Novel applications of sleep pharmacology as delirium therapeutics

Sleep-wake and circadian disruption (SCD) is a core feature of delirium. It has been hypothesized that SCD contributes to delirium pathogenesis; therefore, interventions that prevent or reverse SCD represent an array of promising opportunities in relation to delirium. This review explores the relationship between sleep-wake/circadian physiology and delirium pathophysiology with a focus on neurotransmitter systems. Across potential targets aimed at preventing or treating delirium, three broad approaches are considered: 1. Pharmacological mechanisms that contribute to physiological sleep may preserve or restore next-day cognition in patients with or at risk for delirium (e.g., alpha 2 agonists, dopamine 2 antagonists, serotonin 2 A antagonists, dual orexin receptor antagonists, or GHB agonists); 2. Pharmacological mechanisms that promote wakefulness during the day may combat hypoactive delirium (e.g., adenosine 2 A antagonists, dopamine transporter antagonists, orexin agonists, histamine 3 antagonists); and 3. Melatonergic and other circadian interventions could strengthen the phase or amplitude of circadian rhythms and ensure appropriately entrained timing in patients with or at risk for delirium (e.g., as informed by a person's preexisting circadian phase).