IUPHAR review: Moving beyond dopamine-based therapeutic strategies for schizophrenia

In the following we comprehensively review approaches to treating schizophrenia that do not primarily involve dopamine antagonism or partial agonism. Following 70 years of broadly similar dopamine D₂ receptor antagonist/partial agonist drugs, Cobenfy™ was approved as a novel antipsychotic in September 2024. Cobenfy™ is a combination formulation of xanomeline, a muscarinic cholinergic M₁/M₄ receptor agonist and trospium, a peripherally restricted muscarinic antagonist included to offset peripheral side effects of xanomeline. This approval has reinvigorated optimism in the field and raised important questions for the future direction of antipsychotic drug development. We review therapeutic strategies beyond dopamine that have been and are currently being investigated to address whether there are a sufficient number of novel approaches to maintain the momentum of this breakthrough and question why it has taken so long. The current pipeline of late-stage compounds is low and potentially constrained by historical setbacks and challenges in clinical trial design for schizophrenia. This success rate has future potential to improve given the range of biomarkers in development designed to enable greater precision in future clinical trials. Cobenfy™ approval demonstrates that with combination formulations designed to improve side effect profiles and optimised clinical trial design it is possible to generate tolerable and efficacious treatment options for patients beyond a solely dopaminergic framework. We conclude that advances in understanding the neurobiology of schizophrenia, while not complete, has generated a diverse and well justified pool of potentially novel and repurpose-ready approaches, with mechanisms beyond simple dopamine D₂ antagonism/partial agonism.