WIP Special

The FOCUS study: The efficacy of xanomeline-trospium in treating cognitive impairment in psychosis: A randomised, double-blind active-controlled clinical trial 

Presented by Rob McCutcheon

Abstract: Cognitive impairments are a core feature of psychotic disorders such as schizophrenia, with substantial impacts on treatment adherence, hospitalisation, and long-term functional outcomes. Despite their clinical significance, cognitive symptoms are not effectively addressed by current treatments, all of which target dopamine D2 receptors and primarily alleviate positive symptoms. Xanomeline-trospium, a novel muscarinic receptor agonist-antagonist combination recently approved by the FDA, has shown efficacy in treating the positive and negative symptoms of schizophrenia.

 The FOCUS study is a randomised, double-blind active-controlled clinical trial that aims to evaluate the efficacy of xanomeline-trospium compared to a standard dopamine D2 receptor antagonist in improving cognitive symptoms in individuals with early psychosis. Participants will be randomised 1:1 to receive either xanomeline-trospium or a standard D2 antagonist (risperidone or lurasidone) with a six-week treatment phase followed by an optional 52-week single-blind extension.

 In addition to clinical and cognitive measures, the study incorporates a comprehensive neuroimaging component. MRI (fMRI spatial memory, resting state, 1H-MRS, and neuromelanin) and MEG (ASSR, MMN, spatial memory, language processing, resting state) will be used to characterise the neurobiological effects of muscarinic versus dopaminergic modulation in psychosis. Furthermore, the study will explore whether baseline imaging markers can predict treatment response, with the aim of identifying biomarkers that could inform future precision psychiatry approaches.