What Cobenfy Teaches Us About the Future of Psychiatric Drug Development
The approval of Cobenfy (xanomeline-trospium) marks more than just the arrival of a new antipsychotic. It’s a signal—subtle but decisive—that the center of gravity in psychiatry may be shifting. For the first time in decades, we have a schizophrenia treatment that doesn’t target dopamine. That’s a headline, yes. But the real story is what it reveals about where psychiatric drug development may be headed next.
Beyond Dopamine: A New Kind of Intervention
Cobenfy works through muscarinic receptors—part of the cholinergic system—offering a pathway into domains like cognitive function and motivational engagement that have historically been resistant to treatment. In our own inpatient setting, we’ve seen cases where patients previously unresponsive to dopamine-targeting drugs showed marked improvement with Cobenfy, particularly in domains long dismissed as untreatable “negative symptoms.”
But the most important question isn’t does it work—it’s why. That’s where the model breaks open.
From Observation to Mechanism: Backtranslation Begins
When a drug like Cobenfy produces unanticipated gains, it creates a unique opportunity for backtranslation. In my lab, we’ve turned to animal models to explore how muscarinic modulation affects frontal cortical circuits responsible for sustained engagement, rule-based behavior, and decision-making. These are the very domains patients often describe as being “offline” in psychosis—not overt hallucinations or delusions, but the feeling of not being plugged in to the world’s expectations.
To get at this, we’re using single-cell resolution recordings from the frontal cortex to ask how muscarinic agents reshape cognitive control. But our aim isn’t just cortical. Informed by our DBS work and broader computational frameworks, we’re examining the role of thalamocortical circuits, especially the mediodorsal (MD) thalamus, in mediating engagement and belief updating. The thalamus, far from being a passive relay, appears to act as a contextual inference engine—a kind of hidden state generator that supports flexible cognition.
If Cobenfy has a circuit-level signature, we suspect it may involve unlocking thalamocortical loops that promote alignment with the task at hand—a kind of neurobiological re-engagement with reality.
Cobenfy as a Test Case for Algorithmic Psychiatry
These observations speak to a larger need: psychiatry can no longer afford to treat molecules and symptoms as though they exist in isolation. We need a framework that links interventions at the molecular level to computational operations of the brain, and from there to clinical manifestations.
This is the project of algorithmic psychiatry—a model I explore in a recent co-authored perspective in Cell Reports Medicine. There, we argue that psychiatric disorders may be best understood as failures of computation, not chemical imbalances: disruptions in belief updating, loss of control over long-range planning, breakdowns in state estimation. Molecules like Cobenfy are useful not just because they help some patients, but because they force us to refine our understanding of which computational processes have been rebalanced.
The Path Ahead: From Circuits to Treatments
Cobenfy is not a miracle drug—but it is a conceptual milestone. It breaks the mold and gives us a reason to dig deeper into the neural systems it affects. More importantly, it gives us a reason to restructure how we develop and evaluate psychiatric treatments—starting from circuits and working outward.
If dopamine was the story of the 20th century in psychiatry, muscarinic modulation—and the circuit-level insight it demands—may be one part of the 21st