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.

Tim, a young man in his mid-20s, had been struggling with schizophrenia for years. Despite multiple antipsychotic trials, his symptoms remained poorly controlled. He experienced severe side effects—weight gain, sedation, and akathisia—that made him noncompliant with his medications. His family described him as increasingly withdrawn, with frequent outbursts of agitation and difficulty managing his behavior. Tim’s life seemed stuck in a cycle of hospitalizations and unstable living situations.

When Tim was started on Cobenfy (xanomeline/trospium), the change was nothing short of remarkable. Within weeks, he began to engage more with his family and treatment team. The “empty look” in his eyes was replaced by a spark of vitality. He started attending therapy sessions regularly and even expressed interest in finding a part-time job. Most importantly, Tim became compliant with his medication, something he had resisted for years due to side effects. For Tim, Cobenfy wasn’t just another medication—it was a lifeline.

Cobenfy: A Novel Approach to Schizophrenia Treatment

Cobenfy, a combination of xanomeline (a muscarinic M1/M4 receptor agonist) and trospium (a peripheral anticholinergic), represents a significant departure from traditional antipsychotics, which primarily target dopamine D2 receptors. By modulating muscarinic signaling, Cobenfy addresses both positive and negative symptoms of schizophrenia, offering hope for patients like Tim who have not responded to conventional treatments.

Who Might Benefit from Cobenfy?

In my practice, I’ve found Cobenfy particularly useful in three specific patient populations:

1. Treatment-Resistant Patients on Clozapine: For patients who have tried clozapine—often considered the gold standard for treatment-resistant schizophrenia—but still experience residual symptoms, Cobenfy can provide an additional layer of relief. It seems to address symptoms that clozapine alone cannot fully resolve.
2. Patients Intolerant to D2 Antagonists: Many individuals struggle with the side effects of traditional antipsychotics, which primarily target dopamine D2 receptors. These side effects—ranging from extrapyramidal symptoms to metabolic issues—can be debilitating. Cobenfy, with its distinct mechanism of action, offers an alternative with a more favorable side effect profile.
3. Patients with Prominent Negative and Cognitive Symptoms: Negative symptoms (e.g., social withdrawal, blunted affect) and cognitive deficits are often the most challenging to treat. Cobenfy appears to have a unique ability to address these symptoms, which are typically less responsive to conventional antipsychotics.

Anecdotal Observations: When Cobenfy Works, It Works Quickly

One of the most striking aspects of Cobenfy is the speed and clarity of its effects in responders. Here’s what I’ve observed anecdotally:

1. The “Light Bulb” Effect: When Cobenfy works, the change is often dramatic and rapid. Patients who previously had an “empty look”—a hallmark of psychosis—suddenly appear more present and engaged. It’s as if a “light bulb” has turned on, illuminating their personality and vitality.
2. Improved Social Engagement: Patients become more interactive, initiating conversations and showing interest in their surroundings. This is particularly notable in individuals who were previously withdrawn or isolated due to negative symptoms.
3. Favorable Side Effect Profile: Compared to traditional antipsychotics, Cobenfy is generally well-tolerated. This makes it an attractive option for patients who have struggled with the side effects of D2 antagonists.

The Science Behind Cobenfy: What Does the Research Say?

Cobenfy’s mechanism of action is rooted in its ability to activate muscarinic M1 and M4 receptors, which play a critical role in modulating dopamine and glutamate signaling in the brain. Research suggests that muscarinic agonists like xanomeline can improve both positive and negative symptoms of schizophrenia by restoring balance to these neurotransmitter systems.

• Clinical Trials: A phase 2 clinical trial published in The New England Journal of Medicine (Brannan et al., 2021) demonstrated that xanomeline significantly reduced both positive and negative symptoms in patients with schizophrenia, with a side effect profile comparable to placebo when combined with trospium to mitigate peripheral cholinergic effects.
• Neurobiological Insights: Studies have shown that muscarinic receptors are densely expressed in brain regions implicated in schizophrenia, such as the prefrontal cortex and hippocampus. Activation of these receptors enhances cortical connectivity and improves cognitive function, which may explain Cobenfy’s efficacy in addressing negative and cognitive symptoms (Shekhar et al., 2008).
• Psychosis Biotypes: Research by Keshavan, Tamminga, and others has proposed that schizophrenia comprises distinct biotypes, each with unique underlying biological mechanisms. For example, one biotype may be characterized by glutamatergic dysfunction, while another may involve muscarinic receptor abnormalities (Clementz et al., 2016). This framework could help explain why some patients respond dramatically to Cobenfy while others do not.

The Challenge of Predicting Response

While Cobenfy’s potential is exciting, one of the biggest challenges is predicting who will respond to it. Currently, we lack reliable biomarkers or clinical indicators to identify these patients a priori. However, emerging research offers some promising avenues:

1. M1 PET Imaging: Experimental techniques like M1 muscarinic receptor PET imaging may help identify patients with specific receptor profiles that make them more likely to respond to Cobenfy. This could pave the way for personalized treatment approaches.
2. AI and Machine Learning: As we collect more data on Cobenfy’s effects, AI-driven tools could analyze patterns in treatment response, helping clinicians make more informed decisions. Imagine a future where an AI agent could predict the best treatment for a patient based on their clinical profile and biomarker data.

What Cobenfy Tells Us About Schizophrenia

Cobenfy’s varied response rates underscore a critical point: schizophrenia is not a monolithic condition. Instead, it likely encompasses multiple biological substrates, each with distinct pathophysiological mechanisms. The fact that some patients respond dramatically to Cobenfy while others do not suggests that muscarinic signaling plays a key role in certain subtypes of schizophrenia.

This heterogeneity also highlights the importance of moving beyond a one-size-fits-all approach to treatment. By combining clinical observation, advanced imaging techniques, and computational tools, we may eventually be able to tailor treatments to individual patients, maximizing efficacy and minimizing side effects.

Conclusion

Cobenfy represents a significant step forward in the treatment of schizophrenia, particularly for patients who have not found relief with traditional antipsychotics. Its ability to rapidly improve negative and cognitive symptoms, coupled with its favorable side effect profile, makes it a valuable addition to our therapeutic arsenal. However, much work remains to be done in understanding who will benefit most from this medication.

As we continue to explore the biological underpinnings of schizophrenia, tools like M1 PET imaging, psychosis biotyping, and AI-driven analysis may help us unlock the full potential of treatments like Cobenfy. For now, the “light bulb” moments I’ve witnessed in my practice—like Tim’s remarkable transformation—serve as a powerful reminder of how far we’ve come and how much further we can go.

References

1. 1. Brannan, S. K., et al. (2021). The New England Journal of Medicine, 384(12), 1124-1135.
   2. Shekhar, A., et al. (2008). Neuropsychopharmacology, 33(7), 1607-1616.
   3. Clementz, B. A., et al. (2016). American Journal of Psychiatry, 173(4), 373-384.

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