Chronic divalproex sodium to attenuate agitation and clinical progression of
Alzheimer disease.
Author(s): Tariot PN, Schneider LS, Cummings J, Thomas RG, Raman R, Jakimovich LJ, Loy R,
Bartocci B, Fleisher A, Ismail MS, Porsteinsson A, Weiner M, Jack CR Jr, Thal L,
Aisen PS; Alzheimer's Disease Cooperative Study Group.
Collaborators: Vicari S, Schneider L, Corey-Bloom J, Barbas N, Bell K, Duara R,
Rosenberg P, Ismail MS, Mulnard R, Weiner M, Tune L, Burns J, Ringman J, Farlow
M, Ahern G, Solomon P, Wu JC, Mintzer J, Charleston N, Martinez W, Geldmacher D,
Grossberg G, Lebedeva Z, Sabbagh M, Obisesan T, Thein S, Diego S, Baskys A, Beach
L, Lerner A, Petrie W, Kittur S, Gupta S, Bates V, Zabar Y, Zimmerman E, Foley K,
Care H, Schultz S, Ott B, Yesavage J, Alto P, Bernick C, Health B, Karlawish J.
Affiliation(s): Banner Alzheimer's Institute, 901 E Willetta St., Phoenix, AZ 85006, USA.
pierre.tariot@bannerhealth.com
Publication date & source: 2011, Arch Gen Psychiatry. , 68(8):853-61
CONTEXT: Agitation and psychosis are common in Alzheimer disease and cause
considerable morbidity. We attempted to delay or to prevent agitation and
psychosis with the use of divalproex sodium (valproate).
OBJECTIVE: To determine whether treatment with valproate could delay or prevent
emergence of agitation or psychosis.
DESIGN, SETTING, AND PATIENTS: A multicenter, randomized, double-blind,
placebo-controlled trial of flexible-dose valproate in 313 (of 513 screened)
individuals with moderate Alzheimer disease who had not yet experienced agitation
or psychosis. The study was conducted from November 1, 2005, through March 31,
2009, at 46 sites in the United States.
INTERVENTION: Participants were randomly assigned to valproate treatment at a
target dose of 10 to 12 mg per kilogram of body weight per day or
identical-appearing placebo for 24 months followed by a 2-month period of
single-blind placebo treatment.
MAIN OUTCOME MEASURE: Time to emergence of clinically significant agitation or
psychosis.
RESULTS: A total of 122 participants (59 receiving valproate and 63 receiving
placebo) completed 24 months of treatment while taking study medication; 42 (27
receiving valproate and 15 receiving placebo) reached 24 months having
discontinued study medication; 150 reached month 26. There was no difference
between groups in time to emergence of agitation or psychosis (Cox proportional
hazard ratio, 0.96; P = .88). There was no difference between groups in change on
any secondary outcome. The valproate group had higher rates of somnolence, gait
disturbance, tremor, diarrhea, and weakness. Eighty-eight participants underwent
magnetic resonance imaging scans at baseline and 12 months; the valproate group
showed greater loss in hippocampal and whole-brain volume, accompanied by greater
ventricular expansion (P < .001).
CONCLUSION: Valproate treatment did not delay emergence of agitation or psychosis
or slow cognitive or functional decline in patients with moderate Alzheimer
disease and was associated with significant toxic effects.
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