Median dose 1000 mg/day. Individual adverse effects which were found in one or more studies to be more frequent in the valproatetreated group were sedation, gastrointestinal symptoms, and UTI. Comparison 2 Divalproex versus placebo, Outcome 17 Total number of participants with other infection by 6 weeks. 6 weeks of valproate/placebo followed by 2 weeks of washout period followed by 6 weeks of valproate/placebo. The median dose for treated participants at the end of six weeks was 1000 mg/day. Agitation is reported in up to 90% of people with dementia (Alzheimer's Society 2011a). The low number of included studies meant that the number of participants were not sufficient for such analysis. More research on the use of Suttorp M, A fourth study reported that the mean incidence of adverse effects was low during three weeks of observation in both sodium valproate (0.17) and placebo (0.02) groups, but the study provided no description of the types of adverse reactions or actual numbers of adverse events experienced, so we could not include this study in the metaanalysis (Sival 2002). A conceptual review, An observational study of agitation in agitated nursing home residents, Antecedents and interventions for aggressive behavior of patients at a geropsychiatric state hospital. Egger M, being able to get an erection, but not having it last long enough for sex. Devanand DP, Efficacy data were analysed according to intentiontotreat principles, using last observation carried forward for subjects who dropped out after randomisation. The premature termination of one study, in which 47 (54%) treated participants dropped out before the protocol could be completed, severely limited the confidence that could be placed on the conclusion of the study authors that divalproex sodium improved agitation of people with dementia (Tariot 2001). Mahler LL, This tool assesses how the randomisation sequence was generated, how allocation was concealed, the integrity of blinding (participants, raters, and personnel), the completeness of outcome data, selective reporting, and other biases. Researchers decreased the dose by 125 mg/day if a participant experienced adverse effects. Oxazepam 1030 mg/day given if required for severe anxiety. Change from baseline at 6 weeks (ITT), 9 Physical SelfMaintenance Scale total score. The mean change from baseline for agitation and aggression was 5.34 points. In light of the uncertainty regarding which version Tariot 2005 used, we repeated the pooled analysis of change in total CMAI score after excluding data from Tariot 2005 (MD 1.96, 95% CI 6.18 to 10.10; 70 participants, 2 studies; very lowquality evidence, downgraded due to risk of bias, inconsistency, and imprecision). Rafaelson OJ, Robust randomised controlled trial evidence regarding valproate preparations for aggression in people who have dementia is limited, and we identified only five studies for inclusion in this review. Comparison 2 Divalproex versus placebo, Outcome 28 Total number of participants with serious adverse events by 6 weeks. We searched ALOIS (www.medicine.ox.ac.uk/alois), which is the Cochrane Dementia and Cognitive Improvement Group's (CDCIG) Specialized Register on 2 October 2014. We included only the results from the first part of the study in this review and obtained firstphase data from the study authors for all participants; for this reason, we considered the risk of attrition bias to be low. Dementia: Supporting People with Dementia and their Carers in Health and Social Care. Pooled analysis of the number of SAEs for the two studies which did report data indicated that participants treated with valproate were more likely to experience SAEs (OR 4.77, 95% CI 1.00 to 22.74; 228 participants, 2 studies; Analysis 2.28; very lowquality evidence, downgraded due to risk of bias, inconsistency, and imprecision) (Porsteinsson 2001; Tariot 2001). Consultation-liaison psychiatrists are frequently confronted with cases where dangerous agitation compromises the patient's immediate safety and eventual recovery from medical/surgical illness. The most recent search was performed in December 2017. Falls, respiratory, skin or joint problems, and infections (other than UTI) were no more frequent in valproatetreated than in placebotreated participants. We excluded most studies on the basis of the study design (e.g. This was further limited since one study closed prematurely and that separate firstphase data were not available from the crossover trials for inclusion in the review analysis (Herrmann 2007 for some data; Sival 2002). Participants and investigators blinded to treatment allocation. Mellow, AM, Solano-Lopez, C, Davis, S. Sodium valproate in the treatment . Jakimovich LJ, We wanted to review the evidence about how effective and safe it is to give valproate preparations to people with dementia to treat agitation. The quality of evidence on agitation measured with the CMAI was lower, but metaanalysis of three studies that reported the change in total CMAI score between baseline and six weeks also suggested no effect on agitated behaviour (MD 1.84, 95% CI 6.02 to 2.34, 217 participants, 3 studies; I2 = 52%; Analysis 1.3; very lowquality evidence, downgraded due to risk of bias, inconsistency, and imprecision) (Herrmann 2007; Porsteinsson 2001; Tariot 2005). We found too few studies to allow assessment of possible publication bias using funnel plots and Egger's test for asymmetry (Egger 1997). It can include verbal behaviours, such as shouting, and physical behaviours, such as wandering or physical aggression. Comparison 2 Divalproex versus placebo, Outcome 22 Total number of participants with dehydration by 6 weeks. Given that the study was described as doubleblind, it was likely that the rater was blind to treatment allocation but this is not stated explicitly. Divalproex Sodium was donated by Abbott Park Laboratories. None of the valproate preparations are licensed for the management of agitated behaviour in people with dementia; therefore, use of for this purpose is offlabel. Review revised in line with MECIR standards. They had no contact with the participants, investigators, the ward team, or participant's relatives. Comparison 1 Valproate preparations versus placebo, Outcome 7 Neuropsychiatric Inventory Agitation/Aggression subscore. No information given. aDowngraded one level for imprecision due to small number of participants. We found moderatequality 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). The original protocol proposed analysis treatment efficacy by type of dementia, degree of dementia, age, and sex if number of participants was sufficient. An updated search was performed for this review on 04 November 2016. A type of medication that has been used to treat agitated behaviour in people who have dementia is valproate, which is available in several different preparations (valproic acid, divalproex sodium, sodium valproate, and valproate semisodium). BPSD is associated with significant morbidity, rapid functional decline, and psychiatric hospitalization, and there are currently no medications approved by the Food and Drug Administration (FDA) for its treatment. Children 10 years of age: Initially, 10-15 mg/kg daily. We also extracted data about ongoing studies, including study name, methods, participants, interventions, outcomes, starting date, contact information, and notes. Prospective, multicentre, randomised, doubleblind, placebocontrolled, parallelarm, flexibledose study. Higgins JP, Herrmann N, A detailed description of each study is given in the Characteristics of included studies table. Cox C, The CGI uses a 7point scale with scores ranging from 1 (no aggressive behaviour) to 7 (severely aggressive behaviour). All studies included in this review indicated that participants were randomly allocated to treatments groups. Low-dose sodium valproate has a therapeutic effect on the psychological and behavioral symptoms of dementia, with few side effects. Two review authors independently screened the retrieved studies against the inclusion criteria and extracted data and assessed methodological quality of the included studies. The search terms used were: valproic OR valproate OR divalproex. All five studies examined the tolerability, adverse effects, and safety of valproate preparations. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). 1 Brief Psychiatric Rating Scale (BPRS) total score. In Tariot 2005, participants commenced sprinkle formulation divalproex sodium 125 mg twice daily for three days, which was increased in 125 mg increments every three days to 750 mg/day or up to a maximum dose 1000 mg/day. Appropriate steps should then be taken to address those factors, and a period of 'watchful waiting' should be observed, if possible, as in many cases symptoms will improve or resolve over four to six weeks (Alzheimer's Society 2011a). A widely accepted definition of agitation is: "inappropriate verbal, vocal, or motor activity that is not explained by needs or confusion per se" (Billig 1991; CohenMansfield 1989). Herrmann 2007 used the NPI and its agitation subscale at their primary outcome measure. No results from the first phase of the study were available. 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. We used the mean difference (MD) to measure the treatment effect. Outcome measures were completed by blinded raters. Two studies failed to state explicitly whether all staff involved in the study were blind to the treatment allocation of the participants (unclear risk of bias; Herrmann 2007; Tariot 2001), and two failed to state whether research staff completing the outcome measures were blinded (unclear risk of bias; Herrmann 2007; Sival 2002). For the purpose of this updated review, the data were entered into Review Manager 5 (Review Manager 2014). Where inadequate details of randomisation and other characteristics of the trials were provided, we contacted authors of the studies to obtain further information. Cohen LA, The mean change from baseline for agitation and aggression was 1.88 points. Porsteinsson 2001 used chloral hydrate. Divalproex sodium delayedrelease tablets or placebo given for 6 weeks. Tariot 2005 stated that they used a 36item version of CMAI, whereas the most commonly used version is the 29item version. The included studies varied in the reporting of serious adverse events (SAE) during their treatment period. The scales included but were not limited to: CohenMansfield Agitation Inventory (CMAI; Social Dysfunction and Agitation Scale (SDAS; Clinical Global Impression Scale for Aggression (CGI; Behavior Observation Scale of Intramural Psychogeriatric Patients (GIP; Effect on carers (carers' psychological morbidity or burden). All three studies used the 18item scale but two studies rated items 0 to 6 (Tariot 2001; Tariot 2005), whereas one study rated items 1 to 7 (Porsteinsson 2001). et al. Participants in Herrmann 2007 received valproate 125 mg liquid suspension twice daily, increased to 500 mg twice daily over the first two weeks. In this 2018 updated review, we excluded participants receiving chronic therapy with other psychoactive medications from the review except for those studies where treatment with an additional psychotropic medication was permitted in the study protocol. 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). In Porsteinsson 2001, 2/28 participants in the divalproex group had developed a significant decrease in platelet count, but not to the level of thrombocytopenia. et al. An update search was performed for this review on 30 July 2010. Sodium valproate in the treatment of aggressive behavior in patients with dementia a randomised placebo controlled clinical trial. The GIP consists of 14 observational scales to describe agitated and aggressive behaviour. Comparison 2 Divalproex versus placebo, Outcome 1 Total number of participants with sedation at 6 weeks. Valproic acid (VPA) (Chemical Abstracts Service Registry Number 1069-66-5) as well as sodium valproate, are widely used as an antiepileptic drug and a mood stabilizer. Due to the low number of included studies, subgroup analysis was not possible. Some of the side effects associated with valproate were sleepiness, feeling sick, being sick, watery stools, and urinary tract infections. AD: Alzheimer's disease; ADCS: Alzheimer's Disease Cooperative Study Activities ; BPRS: Brief Psychiatric Rating Scale; BPSD: behavioural and psychological symptoms associated with dementia; CDR: Clinical Dementia Rating; CERAD: Consortium to Establish a Registry for Alzheimer's Disease; CMAI: CohenMansfield Agitation Index; CNS: central nervous system; DAT: dementia of the Alzheimer type; DSMIV: Diagnostic and Statistical Manual of Mental Disorders, 4th edition; EEG: electroencephalograph; GIP: Behavior Observation Scale of Intramural Psychogeriatric Patients; MMSE: MiniMental State Examination; NINCDSADRDA: National Institute of Neurological and Communicative Disorders and StrokeAlzheimer's Disease and Related Disorders Association; NPI: Neuropsychiatric Inventory; PD: Parkinson's disease; SD: standard deviation; SDAS9: 9item Social Dysfunction and Agitation Scale; VaD: vascular dementia. Where data were suitable for a metaanalysis, we presented the effect estimate from a fixedeffect model. There was similarly a high level of uncertainty about the result on the NPI agitation/aggression subscale, which showed no clear evidence of a difference between groups (MD 1.43, 95% CI 2.48 to 5.34; 14 participants, 1 study; Analysis 1.7; very lowquality evidence, downgraded one level due to risk of bias and two levels due to imprecision). Mean scores at baseline were 7.4 (Tariot 2001), 6.8 (Porsteinsson 2001), 4.5 (Herrmann 2007), and 10.8 (range 4 to 24) (Tariot 2005). Valproic acid is also used to treat the manic phase of bipolar disorder (manic-depressive illness), and helps prevent migraine headaches. We attempted to delay or to prevent agitation and psychosis wit [Skip to Navigation] Dementia should have been diagnosed according to the classifications provided by Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSMIV) (APA 1994), International Classification of Diseases, 10th edition (ICD10) (WHO 1991), Diagnostic and Statistical Manual of Mental Disorders, 3rd edition (DSMIII) (APA 1980), or Diagnostic and Statistical Manual of Mental Disorders, 3rd revised edition (DSMIIIR) (APA 1987). We did not conduct any sensitivity analyses. Change from baseline at 6 weeks (ITT), 3 CohenMansfield Agitation Index. Blinding of outcome assessment (detection bias). Cameron RL, Review/update the information highlighted below and resubmit the form. The conclusions of this updated review were in keeping with the NICE evidence summary on the use of valproate preparations for agitation and aggression in dementia which stated that such medications were no more effective than placebo, and that adverse effects were more common in people taking them (NICE 2015). Eryavec G. A placebocontrolled trial of valproate for agitation and aggression in Alzheimer's disease, Dementia and Geriatric Cognitive Disorders. All included studies aimed to assess the effect of valproate treatments on agitation, aggression, mania, and overall function of people with dementia. Drug and placebo tablets were visually identical. One treatment option that has been evaluated is the antiepileptic drug valproate. Pollock BG, Comparison 1 Valproate preparations versus placebo, Outcome 4 BPRS hostility factor. Sodium valproate . One participant was excluded from the analysis due to protocol violation (low risk of attrition bias). The included studies used several different scales to assess change in agitated and aggressive behaviour. Gray K, The quality of evidence in this review ranged from moderate to very low on a range of different outcome measures and overall did not indicate any benefit of valproate for the treatment of agitation in people with dementia. Erectile dysfunction (ED) is often a symptom . Sodium valproate 240 mg twice daily. We were able to pool data on agitation/aggression measured with the BPRS from two studies and the CMAI from three studies. This review demonstrates that there is insufficient evidence to change current treatment guidelines. Brackman D, The development of an observerscale for measuring social dysfunction and aggression. Tariot P, Acetylcholinesterase inhibitors and memantine are licensed for the treatment of cognitive symptoms in Alzheimer's disease and there is some evidence that these medications may positively impact on agitated behaviour, although there is no evidence that they specifically improve agitation (NICE 2006). While this would lead to disparity in total scores in each study, analysis of change in score in each study were still comparable. 2 additional participants discontinued treatment with placebo early (reasons not stated), but completed all study assessments. Most studies lasted for six weeks, although one was only three weeks long. Porsteinsson AP, Among anticonvulsants, carbamazepine and valproate preparations have both been used widely. Thomas MS, For most studies, the number of dropouts were not disproportionate between the treatment and the placebo groups (Porsteinsson 2001: 7% divalproex versus 14% placebo; Sival 2002: 0% valproate versus 5% placebo; Tariot 2005: 15% divalproex versus 18% placebo; Herrmann 2007: 7% valproate versus 7% placebo). Morris S, Risperidone is the only antipsychotic licensed for people with dementia, and guidelines recommend treatment should be used for no longer than 12 weeks. The SDAS9 measures several aspects of behaviour to do with patient interaction with other people, and physical and verbal aggression. Information obtained from the author suggested that they actually used the 29item version of the scale. These SAEs were four hospitalisations (for cellulitis, dehydration, pneumonia, myocardial infarction, and constipation) and one cerebrovascular accident; all were considered to be unrelated to the study drug. Tariot 2001 permitted shortterm use of lorazepam, oxazepam, or chloral hydrate as needed. et al. Often clear information regarding concomitant medication was not reported. All included studies reported that there were participants who dropped out during the study period. People receiving stable therapy with other psychoactive medications, including cholinesterase inhibitors, memantine, and antidepressants, could be included if this was permitted in the study protocol. Jackson W, It has been shown to worsen the stress experienced by family carers, increase the risk of injury, and increase the need for people with dementia to move into institutional care. Silver JM, We took a pragmatic approach to avoid risking the loss of relevant evidence and included studies despite this information not being explicitly reported. Cutler AJ, Specifically, variations in method, type of medication, dosage, duration of treatment, and use of different outcome measures in these studies made it difficult to apply metaanalysis. Further, since participants had been on therapy for varying periods of time when the study was terminated, interpretation of the effects of treatment was difficult. Randomisation was blocked by site, but no specific information regarding sequence generation process given to permit judgement of low risk or high risk. Clinical diagnosis of Alzheimer's disease: report of the NINCDSADRDA workgroup under the auspices of the Department of Health and Human Services Task Force on Alzheimer's Disease. The methods of evaluating the participants also varied between the studies, with use of different scales to assess agitation and aggression, and response to therapy. We included only randomised, placebocontrolled trials. Forester B, Change from baseline at 6 weeks (ITT), 5 Overt Aggression Scale total score. Vist GE, Change from baseline at 6 weeks (ITT). Very lowquality evidence from three studies which measured agitation with the CohenMansfield Agitation Index (CMAI) were consistent with a lack of effect of valproate treatment on agitation. Valproate preparations for agitation in dementia. Adunuri N, In Sival 2002, study participants received sodium valproate 240 mg twice daily for three weeks. Scribney W, Schneider L, It is possible that pooling of clinically diverse studies may have concealed important benefits or harms. Dosage titrated to 5001000 mg/day. Ewing B, The dose could then be increased to a maximum of 1500 mg/day or decreased based on efficacy and tolerability as determined by a blinded study physician. We presented key outcomes in Table 1, including, for each outcome, a summary of the amount of data, the magnitude of the effect size, and the overall quality of the evidence (Schnemann 2011). Blinding of participants and personnel (performance bias). See Table 2 for a description of the participants' characteristics at baseline in all studies. We analysed change in outcome measure from pre to posttreatment. The BPRS measures physical and verbal aggression, hallucinatory behaviour, and abnormal thought content. 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). 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