Concomitant Valproate Research Articles

When, Why and How to Re-challenge Clozapine in Schizophrenia Following Myocarditis.

Clozapine-induced myocarditis (CIM) is among the most important adverse events limiting the use of clozapine as the most effective treatment for schizophrenia. CIM necessitates the immediate termination of clozapine, often resulting in its permanent discontinuation with considerable detrimental effects on patients' psychopathology and long-term outcome. Consequently, a clozapine re-challenge after CIM is increasingly regarded as a viable alternative, with published reports indicating a success rate of approximately 60%. However, published cases of re-challenges after CIM remain limited. Here, we provide a narrative review of the current state of research regarding the epidemiology, pathophysiology, risk factors, diagnosis and clinical management of CIM as well as a synthesis of current recommendations for re-challenging patients after CIM. This includes a step-by-step guide for this crucial procedure based on the current evidence regarding the pathophysiology and risk factors for CIM. Slow dose titration regimes and addressing risk factors including concomitant valproate and olanzapine are crucial both to prevent CIM and to ensure a safe and successful re-challenge. Furthermore, we discuss the utility of C-reactive protein, troponin, N-terminal-pro hormone and brain natriuretic peptide, therapeutic drug-monitoring and cardiac magnetic resonance imaging for CIM screening and diagnosis as well as for post-CIM re-challenges.

Influence of Clinical and Genetic Factors on Propofol Dose Requirements: A Genome-wide Association Study.

Propofol is a widely used intravenous hypnotic. Dosing is based mostly on weight, with great interindividual variation in consumption. Suggested factors affecting propofol requirements include age, sex, ethnicity, anxiety, alcohol consumption, smoking, and concomitant valproate use. Genetic factors have not been widely explored. This study considered 1,000 women undergoing breast cancer surgery under propofol and remifentanil anesthesia. Depth of anesthesia was monitored with State Entropy (GE Healthcare, Finland). Propofol requirements during surgery were recorded. DNA from blood was genotyped with a genome-wide array. A multivariable linear regression model was used to assess the relevance of clinical variables and select those to be used as covariates in a genome-wide association study. Imputed genotype data were used to explore selected loci further. In silico functional annotation was used to explore possible consequences of the discovered genetic variants. Additionally, previously reported genetic associations from candidate gene studies were tested. Body mass index, smoking status, alcohol use, remifentanil dose (ln[mg · kg-1 · min-1]), and average State Entropy during surgery remained statistically significant in the multivariable model. Two loci reached genome-wide significance (P < 5 × 10-8). The most significant associations were for single-nucleotide polymorphisms rs997989 (30 kb from ROBO3), likely affecting expression of another nearby gene, FEZ1, and rs9518419, close to NALCN (sodium leak channel); rs10512538 near KCNJ2 encoding the Kir2.1 potassium channel showed suggestive association (P = 4.7 × 10-7). None of these single-nucleotide polymorphisms are coding variants but possibly affect the regulation of nearby genes. None of the single-nucleotide polymorphisms previously reported as affecting propofol pharmacokinetics or pharmacodynamics showed association in the data. In this first genome-wide association study exploring propofol requirements, This study discovered novel genetic associations suggesting new biologically relevant pathways for propofol and general anesthesia. The roles of the gene products of ROBO3/FEZ1, NALCN, and KCNJ2 in propofol anesthesia warrant further studies.

Population pharmacokinetics and dosing optimization of olanzapine in Chinese paediatric patients: Based on the impact of sex and concomitant valproate on clearance.

Olanzapine is an atypical antipsychotic drug used for mental disorders. There are limited studies providing sufficient pharmacokinetic data, thus the variability of concentrations of olanzapine used in Chinese paediatric patients aged 10 to 17 years remains to be evaluated. Therapeutic drug monitoring data were collected from 151 paediatric patients aged 10 to 17 years who received olanzapine. The model was developed with a NONMEM software program. The final model validation and evaluation were assessed by bootstrap, diagnostic scatter plots, and normalized prediction distribution error (NPDE). Regimens of different dosages were simulated to reach the target concentration levels of 20 ng/ml, by using the final model with typical parameters. The one-compartment model was considered the best fit for the data. Typical estimates of the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) in the final model were 0.142 h-1 , 15.4L/h, and 322 L, respectively. Sex and concomitant valproate (VPA) were included as significant predictors of olanzapine clearance, which was described by the following equation: CL/F=15.4 × (1 + 0.546 × SEX) × (1 + 0.264 × VPA). Results of Monte-Carlo simulation suggested that male paediatric patients with concomitant VPA were advised to take no less than 15 mg per day of olanzapine orally, and in female paediatric patients with concomitant VPA, a dosing regimen of 10mg may be sufficient to achieve the therapeutic range of olanzapine. Our results identified concomitant valproate and sex as significant covariates in olanzapine population pharmacokinetics. Our model may be a useful tool for recommending dosage adjustments for physicians. The pharmacokinetics of olanzapine in patients aged 10 to 17 years was generally similar to that of adults and the elderly.

161 Two-centre audit of cannabidiol use in adults with Dravet syndrome

BackgroundCannabidiol is a newly-available treatment option for seizures in Dravet syndrome (DS).MethodsAdults in a cannabidiol early access programme at two epilepsy centres were included. Can- nabidiol was titrated up to 20mg/kg, as tolerated. The primary outcome measure was &gt;30% reduction in convulsive seizures assessed at three months of treatment. Secondary outcome measures included later reduction in seizures and incidence of adverse drug reactions (ADRs).ResultsEighteen individuals (seven female; median age 27.5 years) with SCN1A mutation-positive DS took part. Median follow-up was 166 days; nine individuals continued on maintenance treatment. Median maximum dose was 18.6mg/kg/day. Four individuals (22.2%) had a &gt;30% reduction in convulsive seizures by three months; in two, this became evident after three months. ADRs occurred in 14 (77.8%). Commonest ADRs were somnolence and derangement of LFTs (all 18 took concomitant valproate), occurring in eight and seven individuals, respectively. ADRs led to discontinuation in three, including a seizure-free individual. Twelve people (66.7%) required dosage changes to other antiepileptic drugs.ConclusionCannabidiol was effective in a fifth of patients. Two additional patients showed later reduction in seizure frequency, suggesting longer follow-up is warranted. Treatment was complicated by ADRs. Dose adjustments of other antiepileptic drugs may be needed.k.silvennoinen@ucl.ac.uk

A Practical Guide to the Treatment of Dravet Syndrome with Anti-Seizure Medication.

Dravet syndrome is a severe developmental and epileptic encephalopathy characterised by refractory seizures and cognitive dysfunction. The treatment is challenging, not least because the seizures are highly drug resistant, requiring multiple anti-seizure medications (ASMs), while some ASMs can exacerbate seizures. Initial treatments include the broad-spectrum ASMs valproate (VPA), and clobazam (CLB) in some regions; however, they are generally insufficient to control seizures. With this in mind, three adjunct ASMs have been approved specifically for the treatment of seizures in patients with Dravet syndrome: stiripentol (STP) in 2007 in the European Union and 2018 in the USA, cannabidiol (CBD) in 2018/2019 (in combination with CLB in the European Union) and fenfluramine (FFA) in 2020. These “add-on” therapies (mostly to VPA/CLB) are used as escalation therapies, with the choice dependent on availability in different countries, patient characteristics and caregiver preferences. Topiramate is also frequently used, with evidence of efficacy in Dravet syndrome, and there is anecdotal evidence of efficacy with bromide, which is frequently used in Germany and Japan. With a growing treatment landscape for Dravet syndrome, there can be practical challenges for clinicians, particularly with issues associated with polypharmacy. This practical guide provides an overview of these main ASMs including their indications/contraindications, mechanism of action, efficacy, safety and tolerability profile, dosage requirements, and laboratory and clinical parameters to be evaluated. Standard laboratory and clinical parameters include blood counts, liver function tests, serum concentrations of ASMs, monitoring the growth of children, as well as weight loss and acceleration of behavioural problems. Regular cardiac monitoring is also important with FFA as it has previously been associated with cases of cardiac valve disease when used in adults at high doses (up to 120 mg/day) in combination with phentermine as a therapy for obesity. Importantly, no signs of heart valve disease have been documented to date at the low doses used in patients with developmental and epileptic encephalopathies. In addition, potential drug–drug interactions and their consequences are a key consideration in everyday practice. Interactions that potentially require dosage adjustments to alleviate adverse events include the following: STP + CLB resulting in increased plasma concentrations of CLB and its active metabolite norclobazam may increase somnolence, and an interaction with STP and VPA may increase gastrointestinal adverse events. Cannabidiol has a bi-directional interaction with CLB producing an increase in plasma concentrations of 7-OH-CBD and norclobazam resulting in the potential for increased somnolence and sedation. In addition, CBD is associated with elevations of liver transaminases particularly in patients taking concomitant VPA. The interaction between FFA and STP requires a dose reduction of FFA. Furthermore, concomitant administration of VPA with topiramate has been associated with encephalopathy and/or hyperammonaemia. Finally, we briefly describe other ASMs used in Dravet syndrome, and current key clinical trials.Graphical abstract Supplementary InformationThe online version contains supplementary material available at 10.1007/s40263-022-00898-1.

Cannabinoids and CBD in clinical practice

Derivates are phytocannabinoids with active properties on the endocannabinoid system. Cannabidiol (CBD) antiepileptic effects were described in animal models, recently leading to clinical application. High quality data on efficacy of CBD enriched compounds as adjunctive therapy in epilepsy patients derives from RCTs with plant-derived pure CBD solution (10-20 mg/kg/day) in children/adolescents with Dravet or Lennox Gastaut Syndromes; 25-50 mg/kg/day in Tuberous Sclerosis. A 50% seizure reduction was observed in 36–49% of cases compared to 15–27% in placebo groups, supporting current clinical guidelines. Responder rates of 42–62% were reported in observational studies including a wider spectrum of ages and epilepsies. Frequent (78–92%), mild-moderate adverse effects (AE) are usually early and transient; serious AE were mostly associated to concomitant valproate (hepatic toxicity) or clobazam (sedation, pneumonia, respiratory failure). Deleterious cognitive and behavioural long-term effects of prolonged exposure to cannabinoids (mostly tetrahydrocannabinol-THC) during brain development are well described. No significant changes were found after 1-year of CBD treatment. Positive effects on alertness, communication, mood and sleep could be additional benefits, with impact on quality of life. CBD undergo a complex metabolism including CYP2C19, CYP3A4 inhibition, favouring pharmacokinetic interactions; therefore, drugs monitoring is recommended. Few observational studies using CBD enriched extracts (CBD:THC 1:50, 1:20) reported similar efficacy. Synthetic and plant-derived CBD seem to have similar pharmacokinetics, efficacy and AE profile. Current challenges in clinical practice include limited data on: efficacy, predictive factors of response/AE, safety and dosing of many currently used compounds. Costs, availability, cultural factors and local regulations are additional barriers to face.

Risk factors for early-phase clozapine discontinuation: A nested case-control study.

Safe and efficient methods for introducing clozapine to patients with treatment-resistant schizophrenia (TRS) are needed. We investigated risk factors for clozapine discontinuation in the early phase of its introduction. We conducted a nested case-control study at 14 psychiatric hospitals in Chiba, Japan. Data from pre-registered TRS patients were collected at 7 time points within 12 weeks before and after the start of clozapine introduction. We examined the demographic data, prior and concomitant psychotropic drugs, strategies for switching from prior antipsychotics, and blood test and Global Assessment of Function results. The Clinical Global Impression-Severity Scale was retrospectively scored at 12 weeks before and after clozapine introduction. Of 228 patients, clozapine treatment was continued in 213 (93.4 %) and discontinued in 15 (6.6 %) patients within 12 weeks. Clinical symptoms were improved to mild symptoms with a response rate of 14.9 %. Prior antipsychotics and concomitant psychotropic drugs except for mood stabilizers were significantly decreased. Histories of smoking (OR = 3.32, 95 %CI: 1.11-9.93) and antipsychotic treatment at chlorpromazine-equivalent doses <1200 mg within the past 5 years (OR = 3.93, 95 %CI: 1.24-12.50), but not antipsychotic switching strategy, were associated with clozapine discontinuation. Eosinophilia was the most frequent reason for discontinuation (n = 3, 20 %) and was associated with concomitant valproate at 4 weeks after the introduction. Clozapine is an effective option for TRS patients (especially those treated with higher doses of prior antipsychotics) in Japan. Clinicians should be cautious about concomitant valproate in the early phase of clozapine introduction due to a high risk of eosinophilia.

Considerations of HLA, Renal Failure, Valproic Acid Use, and Current Treatment Guidelines in Clozapine-Induced Agranulocytosis

Clozapine, the choice atypical antipsychotic for refractory schizophrenia, schizoaffective disorder, and bipolar disorder, has been shown to reduce positive and negative symptoms of schizophrenia. Clozapine, though beneficial in reducing the need for hospitalization, rehabilitation, and health care costs, is known as a drug of last resort due to its potential adverse event of clozapine-induced agranulocytosis, which holds a case fatality rate between 4.2 and 16%. Herein, we describe a female patient with longstanding schizoaffective disorder and chronic kidney disease who suffered from clozapine-induced agranulocytosis after failing two other atypical antipsychotics. Retrospective considerations of this case and management highlight risk factors such as HLA status, renal failure, and concurrent valproic acid use which presently do not have official screening, guidelines, or restrictions in place when prescribing clozapine. Additionally, there are no specific clozapine-induced agranulocytosis management recommendations such as G-CSF/filgrastim dose, timing of bone marrow aspirate and biopsy, and use of concomitant valproate. We propose that further comprehensive official screening, monitoring, and guidelines in the prescribing of clozapine, and further guidelines in the treatment of clozapine induced agranulocytosis, could increase the cost-effectiveness of clozapine treatment, and decrease the incidence, and morbidity of this feared adverse event.

Cannabidiol in conjunction with clobazam: analysis of four randomized controlled trials.

ObjectivesTo assess the efficacy and safety profile of add‐on cannabidiol (CBD) in patients with Lennox–Gastaut syndrome (LGS) and Dravet syndrome (DS) on clobazam and in the overall population of four randomized, controlled phase 3 trials.MethodsPatients received plant‐derived, highly purified CBD medicine (Epidiolex® in the USA; Epidyolex® in Europe; 100 mg/ml oral solution) at a dose of 10 or 20 mg/kg/day, or placebo for 14 weeks. A subgroup analysis of patients on clobazam and meta‐analysis by syndrome were conducted. The primary endpoint was percentage reduction in primary seizure type during the treatment period.Results396 patients with LGS (49% on clobazam) and 318 patients with DS (64% on clobazam) were included. CBD treatment resulted in a reduction in primary seizure frequency vs placebo in the overall population (treatment ratio [95% confidence interval]: LGS, 0.70 [0.62‐0.80]; DS, 0.71 [0.60‐0.83]) and in patients receiving clobazam (LGS, 0.56 [0.47‐0.67]; DS, 0.63 [0.52‐0.77]). The antiseizure efficacy of CBD was also demonstrated across other endpoints vs placebo (≥50% responder rate, total seizure frequency, number of seizure‐free days, and Subject/Caregiver Global Impression of Change scores) in the overall populations and in patients receiving clobazam. There were higher incidences of somnolence and sedation in patients on CBD and clobazam. Most incidences of elevated transaminases occurred in patients on concomitant valproate and, to a lesser extent, clobazam.ConclusionsAdd‐on CBD was effective in reducing seizures in the overall populations and in conjunction with clobazam. Somnolence and sedation occurred more frequently in patients on CBD and clobazam.

A phase 2a randomised, double-blind, placebo-controlled, parallel-group, add-on clinical trial of ebselen (SPI-1005) as a novel treatment for mania or hypomania

RationaleLithium is an effective prophylactic and anti-manic treatment in bipolar disorder; however, its use is declining through perceived poor tolerance and toxicity. Lithium inhibits inositol monophosphatase (IMPase), a probable key therapeutic mechanism. The anti-inflammatory drug, ebselen, also inhibits IMPase and appears well-tolerated and safe.ObjectivesTo assess the efficacy of adjunctive ebselen in mania using the Young Mania Rating Scale (YMRS) (primary outcome) and the Altman Self-Rating Mania (ASRM) Scale and Clinical Global Impression-Severity Scale (CGI-S) among the secondary outcomes.MethodsRandomised, double-blind, placebo-controlled, parallel-group trial conducted between October 2017 and June 2019, at Oxford Health NHS Foundation Trust. Pharmacy-controlled randomisation was computer-generated, with full allocation concealment. In/outpatients (n = 68) aged 18–70, experiencing mania or hypomania, were assigned to 3 weeks ebselen (600 mg bd) (n = 33) or placebo (n = 35). Participants received usual clinical care and psychotropic medication.ResultsEbselen was numerically, but not statistically, superior to placebo in lowering scores on the YMRS (adjusted mean difference and 95% confidence interval, − 1.71 (− 5.34 to 1.91), p = 0.35) and ASRM (− 1.36 (− 3.75 to 1.17), p = 0.29). However, scores on the CGI-S were significantly lower at week 3 in ebselen-treated participants (adjusted mean difference, − 0.58 (− 1.14 to − 0.03), p = 0.04). A post hoc analysis excluding patients taking concomitant valproate treatment magnified the difference between ebselen and placebo on the YMRS. Adverse events were comparable between groups, and mild.ConclusionsEbselen merits further investigation where concomitant psychotropic medication is better controlled and participants taking valproate are excluded. If effective, ebselen’s superior tolerance and safety could make it a useful alternative to lithium.Trial registrationTrial Registry: www.clinicaltrials.gov, Identifier: NCT03013400.

Clinical implications of trials investigating drug-drug interactions between cannabidiol and enzyme inducers or inhibitors or common antiseizure drugs.

Highly purified cannabidiol (CBD) has demonstrated efficacy with an acceptable safety profile in patients with Lennox‐Gastaut syndrome or Dravet syndrome in randomized, double‐blind, add‐on, controlled phase 3 trials. It is important to consider the possibility of drug‐drug interactions (DDIs). Here, we review six trials of CBD (Epidiolex/Epidyolex; 100 mg/mL oral solution) in healthy volunteers or patients with epilepsy, which investigated potential interactions between CBD and enzymes involved in drug metabolism of common antiseizure drugs (ASDs). CBD did not affect CYP3A4 activity. Induction of CYP3A4 and CYP2C19 led to small reductions in exposure to CBD and its major metabolites. Inhibition of CYP3A4 activity did not affect CBD exposure and caused small increases in exposure to CBD metabolites. Inhibition of CYP2C19 activity led to a small increase in exposure to CBD and small decreases in exposure to CBD metabolites. One potentially clinically important DDI was identified: combination of CBD and clobazam (CLB) did not affect CBD or CLB exposure, but increased exposure to major metabolites of both compounds. Reduction of CLB dose may be considered if adverse reactions known to occur with CLB are experienced when it is coadministered with CBD. There was a small increase of exposure to stiripentol (STP) when coadministered with CBD. STP had no effect on CBD exposure but led to minor decreases in exposure to CBD metabolites. Combination of CBD and valproate (VPA) did not cause clinically important changes in the pharmacokinetics of either drug, or 2‐propyl‐4‐pentenoic acid. Concomitant VPA caused small increases in exposure to CBD metabolites. Dose adjustments are not likely to be necessary when CBD is combined with STP or VPA. The safety results from these trials were consistent with the known safety profile of CBD. These trials indicate an overall low potential for DDIs between CBD and other ASDs, except for CLB.

Dose-Ranging Effect of Adjunctive Oral Cannabidiol vs Placebo on Convulsive Seizure Frequency in Dravet Syndrome

Clinical evidence supports effectiveness of cannabidiol for treatment-resistant seizures in Dravet syndrome, but this trial is the first to evaluate the 10-mg/kg/d dose. To evaluate the efficacy and safety of a pharmaceutical formulation of cannabidiol, 10 and 20 mg/kg/d, vs placebo for adjunctive treatment of convulsive seizures in patients with Dravet syndrome. This double-blind, placebo-controlled, randomized clinical trial (GWPCARE2) recruited patients from April 13, 2015, to November 10, 2017, with follow-up completed on April 9, 2018. Of 285 patients screened from 38 centers in the United States, Spain, Poland, the Netherlands, Australia, and Israel, 86 were excluded, and 199 were randomized. Patients were aged 2 to 18 years with a confirmed diagnosis of Dravet syndrome and at least 4 convulsive seizures during the 4-week baseline period while receiving at least 1 antiepileptic drug. Data were analyzed from November 16 (date of unblinding) to December 13 (date of final outputs), 2018, based on intention to treat and per protocol. Patients received cannabidiol oral solution at a dose of 10 or 20 mg/kg per day (CBD10 and CBD20 groups, respectively) or matched placebo in 2 equally divided doses for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were blinded to group assignment. The primary outcome was change from baseline in convulsive seizure frequency during the treatment period. Secondary outcomes included change in all seizure frequency, proportion with at least a 50% reduction in convulsive seizure activity, and change in Caregiver Global Impression of Change score. Of 198 eligible patients (mean [SD] age, 9.3 [4.4] years; 104 female [52.5%]), 66 were randomized to the CBD10 group, 67 to the CBD20 group, and 65 to the placebo group, and 190 completed treatment. The percentage reduction from baseline in convulsive seizure frequency was 48.7% for CBD10 group and 45.7% for the CBD20 group vs 26.9% for the placebo group; the percentage reduction from placebo was 29.8% (95% CI, 8.4%-46.2%; P = .01) for CBD10 group and 25.7% (95% CI, 2.9%-43.2%; P = .03) for the CBD20 group. The most common adverse events were decreased appetite, diarrhea, somnolence, pyrexia, and fatigue. Five patients in the CBD20 group discontinued owing to adverse events. Elevated liver transaminase levels occurred more frequently in the CBD20 (n = 13) than the CBD10 (n = 3) group, with all affected patients given concomitant valproate sodium. Adjunctive cannabidiol at doses of 10 and 20 mg/kg/d led to similar clinically relevant reductions in convulsive seizure frequency with a better safety and tolerability profile for the 10-mg/kg/d dose in children with treatment-resistant Dravet syndrome. Dose increases of cannabidiol to greater than 10 mg/kg/d should be tailored to individual efficacy and safety. ClinicalTrials.gov Identifier: NCT02224703.

&lt;p&gt;Cannabinoids in the Treatment of Epilepsy: Current Status and Future Prospects&lt;/p&gt;

Cannabidiol (CBD) is one of the prominent phytocannabinoids found in Cannabis sativa, differentiating from Δ9-tetrahydrocannabinol (THC) for its non-intoxicating profile and its antianxiety/antipsychotic effects. CBD is a multi-target drug whose anti-convulsant properties are supposed to be independent of endocannabinoid receptor CB1 and might be related to several underlying mechanisms, such as antagonism on the orphan GPR55 receptor, regulation of adenosine tone, activation of 5HT1A receptors and modulation of calcium intracellular levels. CBD is a lipophilic compound with low oral bioavailability (6%) due to poor intestinal absorption and high first-pass metabolism. Its exposure parameters are greatly influenced by feeding status (ie, high fat-containing meals). It is mainly metabolized by cytochrome P 450 (CYP) 3A4 and 2C19, which it strongly inhibits. A proprietary formulation of highly purified, plant-derived CBD has been recently licensed as an adjunctive treatment for Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), while it is being currently investigated in tuberous sclerosis complex. The regulatory agencies’ approval was granted based on four pivotal double-blind, placebo-controlled, randomized clinical trials (RCTs) on overall 154 DS patients and 396 LGS ones, receiving CBD 10 or 20 mg/kg/day BID as active treatment. The primary endpoint (reduction in monthly seizure frequency) was met by both CBD doses. Most patients reported adverse events (AEs), generally from mild to moderate and transient, which mainly consisted of somnolence, sedation, decreased appetite, diarrhea and elevation in aminotransferase levels, the last being documented only in subjects on concomitant valproate therapy. The interaction between CBD and clobazam, likely due to CYP2C19 inhibition, might contribute to some AEs, especially somnolence, but also to CBD clinical effectiveness. Cannabidivarin (CBDV), the propyl analogue of CBD, showed anti-convulsant properties in pre-clinical studies, but a plant-derived, purified proprietary formulation of CBDV recently failed the Phase II RCT in patients with uncontrolled focal seizures.

Cannabis for the Treatment of Epilepsy: an Update.

For millennia, there has been interest in the use of cannabis for the treatment of epilepsy. However, it is only recently that appropriately powered controlled studies have been completed. In this review, we present an update on the research investigating the use of cannabidiol (CBD), a non-psychoactive component of cannabis, in the treatment of epilepsy. While the anticonvulsant mechanism of action of CBD has not been entirely elucidated, we discuss the most recent data available including its low affinity for the endocannabinoid receptors and possible indirect modulation of these receptors via blocking the breakdown of anandamide. Additional targets include activation of the transient receptor potential of vanilloid type-1 (TRPV1), antagonist action at GPR55, targeting of abnormal sodium channels, blocking of T-type calcium channels, modulation of adenosine receptors, modulation of voltage-dependent anion selective channel protein (VDAC1), and modulation of tumor necrosis factor alpha release. We also discuss the most recent studies on various artisanal CBD products conducted in patients with epilepsy in the USA and internationally. While a high percentage of patients in these studies reported improvement in seizures, these studies were either retrospective or conducted via survey. Dosage/preparation of CBD was either unknown or not controlled in the majority of these studies. Finally, we present data from both open-label expanded access programs (EAPs) and randomized placebo-controlled trials (RCTs) of a highly purified oral preparation of CBD, which was recently approved by the FDA in the treatment of epilepsy. In the EAPs, there was a significant improvement in seizure frequency seen in a large number of patients with various types of treatment-refractory epilepsy. The RCTs have shown significant seizure reduction compared to placebo in patients with Dravet syndrome and Lennox-Gastaut syndrome. Finally, we describe the available data on adverse effects and drug-drug interactions with highly purified CBD. While this product is overall well tolerated, the most common side effects are diarrhea and sedation, with sedation being much more common in patients taking concomitant clobazam. There was also an increased incidence of aspartate aminotransferase and alanine aminotransferase elevations while taking CBD, with many of the patients with these abnormalities also taking concomitant valproate. CBD has a clear interaction with clobazam, significantly increasing the levels of its active metabolite N-desmethylclobazam in several studies; this is felt to be due to CBD's inhibition of CYP2C19. EAP data demonstrate other possible interactions with rufinamide, zonisamide, topiramate, and eslicarbazepine. Additionally, there is one case report demonstrating need for warfarin dose adjustment with concomitant CBD. Understanding of CBD's efficacy and safety in the treatment of TRE has expanded significantly in the last few years. Future controlled studies of various ratios of CBD and THC are needed as there could be further therapeutic potential of these compounds for patients with epilepsy.

Interactions between cannabidiol and commonly used antiepileptic drugs.

To identify potential pharmacokinetic interactions between the pharmaceutical formulation of cannabidiol (CBD; Epidiolex) and the commonly used antiepileptic drugs (AEDs) through an open-label safety study. Serum levels were monitored to identify interactions between CBD and AEDs. In 39 adults and 42 children, CBD dose was started at 5 mg/kg/day and increased every 2 weeks by 5 mg/kg/day up to a maximum of 50 mg/kg/day. Serum AED levels were obtained at baseline prior to CBD initiation and at most study visits. AED doses were adjusted if it was determined that a clinical symptom or laboratory result was related to a potential interaction. The Mixed Procedure was used to determine if there was a significant change in the serum level of each of the 19 AEDs with increasing CBD dose. AEDs with interactions seen in initial analysis were plotted for mean change in serum level over time. Subanalyses were performed to determine if the frequency of sedation in participants was related to the mean serum N-desmethylclobazam level, and if aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were different in participants taking concomitant valproate. Increases in topiramate, rufinamide, and N-desmethylclobazam and decrease in clobazam (all p < 0.01) serum levels were seen with increasing CBD dose. Increases in serum levels of zonisamide (p = 0.02) and eslicarbazepine (p = 0.04) with increasing CBD dose were seen in adults. Except for clobazam and desmethylclobazam, all noted mean level changes were within the accepted therapeutic range. Sedation was more frequent with higher N-desmethylclobazam levels in adults (p = 0.02), and AST/ALT levels were significantly higher in participants taking concomitant valproate (p < 0.01). Significantly changed serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine were seen. Abnormal liver function test results were noted in participants taking concomitant valproate. This study emphasizes the importance of monitoring serum AED levels and LFTs during treatment with CBD.

Encephalopathy induced by levetiracetam in an elderly woman

Levetiracetam is frequently used in the elderly considering its favorable pharmacological profile, efficacy, and good tolerance. We reported an encephalopathy with levetiracetam in an elderly subject who had no renal failure, no concomitant valproate medication, and no other additional co-morbidities. Levetiracetam should be discontinued when this condition is suspected.

Valproate (VPA)-associated hyperammonemic encephalopathy independent of elevated serum VPA levels: 21 cases in China from May 2000 to May 2012

Valproate (VPA) is a medication that is widely used in the treatment of neurological and psychiatric disorders, such as epilepsy and bipolar disorder. Valproate-induced hyperammonemic encephalopathy (VHE) is a rare central nervous system adverse effect of this medication that is characterized by impaired consciousness, which can range from drowsiness to coma; increased seizure frequency; acute cognitive symptoms; and gastrointestinal symptoms. In this manuscript, we report a single case and also review previous cases of VHE (n=20) in Chinese patients to identify risk factors for VHE. Increasing clinicians’ awareness of VHE during concomitant VPA therapy is of utmost importance. Serum ammonia level is a useful and important diagnostic test. The discontinuation of VPA is currently the mainstay of treatment for VHE.

Effects of Concomitant Lamotrigine or Valproate Therapy on Clobazam for Lennox-Gastaut Syndrome: Subanalyses of the CONTAIN Trial (P06.120)

Objective: We conducted a subanalysis of a Phase III trial to evaluate clobazam9s efficacy with concomitant lamotrigine or valproate therapy. Background In CONTAIN,1 clobazam, a 1,5-benzodiazepine, significantly decreased weekly frequency of drop and total seizures associated with LGS.1 Design/Methods: CONTAIN, a double-blind, placebo-controlled study, compared 3 dosages of clobazam with placebo as adjunctive therapy for LGS. Patients 2–60 years of age with LGS enrolled.1 In this post-hoc subanalysis, we evaluated results from baseline to 12-week maintenance phase for patients who also received lamotrigine or valproate therapy. We also used a popPK model to assess interactions of clobazam and its active metabolite (N-CLB) with lamotrigine and valproate. Results: As reported1, 301 patients were screened, 238 were randomized, 217 comprised the mITT population, and 177 completed the study. At baseline, patients9 mean age was 12.4 years, and 60.5% were male. Demographics/clinical characteristics were similar between groups. Clobazam significantly decreased weekly frequencies of drop and total seizures associated with LGS.1 For 72 patients receiving concomitant lamotrigine, all clobazam groups achieved a greater mean percentage decrease in average weekly rate of drop seizures from baseline to maintenance period vs. placebo. For 113 patients receiving concomitant valproate, all dosage groups had a greater mean reduction in average weekly rate of drop attacks vs. placebo. Efficacy was dosage-dependent for patients receiving clobazam and either concomitant lamotrigine or valproate, consistent with overall results. Kruskal-Wallis analysis indicated no significant effects between clobazam or N-CLB and lamotrigine or valproate concentrations. Conclusions: In CONTAIN, clobazam was consistently efficacious in decreasing weekly rates of drop seizures from baseline to maintenance phase vs. placebo for patients receiving either concomitant lamotrigine or valproate. Efficacy was dosage-dependent, consistent with overall results. No dosage adjustment of lamotrigine or valproate appears to be required when coadministered with clobazam. 1Ng YT, et al. Neurology. 2011;77:1473–81. Supported by: Lundbeck Inc. Disclosure: Dr. Renfroe has received research support from Lundbeck Inc. Dr. Conry has received personal compensation for activities with Lundbeck Research USA, Inc., and ID&A. Dr. Conry has received personal compensation for activities with Lundbeck Research USA, Inc., Marinus, Eisai Inc., King, and Abbott Laboratories, Inc. Dr. Ng has received personal compensation for activities with UCB Pharma, Cyberonics, Inc., and Lundbeck Research USA, Inc. Dr. Ng has received research support from UCB Pharma. Dr. Drummond has received personal compensation for activities with Lundbeck, Inc. as an employee. Dr. Owen has received personal compensation for activities with Lundbeck Research USA, Inc.

Potential Interaction Between Valproic Acid and Doripenem

A potential interaction between valproate (VPA) and doripenem leading to decreased valproic acid concentrations in two patients is described. In the first patient case, a 54-year-old female presented to the emergency department following a seizure episode after stopping her medications a few days prior. She was given a 1500 mg (23 mg/kg) intravenous (IV) bolus dose of valproate and restarted on her home regimen of divalproex sodium 750 mg daily which quickly resulted in valproic acid blood concentrations within the reference range. The patient was later started on doripenem 500 mg IV every 8 hours and subsequent valproic acid concentrations decreased by 62%. The second patient was a 54-year-old female transferred from an outlying facility following a motor vehicle accident. The patient was receiving valproate 1250 mg IV every 8 hours for seizure prophylaxis following a traumatic brain injury. She developed pneumonia and was started on doripenem 500mg IV every 8 hours. Valproic acid concentrations decreased by 69% within two days. This case report describes two patients receiving concomitant valproate and doripenem resulting in a 62% and 69% reduction in valproic acid concentration.

Add-on lamotrigine in pediatric epilepsy in India

Lamotrigine is a newer antiepileptic drug useful as oral adjunctive therapy in refractory epilepsy. Indian data on use of lamotrigine is limited. This study was conducted to evaluate add-on lamotrigine in Indian children with epilepsy. Twenty children (median age 90 months) receiving lamotrigine as add-on therapy for mean 26.7 (19.1) months, were followed for a median period of 7.9 (6-10) months. Follow-up was done every two weeks. The most common seizures types were either generalized tonic-clonic (6, 30%) or myoclonic (8, 40%). The average dose used was 3.86 mg/kg/day (with concomitant valproate). Good response (>50% reduction) or complete seizure control was seen in 72% patients. Side effects were seen in 27.5% patients and were mild in more than half of these. Lamotrigine was stopped in two patients due to adverse reactions, which resolved on stopping the drug. Lamotrigine was observed to be an effective, add-on, broad-spectrum antiepileptic with 'mild' side effects in Indian children.