Can Depakote (valproic acid) be used to treat sundowning in a patient with dementia who is already taking it for seizures or bipolar disorder?

Depakote (Valproic Acid) for Sundowning in Dementia

Valproic acid should NOT be used to treat sundowning in patients with dementia, even if they are already taking it for seizures or bipolar disorder, because high-quality evidence demonstrates it is ineffective for agitation and behavioral symptoms while causing significantly higher rates of adverse effects including sedation, gastrointestinal symptoms, urinary tract infections, and functional decline. 1

Evidence Against Valproic Acid for Sundowning

Lack of Efficacy

• A 2018 Cochrane systematic review of five randomized controlled trials (430 participants) found that valproate preparations are probably ineffective for treating agitation in dementia, with no significant improvement on the Brief Psychiatric Rating Scale total score (MD 0.23,95% CI -2.14 to 2.59) or BPRS agitation factor (MD -0.67,95% CI -1.49 to 0.15) over six weeks. 1

• Three studies measuring agitation with the Cohen-Mansfield Agitation Inventory consistently showed no benefit of valproate treatment for behavioral symptoms. 1

• The Cochrane review concluded that "valproate therapy cannot be recommended for management of agitation in dementia" and that "further research may not be justified" given the increased risk of adverse effects. 1

Significant Adverse Effects

• Valproate-treated patients experienced twice the rate of adverse effects compared to placebo (OR 2.02,95% CI 1.30 to 3.14), including sedation, nausea, vomiting, diarrhea, and urinary tract infections. 1

• Serious adverse events were nearly five times more common in valproate-treated participants (OR 4.77,95% CI 1.00 to 22.74), though the quality of this evidence was very low. 1

• Valproate treatment was associated with worse functional ability on the Physical Self-Maintenance Scale (MD 1.19,95% CI 0.40 to 1.98), indicating decline in activities of daily living. 1

• In one trial, 22% of treated patients dropped out due to adverse effects, and the study had to be discontinued prematurely due to the high dropout rate (54% treated vs. 29% controls). 2

Recommended Treatment Approach for Sundowning

First-Line: Non-Pharmacological Interventions

• Implement morning bright light therapy at 2,500-5,000 lux for 1-2 hours daily (09:00-11:00 AM), positioned approximately 1 meter from the patient, which consolidates nighttime sleep, reduces daytime napping, decreases agitated behavior, and enhances circadian rhythm amplitude. 3

• Establish consistent daily schedules for exercise, meals, and bedtime to regulate disrupted circadian rhythms caused by suprachiasmatic nucleus degeneration in Alzheimer's disease. 3

• Schedule activities earlier in the day when the patient is most alert, avoiding overstimulation in late afternoon. 3

• Reduce nighttime light, noise, and household clutter to minimize awakenings and confusion. 3

• Implement 50-60 minutes of total daily physical activity distributed throughout the day, including 5-30 minute walking sessions. 3

Second-Line: Pharmacological Options (Only After Non-Pharmacological Failure)

• If not already prescribed, initiate a cholinesterase inhibitor (donepezil 10 mg daily or rivastigmine up to 6 mg twice daily), as these medications can reduce behavioral and psychopathologic symptoms including sundowning. 3

• For depression contributing to evening behavioral symptoms, use SSRIs (citalopram 10-40 mg daily or sertraline) as first-line, which have minimal anticholinergic effects and demonstrated efficacy in reducing agitation (mean difference -0.89 on CMAI scores, 95% CI -1.22 to -0.57). 3, 4

• Reserve atypical antipsychotics only for severe, dangerous symptoms (delusions, hallucinations, severe psychomotor agitation, combativeness) unresponsive to other measures: risperidone starting 0.25 mg at bedtime (maximum 2-3 mg daily) or olanzapine starting 2.5 mg at bedtime (maximum 10 mg daily). 3

Critical Management Considerations

If Patient Is Already Taking Valproate for Seizures

• Continue valproate for seizure control as indicated, since discontinuation could precipitate seizures. 5

• Do NOT increase the dose or expect improvement in sundowning symptoms, as the evidence clearly demonstrates valproate is ineffective for behavioral symptoms in dementia. 1

• Implement the non-pharmacological interventions above as primary treatment for sundowning, particularly bright light therapy. 3

• Monitor closely for adverse effects including sedation, gastrointestinal symptoms, and functional decline, which may worsen sundowning. 1

Medications to Strictly Avoid

• The American Academy of Sleep Medicine provides a STRONG AGAINST recommendation for sleep-promoting medications (benzodiazepines, hypnotics) in elderly dementia patients due to significantly increased risks of falls, cognitive decline, confusion, and mortality. 3, 6

• Melatonin has a WEAK AGAINST recommendation in elderly dementia patients, as high-quality trials show no improvement in total sleep time with potential harm including detrimental effects on mood and daytime functioning. 3, 6

• Avoid anticholinergic medications (hydroxyzine, diphenhydramine) which worsen confusion, agitation, and cognitive function in dementia patients. 4

Common Pitfalls to Avoid

• Do not assume that because valproate is effective for seizures or bipolar disorder, it will help with sundowning—the evidence clearly demonstrates it does not. 1

• Do not ignore underlying medical issues such as pain, infection, constipation, or medication side effects that can worsen evening agitation. 3

• Do not jump to antipsychotics first—they carry significant mortality risk (1.6-1.7 times higher than placebo) and should be reserved only for dangerous behaviors unresponsive to all other interventions. 4

• After behavioral symptoms are controlled for 4-6 months with any medication, attempt periodic dose reduction to determine if continued medication is necessary. 3