In fall 2024, xanomeline trospium chloride (XT) was approved by the U.S. Food and Drug Administration for the treatment of adults with schizophrenia. In an earlier post, we reviewed evidence that this medication can improve both positive and negative symptoms associated with this illness.

Positive symptoms include hallucinations (hearing or seeing things that aren’t there), delusions (fixed, false beliefs), and thought disorder (disruption of organized thought and communication). Negative symptoms include constricted affect, decreased motivation, and diminished social interactions.

In addition to positive and negative symptoms, individuals with schizophrenia often have cognitive deficits that involve diminished executive function (for example, skills involved with planning and problem solving), decreased attention, and reduced memory skills. Cognitive deficits interfere with an individual’s ability to work productively and perform various tasks.

XT has a mechanism of action that differs from other antipsychotic medications currently used to treat schizophrenia. It stimulates specific acetylcholine receptors (called muscarinic receptors) in the brain while limiting stimulation of these receptors in the peripheral nervous system (for example, in the gastrointestinal system).

The brain’s acetylcholine system is known to influence cognitive functions. In animal models of cognitive deficits, augmenting the acetylcholine system has been shown to result in cognitive improvement.

In a recent paper published in the American Journal of Psychiatry, William Horan and colleagues report results from phase three clinical trials regarding the effects of XT on cognitive function in people with schizophrenia.

Study design

These investigators analyzed combined data from two similarly designed phase three clinical trials of XT in individuals hospitalized with acute psychotic exacerbations of schizophrenia. They examined the effects of XT versus placebo on cognitive function in the total group of 307 participants, a subgroup with normal cognitive function at baseline, and another subgroup with impaired cognitive function at baseline. Individuals were classified as having impaired cognitive function if they scored “one or more standard deviations below the healthy normative standard” on a battery of four cognitive tests included in the Cambridge Neuropsychological Test Automated Battery (CANTAB), a computerized (tablet-based) battery. The four tests examined executive function, visual memory, sustained attention, and verbal recall and recognition. Forty-five percent of individuals fulfilled the definition of cognitive impairment. Individuals were tested at baseline and again after three and five weeks of treatment. Individuals in the cognitively impaired group did not differ significantly from the “within-normal-limits” group in demographic or clinical characteristics at baseline. All study participants had discontinued taking other psychoactive medications, including antipsychotics, prior to the baseline visit.

Results

XT did not have a significant effect on cognitive function in people whose cognitive scores were within normal limits at baseline. In those with cognitive impairment, five weeks of XT treatment was associated with significant improvement in cognitive function when compared with placebo. Thirty-nine percent of the cognitively impaired group receiving XT achieved a 0.50 standard deviation improvement compared to 19 percent of those receiving a placebo. Twenty-eight percent of those receiving XT demonstrated a 0.70 standard deviation improvement compared with 6.8 percent of those receiving a placebo.

Improvements were noted in tests associated with executive function, sustained attention, and verbal recall. There was no statistically significant improvement in the visual memory task.

As previously noted, XT is associated with improvements in both positive and negative symptoms. After factoring in changes in these symptoms, cognitive improvement was still significant.

Reflections

Recently, substantial progress has been made in developing new classes of medications for treating several psychiatric conditions. XT represents a new medication with a different mechanism of action than other currently available drugs for treating schizophrenia. Like traditional antipsychotics, this drug helps decrease positive symptoms. However, it also decreases negative symptoms and, in those with cognitive deficits, improves cognition. It is likely that this drug represents the first of many new medications for treating schizophrenia that work via the acetylcholine system. Other medications with different mechanisms of action are also under investigation. Hopefully, over the next decade, persons suffering from chronic psychotic illnesses will have treatments that alleviate much of their suffering.

This post was written by Eugene Rubin MD, PhD and Charles Zorumski MD