IUPHAR review: Moving beyond dopamine-based therapeutic strategies for schizophrenia
Year: 2025
Type: review
Abstract: In the following we comprehensively review novel approaches to treating schizophrenia that do not primarily involve dopamine antagonism or partial agonism. Following 70 years of broadly similar dopamine D 2 receptor antagonist/partial agonist drugs, Cobenfy TM was approved as a novel antipsychotic in September 2024. Cobenfy TM is a combination formulation of xanomeline, a muscarinic cholinergic M 1 /M 4 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 TM 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 outside of the 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 D 2 antagonism/partial agonism.
Source: Pharmacological Research
Authors: Paula M. Moran, Kiri T. Granger
Institution: University of Nottingham
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,130
OpenAlex ID: W4410048428