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BMJ Open Jul 2019The aim of this systematic review was to assess the efficacy and safety of pharmacological agents in the management of agitated behaviours following traumatic brain...
OBJECTIVE
The aim of this systematic review was to assess the efficacy and safety of pharmacological agents in the management of agitated behaviours following traumatic brain injury (TBI).
METHODS
We performed a search strategy in PubMed, OvidMEDLINE, Embase, CINAHL, PsycINFO, Cochrane Library, Google Scholar, Directory of Open Access Journals, LILACS, Web of Science and Prospero (up to 10 December 2018) for published and unpublished evidence on the risks and benefits of 9 prespecified medications classes used to control agitated behaviours following TBI. We included all randomised controlled trials, quasi-experimental and observational studies examining the effects of medications administered to control agitated behaviours in TBI patients. Included studies were classified into three mutually exclusive categories: (1) agitated behaviour was the presenting symptom; (2) agitated behaviour was not the presenting symptom, but was measured as an outcome variable; and (3) safety of pharmacological interventions administered to control agitated behaviours was measured.
RESULTS
Among the 181 articles assessed for eligibility, 21 studies were included. Of the studies suggesting possible benefits, propranolol reduced maximum intensities of agitation per week and physical restraint use, methylphenidate improved anger measures following 6 weeks of treatment, valproic acid reduced weekly agitated behaviour scale ratings and olanzapine reduced irritability, aggressiveness and insomnia between weeks 1 and 3 of treatment. Amantadine showed variable effects and may increase the risk of agitation in the critically ill. In three studies evaluating safety outcomes, antipsychotics were associated with an increased duration of post-traumatic amnesia (PTA) in unadjusted analyses. Small sample sizes, heterogeneity and an unclear risk of bias were limits.
CONCLUSIONS
Propranolol, methylphenidate, valproic acid and olanzapine may offer some benefit; however, they need to be further studied. Antipsychotics may increase the length of PTA. More studies on tailored interventions and continuous evaluation of safety and efficacy throughout acute, rehabilitation and outpatient settings are needed.
PROSPERO REGISTRATION NUMBER
CRD42016033140.
Topics: Antipsychotic Agents; Brain Injuries, Traumatic; Humans; Psychomotor Agitation; Psychoses, Substance-Induced; Randomized Controlled Trials as Topic
PubMed: 31289093
DOI: 10.1136/bmjopen-2019-029604 -
The Cochrane Database of Systematic... Jun 2019Bipolar disorder is a common condition associated with high morbidity; developing efficacious, safe treatments is therefore essential. Lithium is an effective...
BACKGROUND
Bipolar disorder is a common condition associated with high morbidity; developing efficacious, safe treatments is therefore essential. Lithium is an effective maintenance treatment for bipolar disorder. It acts as mood stabiliser and reduces the risk of suicide. However, evidence assessing the efficacy of lithium in the treatment of acute mania is less robust. Current evidence-based guidelines cite multiple anti-dopaminergic and mood-stabilising agents as initial treatments: more definite evidence is needed to decide if lithium should be the first-line therapy.
OBJECTIVES
1. To assess the effects of lithium in comparison with placebo or other active treatment in alleviating the acute symptoms of a manic or mixed episode in people with bipolar disorder.2. To review the acceptability and tolerability of treatment with lithium in comparison with placebo or other active treatments in alleviating the acute symptoms of a manic or mixed episode in people with bipolar disorder.
SEARCH METHODS
We searched the Cochrane Common Mental Disorders Controlled Trials Register, CENTRAL, MEDLINE, Embase, and PsycINFO. We also searched the World Health Organization trials portal (ICTRP) and ClinicalTrials.gov. We checked the reference lists of all included studies and relevant systematic reviews. We have incorporated studies from searches to 18 May 2018 into the current analyses.
SELECTION CRITERIA
Prospective randomised controlled studies comparing lithium with placebo or alternative drug treatment in treatment of acute mania. We included anyone with bipolar disorder, male and female, of any age.
DATA COLLECTION AND ANALYSIS
At least two review authors independently extracted data and assessed methodological quality. We used odds ratios (ORs) to analyse binary efficacy outcomes, and mean differences (MDs) or standardised mean differences (SMDs) for continuously distributed outcomes. We used a fixed-effect model unless heterogeneity was moderate or substantial, in which case we used a random-effects model. We used Review Manager 5 to analyse data. We assessed the certainty of evidence for individual outcomes using the GRADE approach.
MAIN RESULTS
We found 36 randomised controlled studies comparing lithium with placebo, one of 12 drugs, or electroconvulsive therapy for treatment of acute mania. Studies included male and female participants (n = 4220), of all ages, who all fitted criteria for a manic episode within the context of a diagnosis of bipolar disorder.Risk of bias was variable; 12 studies had a high risk of bias in one domain and 27 gave inadequate information on randomisation leading to an 'unclear' rating for selection bias.Lithium versus placeboHigh-certainty evidence found that lithium was an effective treatment for acute mania and was more effective than placebo at inducing a response (OR 2.13, 95% confidence interval (CI) 1.73 to 2.63; participants = 1707; studies = 6; I = 16%; high-certainty evidence), or remission (OR 2.16, 95% CI 1.73 to 2.69; participants = 1597; studies = 5; I = 21%; high-certainty evidence).Lithium was more likely than placebo to cause tremor (OR 3.25, 95% CI 2.10 to 5.04; participants = 1241; studies = 6; I = 0%; high-certainty evidence), and somnolence (OR 2.28, 95% CI 1.46 to 3.58; participants = 1351; studies = 7; I = 0%; high-certainty evidence).There was insufficient evidence to determine the effect of lithium for all-cause dropouts (OR 0.76; 95% CI 0.46 to 1.25; participants = 1353; studies = 7; I = 75%; moderate-certainty evidence), and weight gain (OR 1.48, 95% CI 0.56 to 3.92; participants = 735, studies = 3; I= 51%; moderate-certainty evidence).Lithium versus antipsychotics or mood stabilisersFor the outcome of inducing a response, there was only very low-certainty evidence regarding lithium compared to haloperidol (MD -2.40, 95% CI -6.31 to 1.50; participants = 80; studies = 3; I = 95%), quetiapine (OR 0.66, 95% CI 0.28 to 1.55; participants = 335; studies = 2; I = 71%), and carbamazepine (SMD 0.21, 95% CI -0.18 to 0.60; participants = 102; studies = 3; I = 0%).Lithium was probably less likely to induce a response than olanzapine (OR 0.44, 95% CI 0.20 to 0.94; participants = 180; studies = 2; I = 0%; moderate-certainty evidence).Lithium may be less likely to induce a response than risperidone (MD 7.28, 95% CI 5.22 to 9.34; participants = 241; studies = 3; I = 49%; low-certainty evidence).There was no evidence of a difference between lithium and valproate (OR 1.22, 95% CI 0.87 to 1.70; participants = 607; studies = 5; I = 22%; moderate-certainty evidence).There was moderate-certainty evidence that lithium was more effective than topiramate at treating acute mania (OR 2.28, 95% CI 1.63 to 3.20; participants = 660; studies = 1).Data on adverse events for these comparisons contained too few studies to provide high-certainty evidence.
AUTHORS' CONCLUSIONS
This systematic review indicates that lithium is more effective than placebo as a treatment for acute mania but increases the risk for somnolence and tremor. Limited evidence suggests little or no difference between lithium and other mood stabilisers (valproate, carbamazepine) or antipsychotics (risperidone, quetiapine, haloperidol). Olanzapine may be an exception, as it is probably slightly more effective than lithium. There is uncertain evidence that risperidone may also be more effective than lithium. Lithium is probably more effective at treating acute mania than topiramate. When compared to placebo, lithium was more likely to cause adverse events. However, when compared to other drugs, too few studies provided data on adverse effects to provide high-certainty evidence. More, rigorously designed, large-scale studies are needed to definitively conclude if lithium is superior to other interventions in treating acute mania.
Topics: Acute Disease; Antipsychotic Agents; Bipolar Disorder; Humans; Lithium Compounds; Randomized Controlled Trials as Topic; Valproic Acid
PubMed: 31152444
DOI: 10.1002/14651858.CD004048.pub4 -
Medical Acupuncture Apr 2019A Cochrane Systematic Review published by Linde et al. in 2016 found moderate evidence suggesting that acupuncture is "at least non-inferior" to conventional... (Review)
Review
A Cochrane Systematic Review published by Linde et al. in 2016 found moderate evidence suggesting that acupuncture is "at least non-inferior" to conventional prophylactic drug treatments (flunarizine, metoprolol, and valproic acid) for episodic migraine prophylaxis. The evidence for the efficacy of these conventional treatments must be verified to strengthen and validate the original comparison made in Linde et al.'s 2016 review. The aim of the current authors' systematic review was to verify the efficacy of the conventional treatments used in Linde et al.'s 2016 comparison with acupuncture. Search strategies were applied to find studies that could verify the efficacy of conventional treatments for treating episodic migraines. Relevant outcomes and dosages were extracted from the retrieved studies. Each study's quality was assessed, using the Cochrane's collaboration tool for assessing risk of bias and the Cochrane GRADE [Grading of Recommendations Assessment, Development, and Evaluation] scale. There is high-quality evidence suggesting that prophylactic drug treatment, at the treatment dosage ranges used in Linde et al.'s 2016 review, reduced headache frequency at a 3-month follow-up, compared to placebo. Headache frequency at a 6-month follow-up, and responses (at least 50% reduction of headache frequency) at 3-month and 6-month follow-ups could not be assessed. These findings strengthened Linde et al.'s 2016 comparison of conventional treatments and acupuncture for reducing headache frequency at a 3-month follow-up. For episodic migraine prophylaxis, moderate evidence suggests that acupuncture is "at least non-inferior," to now-, conventional treatments. This raises significant questions in the debate concerning claims that acupuncture is a placebo-based treatment and the prescriptions of proven conventional treatments that have similar effects as acupuncture.
PubMed: 31031874
DOI: 10.1089/acu.2019.1337 -
Seizure Jul 2019We systematically reviewed studies to provide current evidence about the incidence and risk of alopecia in patients undergoing valproic acid (VPA) therapy. (Meta-Analysis)
Meta-Analysis
PURPOSE
We systematically reviewed studies to provide current evidence about the incidence and risk of alopecia in patients undergoing valproic acid (VPA) therapy.
METHODS
We retrieved relevant publications and gathered data on alopecia in patients taking VPA and other drugs from prospective studies.
RESULTS
Twenty-five articles met the inclusion criteria, and the overall incidence of alopecia in patients receiving VPA therapy was 11% (95% confidence interval (CI): 0.08-0.13). The pooled risk of alopecia showed a significant difference between patients treated with VPA and all other drugs (odds ratio (OR) 5.02, 95% CI: 3.58-7.03), other epileptic drugs (AEDs) (OR 4.82, 95% CI: 3.32-7.00) and other non-AEDs (OR 5.84, 95% CI: 2.67-12.81). Compared to other drugs, VPA increased the risk of alopecia both in patients with migraine headaches (OR 6.05, 95% CI: 2.89-12.63) and patients with epilepsy (OR 5.29, 95% CI: 3.53-7.92), and the increase risk was reported more frequently in patients with migraine. Both lower doses (OR 4.38, 95% CI: 2.32-8.25) and shorter treatments (OR 4.98, 95% CI: 2.41-10.25) with VPA posed a high risk of alopecia compared to other drugs, as did higher doses and longer treatment times.
CONCLUSIONS
Based on our findings, VPA was significantly associated with a risk of alopecia compared to other drugs, and the risk did not depend on the dose and treatment time.
Topics: Alopecia; Anticonvulsants; Epilepsy; Humans; Incidence; Prospective Studies; Valproic Acid
PubMed: 30981051
DOI: 10.1016/j.seizure.2019.04.003 -
Molecular Autism 2019Autism (MIM 209850) is a multifactorial disorder with a broad clinical presentation. A number of high-confidence ASD risk genes are known; however, the contribution of...
Autism (MIM 209850) is a multifactorial disorder with a broad clinical presentation. A number of high-confidence ASD risk genes are known; however, the contribution of non-genetic environmental factors towards ASD remains largely uncertain. Here, we present a bioinformatics resource of genetic and induced models of ASD developed using a shared annotation platform. Using this data, we depict the intricate trends in the research approaches to analyze rodent models of ASD. We identify the top 30 most frequently studied phenotypes extracted from rodent models of ASD based on 787 publications. As expected, many of these include animal model equivalents of the "core" phenotypes associated with ASD, such as impairments in social behavior and repetitive behavior, as well as several comorbid features of ASD including anxiety, seizures, and motor-control deficits. These phenotypes have also been studied in models based on a broad range of environmental inducers present in the database, of which gestational exposure to valproic acid (VPA) and maternal immune activation models comprising lipopolysaccharide (LPS) and poly I:C are the most studied. In our unique dataset of rescue models, we identify 24 pharmaceutical agents tested on established models derived from various ASD genes and CNV loci for their efficacy in mitigating symptoms relevant for ASD. As a case study, we analyze a large collection of Shank3 mouse models providing a high-resolution view of the in vivo role of this high-confidence ASD gene, which is the gateway towards understanding and dissecting the heterogeneous phenotypes seen in single-gene models of ASD. The trends described in this study could be useful for researchers to compare ASD models and to establish a complete profile for all relevant animal models in ASD research.
Topics: Animals; Autistic Disorder; Databases, Genetic; Disease Models, Animal; Mice; Phenotype; Rats; Translational Research, Biomedical
PubMed: 30911366
DOI: 10.1186/s13229-019-0263-7 -
PloS One 2019Headaches are a common source of pain and suffering. The study's purpose was to assess beta-blockers efficacy in preventing migraine and tension-type headache. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Headaches are a common source of pain and suffering. The study's purpose was to assess beta-blockers efficacy in preventing migraine and tension-type headache.
METHODS
Cochrane Register of Controlled Trials; MEDLINE; EMBASE; ISI Web of Science, clinical trial registries, CNKI, Wanfang and CQVIP were searched through 21 August 2018, for randomized trials in which at least one comparison was a beta-blocker for the prevention of migraine or tension-type headache in adults. The primary outcome, headache frequency per month, was extracted in duplicate and pooled using random effects models.
DATA SYNTHESIS
This study included 108 randomized controlled trials, 50 placebo-controlled and 58 comparative effectiveness trials. Compared to placebo, propranolol reduced episodic migraine headaches by 1.5 headaches/month at 8 weeks (95% CI: -2.3 to -0.65) and was more likely to reduce headaches by 50% (RR: 1.4, 95% CI: 1.1-1.7). Trial Sequential Analysis (TSA) found that these outcomes were unlikely to be due to a Type I error. A network analysis suggested that beta-blocker's benefit for episodic migraines may be a class effect. Trials comparing beta-blockers to other interventions were largely single, underpowered trials. Propranolol was comparable to other medications known to be effective including flunarizine, topiramate and valproate. For chronic migraine, propranolol was more likely to reduce headaches by at least 50% (RR: 2.0, 95% CI: 1.0-4.3). There was only one trial of beta-blockers for tension-type headache.
CONCLUSIONS
There is high quality evidence that propranolol is better than placebo for episodic migraine headache. Other comparisons were underpowered, rated as low-quality based on only including single trials, making definitive conclusions about comparative effectiveness impossible. There were few trials examining beta-blocker effectiveness for chronic migraine or tension-type headache though there was limited evidence of benefit.
REGISTRATION
Prospero (ID: CRD42017050335).
Topics: Adrenergic beta-Antagonists; Adult; Clinical Trials as Topic; Female; Humans; Male; Migraine Disorders; Propranolol; Tension-Type Headache; Topiramate; Valproic Acid
PubMed: 30893319
DOI: 10.1371/journal.pone.0212785 -
The Cochrane Database of Systematic... Feb 2019This is an updated version of the Cochrane Review previously published in 2017.Absence seizures (AS) are brief epileptic seizures which present in childhood and...
BACKGROUND
This is an updated version of the Cochrane Review previously published in 2017.Absence seizures (AS) are brief epileptic seizures which present in childhood and adolescence. Depending on clinical features and electroencephalogram (EEG) findings they are divided into typical, atypical absences, and absences with special features. Typical absences are characterised by sudden loss of awareness and an EEG typically shows generalised spike wave discharges at three cycles per second. Ethosuximide, valproate and lamotrigine are currently used to treat absence seizures. This review aims to determine the best choice of antiepileptic drug for children and adolescents with AS.
OBJECTIVES
To review the evidence for the effects of ethosuximide, valproate and lamotrigine as treatments for children and adolescents with absence seizures (AS), when compared with placebo or each other.
SEARCH METHODS
For the latest update we searched the Cochrane Register of Studies (CRS Web, 29 May 2018), which includes the Cochrane Epilepsy Group's Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid, 1946 to 29 May 2018), ClinicalTrials.gov (29 May 2018) and the WHO International Clinical Trials Registry Platform (ICTRP, 29 May 2018). Previously we searched Embase (1988 to March 2005) and SCOPUS (1823 to 31 March 2014), but this is no longer necessary because randomised controlled trials (RCTs) and quasi-RCTs in Embase and SCOPUS are now included in CENTRAL. No language restrictions were imposed. In addition, we contacted Sanofi Winthrop, Glaxo Wellcome (now GlaxoSmithKline) and Parke Davis (now Pfizer), manufacturers of sodium valproate, lamotrigine and ethosuximide respectively.
SELECTION CRITERIA
Randomised parallel group monotherapy or add-on trials which include a comparison of any of the following in children or adolescents with AS: ethosuximide, sodium valproate, lamotrigine, or placebo.
DATA COLLECTION AND ANALYSIS
Outcome measures were: (1) proportion of individuals seizure free at one, three, six, 12 and 18 months post randomisation; (2) people with a 50% or greater reduction in seizure frequency; (3) normalisation of EEG and/or negative hyperventilation test; and (4) adverse effects. Data were independently extracted by two review authors. Results are presented as risk ratios (RR) with 95% confidence intervals (95% CIs). We used GRADE quality assessment criteria to evaluate the certainty of evidence derived from all included studies.
MAIN RESULTS
On the basis of our selection criteria, we included no new studies in the present review. Eight small trials (total number of participants: 691) were included from the earlier review. Six of them were of poor methodological quality (unclear or high risk of bias) and seven recruited less than 50 participants. There are no placebo-controlled trials for ethosuximide or valproate, and hence, no evidence from RCTs to support a specific effect on AS for either of these two drugs. Due to the differing methodologies used in the trials comparing ethosuximide, lamotrigine and valproate, we thought it inappropriate to undertake a meta-analysis. One large randomised, parallel double-blind controlled trial comparing ethosuximide, lamotrigine and sodium valproate in 453 children with newly diagnosed childhood absence epilepsy found that at 12 months, the freedom-from-failure rates for ethosuximide and valproic acid were similar and were higher than the rate for lamotrigine. The frequency of treatment failures due to lack of seizure control (P < 0.001) and intolerable adverse events (P < 0.037) was significantly different among the treatment groups, with the largest proportion of lack of seizure control in the lamotrigine cohort, and the largest proportion of adverse events in the valproic acid group. Overall, this large study demonstrates the superior effectiveness of ethosuximide and valproic acid compared to lamotrigine as initial monotherapy aimed to control seizures without intolerable adverse effects in children with childhood absence epilepsy. The risk of bias for this study was low. We rated the overall certainty of the evidence available from the included studies to be moderate or high.
AUTHORS' CONCLUSIONS
Since the last version of this review was published, we have found no new studies. Hence, the conclusions remain the same as the previous update. With regards to both efficacy and tolerability, ethosuximide represents the optimal initial empirical monotherapy for children and adolescents with AS. However, if absence and generalised tonic-clonic seizures coexist, valproate should be preferred, as ethosuximide is probably inefficacious on tonic-clonic seizures.
Topics: Adolescent; Anticonvulsants; Child; Epilepsy, Absence; Ethosuximide; Humans; Lamotrigine; Randomized Controlled Trials as Topic; Valproic Acid
PubMed: 30734919
DOI: 10.1002/14651858.CD003032.pub4 -
The Cochrane Database of Systematic... Jan 2019Topiramate is a newer broad-spectrum antiepileptic drug (AED). Some studies have shown the benefits of topiramate in the treatment of juvenile myoclonic epilepsy (JME).... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Topiramate is a newer broad-spectrum antiepileptic drug (AED). Some studies have shown the benefits of topiramate in the treatment of juvenile myoclonic epilepsy (JME). However, there are no current systematic reviews to determine the efficacy and tolerability of topiramate in people with JME. This is an update of a Cochrane Review first published in 2015, and last updated in 2017.
OBJECTIVES
To evaluate the efficacy and tolerability of topiramate in the treatment of JME.
SEARCH METHODS
For the latest update, on 10 July 2018 we searched the Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group's Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid 1946- ), and ClinicalTrials.gov. We also searched ongoing trials registers, reference lists and relevant conference proceedings, and contacted study authors and pharmaceutical companies.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) investigating topiramate versus placebo or other AED treatment for people with JME, with the outcomes of proportion of responders and proportion of participants experiencing adverse events (AEs).
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted data, cross-checked the data for accuracy and assessed the methodological quality. We performed no meta-analyses due to the limited available data.
MAIN RESULTS
We included three studies with a total of 83 participants. For efficacy, a greater proportion of participants in the topiramate group had a 50% or more reduction in primarily generalized tonic-clonic seizures (PGTCS) compared with participants in the placebo group. There were no significant differences between topiramate and valproate in participants responding with a 50% or more reduction in myoclonic seizures or in PGTCS, or becoming seizure-free. Concerning tolerability, we ranked AEs associated with topiramate as moderate to severe, while we ranked 59% of AEs linked to valproate as severe complaints. Moreover, systemic toxicity scores were higher in the valproate group than the topiramate group.Overall we judged all three studies to be at high risk of attrition bias and at unclear risk of reporting bias. We judged all three studies to be at low to unclear bias for the remaining risk of bias domains (random sequence, allocation, blinding). We judged the quality of the evidence from the studies to be very low.
AUTHORS' CONCLUSIONS
We have found no new studies since the last version of this review was published in 2017. This review does not provide sufficient evidence to support topiramate for the treatment of people with JME. Based on the current limited available data, topiramate seems to be better tolerated than valproate, but has no clear benefits over valproate in terms of efficacy. Well-designed, double-blind RCTs with large samples are required to test the efficacy and tolerability of topiramate in people with JME.
Topics: Adolescent; Anticonvulsants; Child; Humans; Myoclonic Epilepsy, Juvenile; Randomized Controlled Trials as Topic; Seizures; Topiramate; Treatment Outcome; Valproic Acid; Young Adult
PubMed: 30687937
DOI: 10.1002/14651858.CD010008.pub4 -
The Cochrane Database of Systematic... Oct 2018Agitation 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... (Meta-Analysis)
Meta-Analysis
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.
Topics: Aged; Aggression; Antimanic Agents; Cognition; Dementia; Humans; Psychomotor Agitation; Randomized Controlled Trials as Topic; Treatment Outcome; Valproic Acid
PubMed: 30293233
DOI: 10.1002/14651858.CD003945.pub4 -
Frontiers in Medicine 2018Valproic acid (VPA) has been approved for the treatment of seizure disorders. It is also commonly used in psychiatric disorders, such as schizophrenia spectrum...
Valproic acid (VPA) has been approved for the treatment of seizure disorders. It is also commonly used in psychiatric disorders, such as schizophrenia spectrum disorders. With increasing administration, reports of intoxications are more frequently reported. The most common findings of VPA intoxication are central nervous system depression, respiratory depression, hypotension, metabolic acidosis, and elevated lactate, among others. We describe a case report of VPA intoxication with hemodiafiltration (HDF) as extracorporeal treatment (ECTR) for removal of VPA. This treatment modality has only rarely been reported in the current literature. In addition, we performed an updated systematic literature review (SLR) of additional cases on the topic ranging from December 1st, 2014 to April 20th, 2018. We searched MEDLINE and Web of Science for relevant references. In the presented case, VPA intoxication occurred in a 46-year-old female patient after oral ingestion of 56 g of VPA. In addition to vasopressors and endotracheal intubation, we administered L-Carnitine (L-Car) and performed hemodiafiltration treatment. After intravenous therapy with L-Car and simultaneous HDF sessions, we observed full recovery without neurological sequelae. The SLR identified 8 additional articles reporting favorable outcomes with extracorporeal treatments in most cases. HDF and other extracorporeal procedures are safe and effective therapeutic options in patients with VPA intoxication. The choice of ECTR modality mainly depends on local experience and the setting. In the present case, ingestion of 56 g was successfully treated with HDF. These findings are in line with several other case reports describing positive outcomes. Extracorporeal treatment, including HDF, should be considered early in the management of VPA intoxication. Supporting evidence is emerging, but it is of limited quality.
PubMed: 30148132
DOI: 10.3389/fmed.2018.00224