When I read the recent Psychiatric Times reflection on the first year of Cobenfy in real-world practice, I found myself agreeing with much of what was said because the article finally acknowledged what many of us have learned the hard way: the medication itself has not been the limiting factor. Implementation has (Weiden, 2026).
The discussion around switching and attachment, in particular, resonated deeply. I could not agree more that switching skills can make or break outcomes. In community psychiatry, switching is rarely a neutral act. It is often the most destabilizing or stabilizing intervention we make. I have lost many a client back to hospitalization not because a new medication failed, and not because the prior medication was ideal, but because the transition itself disrupted something fragile and hard-won. This is not a new problem in psychiatry, and the importance of thoughtful switching has been well described long before muscarinic agents entered the picture (Weiden & Buckley, 2007).
Attachment to a medication is real. For clients living with chronic psychotic illness, medications often represent safety, predictability, and identity, even when they come with trade offs. When that attachment is severed too abruptly or without sufficient scaffolding, the nervous system responds long before clinicians have time to react. Regression rarely announces itself dramatically. It begins quietly, sleep disruption, rising anxiety, slipping concentration, inconsistent adherence, increasing disorganization. By the time hallucinations or paranoia return, the trajectory is already set. Hospitalization then feels inevitable, not because the illness suddenly worsened, but because cognitive stability was lost during the transition. This pattern aligns closely with what we know about cognition as a primary determinant of functional outcome in schizophrenia (Bowie & Harvey, 2006; Green et al., 2000).
This challenge becomes even more complex when switching from the “pines.” Clozapine, olanzapine, and quetiapine carry real anticholinergic burden, and concerns about ileus are entirely valid. One ileus is one too many. At the same time, fear has a way of flattening nuance. I have watched reasonable caution turn into avoidance, and avoidance turn into therapeutic paralysis. The result is often that clients remain cognitively stalled on regimens that suppress behavior but never restore function, despite long-standing evidence that symptom suppression alone does not predict recovery (Bowie & Harvey, 2006).
Over time, I have struggled to identify the safest and most effective way to implement these transitions. There is no universal roadmap, and the clinical trial data do not reflect the complexity of real-world practice. Through experience, iteration, careful observation, and some significantly helpful post hoc exploratory data, I have arrived at an approach that I believe minimizes regression while respecting gastrointestinal risk. These post hoc signals, while not definitive, are consistent with emerging evidence that muscarinic receptor agonism may influence cognitive domains independently of positive symptom control (Horan et al., 2024; Olgiati et al., 2023). I am intentionally not outlining a public dosing or switching schedule here. It is not on label, and nuanced clinical judgment does not translate well into rigid formulas.
What I will say, based on repeated clinical experience, is that the difference between the 100 mg and 125 mg formulation is not trivial. In my opinion, the additional 10 mg of trospium in the 125 mg dose makes a meaningful difference in tolerability and stability during these transitions. It is not dramatic or immediate, but clinically it often represents the difference between a client settling into the medication versus unraveling during the process. This observation mirrors real-world reports emphasizing the importance of individualized titration and tolerability management with xanomeline–trospium (Price & Price, 2025).
The case highlighted in the Psychiatric Times article brings this into sharp focus. The 18-year-old described did not simply experience symptom reduction. He returned to college. He demonstrated good concentration, resolution of psychosis, improved social-emotional communication, and insight that exceeded his premorbid baseline (Price & Price, 2025; Weiden, 2026). That detail should not be glossed over. Returning to college is not a proxy for symptom control. It is a marker of cognitive recovery.
That is exactly why this case matters, and what I have been saying this entire time.
In my prior blog articles on schizophrenia, I have repeatedly argued that we have spent far too much time measuring symptoms and not nearly enough time understanding function. Schizophrenia is not defined by the presence of hallucinations alone, and recovery is not determined by their absence. Functional outcome is driven by cognition. Attention, working memory, processing speed, and the ability to organize thought determine whether someone can learn, work, maintain relationships, and live independently. When cognition falters, everything else follows. a conclusion consistently supported across decades of outcome research (Bowie & Harvey, 2006; Green et al., 2000).
You can quiet voices without restoring function. You cannot restore function without addressing cognition.
This is why muscarinic based treatments matter, not because they are novel, but because they reopen a door that has been largely closed in schizophrenia treatment. For the first time, we are seeing credible signals that cognition may be modifiable, not merely as a downstream effect of symptom suppression, but as a domain worth targeting in its own right (Horan et al., 2024; Olgiati et al., 2023).
The real risk now is not the medication. It is implementation. If we rush switches, underestimate attachment, or allow fear to override thoughtful cross-titration, we will continue to see early discontinuation, regression, and avoidable hospitalizations. Not because the medication failed, but because we did not give the brain time to adapt.
Cognition does not rebound on our timeline. It requires stability, patience, and respect for the systems we are asking to reorganize. If we want fewer hospitalizations and more people returning to school, work, and meaningful life roles, switching can no longer be treated as an afterthought. It is the intervention. And cognition must remain at the center of the conversation, because it is, and always has been, the driver.
Bowie, C. R., & Harvey, P. D. (2006). Cognitive deficits and functional outcome in schizophrenia. Neuropsychiatric Disease and Treatment, 2(4), 531–536. https://doi.org/10.2147/nedt.2006.2.4.531
Green, M. F., Kern, R. S., Braff, D. L., & Mintz, J. (2000). Neurocognitive deficits and functional outcome in schizophrenia: Are we measuring the “right stuff”? Schizophrenia Bulletin, 26(1), 119–136. https://doi.org/10.1093/oxfordjournals.schbul.a033430
Horan, W. P., et al. (2024). Cognitive outcomes associated with muscarinic receptor agonism in schizophrenia: Post hoc analyses from the EMERGENT trials. American Journal of Psychiatry. Advance online publication.
Kaul, M., et al. (2024). Efficacy and safety of xanomeline–trospium in adults with schizophrenia: Results from phase 3 randomized controlled trials. Schizophrenia, 10, Article 112. https://doi.org/10.1038/s41537-024-00421-7
Olgiati, P., et al. (2023). Comparative effects of antipsychotics on cognitive domains in schizophrenia: A systematic review and network meta-analysis. International Clinical Psychopharmacology, 38(5), 229–240. https://doi.org/10.1097/YIC.0000000000000408
Price, M. Z., & Price, R. L. (2025). Early outpatient clinical experience with xanomeline and trospium chloride for schizophrenia: A case report. Frontiers in Psychiatry, 16, 1630574. https://doi.org/10.3389/fpsyt.2025.1630574
Weiden, P. J., & Buckley, P. F. (2007). Reducing the burden of side effects during long-term antipsychotic therapy: The role of switching medications. Journal of Clinical Psychiatry, 68(Suppl 6), 14–23.
Weiden, P. J. (2026). From approval to practice: How has Cobenfy’s new mechanism of action impacted psychiatry? Psychiatric Times, 43(1), 9–15.
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