Rishi Kakar, MD, is the chief scientific officer and medical director of Segal Trials. 

Rishi Kakar, MD

Unmet Needs, Future Research in Schizophrenia and Muscarinic Agonists

xanomeline and tropsium chloride capsules (Cobenfy, formerly KarXT)

, signals a transformative shift in psychopharmacology, ushering in what leading subject matter experts are calling the "third wave" of drug development. Historically, the field has evolved from the introduction of tricyclic antidepressants and typical antipsychotics in the 1950s to the atypical antipsychotics of the 1980s, which focused on improved tolerability and safety.

As Andrew Cutler, MD, notes in the segment, this new generation leverages innovative mechanisms—particularly targeting acetylcholine alongside dopamine—aiming to address the heterogeneous nature of schizophrenia. With a range of muscarinic agonists in development, there is hope for better management of cognitive impairments and negative symptoms that have long been inadequately treated.

“We're entering an era that I'm calling the ‘muscarinic wars’ right now, which is like the old atypical wars that I lived through before Rishi entered the field, probably in the 90s, when we had a number of these atypicals,” Cutler said. “It was terrific because they're all different. Some patients we know do better with one than another, and I think the same will hold true here.”

Rishi Kakar, MD, echoed this same sentiment—noting, in his 15 years conducting studies, he has noticed more enthusiasm among clinicians with the paradigm shift.

“Let's ride the wave and see where we go,” said Kakar, on entering this new era in management.

Mechanism of Action of Xanomeline and Trospium Chloride Capsules

Applying EMERGENT Trial Results to Real-World Clinical Practice for Schizophrenia

Balancing the Benefits and Risks of Xanomeline and Trospium Chloride Capsules

(Moderator) is a former practicing psychiatrist and is the founder and chief executive officer of Terran Biosciences.

is a clinical associate professor in the Department of Psychiatry and Behavioral Sciences at SUNY Upstate Medical University and the chief medical officer of the Neuroscience Education Institute.

is a psychiatrist based out of southern Florida as well as the medical director and chief scientific officer of Segal Trials. Kakar served as the principal investigator on the pivotal EMERGENT trials.

Relevant disclosures for Cutler include Karuna, Bristol Myers Squibb, and 

. Relevant disclosures for Kakar include Karuna, Bristol Myers Squibb, and others. Relevant disclosures for Clark include Terran Biosciences.

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The approval of new schizophrenia treatments, such as xanomeline and tropsium chloride capsules, marks a significant advancement in psychopharmacology, heralding a "third wave" of drug development. This new generation of treatments targets acetylcholine alongside dopamine, aiming to address cognitive impairments and negative symptoms inadequately treated by previous medications. Experts like Andrew Cutler and Rishi Kakar highlight the potential for diverse patient responses, similar to the "atypical wars" of the 1990s. The enthusiasm among clinicians suggests a promising future for schizophrenia management.

In part 5 of 5, experts discuss ongoing unmet needs and future research priorities in schizophrenia management.

In this segment of our latest HCPLive Special Report on the 

recent approval of xanomeline and tropism chloride capsules (Cobenfy)

, conversation shifts to the critical issue of medication adherence in patients with schizophrenia. Research has indicated that adherence rates for oral medications have dropped below 50%. Rishi Kakar, MD, lead investigator of the EMERGENT trials, opened the conversation by emphasizing the multifaceted reasons behind nonadherence, highlighting that medication frequency, tolerability, and caregiver perspectives play significant roles.

Andrew Cutler, MD, expanded on the topic, explaining that factors such as inadequate efficacy, intolerable adverse events, and anosognosia can contribute to low adherence rates in patients with mental illness.

The conversation also touched on the advantages of long-acting injectable (LAI) antipsychotics, which are increasingly being adopted in clinical practice. Cutler and Kakar discuss the benefits of LAIs in terms of convenience and improved tolerability, especially for patients who struggle with daily medication reminders. They acknowledge the potential for new muscarinic agonists to be developed into LAIs, while also stressing the importance of maintaining oral medication options for patients who may not prefer injectables.

The discussion centers on the challenges of medication adherence in schizophrenia, with adherence rates for oral medications falling below 50%. Factors such as medication frequency, tolerability, and caregiver perspectives are highlighted as contributing to nonadherence. Long-acting injectable (LAI) antipsychotics are presented as a beneficial alternative, offering convenience and improved tolerability. The potential for developing new muscarinic agonists into LAIs is acknowledged, while maintaining oral options for those who prefer them. The conversation involves experts with relevant disclosures from pharmaceutical companies.

In part 4 of 5, experts discuss medication adherence to schizophrenia treatments, particularly of xanomeline and trospium choloride capsules for schizophrenia.

In this segment of our HCPLive Special Report on the

 recent approval of xanomeline and tropism chloride capsules (Cobenfy)

, leading subject matter experts discuss their interpretation of clinical trial data from the pivotal EMERGENT trials and their impact on schizophrenia treatment.

The US Food and Drug Administration (FDA) approved xanomeline and trospium chloride capsules, formerly KarXT, for the treatment of schizophrenia. The decision followed 2 critical phases of the trials: the 5-week acute studies focusing on symptom reduction and the open-label studies assessing safety and sustained efficacy over 52 weeks. The trials measured symptom improvement using the Positive and Negative Syndrome Scale (PANSS), which showed a significant difference between the treatment and placebo groups.

A principal investigator of the EMERGENT trials, Rishi Kakar, MD, noted that 75% of patients maintained their improvements by the end of the 52-week trial period. Although acknowledging that the drug may not be suitable for all patients, Kakar said the trials reveal a fundamental new approach to schizophrenia treatment. Andrew J. Cutler joined in to underline the significance of these findings and their current implications, particularly for patients who may not respond fully to current antipsychotic therapies.


The FDA has approved xanomeline and trospium chloride capsules for schizophrenia treatment, following the pivotal EMERGENT trials. These trials included 5-week acute studies and 52-week open-label studies, demonstrating significant symptom improvement using the PANSS scale. Principal investigator Rishi Kakar, MD, highlighted that 75% of patients maintained improvements over 52 weeks, suggesting a novel approach to schizophrenia treatment. Andrew J. Cutler emphasized the importance of these findings, especially for patients unresponsive to current antipsychotic therapies. The report also covers the drug's mechanism, real-world application, and future research needs.

In part 3 of 5, experts discuss the pivotal trials evaulating xanomeline and trospium chloride capsules (Cobenfy) for schizophrenia.

Mechanism of Action of Xanomeline and Trospium Chloride Capsules in Schizophrenia

approval of xanomeline and tropism chloride capsules

, panelists discussed the drug’s unique mechanism, marking a significant departure from traditional antipsychotic treatments that focus on dopamine antagonism.

Formerly referred to as KarXT, xanomeline and tropism chloride capsules were approved by the US Food and Drug Administration (FDA) to treat schizophrenia on September 26, 2024. This medication offers a novel way to manage schizophrenia by modulating acetylcholine pathways, which indirectly affect dopamine release. Xanomeline, a muscarinic receptor agonist, specifically targets the M1 and M4 receptors in the brain, whereas trospium remains in the periphery to mitigate adverse events. Experts highlighted the importance of this alternative pathway in reducing common adverse events associated with dopamine receptor blockers, including weight gain, metabolic disturbances, and drug-induced movement disorders.

“I don't think we have to totally give up dopamine here. We're not asking clinicians to give up dopamine,” said Andrew J. Cutler, MD, who has researched dopamine theory of schizophrenia. “Acetylcholine, I like to say, dances with dopamine. So, if you lower acetylcholine, you're going to lower dopamine, and one way to do that is through these acetylcholine receptors the audience may know we have muscarinic and nicotinic, and these muscarinic receptors end up toning down the dopamine release. It’s very exciting because we maybe can get away from some of the collateral damage of… blocking these postsynaptic d2, receptors.”

The recent FDA approval of xanomeline and trospium chloride capsules (Cobenfy) for schizophrenia introduces a novel treatment approach by targeting acetylcholine pathways, diverging from traditional dopamine antagonism. Xanomeline, a muscarinic receptor agonist, targets M1 and M4 receptors, while trospium mitigates peripheral adverse effects. This mechanism potentially reduces common side effects of dopamine blockers, such as weight gain and movement disorders. Experts emphasize the complementary role of acetylcholine in modulating dopamine, offering a promising alternative to current antipsychotic therapies without abandoning dopamine modulation entirely.

In part 2 of 5, experts discuss the unique mechanism of xanomeline and trospium choloride capsules for the treatment of schizozphrenia.

Rishi Kakar, MD

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