Abstract
Agitation affects up to 70% of older people with dementia. Valproic acid derivatives have been used for the past 10 years to control agitation in dementia, but no systematic review of the effectiveness of this treatment has been published to date. A systematic review of 2004 examined three randomised, placebo-controlled trials of the effect of valproate therapy on older people with dementia who were agitated. The review was updated (October 2008) to include two additional studies. To determine whether evidence supports the use of valproate preparations in the treatment of agitation of people with dementia. The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS were searched on 7 February 2008 using the terms: valproic OR valproate OR divalproex* . The CDCIG Specialized Register contains records from all major health care databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many trials databases and grey literature sources. 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 in 2004 of the pooled results was limited 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 and from confidential laboratory reports. 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 analyse 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 valproate preparation 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 (480 mg/d - 1000 mg/d), as did duration of therapy (3 weeks - 6 weeks), 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.An updated systematic review (October 2008) of two new studies (Tariot 2005, Herrmann 2007) applied meta-analysis to the effect of valproate on agitation in demented patients and also combined these studies with the earlier reports to examine adverse effects among valproate treated patients. Because the study of Herrmann et al involved a cross-over design, only those results from the first part of this study were included in the updated review.The new meta-analysis of pooled results showed no improvement of agitation among valproate treated patients, compared with controls, and showed an increase in adverse events (falls, infection, gastrointestinal disorders) among valproate treated patients. The updated review corroborates the earlier findings that valproate preparations are ineffective in treating agitation among demented patients, and that valproate therapy 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 therapy cannot be recommended for management of agitation in dementia.
Highlights
Agitation has been reported in up to 90% of people with dementia
Individual adverse events that were more frequent in the valproate-treated group included sedation, gastrointestinal symptoms, and urinary tract infections. This updated review corroborates earlier findings that valproate preparations are probably ineffective in treating agitation in people with dementia, but are associated with a higher rate of adverse effects, and possibly of serious adverse events (SAE)
The National Institute for Health and Care Excellence (NICE) guideline on supporting people with dementia and their carers suggests that people with dementia who present with non-cognitive symptoms or challenging behaviour should be offered pharmacological intervention in the first instance “only if they are severely distressed or there is an immediate risk of harm to the person or others” and that a thorough assessment of possible causes of the behaviour should be carried out as soon as possible (NICE 2016)
Summary
Agitation in people with dementia worsens carer burden, increases the risk of injury, and adds to the need for institutionalisations (Livingstone 2014). Current guidelines recommend that people with dementia who develop non-cognitive symptoms or behaviours that cause them distress or challenge those who provide their care should first have a comprehensive assessment to determine likely causative factors, such as physical illness, depression, pain, adverse effects of medication, personal or psychosocial factors, or aspects of their physical environment. There is some evidence of modest benefits of antipsychotics in around 50% of people with dementia, but they are associated with adverse effects such as sedation, parkinsonism, gait disturbance, dehydration, falls, chest infection, accelerated cognitive decline, and stroke, and they are associated with increased mortality in the long term (Alzheimer’s Society 2011b; Maher 2011). Carbamazepine and valproate preparations have both been used widely
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
