Social Workers: 0.50 ASWB ACE CE Credit

Physician Assistants/Physician Associates: 0.50 AAPA Category 1 CME credit

Nurse Practitioners/Nurses: 0.50 Nursing contact hour

Pharmacists: 0.50 contact hour (0.05 CEUs)

Physicians: maximum of 0.50 AMA PRA Category 1 Credit™

Released: July 24, 2025

Expiration: July 23, 2026

Joseph P. McEvoy
Joseph P. McEvoy, MD
CME/CE Information

Activity

Progress
1 2
Course Completed

History
Andrew had been less outgoing, a less gifted student (although he studied diligently), and less talented as an athlete than his older brother and sister. After high school, his brother and sister proceeded to college; Andrew took a job at the local grocery store. His family is loving and supportive, and his parents were pleased that he chose to continue living with them. They were getting older, and he helped them with chores and yard work. He had a few friends with whom he would play video games or go to the movies.

At the age of 20, Andrew underwent a significant transformation over the course of several months. His parents gradually realized that he had become less engaged with them. He spent most of his time at home in his room and had stopped spending time with his friends. His parents knew the manager of the local grocery store and contacted her. She and other employees had noticed similar disengagements by Andrew. Both his parents and the grocery store staff had observed him talking to himself.

Andrew’s mother’s sister had a psychotic break in her late 20s. Her psychosis remitted after several months of treatment with antipsychotic medication. She was unable to return to competitive employment and received a disability check. She has a part-time supported job at a local church helping with housekeeping, and she can live independently. She has dinner with Andrew’s nuclear family once a week. In recent years, she has gained a substantial amount of weight, likely related to taking a second-generation antipsychotic (SGA) medication. She takes metformin for type 2 diabetes (T2D).

Given this family history of a psychotic disorder,1 Andrew’s parents suggested that he see a psychiatrist, and he agreed. He told the psychiatrist that he had been receiving messages from the television and through telepathy for the preceding several months.2 He reported having trouble engaging with others3 and organizing and completing tasks at home and at work.4 His sleep had become interrupted by frequent nighttime awakenings.5

Because of Andrew’s family history of weight gain and diabetes with SGAs,6 the psychiatrist chose to treat him with haloperidol 5 mg,7 benztropine 2 mg,8 and lorazepam 1 mg, all taken by mouth at bedtime.9 He slept through the night with these medications. Of note, Andrew has no personal or family history of addiction,10 including no cigarette smoking. Over several weeks, the messages became less frequent, less intrusive, and less distressing. However, he experienced subjective and observed restlessness, only partly relieved by propranolol 40 mg by mouth twice daily11; mild constipation; and clouding of his thinking, in particular, difficulty retaining new material in his memory.

The psychiatrist recommended Andrew switch to a new combination medication (xanomeline/trospium). The active agent in the combination is xanomeline, an agonist at muscarinic acetylcholine receptors in both the central and peripheral nervous systems.12 Preclinical studies have shown that, through its M1 and M4 agonism, xanomeline reduces dopamine neurotransmission in the brain.13 Excessive synthesis and release of dopamine in brain regions that assign salience to items of sensory experience and intrapsychic life correlate with the presence and severity of early psychosis.13

However, xanomeline is a weaker, but still significant, M2 and M3 agonist.14 In the peripheral nervous system, M2 and M3 agonism results in poorly tolerated side effects such as nausea and vomiting, excessive salivation, and bradycardia.15 Trospium is an antagonist at M1, M2, M3, M4, and M5 muscarinic acetylcholine receptors.15

Trospium is highly hydrophilic, and it penetrates the blood-brain barrier poorly.16 By blocking M2 and M3 muscarinic acetylcholine receptors in the periphery, it mitigates the cholinergic side effects of xanomeline (nausea and vomiting, excessive salivation, bradycardia).17 Because it cannot enter the central nervous system, it does not interfere with the therapeutic actions of xanomeline at central M1 and M4 muscarinic acetylcholine receptors.

Andrew, a 20-year-old male with new-onset psychosis and a family history of SGA-induced metabolic syndrome, has shown partial improvement with haloperidol but is experiencing distressing side effects.

How do we initiate treatment with xanomeline/trospium?