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Preliminary real-world predictors of response to muscarinic targeting in psychosis

Nature Mental Health volume 3, pages 1512–1518 (2025)Cite this article

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Abstract

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.

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Fig. 1: Hierarchical clustering reveals three clusters of patients based on their features.
Fig. 2: Heatmap showing the prevalence of clinical features across clusters.
Fig. 3: Plot showing patient clustering in MDS space.
Fig. 4: LDA results for responsive versus nonresponsive groups.
Fig. 5: LDA feature weights ordered by absolute magnitude.

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Data availability

All data related to this Article are available via GitHub at https://github.com/orgs/Halassa-Lab/repositories.

Code availability

Code is available via GitHub at https://github.com/orgs/Halassa-Lab/repositories.

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Acknowledgements

I thank D. Ongur, S. Fitzpatrick, D. Rothman and A. Jaffe for feedback on the data and recommendations for improvement. I thank P. R. Halassa for assistance with my code, and R. D. Wimmer for discussions and help with manuscript preparation and revision.

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Authors and Affiliations

  1. Departments of Neuroscience and Psychiatry, Tufts University School of Medicine, Boston, MA, USA

    Michael M. Halassa

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  1. Michael M. Halassa
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M.M.H. analyzed the data and wrote the manuscript.

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Correspondence to Michael M. Halassa.

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The author declares no competing interests.

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Nature Mental Health thanks Alessandro di Lisi and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 LDA results with equivocal patients included post classification.

Equivocal patients (n = 5) were grouped with the non-responders when projected onto the LDA principal vector.

Extended Data Fig. 2 LDA results for the combined cohort 1 and cohort 2 dataset.

LDA derived discriminant function revealed clear separation between responsive and non-responsive patient groups (n = 49).

Extended Data Fig. 3 LDA feature weights for the combined dataset ordered by absolute magnitude.

Note that this matches the original datasets with an increase in Intellectual disability negative weights and a slight decrease in stimulant use predictive value. Total n = 49 patients.

Extended Data Table 1 Patient demographics of cohort 2
Full size table

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Halassa, M.M. Preliminary real-world predictors of response to muscarinic targeting in psychosis. Nat. Mental Health 3, 1512–1518 (2025). https://doi.org/10.1038/s44220-025-00529-w

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