Is Depakote (valproate) suitable for treating delirium?

Depakote (Valproate) Should Not Be Used for Delirium Treatment

Depakote (valproate) is not recommended for the routine treatment of delirium as there is insufficient evidence supporting its efficacy and safety for this indication. 1

Current Guideline Recommendations for Delirium Management

Antipsychotics and Other Medications

• Haloperidol and risperidone have no demonstrable benefit in the symptomatic management of mild-to-moderate delirium and are not recommended [I, D] 1
• Current guidelines suggest not routinely using haloperidol, atypical antipsychotics, or statins to treat delirium (conditional recommendation, low quality of evidence) 1
• Olanzapine, quetiapine, and aripiprazole may offer some benefit in the symptomatic management of delirium [III-V, C], though evidence is limited 1
• Dexmedetomidine may be considered for delirium in mechanically ventilated adults where agitation is precluding weaning/extubation (conditional recommendation, low quality of evidence) 1

Benzodiazepines

• Benzodiazepines are effective at providing sedation and anxiolysis in the acute management of severe symptomatic distress associated with delirium [II, C] 1
• However, benzodiazepines are not considered part of the initial strategy in delirium management as they are sedating, potentially deliriogenic, and increase fall risk 1
• Benzodiazepines do have a first-line role in the management of alcohol or benzodiazepine withdrawal 1

Evidence Regarding Valproate (Depakote) for Delirium

Limited Evidence Base

• No randomized controlled trials have evaluated the effect of valproic acid in delirium 2
• Available evidence is limited to retrospective studies, case series, and case reports 2
• A 2022 systematic review identified only 252 patients across 10 studies (mostly in ICU settings) with no high-quality evidence supporting routine use 2

Potential Risks

• Valproate can actually induce delirium in some patients, particularly elderly patients with dementia 3
• Common side effects include hyperammonemia (12-19%) and thrombocytopenia (9-13%) 2
• Requires careful liver function monitoring as it can cause hepatic impairment 4

Limited Potential Applications

• Some case reports suggest valproic acid might be considered as an adjunctive treatment when conventional therapy with benzodiazepines and/or antipsychotics produces suboptimal responses or concerning side effects 5
• A 2024 retrospective cohort study found no significant difference in delirium-free days between valproic acid and other non-VPA medications in ICU patients 6

Best Practice Approach to Delirium Management

First-Line Approach

• Non-pharmacological interventions should be prioritized as the cornerstone of delirium management 1
• Identify and treat underlying causes of delirium (infections, metabolic disturbances, medication effects, etc.) 1
• In opioid-associated delirium, consider opioid rotation to fentanyl or methadone, or dose reduction [V, B] 1

Pharmacological Management (When Necessary)

• Pharmacological interventions should be limited to patients with distressing delirium symptoms or safety concerns 1
• For hyperactive delirium with severe distress or safety concerns:
  • Consider atypical antipsychotics like olanzapine, quetiapine, or aripiprazole at the lowest effective dose for the shortest time possible 1
  • Reserve benzodiazepines for severe agitation or alcohol/benzodiazepine withdrawal 1
• For hypoactive delirium without delusions or perceptual disturbances, methylphenidate may improve cognition [V, C] 1

Conclusion

Based on current guidelines and available evidence, Depakote (valproate) should not be routinely used for delirium management. The evidence supporting its use is limited and of low quality, while established guidelines recommend other approaches. When pharmacological management is necessary, atypical antipsychotics have more supporting evidence, though even these should be used judiciously and only when non-pharmacological approaches are insufficient.