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Meta-Analysis
. 2018 Oct 5;10(10):CD003945.
doi: 10.1002/14651858.CD003945.pub4.

Valproate preparations for agitation in dementia

Sarah F Baillon  1 , Usha Narayana, Jay S Luxenberg, Andrew V Clifton
Affiliations
Meta-Analysis

Valproate preparations for agitation in dementia

Sarah F Baillon et al. Cochrane Database Syst Rev. .

Abstract

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 moderate-quality evidence from two studies that measured behaviour with the total Brief Psychiatric Rating Scale (BPRS) score (range 0 to 108) 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 meta-analysis 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.

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Conflict of interest statement

SB: none known.

UN: none known.

JL: none known.

AC: none known.

Figures

1
1
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
2
2
Study flow diagram.
1.1
1.1. Analysis
Comparison 1 Valproate preparations versus placebo, Outcome 1 Brief Psychiatric Rating Scale (BPRS) total score. Change from baseline at 6 weeks (intention to treat (ITT)).
1.2
1.2. Analysis
Comparison 1 Valproate preparations versus placebo, Outcome 2 BPRS agitation factor. Change from baseline at 6 weeks (ITT).
1.3
1.3. Analysis
Comparison 1 Valproate preparations versus placebo, Outcome 3 Cohen‐Mansfield Agitation Index. Total Score. Change from baseline at 6 weeks (ITT).
1.4
1.4. Analysis
Comparison 1 Valproate preparations versus placebo, Outcome 4 BPRS hostility factor. Change from baseline at 6 weeks (ITT).
1.5
1.5. Analysis
Comparison 1 Valproate preparations versus placebo, Outcome 5 Overt Aggression Scale total score. Change from baseline at 6 weeks (ITT).
1.6
1.6. Analysis
Comparison 1 Valproate preparations versus placebo, Outcome 6 Neuropsychiatric Inventory total score. Change from baseline at 6 weeks (ITT).
1.7
1.7. Analysis
Comparison 1 Valproate preparations versus placebo, Outcome 7 Neuropsychiatric Inventory Agitation/Aggression subscore. Change from baseline at 6 weeks (ITT).
1.8
1.8. Analysis
Comparison 1 Valproate preparations versus placebo, Outcome 8 Mini‐Mental State Examination total score. Change from baseline at 6 weeks (ITT).
1.9
1.9. Analysis
Comparison 1 Valproate preparations versus placebo, Outcome 9 Physical Self‐Maintenance Scale total score. Change from baseline at 6 weeks (ITT).
2.1
2.1. Analysis
Comparison 2 Divalproex versus placebo, Outcome 1 Total number of participants with sedation at 6 weeks.
2.2
2.2. Analysis
Comparison 2 Divalproex versus placebo, Outcome 2 Total number of participants with nausea, vomiting, or diarrhoea at 6 weeks.
2.3
2.3. Analysis
Comparison 2 Divalproex versus placebo, Outcome 3 Total number of participants with a urinary tract infection by 6 weeks.
2.4
2.4. Analysis
Comparison 2 Divalproex versus placebo, Outcome 4 Total number of participants who had falls by 6 weeks.
2.5
2.5. Analysis
Comparison 2 Divalproex versus placebo, Outcome 5 Total number of participants with general disorders by 6 weeks.
2.6
2.6. Analysis
Comparison 2 Divalproex versus placebo, Outcome 6 Total number of participants with postural instability by 6 weeks.
2.7
2.7. Analysis
Comparison 2 Divalproex versus placebo, Outcome 7 Total number of participants with weakness by 6 weeks.
2.8
2.8. Analysis
Comparison 2 Divalproex versus placebo, Outcome 8 Total number of participants with cardiovascular problems by 6 weeks.
2.9
2.9. Analysis
Comparison 2 Divalproex versus placebo, Outcome 9 Total number of participants with oedema by 6 weeks.
2.10
2.10. Analysis
Comparison 2 Divalproex versus placebo, Outcome 10 Total number of participants with a fever by 6 weeks.
2.11
2.11. Analysis
Comparison 2 Divalproex versus placebo, Outcome 11 Total number of participants with a respiratory problem by 6 weeks.
2.12
2.12. Analysis
Comparison 2 Divalproex versus placebo, Outcome 12 Total number of participants with ataxia at 6 weeks.
2.13
2.13. Analysis
Comparison 2 Divalproex versus placebo, Outcome 13 Total number of participants with a skin problem at 6 weeks.
2.14
2.14. Analysis
Comparison 2 Divalproex versus placebo, Outcome 14 Total number of participants with trauma (other than falls) by 6 weeks.
2.15
2.15. Analysis
Comparison 2 Divalproex versus placebo, Outcome 15 Total number of participants with thrombocytopenia by 6 weeks.
2.16
2.16. Analysis
Comparison 2 Divalproex versus placebo, Outcome 16 Total number of participants with joint problems by 6 weeks.
2.17
2.17. Analysis
Comparison 2 Divalproex versus placebo, Outcome 17 Total number of participants with other infection by 6 weeks.
2.18
2.18. Analysis
Comparison 2 Divalproex versus placebo, Outcome 18 Total number of participants with hallucinations by 6 weeks.
2.19
2.19. Analysis
Comparison 2 Divalproex versus placebo, Outcome 19 Total number of participants with accidental injury by 6 weeks.
2.20
2.20. Analysis
Comparison 2 Divalproex versus placebo, Outcome 20 Total number of participants with anorexia by 6 weeks.
2.21
2.21. Analysis
Comparison 2 Divalproex versus placebo, Outcome 21 Total number of participants with weight loss by 6 weeks.
2.22
2.22. Analysis
Comparison 2 Divalproex versus placebo, Outcome 22 Total number of participants with dehydration by 6 weeks.
2.23
2.23. Analysis
Comparison 2 Divalproex versus placebo, Outcome 23 Total number of participants with metabolism and nutritional disorders by 6 weeks.
2.24
2.24. Analysis
Comparison 2 Divalproex versus placebo, Outcome 24 Total number of participants with psychiatric disorders by 6 weeks.
2.25
2.25. Analysis
Comparison 2 Divalproex versus placebo, Outcome 25 Total number of participants with other gastrointestinal problem by 6 weeks.
2.26
2.26. Analysis
Comparison 2 Divalproex versus placebo, Outcome 26 Total numbers of participants with nervous system disorders by 6 weeks.
2.27
2.27. Analysis
Comparison 2 Divalproex versus placebo, Outcome 27 Total number of participants with any adverse event by 6 weeks.
2.28
2.28. Analysis
Comparison 2 Divalproex versus placebo, Outcome 28 Total number of participants with serious adverse events by 6 weeks.
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Update of

Comment in

References

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