Xanomeline-Trospium and Iclepertin Show Promise in Managing Cognitive Impairment in Schizophrenia

Schizophrenia affects roughly 24 million people worldwide. Among other things, it causes deficits in cognitive skills such as memory, attention, processing speed, and problem-solving. Despite that, no treatments are available for cognitive impairment linked to schizophrenia (CIAS).

Cognitive Impairment in Schizophrenia

Cognitive dysfunction is a core feature of schizophrenia and remains a major cause of the long-term disability associated with the disorder. Disruptions in cognitive abilities can hamper social understanding, sensory processing, problem-solving skills, and memory. 

While established methods exist to assess cognitive dysfunction, no medications have proven effective so far. While schizophrenia patients might experience some level of cognitive issues, those with notable cognitive impairment typically struggle more with social interactions, are less likely to live on their own, and struggle to stay employed.

However, as we learn more about the mechanisms behind schizophrenia and CIAS, researchers are exploring new options. Xanomeline-trospium appears to be a strong contender for addressing schizophrenia’s symptoms. Recent phase 2 trial results suggest it also might help with cognitive function.

Today, iclepertin is the only drug in phase 3 trials specifically designed to tackle CIAS.

Post Hoc Analysis of Phase 2 KarXT Trial 

Researchers designed the phase 2 EMERGENT-1 study as a randomized, double-blind trial. The team administered either KarXT or a placebo to 182 adult participants for five weeks.

The drug achieved its primary endpoint of change in the Positive and Negative Syndrome Scale (PANSS) total score. Researchers included the potential benefits of treating CIAS as an exploratory endpoint, but they failed to observe any significant effect.

A post hoc subgroup analysis uncovered more optimistic results. In one subgroup with clinically meaningful cognitive impairment, results for 60 patients showed statistically significant improvement in cognitive performance.

A separate subgroup analysis removed outliers with excessive intraindividual variability in cognitive performance. After excluding eight patients with this variability, the results showed a statistically significant overall treatment effect of KarXT compared with placebo. The effects of KarXT in this subgroup did not relate to improvements in PANSS total scores. The researchers suggest that the drug could have a separate and meaningful impact on cognition.

Novel Mechanisms for Cognitive Improvement

Rather than binding to dopamine receptors, like all approved schizophrenia treatments, KarXT exhibits therapeutic effects mediated through direct agonism of muscarinic acetylcholine receptors (mAChRs).

Preclinical studies have indicated that mAChRs play a role in learning and memory circuits and have shown efficacy in reversing cognitive impairment in schizophrenia and Alzheimer’s disease (AD). Researchers have linked both M1 and M4 with the regulation of midbrain dopamine circuits, which sparked their interest in schizophrenia. Xanomeline, which preferentially activates M1 and M4 muscarinic receptors, has improved cognition in AD patients.

KarXT was developed as a combination of xanomeline with trospium chloride, a peripheral muscarinic receptor antagonist, to prevent adverse peripheral cholinergic effects. Further research should illuminate the possibilities of its application to improve cognition in various disease states.

Researchers have also tied prolonged hypofunction at the NMDA receptor with impaired cognitive function in schizophrenia patients. Many agents have attempted to increase excitatory input to NMDA receptors but failed to see cognitive benefits in patients. Iclepertin is a selective glycine transporter 1 (GlyT1) inhibitor that enhances glutamatergic signaling and has shown through phase 1 and 2 trials to be safe, well-tolerated, and effective at improving cognition.

A variety of multinational phase 3 trials (CONNEX) are ongoing to confirm these results. Researchers shared the baseline data for CONNEX-X at the 2024 American Psychiatric Association Annual Meeting. The multicenter, multinational, open-label, single-arm extension trial boasted 460 enrollees at the end of May. Researchers reported that data from this trial will provide key evidence supporting its long-term use in chronic disorders such as schizophrenia.

Clinical Takeaways

Cognitive dysfunction is a key aspect of schizophrenia, leading to reduced functioning and quality of life. But a dearth of effective therapies persists. That being said, the investigational agents iclepertin and KarXT show promise as agents with novel mechanisms with the potential to treat cognitive impairment.

Researchers will need to conduct future studies specifically designed to determine the effects on cognitive performance in schizophrenia and other disease states to back up these promising – albeit early – results.

Further Reading

FDA Approves First New Schizophrenia Drug in Years

Research Helps Clear Up Confusion About Cognition

Cognitive Effects of Electroconvulsive Therapy in Schizophrenia