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Acta Psychiatrica Scandinavica Sep 2021Polypharmacy is common in maintenance treatment of bipolar illness, but proof of greater efficacy compared to monotherapy is assumed rather than well known. We... (Review)
Review
OBJECTIVES
Polypharmacy is common in maintenance treatment of bipolar illness, but proof of greater efficacy compared to monotherapy is assumed rather than well known. We systematically reviewed the evidence from the literature to provide recommendations for clinical management and future research.
METHOD
A systematic review was conducted on the use of polypharmacy in bipolar prophylaxis. Relevant papers published in English through 31 December 2019 were identified searching the electronic databases MEDLINE, Embase, PsycINFO, and the Cochrane Library.
RESULTS
Twelve studies matched inclusion criteria, including 10 randomized controlled trials (RCTs). The best drug combination in prevention is represented by lithium + valproic acid which showed a significant effect on time to mood relapses (HR = 0.57) compared to valproic acid monotherapy, especially for manic episodes (HR = 0.51). The effect was significant in terms of time to new drug treatment (HR = 0.51) and time to hospitalization (HR = 0.57). A significant reduction in the frequency of mood relapses was also reported for lithium + valproic acid vs. lithium monotherapy (RR=0.12); however, the trial had a small sample size. Lamotrigine + valproic acid reported significant efficacy in prevention of depressive episodes compared to lamotrigine alone.
CONCLUSIONS
The literature to support a generally greater efficacy with polypharmacy in bipolar illness is scant and heterogeneous. Within that limited evidence base, the best drug combination in bipolar prevention is represented by lithium + valproic acid for manic, but not depressive episodes. Clinical practice should focus more on adequate monotherapy before considering polypharmacy.
Topics: Antimanic Agents; Bipolar Disorder; Humans; Lithium Compounds; Polypharmacy; Valproic Acid
PubMed: 33960396
DOI: 10.1111/acps.13312 -
World Neurosurgery Feb 2024To systematically evaluate the efficacy of valproic acid (VPA) in rats with spinal cord injury (SCI) to reduce the risk of clinical conversion and provide a valuable... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To systematically evaluate the efficacy of valproic acid (VPA) in rats with spinal cord injury (SCI) to reduce the risk of clinical conversion and provide a valuable reference for future animal and clinical studies.
METHODS
We searched scientific databases, including PubMed, Ovid-Embase, Web of Science, and Scopus databases. The relevant literature was searched from the establishment date of the database to June 28, 2023. The search results were screened, data were extracted, and the quality of the literature was evaluated independently by 2 reviewers.
RESULTS
Among 656 nonduplicated references, 14 articles were included for meta-analysis. The summary results showed that the overall Basso, Beattie and Bresnahan scores of the VPA intervention group were significantly higher than those in the control group at 1-6 weeks after VPA intervention. Subgroup analysis showed that the injury model, administration dose, rat strain, country of study, or follow-up duration had no significant effect on the efficacy of VPA on rats with SCI. In addition, mesh analysis showed that high doses of the VPA group had a better effect on SCI rats, compared with the low dose group and the medium dose group.
CONCLUSIONS
To date, this is the first systematic evaluation of the potential effects of VPA on motor recovery in rats with SCI. We concluded that VPA can promote motor recovery in rats with SCI, and higher doses of VPA seem to be more effective in rats with SCI. However, the limited quality and sample of included studies reduced the application of this meta-analysis. In the future, more high-quality, direct comparative studies are needed to explore this issue in depth.
Topics: Rats; Animals; Valproic Acid; Spinal Cord Injuries; Spinal Cord; Recovery of Function; Disease Models, Animal
PubMed: 37923014
DOI: 10.1016/j.wneu.2023.10.135 -
The Canadian Journal of Hospital... 2022Status epilepticus (SE) is a neurologic emergency with potential for substantial mortality and morbidity. Parenteral benzodiazepine is the established first-line... (Review)
Review
BACKGROUND
Status epilepticus (SE) is a neurologic emergency with potential for substantial mortality and morbidity. Parenteral benzodiazepine is the established first-line treatment but fails to control SE in about one-third of patients. Levetiracetam may be used for SE that is refractory to benzodiazepine therapy.
OBJECTIVE
To examine, by means of a systematic review, the role of IV levetiracetam for the treatment of SE in adults.
DATA SOURCES
MEDLINE, Embase, CENTRAL, and CINAHL databases were searched, from inception to August 18, 2020.
STUDY SELECTION AND DATA EXTRACTION
Included in this review were prospective randomized controlled trials comparing levetiracetam with another antiepileptic drug, given with or after a benzodiazepine, in adult patients with SE. The primary outcome was cessation of SE. Quality of evidence was assessed with the Cochrane risk-of-bias tool. Characteristics of the included studies were reported using descriptive statistics.
DATA SYNTHESIS
Five studies compared IV levetiracetam with valproic acid, phenytoin (or its prodrug fosphenytoin), or both. All 5 studies found no statistically significant differences in efficacy or safety end points. There were numerically more cases of hypotension and respiratory failure with phenytoin, and more cases of psychiatric adverse effects (e.g., post-ictal psychosis) with levetiracetam.
CONCLUSIONS
Available evidence suggests that levetiracetam is as effective as valproic acid or phenytoin for the cessation of SE in adults. Other factors should therefore dictate the choice of antiepileptic drug for patients with SE, such as adverse effect profile, logistics of administration, drug cost, inclusion on hospital formularies, and drug availability.
PubMed: 34987263
DOI: 10.4212/cjhp.v75i1.3254 -
CNS & Neurological Disorders Drug... 2022Although Valproate (VPA) has several advantages in controlling seizures, it may cause serious hematological consequences. Hematotoxicity of VPA is particularly important...
PURPOSE
Although Valproate (VPA) has several advantages in controlling seizures, it may cause serious hematological consequences. Hematotoxicity of VPA is particularly important in pediatrics because patients at this age are at a growing risk of leukemia. For a conclusive agreement about the toxicity of VPA, in this study, we systematically reviewed the literature in which the hematological consequences of VPA had been emphasized.
METHODS
A systematic literature search was performed in June 2021 on electronic databases to find original research on the association between VPA therapy and hematotoxicity in pediatric patients. For this purpose, the following search terms "hematotoxicity", "valproic acid" and "pediatrics" with different spellings and similar terms, were searched in the title, keywords, and abstracts of articles. The data were collected and used for qualitative data description.
RESULTS
A total of 36 relevant articles with an overall 1381 study population were included. The results showed that VPA could cause severe hematotoxicity in children even at therapeutic doses. Neutropenia, thrombocytopenia, and bone marrow depression are the most common complications associated with VPA therapy. Also, findings showed that after discontinuation of VPA and starting other antiepileptic drugs or reducing the administered VPA dose, hematologic damages were entirely resolved, and all the hematological parameters improved during two weeks.
CONCLUSION
This review showed that VPA therapy could cause hematotoxicity in children; hence, it is recommended to monitor hematological indices during VPA therapy. Also, according to the suggested mechanistic pathways of VPA side effects, a combination of VPA with antioxidants may reduce hematological side effects.
Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Female; Hematologic Diseases; Humans; Infant; Male; Seizures; Valproic Acid; Young Adult
PubMed: 34382515
DOI: 10.2174/1871527320666210811162345 -
Neuro-oncology Mar 2023This systematic review provides updated insights, from the published literature in the past 5 years, based on the 2017 European Association of Neuro-Oncology (EANO)...
BACKGROUND
This systematic review provides updated insights, from the published literature in the past 5 years, based on the 2017 European Association of Neuro-Oncology (EANO) guidelines for palliative care in adults with malignant brain tumors. It provides an overview of palliative care options, including during the end-of-life phase for patients with malignant brain tumors.
METHODS
A systematic literature search was conducted from 2016 to 2021 focusing on four main topics: (1) symptom management, (2) caregiver needs, (3) early palliative care, and (4) care in the end-of-life phase. An international panel of palliative care experts in neuro-oncology synthesized the literature and reported the most relevant updates. A total of 140 articles were included.
RESULTS
New insights include that: Hippocampal avoidance and stereotactic radiosurgery results in a lower risk of neurocognitive decline in patients with brain metastases; levetiracetam is more efficacious in reducing seizures than valproic acid as first-line monotherapy antiseizure drug (ASD) in glioma patients; lacosamide and perampanel seem well-tolerated and efficacious add-on ASDs; and a comprehensive framework of palliative and supportive care for high-grade glioma patients and their caregivers was proposed. No pharmacological agents have been shown in randomized controlled trials to significantly improve fatigue or neurocognition.
CONCLUSIONS
Since the 2017 EANO palliative care guidelines, new insights have been reported regarding symptom management and end-of-life care, however, most recommendations remain unchanged. Early palliative care interventions are essential to define goals of care and minimize symptom burden in a timely fashion. Interventional studies that address pain, fatigue, and psychiatric symptoms as well as (the timing of) early palliative care are urgently needed.
Topics: Humans; Adult; Terminal Care; Brain Neoplasms; Glioma; Death; Fatigue
PubMed: 36271873
DOI: 10.1093/neuonc/noac216 -
Expert Review of Clinical Pharmacology May 2022This study reviewed all published valproic acid (VPA) population pharmacokinetic (PPK) models in adult patients and assessed them using external validation methods to...
Published population pharmacokinetic models of valproic acid in adult patients: a systematic review and external validation in a Chinese sample of inpatients with bipolar disorder.
BACKGROUND
This study reviewed all published valproic acid (VPA) population pharmacokinetic (PPK) models in adult patients and assessed them using external validation methods to determine predictive performance.
METHODS
Thirteen published PPK models (labeled with letters A to M) not restricted to children were identified in PubMed, Embase, and Web of Science databases. They were evaluated in a sample totaling 411 serum concentrations from 146 adult inpatients diagnosed with bipolar disorder in a Chinese hospital. Serum concentrations of VPA were analyzed by validated ultra-performance liquid chromatography-tandem mass spectrometry. Performance was assessed by four tests (prediction-based diagnostics, visual predictive checks, normalized prediction distribution error, and Bayesian forecasting).
RESULTS
Models K and L, developed in large samples of Chinese and Thai patients, showed good performance in our Chinese dataset. Models H and J demonstrated good performance in 2 and 3 of the 4 tests, respectively. Another seven models exhibited intermediate performance. The models with the worst performance, F and M, could not be improved by Bayesian forecasting.
CONCLUSION
In our validation study, the most important factors contributing to good performance were absence of children, Asian ethnicity, one-compartment models, and inclusion of body weight and VPA dose in previously published models.
Topics: Adult; Anticonvulsants; Bayes Theorem; Bipolar Disorder; Child; China; Epilepsy; Humans; Inpatients; Models, Biological; Valproic Acid
PubMed: 35536685
DOI: 10.1080/17512433.2022.2075849 -
Clinical Toxicology (Philadelphia, Pa.) Oct 2021Valproic acid is a carboxylic acid derivative commonly prescribed for several types of seizure disorders or for acute manic episodes in patients with bipolar disorder....
INTRODUCTION
Valproic acid is a carboxylic acid derivative commonly prescribed for several types of seizure disorders or for acute manic episodes in patients with bipolar disorder. Several cases of valproate-induced pleural effusion have been reported, although the precise pathophysiological mechanism remains unknown.
OBJECTIVE
To describe the presentation of pleural effusion associated with valproate use and to categorize published case reports according to clinical, immunological, and pleural effusion cell type.
METHODS
PubMed/MEDLINE and Embase databases were systematically searched from January 1970 until November 2020 using the following search terms: "valproic acid" OR "valproate" OR "pleural fluid" OR "exudative effusion" OR "transudative effusion" OR "valproic lung adverse events". These searches yielded 171 references of which 135 articles were considered irrelevant, leaving 36 potentially relevant references which were carefully scrutinized. Twenty-eight cases of valproate-induced pleural effusion were identified after excluding two articles reporting five patients with lung parenchymal adverse reactions to treatment with valproic acid; two articles reporting three patients in whom the pleural effusion could not be attributed to valproic acid alone; one case discussing valproate therapy and fungal pleural effusion; and one describing a patient who suffered from severe cardiac failure. There were also two cases, in an abstract form, with pericardial and pleural effusion, but without any further informative details, and, thus, they were also excluded from this survey.
EXUDATIVE EOSINOPHILIC PLEURAL EFFUSION
This was the most common type of valproate-induced pleural effusion reported in 17 out of 28 cases (60.7%), with concurrent peripheral eosinophilia in ten. Acute hypersensitivity reaction, inflammation of the pleural cavity induced by the drug, drug toxicity, and damage to mesothelial cells due to oxidants, comprise the possible pivotal mechanisms.
EXUDATIVE LYMPHOCYTIC PLEURAL EFFUSION
This was reported in two cases, with concurrent pericardial effusion in one. Discontinuation of valproate led to resolution of the effusion, although the underlying pathophysiological mechanisms remain abstruse. Interestingly, a patient presented with recurrent pleural effusion characterized by transition from eosinophilic to lymphocytic predominance after readministration of valproate.
TRANSUDATIVE PLEURAL EFFUSION
Three out of 28 cases (10.7%) were characterized by neutrophilic transudative pleural effusion after long-term therapy with valproate, while concurrent pericardial effusion was also noted in two.
VALPROATE-INDUCED LUPUS ERYTHEMATOSUS WITH PLEURAL EFFUSION
Five patients receiving valproate therapy (17.9% out of the 28 cases) developed drug-induced lupus erythematosus with concurrent pleural effusion that was eosinophilic in three. All patients had positive antinuclear antibodies; anti-histone antibodies were positive in two.
CONCLUSIONS
Valproate-induced pleural effusion is rare, but patients receiving treatment with valproic acid who develop respiratory symptoms should be examined for valproate-induced pleural effusion.
Topics: Adolescent; Adult; Aged; Anticonvulsants; Eosinophilia; Female; Humans; Lupus Erythematosus, Systemic; Male; Middle Aged; Pleural Effusion; Prognosis; Risk Assessment; Risk Factors; Valproic Acid; Young Adult
PubMed: 34259092
DOI: 10.1080/15563650.2021.1945081 -
Neurology Apr 2024To undertake a systematic review of the available literature to examine the relationship between prenatal antiseizure medication (ASM) exposure and adverse postnatal...
BACKGROUND AND OBJECTIVES
To undertake a systematic review of the available literature to examine the relationship between prenatal antiseizure medication (ASM) exposure and adverse postnatal neurodevelopmental outcomes, focusing on social, emotional, behavioral, and adaptive domains of human function, and the frequency of neurodevelopmental and psychiatric disorders in ASM-exposed offspring.
METHODS
Electronic searches of MEDLINE, PsychINFO, and EMBASE were conducted and limited to studies published between 1990 and 2023 in English. Studies were eligible if they prospectively or retrospectively reported neurodevelopmental outcomes of ASM-exposed offspring. The Newcastle-Ottawa scale was used to conduct methodologic quality assessments of included studies, and a narrative synthesis integrated the review findings.
RESULTS
Forty-three studies were included. Valproate has been consistently associated with a 2- to 4-fold increased risk of autism spectrum disorder (ASD), 2- to 5-fold increased risk of intellectual disability (ID), and poor adaptive functioning. Growing evidence indicates that topiramate is associated with a 2-fold increased risk of ASD and 3- to 4-fold increased risk of ID. The risks of adverse neurodevelopmental outcomes for valproate and topiramate seem to be dose dependent. Phenobarbital has been suggested to be associated with deleterious neurodevelopmental effects, but data are limited. Levetiracetam has recently been linked with an increased risk of attention deficit hyperactivity disorder and anxiety disorders in a single study. Carbamazepine has been associated with variable neurodevelopmental outcomes. Lamotrigine seems to be "safe" in terms of postnatal neurodevelopment. Data for oxcarbazepine, phenytoin, and clonazepam are limited but seem to have little-to-no risk of adverse outcomes. Evidence for the remaining ASMs, including gabapentin, pregabalin, lacosamide, zonisamide, clobazam, perampanel, ethosuximide, or brivaracetam, is lacking. Several methodologic limitations impeded data synthesis, including heterogeneity in outcome measures and small samples of monotherapy exposures.
DISCUSSION
The findings of this review support the conclusion that valproate and topiramate use during pregnancy is associated with a significantly increased risk of neurodevelopmental effects on the fetus. Apart from lamotrigine, which seems to be free of adverse neurodevelopmental effects, data for the other ASMs are mixed or inadequate to draw definite conclusions. Further research into the neurodevelopmental effects of prenatal exposure to ASMs, including most newer agents, is much needed.
Topics: Pregnancy; Female; Humans; Valproic Acid; Lamotrigine; Topiramate; Autism Spectrum Disorder; Retrospective Studies; Anticonvulsants
PubMed: 38531021
DOI: 10.1212/WNL.0000000000209175 -
The Cochrane Database of Systematic... Feb 2022Seizures after stroke are an important clinical problem and may result in poor outcomes. The indications of antiepileptic drugs (AEDs) for seizure prophylaxis after... (Review)
Review
BACKGROUND
Seizures after stroke are an important clinical problem and may result in poor outcomes. The indications of antiepileptic drugs (AEDs) for seizure prophylaxis after stroke remain unclear. This is an updated version of the Cochrane Review previously published in 2014.
OBJECTIVES
To assess the effects of AEDs for the primary and secondary prevention of seizures after stroke. For primary prevention, we aimed to assess whether AEDs reduce the likelihood of seizures in people who have a stroke but do not have a seizure. For secondary prevention, we aimed to assess whether AEDs reduce the likelihood of further seizures in people who have a stroke and at least one post-stroke seizure.
SEARCH METHODS
We searched the following databases on 9 March 2021: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to March 08, 2021). CRS Web includes randomised or quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organisation International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialised Registers of Cochrane Review Groups including Epilepsy and Stroke. We also checked the reference lists of articles retrieved from these searches.
SELECTION CRITERIA
We selected randomised and quasi-randomised controlled studies that recruited participants with a clinical diagnosis of stroke, either ischaemic or haemorrhagic. We excluded studies that only recruited participants with subarachnoid haemorrhage, subdural haemorrhage, extradural haemorrhage, or other non-stroke diagnoses such as tumour- or infection-related infarction or haemorrhage. We also excluded studies that recruited only participants who had undergone neurosurgery. We included participants of all ages suffering any seizure type who were assigned to AEDs or placebo groups.
DATA COLLECTION AND ANALYSIS
In accordance with standard methodological procedures expected by The Cochrane Collaboration, two review authors independently assessed trials for inclusion before evaluating trial risk of bias and extracting relevant data. The primary outcome assessed was the proportion of participants who experienced seizures in the follow-up period. We presented results as summary risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes and mean differences (MDs) with 95% CIs for continuous outcomes. Where we had sufficient data, we calculated random-effects (Mantel-Haenszel) meta-analyses for dichotomous outcomes; otherwise, we reported results narratively. We used the I statistic to analyse statistical heterogeneity. We planned to use funnel plots to assess publication bias in meta-analyses with at least 10 included studies. We used the GRADE approach to assess the certainty of the evidence.
MAIN RESULTS
Two studies with a total of 856 subjects were included. AEDs were not shown to be effective in primary prophylaxis of post-stroke seizure (RR 0.65, 95% CI 0.34 to 1.26; 2 studies, 856 participants; moderate-certainty evidence). The first study was a randomised double-blind study comparing valproic acid with placebo for primary seizure prevention up to one year after stroke. The study included 72 adults with intracerebral haemorrhage. There was no difference in the risk of post-stroke seizures (RR 0.88, 95% CI 0.35 to 2.16) or of death (RR 1.20, 95% CI 0.40 to 3.58). The second study was a substudy on the use of diazepam in acute stroke. It was a randomised double-blind study, comparing a three-day diazepam treatment versus placebo for primary seizure prevention up to three months after stroke in 784 adults with acute stroke. There was no evidence of a difference in the risk of post-stroke seizures for all stroke or subgroups of haemorrhagic or ischaemic stroke (RR for all stroke 0.47, 95% CI 0.18 to 1.22). In a subgroup analysis of anterior circulation cortical infarcts, primary prophylaxis with diazepam was associated with a reduced risk of post-stroke seizures (RR 0.21, 95% CI 0.05 to 0.95). Risks of mortality did not differ between the diazepam and the placebo group at two weeks (RR 0.84, 95% CI 0.56 to 1.26) and three months follow-up (RR 0.95, 95% CI 0.72 to 1.26). We assessed both studies to be at a low overall risk of bias. Using the GRADE approach, we assessed the overall certainty of the evidence as low to moderate.
AUTHORS' CONCLUSIONS
There is insufficient evidence to support the routine use of AEDs on the primary and secondary prevention of seizures after stroke. Further well-conducted studies are warranted for this important clinical problem.
Topics: Adult; Anticonvulsants; Brain Ischemia; Humans; Randomized Controlled Trials as Topic; Secondary Prevention; Seizures; Stroke
PubMed: 35129214
DOI: 10.1002/14651858.CD005398.pub4 -
European Journal of Clinical... Aug 2020Cytochrome P450 (CYP) is involved in the metabolism of valproic acid (VPA). Specifically, CYP2C9 and CYP2A6 are the main enzymes responsible for VPA metabolism. However,... (Meta-Analysis)
Meta-Analysis
PURPOSE
Cytochrome P450 (CYP) is involved in the metabolism of valproic acid (VPA). Specifically, CYP2C9 and CYP2A6 are the main enzymes responsible for VPA metabolism. However, the correlation between plasma VPA concentrations and CYP2C9 and CYP2A6 gene variations is uncertain. This meta-analysis aimed to investigate the relationship between CYP2C9 and CYP2A6 variants and plasma concentrations of VPA.
METHODS
The PubMed, Web of Science, and EMBASE databases were searched for qualifying studies published until July 2019. Cohort studies that included standardized plasma VPA concentrations and CYP2C9 and CYP2A6 genotypes were reviewed. The mean difference and 95% confidence intervals (CIs) were evaluated to assess the strength of the relationship. Data analysis was performed using Review Manager (version 5.3) and RStudio (version 3.6).
RESULTS
In total, we analyzed data from six studies involving 807 patients. We found that CYP2C9*3 was associated with standardized plasma VPA concentration; *3 allele carriers had a 0.70-μg/mL higher concentration per mg/kg than non-carriers (95% CI 0.25, 1.15; P = 0.002). We also found a significant association between the CYP2A6*4 and standardized trough VPA concentration; patients with the *4 allele had a 0.48-μg/mL higher concentration per mg/kg than patients without the *4 allele (95% CI 0.10, 0.86; P = 0.01).
CONCLUSION
This meta-analysis demonstrated that CYP2C9*3 and CYP2A6*4 genetic variants affect plasma VPA concentrations. For epilepsy patients with these genotypes, dose adjustment may be necessary to ensure VPA's therapeutic effect.
Topics: Anticonvulsants; Cytochrome P-450 CYP2A6; Cytochrome P-450 CYP2C9; Epilepsy; Humans; Valproic Acid
PubMed: 32385545
DOI: 10.1007/s00228-020-02872-6