Summary: A new study examining real-world hospital data reveals early indicators of who is most likely to benefit from Cobenfy, the first new schizophrenia drug mechanism approved in 50 years. Patients with strong negative symptoms responded best to the xanomeline–trospium combination, showing notable improvements in social behavior and mood.
Those with bipolar-like features or aggression saw little benefit, pointing to multiple biological subtypes of psychosis that respond differently to treatment. These insights support the move toward precision psychiatry—matching medications to patient profiles to reduce years of trial-and-error prescribing.
Key Facts
- Negative Symptoms Improve Most: Social withdrawal and low motivation respond more reliably than hallucinations or mania.
- Biological Subgroups Identified: Distinct response patterns suggest schizophrenia is not one disease but many.
- Precision Psychiatry Pathway: Tracking symptom-specific responses could guide personalized treatment strategies.
Source: Tufts University
Each year, about 100,000 Americans experience psychosis, a serious condition that disrupts thoughts and perceptions so profoundly that it can distort a person’s sense of reality.
Now—just over a year after the first new schizophrenia drug in half a century was approved—a study in Nature Mental Health looks at how patients respond to it, offering early clues for more personalized treatment.
The study, led by Michael Halassa, professor of neuroscience at Tufts University School of Medicine, analyzed electronic medical records from 49 patients hospitalized for schizophrenia, schizoaffective disorder, or bipolar disorder with psychotic features.
All patients were given the new drug, Cobenfy—a combination of xanomeline and trospium chloride—on top of their usual antipsychotic medications after standard treatments failed to adequately control their symptoms.
“The new drug targets different receptors in the nervous system than traditional antipsychotic drugs, which mainly block dopamine D2 receptors in the brain,” says Halassa.
“Clinical trials showed the drug worked well compared with a placebo. But clinicians are still assessing how it performs as part of real-world care.”
Through statistical analyses of two small patient cohorts, Halassa’s exploratory study identified patterns that may help predict who may benefit from the xanomeline-trospium combination therapy and who might not.
The study analyzed clinical data for 24 patients, identifying several predictive clinical features for individuals who responded, did not respond, or had mixed responses to the addition of the new drug.
“A statistical analysis of clinical data from a second group of 25 patients independently replicated these findings, supporting the notion of biologically distinct psychosis subgroups,” says Halassa.
Patients with prominent “negative symptoms”—such as social withdrawal, low motivation, or reduced speech—showed the strongest improvements after receiving the new combination drug with their usual antipsychotic medications, including brighter mood and greater social engagement. Those with a history of stimulant use also tended to respond especially well to the new drug.
In contrast, patients who exhibited aggression or bipolar features (mainly manic symptoms) saw little benefit from adding the new drug to their treatment. Patients with intellectual disabilities also showed limited improvement, though Halassa notes this finding is tentative given the small number of patients with that diagnosis in the study.
The drug’s effects on other symptoms varied. Some patients with hallucinations improved, but not as consistently or dramatically as those with negative symptoms.
Halassa says the results suggest schizophrenia may be less a single disease than a collection of conditions—much like a fever or pain—that can stem from different causes and require different treatments.
He hopes the findings mark an early step toward the development of precision psychiatry, in which treatment-response patterns help guide care as they already do in other areas of medicine, such as cancer and immunology.
To shorten the long and uncertain path to recovery for patients with psychosis, he says researchers need to test whether these emerging patient subgroups can truly predict who responds to which treatments.
That means running clinical trials that compare medications in people with specific cognitive or biological profiles and tracking the precise trajectories of these symptoms over time.
Clinicians will also need to track not just whether symptoms improve, but which ones—and under what kind of drug—to drive more personalized treatments. “If we start treating every symptom response and non-response as valuable data, we could save individuals and families years of trial and error in finding effective treatment,” Halassa says.
Key Questions Answered:
A: It identifies early patterns showing which patients respond best when Cobenfy is added to standard antipsychotic treatment, highlighting key symptom profiles linked to improvement.
A: Patients with prominent negative symptoms—such as social withdrawal, low motivation, and reduced speech—showed the strongest improvements in mood, engagement, and overall functioning.
A: Patients with aggression, manic features, or intellectual disabilities showed minimal benefit, suggesting biologically distinct psychosis subgroups that may require tailored treatments.
About this psychopharmacology and schizophrenia research news
Author: Genevieve Rajewski
Source: Tufts University
Contact: Genevieve Rajewski – Tufts University
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Preliminary real-world predictors of response to muscarinic targeting in psychosis” by Michael Halassa et al. Nature Mental Health
Abstract
Preliminary real-world predictors of response to muscarinic targeting in psychosis
Xanomeline/trospium (Cobenfy) was recently approved by the US Food and Drug Administration for the treatment of adults with schizophrenia.
Despite promising findings in placebo-controlled trials, there is limited understanding of its real-world use.
Here we perform a post-hoc analysis of medical records following Cobenfy add-on administration in an inpatient population. In an initial cohort of 24 patients, ~40% experienced positive responses.
To identify predictive clinical features, we used a combination of hierarchical clustering and linear discriminant analysis, which showed that negative symptoms and stimulant use were the largest predictors of a positive response, while the presence of intellectual delay was negatively predictive.
This pattern was independently replicated in 25 patients. Overall, this work supports the notion of biologically distinct psychosis subgroups and invites further research into the underlying biological substrates.
