Day 1: Systems Neuroscience Enters the Room

The summit opened with workshops, one of which I co-organized with Mikhail Kalinichev (Neurosterix Therapeutics, Geneva) and Rouba Kozak (Foundation for the National Institutes of Health). Mikhail brings deep experience from his years at GSK, Lundbeck, and Ipsen, having helped drive clinical development in schizophrenia-related cognitive impairment. Rouba previously led programs developing many neuro/psych relevant compounds with a focus on precision medicine.

Our workshop centered on how systems neuroscience and computational models of circuit dysfunction—what I’ve called “algorithmic circuit psychiatry”—can refine target selection, inform biomarker development, and guide trial design. This perspective has been underrepresented in drug development but is increasingly seen as essential for psychiatric disorders, where symptom clusters often reflect underlying circuit-level failures. See my earlier post here

A central question emerged: Should biomarker development occur during phase 1-3 clinical trials, or wait until after drug approval? The tension reflects the translational challenge in psychiatric drug development. Without predictive biomarkers, clinical trials must balance stringent selection criteria against practical timelines, often leaving drug developers flying blind.

Left to right: Michael Halassa, Mikhail Kalinichev, Rouba Kozak

Following our session, Paulo Lizano from BIDMC led a compelling workshop on integrating patient-centered outcomes, such as quality of life measures, directly into clinical trial endpoints. As the field increasingly recognizes that pure symptom scales may not fully capture meaningful change, incorporating functional and experiential outcomes feels both scientifically valid and deeply patient-centered.

Day 2: The Rise of Muscarinic Agents

By the second day, one theme dominated: muscarinic receptor agonism has become the most exciting frontier in schizophrenia drug development.

The KarXT/Cobenfy Story

Steve Paul delivered a masterful keynote tracing the long and improbable road to Cobenfy (xanomeline-trospium), the most important advance in psychosis pharmacotherapy since clozapine. Originally developed as a derivative of arecoline (from betel nut) for Alzheimer’s, xanomeline’s repurposing for psychosis required remarkable translational persistence.

Key highlights from Paul’s talk:

• Exceptional CNS penetration: A 10:1 brain-to-plasma ratio, highly atypical for psychiatric agents.
• Side effect complexity: Pro- and anticholinergic effects drive the need for more selective muscarinic agents.
• Domain-specific effects: Cognitive gains, especially in working memory and executive function, often decouple from standard PANSS reductions.

Paul emphasized that head-to-head trials against atypical antipsychotics remain a critical next step.

Steve Paul being introduced by Murali Gopalakrishnan

Steve Paul gave an inspiring and forward-looking talk

From Algorithm to $14 Billion

Andrew Miller, one of Karuna’s original R&D leads, described how 7,410 compound combinations were screened through an algorithm-driven selection process, ultimately resulting in the xanomeline-trospium pairing. Starting with just $4,000 (and critical support from the Wellcome Trust), Karuna’s journey culminated in its $14 billion acquisition by Bristol Myers Squibb—a biotech success story that underscores how unconventional mechanisms can lead to transformative breakthroughs.

Andrew Miller gave a superb talk about the development of KarXT/Cobenfy

Emerging Themes: Biomarkers, Stratification, and Digital Tools

Throughout the summit, multiple sessions drilled into the next central challenge: how to stratify patients, measure meaningful improvement, and de-risk clinical development earlier with predictive biomarkers.

Biomarkers: The Missing Link—and what’s up with Emraclidine?

The panel featuring Nick Brandon (Neumora), Hadile Ounallah-Saad (Clexio), Larry Park (AbbVie), and Rob Goldman (MapLight Therapeutics) emphasized that lack of biomarkers has plagued psychiatric drug development for decades. AbbVie made clear they are not abandoning Emraclidine despite Phase II setbacks. They attribute the setback primarily to suboptimal trial design rather than flaws in the compound itself—a refreshingly sophisticated view that acknowledges how heterogeneity, endpoint selection, and sample stratification can easily derail psychiatric trials.

Right to Left: Nick Brandon (Neumora), Hadile Ounallah-Saad (Clexio), Larry Park (AbbVie), and Rob Goldman (MapLight Therapeutics)

I was particularly happy with the opportunity to discuss early clinical real-world experience with Cobenfy. Having the people who developed this compound in the same room was surreal!

Digital Interventions for Negative Symptoms

Click Therapeutics showcased their work on digital interventions targeting experiential negative symptoms. Their augmented reality glasses, designed to enhance social salience during simulated interactions, represent a highly innovative, non-pharmacological circuit intervention.

The wonderful click team

I had particularly rewarding conversations with Click’s CMO, Shaheen Lakhan, about converging digital therapeutics with systems neuroscience. We’re now collaborating on a forthcoming article about the future of inpatient psychiatry, combining digital augmentation with circuit-level mechanistic frameworks. Stay tuned!

Novel Biology: Retroviruses & Neuroplastogens

• Jonathan Javitt presented provocative data implicating endogenous retroviral elements (HERV-W-ENV) in schizophrenia pathophysiology—a reminder that viral mechanisms may still yield unexpected insights.
• Rajiv Agrawal (Deluxe Therapeutics) introduced DLX-2270, a neuroplastogen targeting synaptic vesicle protein 2A density. While neuroplasticity-based interventions (e.g., ketamine in depression) have gained traction, their application in psychosis remains early-stage.

Long Acting Injectables (LAIs) and Early Intervention

Hannah Brown delivered an excellent talk on the value of long-acting injectables (LAIs) in first-episode psychosis, referencing mirror-image study designs like PRELAPSE. Reconnecting with Hannah—whom I trained alongside in residency—was a highlight, and her combination of methodological rigor and clinical pragmatism was outstanding.

Hannah Brown did a masterful job at emphasizing the importance of LAIs

Was great to connect after 12 years!

The Takeaway: A Field at Inflection Point

The closing day featured Hadile Ounallah-Saad’s exceptional talk on developing an M1/M4 agonist (CLE-905) with different properties than Xanomeline and one that may not need a peripheral antagonist like trospium! If this ends up panning out in human trials, it will be game-changing and will give us a shot at a muscarinic LAI! Go Clexio!

Hadile Ounallah-Saad giving a talk about Clexio’s lead compound CLE-905

My friend Zhong Zhong, CMO for OVID therapeutics gave a superb talk on KCC2 activators as a potential class of antipsychotic medications. My lab is involved in the preclinical side of this endeavor so we’re all hopeful this will end up having some clinical utility!

Zhong talking about KCC2 modulators as disease modifying agents in schizophrenia

Throughout the summit, there was palpable energy. After decades of stagnation, the field appears to have finally cracked open. For too long, psychiatric drug development has been stalled by perceived biological intractability and late-stage trial failures where clinical efficacy predicted pre-clinically failed to materialize. But this summit showcased the tools now available to change that trajectory:

• Systems neuroscience informing target selection
• Circuit models guiding conceptual framing
• Sophisticated biomarkers enabling patient stratification
• Digital augmentation expanding therapeutic options
• Novel molecular targets beyond dopamine

The muscarinic wave, exemplified by xanomeline, validates that genuinely novel mechanisms can succeed in psychiatry, while also reinforcing that circuit-level understanding must drive future drug development.

For those of us working in systems and circuits, it seems obvious that this is the type of neuroscience that pharma needs. This is but one of several facets of the algorithm circuit framework we have been working on for the last several years.

I left Boston energized and cautiously optimistic that we are witnessing the dawn of psychiatry’s own precision medicine revolution. The science is finally catching up to the clinical complexity. Now we need the discipline, patience, and collaborative ambition to build on this momentum.

This piece reflects my experience co-organizing the Systems Neuroscience workshop at the 2025 Innovation in Psychosis Therapeutics Summit and observations from three days of presentations, panels, and discussions with leading researchers, clinicians, and industry executives.

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