Clinical relevance: Research reveals shared cholinergic pathway dysfunction in schizophrenia and Alzheimer’s, leading to the development of a new FDA-approved treatment.

Schizophrenia patients face a higher lifetime risk of dementia, supporting research into cholinergic therapies for both conditions. The FDA approved xanomeline-trospium, a new schizophrenia treatment targeting muscarinic receptors, marking the first novel mechanism in more than 50 years. Ongoing phase 3 trials are evaluating xanomeline-trospium’s potential benefits for Alzheimer’s management.

Schizophrenia and Alzheimer’s might be dramatically different, but the epidemiological link between them hints at shared neuropathologic features.

One meta-analysis showed that schizophrenia patients live with a more than double lifetime dementia risk.

Schizophrenia and Alzheimer’s disease also share deficits in cholinergic pathways, supporting research into the muscarinic agonists in both conditions.

The U.S. Food and Drug Administration (FDA) approved xanomeline and trospium earlier this fall, introducing the first novel mechanism for schizophrenia management in more than half a century. This has forced researchers to revisit the muscarinic agonist xanomeline in Alzheimer’s. The ADEPT phase 3 clinical study program, for example, is evaluating xanomeline-trospium right now.

Cholinergic Pathway Dysfunction in Schizophrenia and Alzheimer’s

The cholinergic system exerts wide-ranging effects on the body – especially cognition and memory. But cholinergic inputs also power muscle movement, temperature regulation, as well as gastrointestinal and genitourinary functions.

And while acetylcholine operates as the common neurotransmitter activating cholinergic receptors, receptor subtypes include muscarinic receptors (with subtypes M1 through M5) and nicotinic receptors (with subtypes N1 and N2).

Cholinergic inputs throughout the body have multiple effects, creating a huge potential for systemic adverse events. For example, anticholinergic drugs could lead to constipation, urinary retention, reduced sweating, increased heart rate, vision changes, and reduced cognitive performance.

On the other hand, cholinergic drugs might cause diaphoresis, bowel urgency, reduced heart rate, and vision changes.

Despite all of this, cholinergic drugs can also boost cognitive performance. For example, the non-selective cholinesterase inhibitor donepezil is indicated for the treatment of Alzheimer’s dementia. But donepezil also might spark a variety of adverse events that can alter gastrointestinal, cardiovascular, genitourinary, neurological, and pulmonary functions.

While cholinergic drugs can help Alzheimer’s patients, research has exposed deficits in cholinergic neurotransmission and loss of cholinergic neurons in the disease’s pathology.

Cholinergic inputs in schizophrenia play a crucial role in regulating dopamine release from parts of the brain. Striatal M3 receptors inhibit dopaminergic outputs, while striatal M4 receptors promote dopaminergic neurotransmission. As a result, the effect of cholinergic drugs must account for receptor subtypes and the specific types of cholinergic receptors targeted with medication.

Targeting Muscarinic Receptors in Schizophrenia

Researchers started working on muscarinic receptor agonists for the management of schizophrenia back in 1957. They started first with a deep dive into a component of the betel nut, the psychoactive alkaloid arecoline. A small, open-label study uncovered early evidence that the naturally derived muscarinic cholinergic agonist arecoline might help manage schizophrenia symptoms, with arecoline exposure leading to brief periods of lucidity.

Subsequent preliminary evaluations confirmed a relationship between greater conception and lower ratings on symptom scales evaluating symptoms in schizophrenia patients. These led to the development of a synthetic derivative of arecoline known as xanomeline with M1 and M4 selectivity.

In Alzheimer’s patients, xanomeline demonstrated preliminary efficacy in the management of cognitive symptoms in a phase 2 trial. In a surprising development, psychotic symptom reductions occurred in proportion to the xanomeline dose. This, researchers insisted, suggested a previously unrecognized antipsychotic action in addition to an expected procognitive pharmacologic effect. Researchers reproduced these findings in a small trial of patients with treatment-resistant schizophrenia. Unfortunately, although xanomeline treatment adverse events didn’t overlap with those in antipsychotic therapies, exaggerated peripheral cholinergic effects curbed effective treatment.

Researchers evaluated xanomeline in combination with the peripheral muscarinic antagonist trospium to mitigate peripheral cholinergic adverse events. Unlike xanomeline, which crosses the blood-brain barrier, trospium is a quaternary amine that doesn’t in pharmacologically relevant amounts. This enables selective targeting of M1 and M4 receptors within the brain with fewer systemic adverse events.. Peripherally, trospium selectively inhibits the same receptors that xanomeline stimulates, countering potential adverse events without getting in the way of  xanomeline’s benefits.

Researchers evaluated the combination of xanomeline and trospium in the five-week randomized, double-blind EMERGENT-1 phase 2 study. And even though they observed adverse events, most of these took place within the first two weeks. And they weren’t severe enough to stop treatment. Importantly, adverse events of somnolence or sedation occurred at similar rates in placebo and treatment groups. 

Researchers also failed to notice any clinically relevant changes in body weight or metabolic parameters typically associated with antipsychotics.

Further phase 3 evaluation in the randomized, double-blind, placebo-controlled, five-week EMERGENT-2 and -3 trials confirmed efficacy on a primary endpoint: total reduction in positive and negative schizophrenia symptoms (PANSS). The trials also demonstrated safety, with similar treatment discontinuation rates in both the treatment and placebo groups.

Both trials observed secondary outcomes, including reductions in PANSS subscales compared to placebo. This indicates a unique efficacy profile that addresses both positive and negative symptoms of schizophrenia.

Targeting Muscarinic Receptors in Alzheimer’s Disease

Although scientists first evaluated xanomeline for use in Alzheimer’s in the late 1990s, the research stalled out. A 1997 publication by Bodick et al. reported a multicenter, placebo-controlled double-blind study involving 343 patients. This six-month study of xanomeline at doses of 75 mg, 150 mg, and 225 mg daily showed improvements in Alzheimer’s Disease Assessment Scale cognitive subscale measures, along with dose-dependent improvements in psychotic symptoms, including vocal outbursts, suspiciousness, delusions, agitation, and hallucinations.

At the highest dose, xanomeline therapy resulted in treatment discontinuation in more than half – 52 percent – of participants, with gastrointestinal adverse events being the most common adverse events reported. As in schizophrenia, researchers designed the addition of the peripheral cholinergic blocker trospium to block peripheral adverse events.

As a result, researchers have returned to xanomeline treatment – paired with trospium – for Alzheimer’s patients, with the ADEPT phase 3 clinical trial program underway right now.

Conclusions

After more than half a century of therapies focused solely on dopaminergic pathways, the combination of xanomeline and trospium represents an important new approach. With evidence of shared pathophysiology in cholinergic pathways mediating symptoms in both schizophrenia and Alzheimer’s, as well as known procognitive effects of cholinergic therapeutics, the development of xanomeline and trospium for Alzheimer’s disease holds promise.

With the continued development of this combination in the management of Alzheimer’s in a series of phase 3 trials, further benefits of therapy could improve outcomes across two very different conditions.