Valproic Acid for Treatment of Hyperactive or Mixed Delirium: Rationale and Literature Review

Background: Delirium is the most often encountered psychiatric diagnosis in the general hospital, with an incidence of up to 82% in the intensive care unit setting and with significant detrimental effects on patients' morbidity and mortality. Antipsychotics are often considered the first-line pharmacological treatment of delirium, but their use may be limited by lack of efficacy, existing contraindications (e.g., prolonged QTc intervals), or resulting side effects (e.g., akathisia). Valproic acid (VP A) is a potential alternative or adjunct treatment. It has multiple mechanisms of action, including effects on neurotransmitter modulation, neuroinflammation, oxidative stress, and transcription, all of which are implicated in the pathophysiology of delirium. Yet, data on the use of this agent in delirium are limited. Objective/Methods: In this article, we discuss postulated mechanisms of VP A action that provide a theoretical basis for its use in the treatment of hyperactive and mixed type delirium, based on the known and theorized pathophysiology of delirium. We also discuss potential side effects and considerations with use of VPA. Conclusions: VPA has multiple modulatory effects on neurotransmitter systems, inflammation, oxidative stress, and transcriptional changes implicated in pathophysiology of delirium. When carefully chosen, VPA can be an effective and well-tolerated treatment option for the management of hyperactive and mixed type delirium. Randomized controlled trials are needed to establish tolerability and efficacy of VP A for treatment of delirium.