The investigation will establish biological plausibility and infrastructure required for a multisite clinical trial evaluating the re-purposing of fluvoxamine to mitigate postoperative delirium risk in geriatric patients undergoing non-cardiac non-intracranial surgery.

Delirium is a disturbance in attention, cognition, and consciousness, an acute physiological consequence of medical events, such as hospital admission, surgery, sepsis, and pharmacological intervention. There are currently no standard pharmacologic interventions to prevent delirium in any setting. 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.

The study assumes that neuroinflammation is a key contributor to the pathogenesis of postoperative delirium, a matter of conjecture. The investigators will directly test systemic inflammation as a proxy for neuroinflammation. The investigation will test whether fluvoxamine may be associated with reduced systemic inflammation, markers of neural dysfunction, and delirium severity.

This potential therapeutic approach has potential generalizability to different clinical settings and already proved useful for COVID-19. The investigators combine the need to develop a collaborative clinical trials platform across diverse healthcare settings with key mechanistic studies that will advance our understanding of the pathogenesis of delirium. These studies will leverage high-density EEG recordings and state-of-the-art plasma biomarker collection, providing key data on the biological plausibility for a fluvoxamine effect.

Inclusion Criteria:

• English-speaking
• elective non-cardiac or non-intracranial surgery requiring at least a 2-day hospital length of stay

Exclusion Criteria:

• Received investigational drug within the last 7 weeks
• lack of capacity to provide informed consent
• prior known intolerance or allergy to SSRIs or fluvoxamine
• planned postoperative ventilation
• drug or alcohol dependence
• preoperative use of non-NSAID medications with drug-drug interactions of Class X (Avoid Combination) or D (Consider Therapy Modification)
• risk of serotonin syndrome (St John's Wort, SSRIs, or TCA)

Study protocol will be released in manuscript form. Outcome data will be uploaded to the OpenNeuro on a rolling basis.

Within three years of study completion

Data use agreements may be required.

Participants randomized using the randomization model in REDCAP. Study drug/placebo will be provided by an external pharmacy. Study drugs will be numbered and patients allocated to study drug using a randomisation model. Unblinding will only occur when the study finishes or if safety issues require.