Is there evidence for the use of Depakote (valproate) in treating delirium in elderly inpatients?

Valproic Acid (Depakote) for Delirium in Elderly Inpatients

There is insufficient evidence to recommend valproic acid (Depakote) for the treatment of delirium in elderly inpatients, and it should not be used as first-line therapy given the lack of high-quality evidence supporting its efficacy and safety in this population.

Current Guideline Recommendations for Delirium Management

First-Line Approach: Non-Pharmacological Interventions

• The American Geriatrics Society strongly recommends multicomponent non-pharmacological interventions as the first-line approach for both prevention and management of delirium in elderly patients 1.
• These interventions include:
  • Ensuring hearing aids and glasses are available and used
  • Providing adequate lighting and minimizing noise
  • Promoting early and frequent mobilization
  • Implementing orientation strategies (clocks, calendars, familiar objects)
  • Protecting sleep-wake cycles
  • Ensuring adequate nutrition and hydration 1

Medication Management in Delirium

• The American Geriatrics Society strongly recommends avoiding medications with high risk for precipitating delirium, including benzodiazepines and anticholinergics 2.
• For pharmacological management of severe agitation in delirium:
  • Antipsychotics may be considered at the lowest effective dose for the shortest possible duration only in patients who are severely agitated and threatening substantial harm to themselves or others 2.
  • Benzodiazepines should not be used as first-line treatment except for alcohol or benzodiazepine withdrawal 2.
  • Both antipsychotics and benzodiazepines should be avoided for hypoactive delirium 2.

Evidence Regarding Valproic Acid (Depakote) in Delirium

Limited Evidence for Valproic Acid

• There is a notable absence of valproic acid in the American Geriatrics Society guidelines for delirium management 2, 1.
• The most recent evidence (2025) on valproic acid for agitated delirium comes from a small retrospective study of only 20 patients with a median age of 81.5 years. This study did not find statistically significant differences in benzodiazepine, opioid, or antipsychotic use when valproic acid was administered 3.
• An older case series (2005) reported six cases where valproic acid was used as an adjunctive treatment for delirium when conventional therapy was inadequate, but this represents very low-quality evidence 4.

Potential Risks of Valproic Acid

• There is a case report of valproate actually inducing hypoactive delirium in a patient, even at therapeutic blood levels 5.
• Elderly patients are particularly vulnerable to medication side effects, and valproic acid has significant potential adverse effects including:
  • Hepatotoxicity
  • Thrombocytopenia
  • Hyperammonemia (which can worsen confusion)
  • Drug interactions
  • Tremor and sedation

Algorithm for Managing Delirium in Elderly Inpatients

1. Identify and treat underlying causes:

   • Perform a medical evaluation to identify contributors to delirium 2
   • Review medications and discontinue high-risk medications
   • Assess for infection, metabolic disturbances, hypoxia, pain, and constipation

2. Implement non-pharmacological interventions (first-line approach):

   • Ensure proper orientation (clocks, calendars, familiar objects)
   • Optimize sensory function (glasses, hearing aids)
   • Promote normal sleep-wake cycles
   • Encourage early mobilization
   • Ensure adequate hydration and nutrition 1

3. For severe agitation threatening patient safety:

   • Consider antipsychotics at the lowest effective dose for the shortest duration possible 2
   • Monitor closely for adverse effects
   • Reassess daily and discontinue as soon as possible

4. Avoid:

   • Routine use of antipsychotics for non-agitated delirium
   • Benzodiazepines (except for alcohol/benzodiazepine withdrawal)
   • Cholinesterase inhibitors
   • Physical restraints 2, 1

Common Pitfalls in Delirium Management

• Failing to recognize hypoactive delirium, which is often missed or misattributed to dementia 1
• Using pharmacological interventions as first-line treatment rather than addressing underlying causes and implementing non-pharmacological approaches 1
• Using physical restraints, which can worsen delirium 1
• Continuing medications initiated for delirium management after resolution - one review found that 47% of patients continued to receive antipsychotics after discharge from the ICU and 33% as outpatients after hospital discharge, without clear indications 2

In conclusion, while there are limited case reports suggesting potential benefit of valproic acid as an adjunctive treatment for delirium, the current evidence is insufficient to recommend its use over established approaches. Management should focus on identifying and treating underlying causes, implementing non-pharmacological interventions, and using antipsychotics only when absolutely necessary for patient safety.