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Epilepsy Research Jul 2024North Sea Progressive Myoclonus Epilepsy (NS-PME) is a rare genetic disorder characterized by ataxia, myoclonus and seizures with a progressive course. Although the...
OBJECTIVE
North Sea Progressive Myoclonus Epilepsy (NS-PME) is a rare genetic disorder characterized by ataxia, myoclonus and seizures with a progressive course. Although the cause of NS-PME is known, namely a homozygous mutation in the GOSR2 gene (c.430 G>T; p. Gly144Trp), sufficient treatment is lacking. Despite combinations of on average 3-5 anti-seizure medications (ASMs), debilitating myoclonus and seizures persist. Here we aimed to gain insight into the most effective anti-convulsive target in NS-PME by evaluating the individual effects of ASMs in a NS-PME Drosophila model.
METHOD
A previously generated Drosophila model for NS-PME was used displaying progressive heat-sensitive seizures. We used this model to test 1. a first-generation ASM (sodium barbital), 2. common ASMs used in NS-PME (clonazepam, valproic acid, levetiracetam, ethosuximide) and 3. a novel third-generation ASM (ganaxolone) with similar mode of action to sodium barbital. Compounds were administered by adding them to the food in a range of concentrations. After 7 days of treatment, the percentage of heat-induced seizures was determined and compared to non-treated but affected controls.
RESULTS
As previously reported in the NS-PME Drosophila model, sodium barbital resulted in significant seizure suppression, with increasing effect at higher dosages. Of the commonly prescribed ASMs, clonazepam and ethosuximide resulted in significant seizure suppression, whereas both valproic acid and levetiracetam did not show any changes in seizures. Interestingly, ganaxolone did result in seizure suppression as well.
CONCLUSION
Of the six drugs tested, three of the four that resulted in seizure suppression (sodium barbital, clonazepam, ganaxolone) are primary known for their direct effect on GABA receptors. This suggests that GABA could be a potentially important target in the treatment of NS-PME. Consequently, these findings add rationale to the exploration of the clinical effect of ganaxolone in NS-PME and other progressive myoclonus epilepsies.
Topics: Animals; Anticonvulsants; Disease Models, Animal; Myoclonic Epilepsies, Progressive; Drosophila; Animals, Genetically Modified; Receptors, GABA-A
PubMed: 38781737
DOI: 10.1016/j.eplepsyres.2024.107380 -
Epidemiology and Psychiatric Sciences May 2024Accumulating studies have assessed mortality risk associated with mood-stabilizers, the mainstay treatment for bipolar disorder (BD). However, existing data were mostly...
AIMS
Accumulating studies have assessed mortality risk associated with mood-stabilizers, the mainstay treatment for bipolar disorder (BD). However, existing data were mostly restricted to suicide risk, focused on lithium and valproate and rarely adequately adjusted for potential confounders. This study aimed to assess comparative mortality risk with all, natural and unnatural causes between lithium, valproate and three frequently prescribed second-generation antipsychotics (SGA), with adjustment for important confounders.
METHODS
This population-based cohort study identified 8137 patients with first-diagnosed BD, who had exposed to lithium ( = 1028), valproate ( = 3580), olanzapine ( = 797), quetiapine ( = 1975) or risperidone ( = 757) between 2002 and 2018. Data were retrieved from territory-wide medical-record database of public healthcare services in Hong Kong. Propensity-score (PS)-weighting method was applied to optimize control for potential confounders including pre-existing chronic physical diseases, substance/alcohol use disorders and other psychotropic medications. PS-weighted Cox proportional-hazards regression was conducted to assess risk of all-, natural- and unnatural-cause mortality related to each mood-stabilizer, compared to lithium. Three sets of sensitivity analyses were conducted by restricting to patients with (i) length of cumulative exposure to specified mood-stabilizer ≥90 days and its medication possession ratio (MPR) ≥90%, (ii) MPR of specified mood-stabilizer ≥80% and MPR of other studied mood-stabilizers <20% and (iii) monotherapy.
RESULTS
Incidence rates of all-cause mortality per 1000 person-years were 5.9 (95% confidence interval [CI]: 4.5-7.6), 8.4 (7.4-9.5), 11.1 (8.3-14.9), 7.4 (6.0-9.2) and 12.0 (9.3-15.6) for lithium-, valproate-, olanzapine-, quetiapine- and risperidone-treated groups, respectively. BD patients treated with olanzapine (PS-weighted hazard ratio = 2.07 [95% CI: 1.33-3.22]) and risperidone (1.66 [1.08-2.55]) had significantly higher all-cause mortality rate than lithium-treated group. Olanzapine was associated with increased risk of natural-cause mortality (3.04 [1.54-6.00]) and risperidone was related to elevated risk of unnatural-cause mortality (3.33 [1.62-6.86]), relative to lithium. The association between olanzapine and increased natural-cause mortality rate was consistently affirmed in sensitivity analyses. Relationship between risperidone and elevated unnatural-cause mortality became non-significant in sensitivity analyses restricted to low MPR in other mood-stabilizers and monotherapy. Valproate- and lithium-treated groups did not show significant differences in all-, natural- or unnatural-cause mortality risk.
CONCLUSION
Our data showed that olanzapine and risperidone were associated with higher mortality risk than lithium, and further supported the clinical guidelines recommending lithium as the first-line mood-stabilizer for BD. Future research is required to further clarify comparative mortality risk associated with individual SGA agents to facilitate risk-benefit evaluation of alternative mood-stabilizers to minimize avoidable premature mortality in BD.
Topics: Humans; Bipolar Disorder; Antipsychotic Agents; Female; Male; Adult; Middle Aged; Valproic Acid; Propensity Score; Antimanic Agents; Cohort Studies; Quetiapine Fumarate; Olanzapine; Hong Kong; Risperidone; Lithium; Cause of Death
PubMed: 38779809
DOI: 10.1017/S2045796024000337 -
JAMA Network Open May 2024Teratogenic outcomes associated with valproic acid use represent a substantial concern for persons of childbearing age. Regulatory agencies worldwide have enhanced...
IMPORTANCE
Teratogenic outcomes associated with valproic acid use represent a substantial concern for persons of childbearing age. Regulatory agencies worldwide have enhanced warnings or implemented risk minimization programs to reduce exposure during pregnancy.
OBJECTIVES
To determine pregnancy rates during valproic acid use and concomitant contraception use across indications.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cohort study used data from the Merative MarketScan commercial claims databases from January 1, 2005, to December 31, 2020, to identify female patients aged 12 to 44 years who initiated valproic acid treatment and had continuous insurance enrollment 6 months before initiation and 9 months after treatment end. A treatment episode included consecutive prescription fills that occurred within 7 days from the end of the days' supply of the previous dispensing. Data were analyzed from March 1 to September 10, 2023.
MAIN OUTCOMES AND MEASURES
Treatment episodes were categorized by inferred indication using diagnoses preceding treatment initiation, including epilepsy, migraine or headache, mood disorders, and unknown or off-label uses. Pregnancy incidence rate ratios (IRRs) were calculated and were adjusted for age and calendar year. Contraceptive use (prescription contraceptives, intrauterine devices, and implants) during treatment was examined.
RESULTS
The cohort included 165 772 valproic acid treatment episodes among 69 390 women (mean [SD] age, 29.8 [10.0] years). Mood disorders (42.5%) were the most common indication, followed by migraine or headache (20.1%), with epilepsy playing a minor role (14.9%). Pregnancy incidence rates during valproic acid use remained unchanged, with a rate of 1.74 (95% CI, 1.14-2.53) per 100 person-years in 2005 and a rate of 1.90 (95% CI, 1.16-3.12) per 100 person-years in 2019. Compared with epilepsy, pregnancy rates were more than double for mood disorder (IRR, 2.16 [95% CI, 1.93-2.42]) and migraine or headache (IRR, 2.01 [95% CI, 1.92-2.09]). Few treatment episodes coincided with contraceptive use (37 012 [22.3%]), and oral dosage forms were the most common (27 069 [73.1%]).
CONCLUSIONS AND RELEVANCE
In this cohort study of patients of childbearing age who used valproic acid, pregnancy rates during valproic acid use did not decrease despite enhanced US Food and Drug Administration safety communications, and contraception use remained low. Patients with migraine and mood disorders accounted for the largest proportion of valproic acid use and had the highest pregnancy rates, while patients with epilepsy had the lowest. These findings suggest a need to enhance efforts to mitigate prenatal exposure to valproic acid, especially for indications where the risk of use during pregnancy outweighs the benefit.
Topics: Humans; Female; Valproic Acid; Pregnancy; Adult; Retrospective Studies; Adolescent; Prenatal Exposure Delayed Effects; Epilepsy; Young Adult; Anticonvulsants; Child; Pregnancy Rate; Mood Disorders; Migraine Disorders; United States
PubMed: 38776082
DOI: 10.1001/jamanetworkopen.2024.12680 -
Heliyon May 2024Autism spectrum disorder (ASD) is a group of developmental diseases characterized by social dysfunction and repetitive stereotype behaviors. Besides genetic mutations,...
Autism spectrum disorder (ASD) is a group of developmental diseases characterized by social dysfunction and repetitive stereotype behaviors. Besides genetic mutations, environmental factors play important roles in the development of ASD. Valproic acid (VPA) is widely used for modeling environmental factor induced ASD in rodents. However, traditional VPA modeling is low-in-efficiency and the phenotypes often vary among different batches of experiments. To optimize this ASD-modeling method, we tested "two-hit" hypothesis by single or double exposure of VPA and poly:IC at the critical time points of embryonic and postnatal stage. The autistic-like behaviors of mice treated with two-hit schemes (embryonic VPA plus postnatal poly:IC, embryonic poly:IC plus postnatal VPA, embryonic VPA plus poly: IC, or postnatal VPA plus poly:IC) were compared with mice treated with traditional VPA protocol. The results showed that all single-hit and two-hit schemes produced core ASD phenotypes as VPA single treatment did. Only one group, namely, mice double-hit by VPA and poly:IC simultaneously at E12.5 showed severe impairment of social preference, social interaction and ultrasonic communication, as well as significant increase of grooming activity and anxiety-like behaviors, in comparation with mice treated with the traditional VPA protocol. These data demonstrated that embryonic two-hit of VPA and poly:IC is more efficient in producing ASD phenotypes in mice than the single-hit of VPA, indicating this two-hit scheme could be utilized for modeling environmental factors induced ASD.
PubMed: 38774072
DOI: 10.1016/j.heliyon.2024.e30617 -
Cureus Apr 2024Fluvoxamine is a major antidepressant of the selective serotonin-reuptake inhibitor class, previously studied as a drug that improves cognitive memory by enhancing...
Fluvoxamine Ameliorates the Damage to the Neuro-Behavioral Status of Rats Caused by the Administration of Valproic Acid by Preventing Cognitive Memory Deficits and Decreased Hippocampal Cellular Proliferation.
Fluvoxamine is a major antidepressant of the selective serotonin-reuptake inhibitor class, previously studied as a drug that improves cognitive memory by enhancing hippocampal cell division and proliferation. Valproic acid (VPA) is a commonly used antiepileptic drug and mood stabilizer that has negative effects on cognitive memory as it inhibits cellular division and proliferation in the hippocampus. This study assessed the protective effects of fluvoxamine treatment versus the memory impairment, decreased hippocampal cellular proliferation, and weight loss produced by VPA treatment. The cognitive memory of 40 male Sprague-Dawley rats was assessed by the novel object location (NOL) test. Immunostaining by Ki67 and glutathione peroxidase 1 (GPX-1) was performed to quantify the number of dividing cells in the subgranular zone (SGZ) of the dentate gyrus and to assess the antioxidant activity of different treatments, respectively. Results showed that the VPA group had fewer Ki67-positive cells than the control group (p < 0.001), indicating reduced hippocampal proliferation. In contrast, the VPA and fluvoxamine combination group showed increased proliferation (p < 0.001) compared to VPA alone. Notably, fluvoxamine treatment significantly differed in cell counts compared to other groups (p < 0.001). Fluvoxamine also attenuated the weight loss caused by VPA (p < 0.0001). Our data suggested that fluvoxamine therapy attenuated the VPA-induced decrease in SGZ cellular proliferation, memory, and weight in rats.
PubMed: 38770498
DOI: 10.7759/cureus.58578 -
Psychiatry and Clinical... Dec 2023This study's purpose is to determine the effects of current episode and the mood stabilizers on chorioretinal layer thicknesses of bipolar disorder (BD) patients using...
BACKGROUND
This study's purpose is to determine the effects of current episode and the mood stabilizers on chorioretinal layer thicknesses of bipolar disorder (BD) patients using spectral-domain optical coherence tomography (SD-OCT).
METHODS
Sixty-seven patients were diagnosed with BD I and using lithium (Li) or valproic acid (VPA), of whom 20 were manic, 24 were depressive, and 23 were in remission, and 49 healthy individuals were included in the study. Peripapillary retinal nerve fiber layer (RNFL), ganglion cell layer, and macular thicknesses of the participants were measured automatically using SD-OCT, and their choroid layer thicknesses were measured manually using the depth imaging mode of SD-OCT. Statistical analysis of the data was performed using Statistical Package for the Social Sciences version 23.0.
RESULTS
The patient group's mean age was 39.78 ± 11.78, and the control group's mean age was 42.06 ± 12.10. The mean disease duration was 13.22 ± 8.23 in the patient group, and 26 patients were using Li. While peripapillary RNFL thicknesses were lower in the patient group ( < .05), other layer measurements were similar between the groups. Moreover, the episodes experienced by BD patients did not affect chorioretinal SD-OCT measurements. The patients on VPA had significantly lower RNFL thicknesses compared to the control and the Li groups, and all chorioretinal measurements were similar between the Li and the control groups.
CONCLUSION
As a result of the study, it was established that neurodegenerative processes play a role in the pathophysiology of BD and the usage of Li is protective against the neurodegeneration of RNFL. Retinal changes measured with SD-OCT can be used for the diagnosis and prognosis of BD and for evaluating responses to mood stabilizers.
PubMed: 38765851
DOI: 10.5152/pcp.2023.23687 -
Pharmacogenomics and Personalized... 2024To investigate the genotype distribution and allelic frequency among the Zhuang and Han schizophrenic populations in Guangxi, examine the correlation between genetic...
PURPOSE
To investigate the genotype distribution and allelic frequency among the Zhuang and Han schizophrenic populations in Guangxi, examine the correlation between genetic variants and standardized blood levels of Valproic Acid (VPA) in schizophrenic patients, and evaluate the effects of age, gender, and Body Mass Index (BMI) on standardized VPA blood concentrations.
PATIENTS AND METHODS
Between February and December 2022, 192 Zhuang and Han schizophrenia patients treated with VPA were studied. Steady-state VPA concentrations were determined using homogeneous enzyme immunoassays, and *1, *2, and *3 loci via q-PCR. genotype distributions between Zhuang and Han groups in Nanning were compared using chi-square tests and contrasted with other ethnicities. Non-parametric tests analyzed VPA variations, identifying critical factors through multivariate stepwise regression.
RESULTS
The study identified five genotypes at the *2 and *3 loci, with the *3/*3 genotype absent in both cohorts. The distribution in Guangxi Zhuang and Han mirrors, yet diverges significantly from Hui and Kazakh groups. Among 192 subjects, VPA blood levels remained consistent across metabolic types and ages 18-60 but varied significantly by gender. Multivariate analysis revealed gender and BMI as significant factors, overshadowing genotype and age.
CONCLUSION
In Guangxi, genetic variants in Zhuang and Han schizophrenia patients demonstrate statistically indistinguishable allelic and metabolic distributions. Gender and BMI can influence standardized VPA blood concentrations in schizophrenia patients. However, in our study cohort, the genotype and age are not the primary determinants of standardized VPA blood levels.
PubMed: 38765788
DOI: 10.2147/PGPM.S457805 -
Scientific Reports May 2024Autism spectrum disorder (ASD) exhibits a gender bias, with boys more frequently affected than girls. Similarly, in mouse models induced by prenatal exposure to valproic...
Autism spectrum disorder (ASD) exhibits a gender bias, with boys more frequently affected than girls. Similarly, in mouse models induced by prenatal exposure to valproic acid (VPA), males typically display reduced sociability, while females are less affected. Although both males and females exhibit VPA effects on neuroinflammatory parameters, these effects are sex-specific. Notably, females exposed to VPA show increased microglia and astrocyte density during the juvenile period. We hypothesized that these distinct neuroinflammatory patterns contribute to the resilience of females to VPA. To investigate this hypothesis, we treated juvenile animals with intraperitoneal bacterial lipopolysaccharides (LPS), a treatment known to elicit brain neuroinflammation. We thus evaluated the impact of juvenile LPS-induced inflammation on adult sociability and neuroinflammation in female mice prenatally exposed to VPA. Our results demonstrate that VPA-LPS females exhibit social deficits in adulthood, overriding the resilience observed in VPA-saline littermates. Repetitive behavior and anxiety levels were not affected by either treatment. We also evaluated whether the effect on sociability was accompanied by heightened neuroinflammation in the cerebellum and hippocampus. Surprisingly, we observed reduced astrocyte and microglia density in the cerebellum of VPA-LPS animals. These findings shed light on the complex interactions between prenatal insults, juvenile inflammatory stimuli, and sex-specific vulnerability in ASD-related social deficits, providing insights into potential therapeutic interventions for ASD.
Topics: Animals; Female; Lipopolysaccharides; Prenatal Exposure Delayed Effects; Pregnancy; Mice; Valproic Acid; Social Behavior; Male; Autism Spectrum Disorder; Microglia; Disease Models, Animal; Behavior, Animal; Astrocytes; Mice, Inbred C57BL
PubMed: 38763939
DOI: 10.1038/s41598-024-62217-6 -
Neurotoxicology May 2024The valproic acid model has been shown to reproduce ASD-like behaviours observed in patients and is now widely validated for construct, face, and predictivity as ASD...
The valproic acid model has been shown to reproduce ASD-like behaviours observed in patients and is now widely validated for construct, face, and predictivity as ASD model in rat. The literature agrees on using a single exposition to 500 mg/kg of VPA at gestational day 12 to induce ASD phenotype with the intraperitoneal route being the most commonly used. However, some studies validated this model with repeated exposure by using oral route. The way of administration may be of great importance in the induction of the ASD phenotype and a comparison is greatly required. We compared two ASD models, one induced by a unique IP injection of 500 mg/kg of body weight at GD12 and the other one by repeated PO administration of 500 mg/kg of body weight/day between GD11 and GD13. The behavioural phenotypes of the offspring were assessed for the core signs of ASD (impaired social behaviour, stereotypical/repetitive behaviours, sensory/communication deficits) as well as anxiety as comorbidity, at developmental and juvenile stages in both sexes. The VPA IP model induced a more literature-compliant ASD phenotype than the PO one. These results confirmed that the mode of administration as well as the window of VPA exposure are key factors in the ASD-induction phenotype. Interestingly, the effects of VPA administration were similar at the developmental stage between both sexes and then tended to differ later in life.
PubMed: 38761921
DOI: 10.1016/j.neuro.2024.05.002 -
The Lancet. Neurology Jun 2024
Topics: Humans; Valproic Acid; Anticonvulsants; Epilepsy
PubMed: 38760090
DOI: 10.1016/S1474-4422(24)00141-8