Valproate preparations for agitation in dementia (Review)

View/ Open
Date
2018-10-05Abstract
Background
Agitation has been reported in up to 90% of people with dementia. Agitation in people with dementia worsens carer burden, increases
the risk of injury, and adds to the need for institutionalisation. Valproate preparations have been used in an attempt to control agitation
in dementia, but their safety and efficacy have been questioned.
Objectives
To determine the efficacy and adverse effects of valproate preparations used to treat agitation in people with dementia, including the
impact on carers.
Search methods
We searched ALOIS - the Cochrane Dementia and Cognitive Improvement Group’s Specialized Register on 7 December 2017 using
the terms: valproic OR valproate OR divalproex. ALOIS 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.
Selection criteria
Randomised, placebo-controlled trials that assessed valproate preparations for agitation in people with dementia.
Data collection and analysis
Two review authors independently screened the retrieved studies against the inclusion criteria and extracted data and assessed methodological
quality of the included studies. If necessary, we contacted trial authors to ask for additional data, including relevant subscales, or
for other missing information. We pooled data in meta-analyses where possible. This is an update of a Cochrane Review last published
in 2009. We found no new studies for inclusion.
Main results
The review included five studies with 430 participants. Studies varied in the preparations of valproate,mean doses (480 mg/day to 1000
mg/day), duration of treatment (three weeks to six weeks), and outcome measures used. The studies were generally well conducted
although some methodological information was missing and one study was at high risk of attrition bias.
The quality of evidence related to our primary efficacy outcome of agitation varied from moderate to very low. We found moderatequality
evidence from two studies that measured behaviour with the total Brief Psychiatric Rating Scale (BPRS) score (range 0 to 108)
Valproate preparations for agitation in dementia (Review)
Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
and with the BPRS agitation factor (range 0 to 18). They found that there was probably little or no effect of valproate treatment over
six weeks (total BPRS: mean difference (MD) 0.23, 95% confidence interval (CI) -2.14 to 2.59; 202 participants, 2 studies; BPRS
agitation factor: MD -0.67, 95% CI -1.49 to 0.15; 202 participants, 2 studies). Very low-quality evidence from three studies which
measured agitation with the Cohen-Mansfield Agitation Index (CMAI) were consistent with a lack of effect of valproate treatment on
agitation. There was variable quality evidence on other behaviour outcomes reported in single studies of no difference between groups
or a benefit for the placebo group.
Three studies, which measured cognitive function using the Mini-Mental State Examination (MMSE), found little or no effect of
valproate over six weeks, but we were uncertain about this result because the quality of the evidence was very low. Two studies that
assessed functional ability using the Physical Self-Maintenance Scale (PSMS) (range 6 to 30) found that there was probably slightly
worse function in the valproate-treated group, which was of uncertain clinical importance (MD 1.19, 95% CI 0.40 to 1.98; 203
participants, 2 studies; moderate-quality evidence).
Analysis of adverse effects and serious adverse events (SAE) indicated a higher incidence in valproate-treated participants. A metaanalysis
of three studies showed that there may have been a higher rate of adverse effects among valproate-treated participants than
among controls (odds ratio (OR) 2.02, 95% CI 1.30 to 3.14; 381 participants, 3 studies, low-quality evidence). Pooled analysis of the
number of SAE for the two studies that reported such data indicated that participants treated with valproate preparations were more
likely to experience SAEs (OR 4.77, 95% CI 1.00 to 22.74; 228 participants, 2 studies), but the very low quality of the data made it
difficult to draw any firm conclusions regarding SAEs. Individual adverse events that were more frequent in the valproate-treated group
included sedation, gastrointestinal symptoms (nausea, vomiting, and diarrhoea), and urinary tract infections.
Authors’ conclusions
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 SAEs. On the basis of this evidence, valproate therapy
cannot be recommended for management of agitation in dementia. Further research may not be justified, particularly in light of the
increased risk of adverse effects in this often frail group of people. Research would be better focused on effective non-pharmacological
interventions for this patient group, or, for those situations where medication may be needed, further investigation of how to use other
medications as effectively and safely as possible.
Description
The file attached to this record is the Publisher's version.
Citation : Baillon, S.F., Narayanan, U., Luxenburg, J.S., Clifton, A. (2018) Valproate preparations for agitation in dementia. Cochrane Database of Systematic Reviews, Issue 10. Art.No.: CD003945.
ISSN : 1469-493X
Research Group : Nursing and Midwifery Research Centre
Research Institute : Institute of Health, Health Policy and Social Care
Peer Reviewed : Yes