Objective: The safety and tolerability of divalproex sodium in dementia has been addressed in previous trials for treatment of agitation in nursing home patients. However, there are no data on the safety and tolerability of divalproex sodium in higher functioning and healthier outpatients with dementia.
Design: We conducted a 10-week randomized, double-blind study which first compared the safety and tolerability of 2 dosages of divalproex sodium delayed-release tablets (target doses of 1,000 mg/d and 1,500 mg/d) to placebo over 8 weeks. We then assessed tolerability and satisfaction when patients titrated to these doses of divalproex sodium delayed-release tablets were switched at week 8 to divalproex sodium extended-release tablets.
Materials and Methods: 20 outpatient subjects were recruited from the Geriatric Neurology and Psychiatry Clinic at Monroe Community Hospital with probable Alzheimer's Disease, MMSE 10-20 inclusive, who had not shown agitation or psychosis during their illness and who lacked agitation and psychosis at baseline as defined by ratings of <1 (minimally evident) using items assessing these features from the NPI. These selection criteria mimicked those for the coming Alzheimer's Disease Cooperative Study (ADCS) trial examining the potential for chronic valproate treatment to delay emergence of symptoms in patients with Alzheimer's Disease. Subjects received 250 mg divalproex sodium during the first week, and dose was increased by 250 mg at the beginning of each subsequent week until the target dose was achieved. Outcome measures included MMSE, NPI, IADL, PSMS, CGI, and adverse experiences recorded by a modified TESS.
Results: 23 dose adjustments were made in 13 subjects due to adverse experiences. The most common of these were sleepiness and tiredness. 6 subjects developed severe adverse experiences rated as "very much a problem" including sleepiness, tiredness, shakiness, and problems walking. At week 8, the average tolerated dose was 810 mg/day or 11.5 mg/kg/day, and doses were maintained through week 10 by 90% of subjects after the week 8 switch to extended-release tablets. Patients and caregivers generally preferred the extended release formulation.
Conclusion: We conclude that a target dose of 10-15 mg/kg/day of divalproex sodium delayed-release is likely to be well-tolerated in outpatients with Alzheimer's Disease, and that switches from delayed-release to extended-release are well-tolerated by our patients. These findings have been used in the final design of the multi-center, placebo-controlled ADCS trial examining the potential for valproate to delay emergence of symptoms in patients with Alzheimer's Disease, and may be relevant in clinical dosing decisions for symptomatic treatment of outpatients with dementia-associated agitation.
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