Valproic acid for agitation in dementia

Agitation affects up to 70% of older people with dementia. Valproic acid has been used for the past 10 years to control agitation in dementia, but no systematic review of the effectiveness of this drug has been published to date. The current study examines three randomized, placebo-controlled trials of the effect of valproic acid on older people with dementia who were agitated.

To determine whether evidence supports the use of valproic acid in the treatment of agitation of people with dementia.

Trials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 10 July 2003 using the terms ("agitat*" or "distur*" or "behavi*" or "aggress*") and "valproic" or "valproate" or "divalpro*." This Register contains articles from all major health care databases and many ongoing trials databases and is regularly updated. The reviewers contacted the authors of publications and drug companies manufacturing valproic acid for additional information.

Randomized, placebo-controlled trials with concealed allocation where agitation and dementia of participants were assessed

1. Two reviewers extracted data from published trials. 2. Odds ratios of average differences were calculated. 3. Only "intention to treat" analyses were included. 4. Analysis compared participants treated with valproic acid with controls.

Meta-analysis of the pooled results of the included trials could not be performed because of the following problems. In Porsteinsson 2001, although the physicians having direct responsibility for patient care were blinded, a non-blinded physician, who had no direct contact with these physicians, adjusted divalproex sodium dosage on the basis of reports from blinded raters. Therefore, because the physician who controlled therapy knew which patients were receiving divalproex, the trial did not satisfy the criterion of concealed allocation. In Tariot 2001, 54% of the treated patients dropped out compared with 29% of control patients. Of all treated patients, 22% dropped out because of adverse effects, and the study had to be discontinued prematurely. The third trial (Sival 2002) had a cross-over design. No results from the first phase of the study were available, and although the statistical section stated, "the t-test for independent samples is used to analyze the two-period cross-over trial", because the samples were not independent - they are the same patients in the treatment and placebo groups - a question must be raised about the correctness of the analyses. The type of valproate used in the trials varied - one used short-acting sodium valproate, one long-acting divalproex sodium, and the third early-onset acting divalproex sodium. Average doses differed (480mg/d - 1000mg/d), as did duration of therapy (3 wks - 6 wks), and ways of evaluating patients and their response to therapy. A limited meta-analysis, pooling the results concerning adverse effects (Porsteinsson 2001, Tariot 2001) revealed the following: Sedation occurred more frequently in patients treated with valproic acid than in controls Urinary tract infection was more common among patients treated with valproic acid than controls Because of differences in identifying adverse effects it was not possible to pool other observations concerning adverse effects between the two studies that were examined.

The trials reviewed should be regarded as preliminary. Individual reports suggest that low dose sodium valproate is ineffective in treating agitation among demented patients, and that high dose divalproex sodium is associated with an unacceptable rate of adverse effects. More research on the use of valproate preparations for agitation of people with dementia is needed. On the basis of current evidence, valproate preparations cannot be recommended for the treatment of agitation in dementia.