Depakote for the Treatment of Behavioral

and Psychological Symptoms of Dementia

(BPSD) in Geriatric Populations
Efficacy
Valproic acid is NOT routinely recommended for treatment of BPSD. Consider when
nonpharmacological and other pharmacological agents have been exhausted.
 A systematic review of literature from 1966 to 2004 showed that 3 randomized
controlled trials investigating valproic acid showed no efficacy (Sink et al 2005)
 Early studies show valproic acid to have some efficacy with tolerable side effects
(Mellow et al 1993; Stoppe et al 1999)
 However, more recent studies show that neither short nor long acting valproic acid
preparations are effective for treating BPSD
o Causes significantly more adverse effects than placebo, particularly sedation
 A 2019 systematic review and Bayesian network meta-analysis showed that valproate
was significantly inferior to multiple therapies, such as aripiprazole, escitalopram,
haloperidol, memantine, and risperidone (Jin & Liu, 2019)
 A review of valproate for agitation in dementia (Lonergan et al, 2004) reported that
o Low-dose sodium valproate was ineffective
o High-dose divalproex sodium was associated with too many intolerable adverse
effects to be appropriate in the target population
Recommendations:

 First-line treatment involves non-pharmacologic therapies (e.g. skills training and

education for caregivers, activity planning, environmental redesign)
 Add pharmacological therapy (in conjunction with non-pharmacological interventions)
based on the most significant symptom clusters affecting the patient
o Antidepressants or mood stabilizers may be more beneficial for treating mood
symptoms found in BPSD
o Antipsychotics may be more appropriate for psychotic and delusional symptoms
Dosage Forms and Strengths
Swallow whole; do not crush or chew:

 Depakene Capsule, Liquid Filled, Immediate Release

o 250 mg valproic acid
 Depakote Tablet, Delayed Release (DR)
o 125 mg, 250 mg, 500 mg divalproex sodium
 Depakote Tablet, Extended Release (ER)
o 250 mg, 500 mg divalproex sodium

FDA Approved for Seizure only:

 Depakote Sprinkle Capsule, DR

o 125 mg divalproex sodium
o Capsules can be swallowed whole or opened and the contents sprinkled on
soft food (option for patients who have difficulty swallowing)
 Depakene Oral Solution, Immediate Release
o 250 mg valproic acid per 5 mL as the sodium salt

Dosage Form Conversion

 Divalproex sodium (Depakote DR) to Divalproex sodium ER (Depakote ER)

o An 8–20% higher divalproex ER daily dose should be used when converting from
a total daily dose of divalproex
o Q12h divalproex to once-daily divalproex ER
 Convert immediately 12 hours after the last divalproex q12h dose
 Causes the least perturbation in plasma VPA
  Divalproex sodium (Depakote DR) to valproic acid immediate release (Depakene oral
solution)
o 1:1 conversion ratio (e.g. 500 mg divalproex sodium = 500 mg valproic acid)
o Use the same dose and timing for valproic acid as for divalproex sodium
 Divalproex sodium ER (Depakote ER) to the valproic acid immediate release (Depakene
oral solution)
1. Convert Depakote ER to Depakote DR
 A 8–20% lower divalproex DR daily dose should be used when
converting from a total daily dose of divalproex ER
2. Convert Depakote DR to Depakene oral solution
 Use the same dose and timing as Depakote DR
 1:1 conversion ratio
Dosing

 Initial divalproex sodium dose: 250–375 mg/day

 Target dose: 625–825 mg/day (total daily dose)
o Aim for lowest dose possible that can manage symptoms
o Adjust dosage based on symptom relief
o Goal is to manage symptoms rather than reaching “target dose”
 Assuming an adequate response has been achieved
o For patients with mild agitation: taper within 2-3 months
o For patients with severe agitation: taper within 3-4 months
 Discontinuation should be achieved within 6–9 months in most patients
 Some patients may require long-term treatment
  Most of studies indicate that divalproex sodium is relatively well tolerated in doses
ranging from 500–1000 mg/day (<15 mg/kg/day)

Adverse Effects

 BOXED WARNING: LIFE THREATENING ADVERSE REACTIONS

o Hepatotoxicity, including fatalities, usually during the first 6 months of
treatment
 Monitor closely, and perform liver function tests prior to therapy and
at frequent intervals thereafter
 Children under the age of two years are at a considerably higher risk
of fatal hepatotoxicity
o Fetal Risk, particularly neural tube defects and other major malformations
o Pancreatitis, including fatal hemorrhagic cases
 Elderly (≥60 years) patients taking divalproex sodium are at a significantly higher risk
of developing thrombocytopenia than non-elderly patients
o A chart review of 39 inpatient psychiatric patients showed that more than
half (53.8%) of the elderly patients but only 13.0% of the nonelderly patients
had at least one episode of thrombocytopenia
 Elderly patients, especially those with dementia, may be more vulnerable to adverse
effects and less likely to report symptoms
 Most common side effects of divalproex sodium in the elderly:
 Somnolence
 Weakness
 Reduced platelet count
 Anorexia
 Weight loss
 Nausea, vomiting, diarrhea
 Respiratory problems
Considerations for Geriatric Populations

 General recommendations
o Reduce starting dose
o Increase dosage more slowly
o Monitor somnolence, fluid and nutritional intake

 Thrombocytopenia – abnormally low platelet levels

o Reports of thrombocytopenia in elderly psychiatric inpatients taking divalproex
sodium
o Risk factors of divalproex sodium-associated thrombocytopenia
 Advanced age, female gender, high doses
 Caution in prescribing this compound in elderly female patients,
especially in doses > 1 g/day
o Elderly patients often take multiple medications that increase risk of bleeding or
thrombocytopenia (e.g. aspirin, other anticoagulants)
 In elderly psychiatric patients, consider the compounded effect of
psychiatric medications that also increase risk of bleeding (e.g. SSRI)
o Titrate dosage slowly
o Routinely monitor platelet counts at baseline as well as during treatment
 There is no established link between plasma concentration and clinical
response, but plasma levels may inform dosage decisions
o Monitor regularly
 Fluid and nutritional intake
 Dehydration
 Somnolence
Monitoring

 Initial workup
o Take a general medical history with special attention to hepatic, hematological,
and bleeding abnormalities
o Obtain baseline complete blood cell counts with differential (CBC with diff), liver
function tests, and pregnancy test (if appropriate)
 Long-term monitoring
o Every 3-6 months, check valproic acid levels, liver function tests, and CBC with
diff
o Valproic acid monitoring
 NOTE: serum concentrations do not correlate with therapeutic effect in
the elderly
 Adjust dose based on symptom response
  Aim for lowest dose possible to minimize adverse effects

o Therapeutic drug monitoring (not conducted routinely)

 Draw trough level within 30 minutes before dose
 Time to steady state (when concentrations remain constant): 2-3 days
 Reference Ranges
 VALPROIC ACID, TOTAL
 Therapeutic: 50 (trough)-125 (peak) mcg/mL
 Critical value: > or =151 mcg/mL

 VALPROIC ACID, FREE

 Therapeutic: 5-25 mcg/mL
 Critical value: >30 mcg/mL

 Valproic acid is normally 85% to 90% protein-bound

 In uremia or during concomitant therapy with other drugs that
are highly protein-bound (such as phenytoin), valproic acid is
displaced from protein
 Results in a higher free fraction of the drug circulating in blood
 Total valproic acid concentration in the blood may underestimate
the disproportionately higher free valproic acid fraction with
o Elderly populations
o Concomitant use of highly protein-bound drugs (usually
>80% bound)
o Hypoalbuminemia
o Pregnancy
o Renal or hepatic failure
 Neurologic activity and toxicity of valproic acid are directly related to the
unbound fraction of drug, adjust dosage based on the free valproic acid
concentration
 High free valproic acid concentration may be associated with toxic effects
 The probability of thrombocytopenia appears to increase significantly at
total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135
mcg/mL (males)
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