Valproate Treatment Research Articles

Valproate treatment induces age- and sex-dependent neuronal activity changes according to a patch clamp study.

Autism spectrum disorder is a heterogeneous neurodevelopmental disorder characterized by impaired social interactions, restricted, and stereotyped behaviors. The valproic acid model is one of the most recognized and broadly used models in rats to induce core symptoms of this disorder. Comorbidity of epilepsy and autism occurs frequently, due to similar background mechanisms that include the imbalance of excitation and inhibition. In this series of experiments, treatment was performed on rat dams with a single 500mg/kg dose i.p. valproate injection on embryonic day 12.5. Intracellular whole-cell patch clamp recordings were performed on brain slices prepared from adolescent and adult offspring of both sexes on pyramidal neurons of the medial prefrontal cortex and entorhinal cortex. Current clamp stimulation utilizing conventional current step protocols and dynamic clamp stimulation were applied to assess neuronal excitability. Membrane properties and spiking characteristics of layer II-III pyramidal cells were analyzed in both cortical regions. Significant sex-dependent and age-dependent differences were found in several parameters in the control groups. Considering membrane resistance, rheobase, voltage sag slope, and afterdepolarization slope, we observed notable changes mainly in the female groups. Valproate treatment seemed to enhance these differences and increase network excitability. However, it is possible that compensatory mechanisms took place during the maturation of the network while reaching the age-group of 3 months. Based on the results, the expression of the hyperpolarization-activated cyclic nucleotide-gated channels may be appreciably affected by the valproate treatment, which influences fundamental electrophysiological properties of the neurons such as the voltage sag. Remarkable changes appeared in the prefrontal cortex; however, also the entorhinal cortex shows similar tendencies.

Pharmacogenetics-Informed Pharmacometabolomics as an Innovative Approach to Assessing the Safety and Risk of Pharmacotherapy with Valproic Acid

Scientific relevance. Valproic acid (VPA) is a psychotropic medicinal product, which may be associated with serious adverse drug reactions (ADRs). While pharmacogenetics and pharmacometabolomics can significantly affect the safety of valproates, there are no unified approaches to predicting, preventing, and correcting VPA-induced ADRs.Aim. This study aimed to collate the results of national and international studies on toxic VPA metabolites and to develop a novel personalised approach to assessing the safety and risks of valproate therapy in real-world clinical practice.Discussion. This study analysed national and international publications reflecting the results of preclinical and clinical studies on toxic VPA metabolites submitted to e-Library, PubMed, Scopus, and Google Scholar in 2012–2022. The inclusion criteria were full-text original articles, systematic reviews, meta-analyses, Cochrane reviews, and clinical cases in Russian or English. According to the analysis results, VPA has 20 studied toxic metabolites, which result from hepatic VPA metabolism involving P-oxidation, acetylation (β-oxidation), and glucuronidation enzymes. The functional activity of these enzymes is genetically determined and associated with heterozygous or homozygous carriage of non-functional/low-function single-nucleotide variant alleles in genes encoding these enzymes. The safety of VPA and its compounds can be improved by transferring the results of preclinical and clinical studies into real-world clinical practice using pharmacogenetics-informed pharmacometabolomics. Pharmacogenetics-informed pharmacometabolomics is a novel and personalised approach that helps, based on pharmacogenetic profiling, identify patients at high risk of VPA-induced ADRs, individually select starting and target doses of VPA and its compounds, determine the timing and frequency for therapeutic drug monitoring and monitoring toxic VPA metabolites in biological fluids (blood, saliva, and urine), and select a strategy for the prevention and correction of VPA-induced ADRs, taking into account patients’ individual pharmacometabolic profiles.Conclusions. The quality of medical care for patients with neurological diseases and mental disorders will improve with proper monitoring of VPA-induced ADRs by all entities involved in the medicinal product life cycle; active involvement of neurologists and psychiatrists in the prediction, prevention, and monitoring of the safety of valproate treatment; and inclusion of specific sections on practical pharmacogenetics-informed pharmacometabolomics and pharmacovigilance in the professional training curricula for neurologists and psychiatrists.

P01 An unusual case of pregnancy associated osteoporosis presenting with bilateral neck of femur fractures

P01 An unusual case of pregnancy associated osteoporosis presenting with bilateral neck of femur fractures

Gad1 knock-out rats exhibit abundant spike-wave discharges in EEG, exacerbated with valproate treatment.

To elucidate the functional role of gamma-aminobutyric acid (GABA)-ergic inhibition in suppressing epileptic brain activities such as spike-wave discharge (SWD), we recorded electroencephalogram (EEG) in knockout rats for Glutamate decarboxylase 1 (Gad1), which encodes one of the two GABA-synthesizing enzymes in mammals. We also examined how anti-epileptic drug valproate (VPA) acts on the SWDs present in Gad1 rats and affects GABA synthesis in the reticular thalamic nucleus (RTN), which is known to play an essential role in suppressing SWD. Chronic EEG recordings were performed in freely moving control rats and homozygous knockout Gad1 (-/-) rats. Buzzer tones (82 dB) were delivered to the rats during EEG monitoring to test whether acoustic stimulation could interrupt ongoing SWDs. VPA was administered orally to the rats, and the change in the number of SWDs was examined. The distribution of GABA in the RTN was examined immunohistochemically. SWDs were abundant in EEG from Gad1 (-/-) rats as young as 2 months old. Although SWDs were universally detected in older rats irrespective of their Gad1 genotype, SWD symptom was most severe in Gad1 (-/-) rats. Acoustic stimulation readily interrupted ongoing SWDs irrespective of the Gad1 genotype, whereas SWDs were more resistant to interruption in Gad1 (-/-) rats. VPA treatment alleviated SWD symptoms in control rats, however, counterintuitively exacerbated the symptoms in Gad1 (-/-) rats. The immunohistochemistry results indicated that GABA immunoreactivity was significantly reduced in the somata of RTN neurons in Gad1 (-/-) rats but not in their axons targeting the thalamus. VPA treatment greatly increased GABA immunoreactivity in the RTN neurons of Gad1 (-/-) rats, which is likely due to the intact GAD2, another GAD isozyme, in these neurons. Our results revealed two opposing roles of GABA in SWD generation: suppression and enhancement of SWD. To account for these contradictory roles, we propose a model in which GABA produced by GAD1 in the RTN neuronal somata is released extrasynaptically and mediates intra-RTN inhibition.

Valproate regulates inositol synthesis by reducing expression of myo-inositol-3-phosphate synthase

Inositol depletion is a hypothesized mechanism of action of mood stabilization drugs used in the treatment of bipolar disorder. It was previously reported that the mood stabilizer valproate (VPA) increased phosphorylation of myo-inositol-3-phosphate synthases (MIPS), the rate limiting enzyme of inositol synthesis. Phosphosites were identified and examination of site-directed mutants suggested that phosphorylation leads to decreased enzymatic activity. In this study, we examined the extent of MIPS phosphorylation in response to VPA and used two interaction screens to identify protein kinases that interact with MIPS. Using an epitope tagged MIPS construct, we determined the fraction of phosphorylated MIPS to be very low (less than 2% of total), and we could not detect phosphorylation of untagged MIPS in response to VPA. In vitro analyses of phosphorylation revealed that putative protein kinases, PKC and CKII, have low specificity toward MIPS. These findings suggest that VPA likely depletes inositol via a mechanism other than MIPS phosphorylation. Consistent with this, mRNA levels of the MIPS-encoding gene INO1 and MIPS protein levels were significantly reduced during the mid-log growth phase in response to VPA treatment. These findings suggest that the mechanism whereby VPA causes inositol depletion is by reducing expression of the rate-limiting enzyme MIPS.

Assessing liver effects of Cannabidiol and Valproate alone and in Combination using Quantitative Systems Toxicology.

In clinical trials of cannabidiol (CBD) for the treatment of seizures in patients with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex, elevations in serum alanine aminotransferase (ALT) >3× the upper limit of normal (ULN) were observed in some patents, but the incidence was much greater in patients who were receiving treatment with valproate (VPA) before starting CBD. To explore potential mechanisms underlying this interaction, we used DILIsym®, a quantitative systems toxicology (QST) model, to predict ALT elevations in a simulated human population treated with CBD alone, VPA alone, and when CBD dosing was starting during treatment with VPA. We gathered in vitro data assessing the potential for CBD, the two major CBD metabolites, and VPA to cause hepatotoxicity via inhibition of bile acid transporters, mitochondrial dysfunction, and production of reactive oxygen species (ROS). Physiologically-based pharmacokinetic (PBPK) models for CBD and VPA were used to predict liver exposure. DILIsym simulations predicted dose-dependent ALT elevations from CBD treatment and this was predominantly driven by ROS production from the parent molecule. DILIsym also predicted VPA treatment to cause ALT elevations which were transient when mitochondrial biogenesis was incorporated into the model. Contrary to the clinical experience, simulation of two weeks treatment with VPA prior to introduction of CBD treatment did not predict an increase the incidence of ALT elevations relative to CBD treatment alone. We conclude that the marked increased incidence of CBD-associated ALT elevations in patients already receiving VPA is unlikely to involve the three major mechanisms of direct hepatotoxicity.

Multiunit Recording of Cerebellar Cortex in Autistic Male Rats during Social Interaction in Enriched Environments.

Autism in humans is a lifelong behavioral disorder that typically manifests in early infancy, primarily affecting boys. It arises from neurodevelopmental changes that significantly impact social behavior, with the cerebellum being one of the principal affected regions. In this study, we investigated the cerebellum in an autism animal model, recording the multiunit activity of cerebellar vermis lobules 6 and 7 (L6 and L7) in male rats with autism-like behavior induced by postnatal valproate treatment. Two groups were formed: control (Ctrl) and experimental (VPA) males, which were further divided based on their living conditions into standard (Std) or enriched environments (EE). Social arenas were used for recording purposes. Both groups and lobules showed increased multiunit amplitude during social interaction (SI) and vertical exploration (VE), with higher amplitudes observed in VPA males. Interestingly, the EE significantly reduced the amplitude during SI, suggesting that EE promotes neural plasticity, resulting in improved social responses with fewer activated neurons, meaning improved activity with less energy consumption. Consequently, EE proves to be a valuable strategy for addressing the challenges associated with autism behavior.

Acute Valproate-Induced Encephalopathy in Status Epilepticus: A Registry-Based Assessment.

Valproate-induced encephalopathy (VIE) affects between 0.1% and 2.5% of patients under long-term epilepsy treatment. Its frequency and characteristics in adults with status epilepticus (SE) is, however, unknown. The aim of this study was to characterize the frequency and the clinico-biological characteristics of VIE in adult SE patients. We reviewed all patients included in our institutional SE registry who were treated for an SE episode between November 2021 and February 2023 and identified 39 patients who received valproate for their SE treatment. Acute VIE was defined by worsening of consciousness having led to the discontinuation of valproate, and improvement of consciousness within 96 hours after discontinuation of valproate during acute hospital treatment. Patients had a mean valproate intravenous loading dose of 34.5mg/kg and a mean maintenance dose of 15.3mg/kg/d (1078mg/d). Four out of 29 patients with measured ammonium had hyperammonemia. We identified four (10%) patients fulfilling acute VIE criteria. Median time from administration of valproate to the occurrence of VIE, and to resolution of VIE after cessation of valproate treatment, was 2 days for each. Three of the four VIE patients had no associated hyperammonemia. Patients who developed VIE more frequently had a history of liver disease (p=0.023), and tended to be younger, but other clinical variables did not differ significantly from patients without VIE, including valproate loading or maintenance doses, SE cause, duration or severity, other concomitant antiseizure medications (none received topiramate, phenobarbital, or primidone). Pending larger studies, VIE in SE seems relatively frequent and difficult to foresee; clinical alertness to symptoms is mandatory, even without hyperammonemia, and valproate withdrawal should be considered in suspected cases.

Valproate pregnancy prevention scheme: what are the barriers to enrolling patients and how do we meet them?

BackgroundThe UK Medicines Health products Regulation Agency instructs that valproate prescriptions should be restricted in women of childbearing age to those consenting to the Pregnancy Prevention Programme (PPP). We assessed...

Single-cell immune profiling reveals broad anti-inflammation response in bipolar disorder patients with quetiapine and valproate treatment

Bipolar disorder (BD) is a common mental disorder characterized by manic and depressive episodes. Mood disorders have been associated with immune dysfunction. The combination of quetiapine and valproate has shown positive effects in treating BD, but the impact on immune dynamics remains less understood. Using single-cell RNA sequencing, we observed that B cells exhibited downregulation of inflammation-related genes, while pro-inflammatory mast and eosinophil cells decreased following treatment. Ribosomal peptide production genes were found to be reduced in both B and Tcells after treatment. Additionally, our findings suggest that the combined therapy effectively alleviates inflammation by reducing myloid-mediated immune signaling pathways. This study provides valuable insights into the immune atlas and uncovers a potential mechanism for immune disorder alleviation in patients with BD treated with quetiapine and valproate.

A pilot study on the effects of early use of valproate sodium on neuroinflammation after traumatic brain injury

To study the effect of early use of sodium valproate on neuroinflammation after traumatic brain injury (TBI). A total of 45 children who visited in Xuzhou Children's Hospital Affiliated to Xuzhou Medical University from August 2021 to August 2022 were enrolled in this prospective study, among whom 15 healthy children served as the healthy control group, and 30 children with TBI were divided into a sodium valproate treatment group and a conventional treatment group using a random number table (n=15 each). The children in the sodium valproate treatment group were given sodium valproate in addition to conventional treatment, and those in the conventional group were given an equal volume of 5% glucose solution in addition to conventional treatment. The serum concentrations of nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3), high-mobility group box 1 (HMGB1), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) were measured in the healthy control group on the day of physical examination and in the children with TBI on days 1, 3, and 5 after admission. Glasgow Outcome Scale-Extended (GOS-E) score was evaluated for the children with TBI 2 months after discharge. Compared with the healthy control group, the children with TBI had significantly higher serum concentrations of NLRP3, HMGB1, TNF-α, and IL-1β on day 1 after admission (P<0.017). The concentration of NLRP3 on day 5 after admission was significantly higher than that on days 1 and 3 after admission in the children with TBI (P<0.017). On days 3 and 5 after admission, the sodium valproate treatment group had a significantly lower concentration of NLRP3 than the conventional treatment group (P<0.05). For the conventional treatment group, there was no significant difference in the concentration of HMGB1 on days 1, 3, and 5 after admission (P>0.017), while for the sodium valproate treatment group, the concentration of HMGB1 on day 5 after admission was significantly lower than that on days 1 and 3 after admission (P<0.017). On day 5 after admission, the sodium valproate treatment group had a significantly lower concentration of HMGB1 than the conventional treatment group (P<0.05). For the children with TBI, the concentration of TNF-α on day 1 after admission was significantly lower than that on days 3 and 5 after admission (P<0.017). On days 3 and 5 after admission, the sodium valproate treatment group had a significantly lower concentration of TNF-α than the conventional treatment group (P<0.05). The concentration of IL-1β on day 3 after admission was significantly lower than that on days 1 and 5 after admission (P<0.017) in the children with TBI. On days 3 and 5 after admission, the sodium valproate treatment group had a significantly lower concentration of IL-1β than the conventional treatment group (P<0.05). The GOS-E score was significantly higher in the sodium valproate treatment group than that in the conventional treatment group 2 months after discharge (P<0.05). Early use of sodium valproate can reduce the release of neuroinflammatory factors and improve the prognosis of children with TBI.

The effect of adding curcumin to sodium valproate in treatment of patients with bipolar disorder in the acute phase of mania: A randomized double-blind clinical trial.

Inflammatory processes play a role in the etiopathogenesis of bipolar disorder type 1. Full therapeutic responses are seldom seen and the ongoing inflammatory processes in the brain could lead to neuronal loss. Curcumin, a relatively safe herbal compound, has been shown to have anti-inflammatory effects. The present randomized double-blind clinical trial study aimed to investigate the effect of adding curcumin to the treatment regimen of BID. This randomized double-blind clinical trial was conducted on 78 patients diagnosed with BID according to the Diagnostic and Statistical Manual of Mental Disorders (DSM 5) criteria. The sample were divided into two groups. Patients in both groups received sodium valproate starting at a dose of 600 milligrams per day and administered up to 20 milligrams per kilogram per day or the highest dosage of the patient's tolerance. Patients in the intervention group also received curcumin as nanomicelle in soft gelatin capsules 40 milligrams per day. The control group received placebo tablets with the same characteristics as the curcumin tablets. They were assessed by a psychiatrist using the Young Mania Rating Scale (YMRS), Mini-Mental State Examination (MMSE), Clinical Global Impression (CGI), and a medication side effect questionnaire at the beginning of the study, as well as in the first, second, and fourth weeks of the study. Among the 78 patients chosen to participate in the project, 54 people completed the trial. No specific side effect was observed in the two groups. Both groups showed an increase in their MMSE scores compared to the beginning of the study (value of p < 0.001). Although this increase was not statistically different between the two groups (value of p = 0.68). The YMRS score of both groups decreased significantly by the end of the study (value of p < 0.001); however, this decrease was not significantly different between the two groups (value of p = 0.64). In addition, the two groups experienced a significant increase in their CGI scores throughout the study (value of p < 0.001), this increase however was not statistically different between the two groups (value of p = 0.88). The present study suggested that curcumin may not be a useful adjuvant agent in the management of patients with BID receiving sodium valproate as treatment.Clinical trial registration: Iranian Registry of Clinical Trials (IRCT), identifier IRCT2016102530504N1.

Testing the extreme male hypothesis in the valproate mouse model; sex-specific effects on plasma testosterone levels and tyrosine hydroxylase expression in the anteroventral periventricular nucleus, but not on parental behavior.

Autism is a neurodevelopmental disorder with a strong male bias in prevalence and severity. The extreme male hypothesis proposed that autism is a manifestation of extreme male traits as evidenced by increased masculine behaviors, hypermasculinization of some brain regions, and alterations in androgen metabolism. In the present study, the extreme male hypothesis was tested in the valproate (VPA) mouse model. Females of the C57BL/6JOlaHsd mouse strain were treated with 500 mg/kg VPA on gestational day 12. Offspring of both sexes were tested at 3 to 4 months of age in the elevated plus maze (EPM), open field, sociability tests, and for parental behavior. After sacrifice at 5 to 6 months of age, plasma testosterone was measured in males, while the brains of both sexes were examined for tyrosine hydroxylase (TH) expression in the anteroventral periventricular nucleus (AVPV). VPA treatment significantly increased plasma testosterone levels and decreased AVPV TH expression in males, whereas the expression of TH in females remained at the same level. In parental behavior test none of the pup-oriented behavior was affected by VPA treatment in both sexes, the exception was nest quality which was lower after VPA exposure in males, but not in females. Our results suggest a hypermasculinizing effect of VPA that occurred specifically in males but not in females, and this effect could be related to changes in androgen physiology. Nevertheless, a generalized interpretation of the extreme male hypothesis on brain and behavior should be avoided due to the complex effects of VPA.

Inhalation of Cananga odorata essential oil relieves anxiety behaviors in autism-like rats via regulation of serotonin and dopamine metabolism

ObjectiveAnxiety is one of the most common symptoms associated with autistic spectrum disorder. The essential oil of Cananga odorata (Lam.) Hook. f. & Thomson, usually known as ylang-ylang oil (YYO), is often used in aromatherapy as a mood-regulating agent, sedative, or hypotensive agent. In the present study, the effects and mechanisms of YYO in alleviating anxiety, social and cognitive behaviors in autism-like rats were investigated. MethodsThe prenatal valproic acid (VPA) model was used to induce autism-like behaviors in offspring rats. The effectiveness of prenatal sodium valproate treatment (600 mg/kg) on offspring was shown by postnatal growth observation, and negative geotaxis, olfactory discrimination and Morris water maze (MWM) tests. Then three treatment groups were formed with varying exposure to atomized YYO to explore the effects of YYO on the anxiety, social and cognitive behaviors of the autistic-like offspring through the elevated plus-maze test, three-chamber social test, and MWM test. Finally, the monoamine neurotransmitters, including serotonin, dopamine and their metabolites, in the hippocampus and prefrontal cortex (PFC) of the rats were measured using a high-performance liquid chromatography. ResultsOffspring of VPA exposure rats showed autism-like behaviors. In the VPA offspring, medium-dose YYO exposure significantly elevated the time and entries into the open arms in the elevated plus-maze test, while low-dose YYO exposure significantly enhanced the social interaction time with the stranger rat in session 1 of the three-chamber social test. VPA offspring treated with YYO exposure used less time to reach the platform in the navigation test of the MWM test. YYO exposure significantly elevated the metabolism of serotonin and dopamine in the PFC of VPA offspring. ConclusionYYO exposure showed the effects in alleviating anxiety and improving cognitive and social abilities in the offspring of VPA exposure rats. The role of YYO was related to the regulation of the metabolism of serotonin and dopamine.Please cite this article as: Zhang N, Wang ST, Yao L. Inhalation of Cananga odorata essential oil relieves anxiety behaviors in autism-like rats via regulation of serotonin and dopamine metabolism. J Integr Med. 2023; 21(2): 205–214.

A pilot study on identifying gene signatures as markers for predicting patient response to antiseizure medications.

The majority of the biomarkers were associated with the diagnosis of epilepsy and few of them can be applied to predict the response to antiseizure medications (ASMs). In this study, we identified 26 significantly up-regulated genes and 32 down-regulated genes by comparing the gene expression profiles of patients with epilepsy that responded to valproate with those without applying any ASM. The results of gene set enrichment analysis indicated that the ferroptosis pathway was significantly impacted (p = 0.0087) in patients who responded to valproate. Interestingly, the gene NCOA4 in this pathway exhibited significantly different expression levels between the two groups, indicating that NCOA4 could serve as a potential biomarker to better understand the mechanism of valproate resistance. In addition, six up-regulated genes SF3A2, HMGN2, PABPN1, SSBP3, EFTUD2, and CREB3L2 as well as six down-regulated genes ZFP36L1, ACRC, SUB1, CALM2, TLK1, and STX2 also showed significantly different expression patterns between the two groups. Moreover, based on the gene expression profiles of the patients with the treatment of valproate, carbamazepine, and phenytoin, we proposed a strategy for predicting the response to the ASMs by using the Connectivity Map scoring method. Our findings could be helpful for better understanding the mechanisms of drug resistance of ASMs and improving the clinical treatment of epilepsy.

Adherence to anti-seizure medications in the Swedish Prospective Regional Epilepsy Database and Biobank for Individualized Clinical Treatment (PREDICT)

The aim of this study was to describe the extent of, and risk factors for, non-adherence to anti-seizure medications (ASMs) in adult people with epilepsy (PWE) in Sweden.A cross-sectional multi-centre study was performed of PWEs in western Sweden, with data from medical records, and a questionnaire filled in by the participants including self-reports on how often ASM doses had been forgotten during the past year. Participants were categorized into adherent if they forgot at 0–1 occasion, and non-adherent if they forgot at 2–10 or >10 occasions. Demographic and clinical factors were compared by Chi2- or Fisher’s test and a logistic regression model was used to find risk factors for non-adherence.In the cohort of 416 PWE aged median 43, IQR 29–62 years, 398 patients were prescribed ASM treatment at inclusion, and 39 % (n = 154) were in the non-adherent group. Significant factors in the multivariable analysis were: younger age, seizure freedom the past year, valproate treatment and experiencing side effects.The rate of self-reported non-adherence was high, illustrating a need for continuous focus on fundamental aspects of epilepsy care. The identified risk factors could enable quality improvement projects and patient education to be directed to those at risk of non-adherence.

Alteration of monoaminergic systems in the caudal medulla and its possible link to diurnal increase of apnea in a mouse model of Rett syndrome.

Methyl-CpG binding protein 2 (MeCP2)-deficient (Mecp2-/y) mice exhibit apneas that resemble respiratory abnormalities observed in Rett syndrome (RTT) patients. The present study aimed to clarify whether Mecp2-/y mice show diurnal variations in apnea as seen in RTT and how the MeCP2 deficiency affects monoaminergic systems that control breathing. In 7-week-old Mecp2-/y mice, 24 h variation of apnea and effects of milnacipran, a serotonin/noradrenaline reuptake inhibitor, on the apnea were evaluated. The number of vesicular monoamine transporter 2 (VMAT2)-immunoreactive puncta in the caudal medulla was counted. Further, the effects of valproate (VPA) on the expression of tyrosine hydroxylase (TH) mRNA in the ventrolateral medulla of mice were assessed by RT-qPCR. Apnea occurred more frequently during the light phase under a 12:12 h light/dark environment in Mecp2-/y mice and milnacipran reduced apnea during the light phase but not during the dark phase. The number of VMAT2-immunoreactive puncta was reduced in Mecp2-/y mice. VPA treatment significantly increased TH mRNA expression in Mecp2-/y mice. Alteration of monoaminergic systems in the caudal medulla of Mecp2-/y mice is potentially relevant to the light-sensitive diurnal increase of apnea, and an improvement in monoaminergic neurotransmission can ameliorate the diurnal increase of apnea in Mecp2-/y mice.

Reduced Volumetric Bone Mineral Density of the Spine in Adolescent Rett Girls with Scoliosis.

In advanced Rett syndrome (RTT), limited or complete loss of ambulation, nutritional problems and scoliosis are unfavorable factors for bone mineral density (BMD). Still, there are few data available in this research area. Spinal quantitative computed tomography (QCT) allows an exact measurement of the volumetric BMD (vBMD) in this patient group. Two examiners measured vBMD of thoracic and lumbar vertebrae on asynchronous calibrated CTs that were acquired prior to surgical scoliosis correction (n = 21, age 13.6 ± 2.5 years). The values were compared to age- and sex-matched healthy controls to additionally derive Z-scores (n = 22, age 13.8 ± 2.0 years). The results showed the most significant reduction of vBMD values in non-ambulatory RTT patients, with p &lt; 0.001 and average BMD-Z-score -1.5 ± 0.2. In the subgroup comparison, non-ambulatory patients with valproate treatment had significant lower values (p &lt; 0.001) than ambulatory patients without valproate therapy, with an average BMD-Z-score of -2.3 ± 0.2. Comparison of the Z-scores to critical BMD thresholds of 120 and 80 mg/cm3 showed normal Z-scores in case of the ambulatory RTT subgroup, as opposed to BMD-Z-scores of the non-ambulatory RTT subgroups, which were partially below osteopenia-equivalent values. Furthermore, valproate treatment seems to have a direct effect on vBMD in RTT patients and when combined with loss of ambulation, BMD-Z-scores are reduced to osteoporosis-equivalent levels or even further.

An individualized medication model of sodium valproate for patients with bipolar disorder based on machine learning and deep learning techniques.

Valproic acid/sodium valproate (VPA) is a widely used anticonvulsant drug for maintenance treatment of bipolar disorders. In order to balance the efficacy and adverse events of VPA treatment, an individualized dose regimen is necessary. This study aimed to establish an individualized medication model of VPA for patients with bipolar disorder based on machine learning and deep learning techniques. The sequential forward selection (SFS) algorithm was applied for selecting a feature subset, and random forest was used for interpolating missing values. Then, we compared nine models using XGBoost, LightGBM, CatBoost, random forest, GBDT, SVM, logistic regression, ANN, and TabNet, and CatBoost was chosen to establish the individualized medication model with the best performance (accuracy = 0.85, AUC = 0.91, sensitivity = 0.85, and specificity = 0.83). Three important variables that correlated with VPA daily dose included VPA TDM value, antipsychotics, and indirect bilirubin. SHapley Additive exPlanations was applied to visually interpret their impacts on VPA daily dose. Last, the confusion matrix presented that predicting a daily dose of 0.5g VPA had a precision of 55.56% and recall rate of 83.33%, and predicting a daily dose of 1g VPA had a precision of 95.83% and a recall rate of 85.19%. In conclusion, the individualized medication model of VPA for patients with bipolar disorder based on CatBoost had a good prediction ability, which provides guidance for clinicians to propose the optimal medication regimen.

Tremor and Movement Slowness Are Two Unrelated Adverse Effects Induced by Valproate Intake

To date, only a few clinical and neurophysiological studies have assessed the features of valproate-induced tremor (VIT), and whether valproate (VPA) affects voluntary movements is underinvestigated. To better characterize the clinical and neurophysiological features of VIT in patients with epilepsy and the effect of VPA on the execution of voluntary movement. We tested 29 patients with VIT (13 taking VPA alone and 16 taking VPA plus other antiepileptics). Patients underwent a neurological examination,video recordingsand kinematic assessments of postural, kinetic, and resting upper limb tremor using a motion analysis system. Movement execution was tested by kinematic assessment of finger tapping. Data of patients with VIT were compared with those of 13 patients with epilepsy taking VPA but without tremor, 13 patients with epilepsy who were not on VPA treatment, 20 patients with Parkinson's disease (PD), and 20 healthy controls (HCs). Clinical and kinematic evaluations showed that tremor in patients taking VPA alone was less severe than tremor in patients taking VPA plus other antiepileptics. All patients taking VPA, regardless of the presence of tremor, performed slower finger tapping compared with HCs, similar to what was observed in PD, although with no sequence effect. Patients with epilepsy without VPA showed a normal motor performance. Tremor and movement slowness are motor signs induced by VPA. VIT severity is exacerbated when VPA is taken in combination with other antiepileptics. VPA-induced slowness occurs regardless of tremor, may precede tremor development, and is not attributed to epilepsy.