FOCUS: Function & Cognition in Early Psychosis

Cognitive deficits are a core feature of the early phases of psychosis. All licensed pharmacological treatments for psychosis act by blocking dopaminergic neurotransmission and do not improve these deficits. Independent lines of research have recently implicated several molecules with therapeutic potential that act on muscarinic, endocannabinoid, and glutamatergic signalling. All impact the balance between excitatory and inhibitory(E/I) signalling, which may be central to the pathophysiology of cognitive deficits. This proposal will use four randomised controlled trials (RCTs) to examine these non-dopaminergic interventions for cognitive symptoms in three workflows: Workflow A involves a RCT of xanomeline-trospium (KarXT) in early psychosis. Xanomeline is a muscarinic agonist with antipsychotic properties, which can be given in combination with the peripheral muscarinic antagonist trospium to ameliorate side effects without reducing efficacy. Secondary analyses suggest that KarXT improves cognitive symptoms of psychosis. Workflow B examines data from Workflow A and three other RCTs in early psychosis examining pro-cognitive interventions (cannabidiol, memantine, and immunotherapy) that act on E-I balance via distinct mechanisms. Workflow C examines subjective experience of cognitive deficits, assesses intervention acceptability, and determines how improving cognition may translate into changes in real-world functioning and quality of life in early psychosis.