Lessons from the history of antipsychotic discovery: part 3 - muscarinic mechanisms.

After more than seven decades in which antipsychotic drug development has been dominated by dopaminergic mechanisms, the recent emergence of a muscarinic receptor-based treatment represents a conceptual shift in the pharmacotherapy of psychosis. This article reviews the history and development of the first clinically effective non-dopaminergic antipsychotic, tracing its origins to unexpected behavioural effects observed during trials of muscarinic agonists developed for Alzheimer's disease. Early studies of the muscarinic agonist xanomeline demonstrated antipsychotic efficacy, but were limited by poor tolerability due to peripheral cholinergic adverse effects. Subsequent progress depended on the dissociation of central therapeutic effects from peripheral side-effects, through the combination of xanomeline with the peripherally restricted muscarinic antagonist trospium. The development of this treatment highlights several broader lessons for psychiatric drug discovery, including the value of revisiting previously abandoned compounds, the benefits of leveraging existing human safety data on the importance of early-phase translational research and the role of innovative companies.