Negative Symptoms May Predict Who Responds to Xanomeline-Trospium in Schizophrenia

In this video, Mike Halassa, professor of psychiatry and biomedical engineering at Virginia Tech with a primary appointment in the Fralin Biomedical Research Institute, discusses negative symptoms in schizophrenia. He describes negative symptoms as withdrawal and apathy encountered in clinical practice, notes their substantial impact on patients’ lives, and says most antipsychotics have minimal effects on negative symptoms and cognition.

Halassa then turns to xanomeline-trospium, which he describes as the first-in-class muscarinic agent to target schizophrenia. He says the pivotal EMERGENT-1, -2, and -3 trials showed impact on positive and negative symptoms, and he notes that the most commonly reported adverse effects are GI and procholinergic effects, including nausea and vomiting.

He also describes his own off-label clinical use of xanomeline-trospium and a retrospective, uncontrolled chart review of 24 patients who received it as an add-on during hospitalization. In that review, supervised classification identified negative symptoms as having the highest coefficients or predictive value. He connects these observations to a post-hoc analysis by Bill Horan, PhD and Steve Brannan, MD from the pivotal trials, which isolated patients with prominent negative symptoms and found a larger and faster effect size, with separation from placebo around week two rather than week three for the full sample. He emphasizes that the subgroup finding was post hoc and not powered, and that the real-world analysis was retrospective and uncontrolled.