title: Chronic divalproex sodium to attenuate agitation and clinical progression of Alzheimer disease.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Banner Alzheimer's Institute, 901 E Willetta St., Phoenix, AZ 85006, USA. pierre.tariot@bannerhealth.com
authors.forename: Pierre N
authors.initials: PN
authors.lastname: Tariot
authors.forename: Lon S
authors.initials: LS
authors.lastname: Schneider
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Cummings
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Thomas
authors.forename: Rema
authors.initials: R
authors.lastname: Raman
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Jakimovich
authors.forename: Rebekah
authors.initials: R
authors.lastname: Loy
authors.forename: Barbara
authors.initials: B
authors.lastname: Bartocci
authors.forename: Adam
authors.initials: A
authors.lastname: Fleisher
authors.forename: M Saleem
authors.initials: MS
authors.lastname: Ismail
authors.forename: Anton
authors.initials: A
authors.lastname: Porsteinsson
authors.forename: Michael
authors.initials: M
authors.lastname: Weiner
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.forename: Leon
authors.initials: L
authors.lastname: Thal
authors.forename: Paul S
authors.initials: PS
authors.lastname: Aisen
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy*; D001284:Atrophy / Q000473:pathology; D001921:Brain / Q000473:pathology; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D016016:Proportional Hazards Models; D011595:Psychomotor Agitation / Q000150:complications / Q000188:drug therapy* / Q000517:prevention & control; D011618:Psychotic Disorders / Q000150:complications / Q000188:drug therapy* / Q000517:prevention & control; D012720:Severity of Illness Index; D014635:Valproic Acid / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D018696:Neuroprotective Agents; D014635:Valproic Acid