Mitigating Delirium with Fluvoxamine Treatment for Non-Cardiac Surgery (MD FluNCS): Feasibility Trials & Mechanistic Insights

ABSTRACT The pathogenesis of postoperative delirium likely involves systemic inflammation, downstream neuroinflammation, and altered synaptic plasticity reflected by elevations in IL-6 and electroencephalographic (EEG) slowing. Furthermore, there are no known pharmacologic interventions for preventing postoperative delirium. Fluvoxamine is an antidepressant that could suppress neuroinflammation through sigma-1 receptor agonism. Fluvoxamine reduces prostaglandin synthesis and cytokine release from human blood. It is concentrates in the brain and neuroprotective via sigma-1 receptors. It improves survival in sepsis animal models and reduces clinical deterioration from COVID-19. Promise in the treatment of delirium is supported by a series of case reports of fluvoxamine treating delirium in older adults and/or intensive care unit. It is not clear whether suppressing neuroinflammation is a viable pathway towards mitigating delirium severity. Furthermore, it is unclear whether fluvoxamine is a feasible pharmacologic intervention for mitigating delirium risk, given societal stigma against antidepressants as well as side effects of nausea and potential drug-drug interactions. To evaluate the safety and feasibility of a multisite investigation on perioperative fluvoxamine, we propose Mitigating Delirium with Fluvoxamine Treatment for Non-Cardiac Surgery (MD FluNCS): Feasibility Trials & Mechanistic Insights. This work will enhance our understanding of core pathogenesis of postoperative delirium in a population at risk for Alzheimer's disease and related dementias. With the rise in the aging population, we hope to provide an intervention to mitigate risk as well as translatable theragnostic biomarkers and approaches for future precision medicine. The investigation will lay the groundwork for a larger scale Phase 3 trial geared toward advancing long-term goal of improving public health and quality of life for those at risk of postoperative delirium and related sequelae.