Clinical and economic implications of epilepsy management across treatment lines in Spain: a real-life database analysis.

BACKGROUND: Epilepsy is a chronic brain disease characterized by recurrent seizures. We investigated real-world management of epilepsy across treatment lines in Spain, including healthcare resource use (HRU) and associated costs. METHODS: This was a retrospective study of real-life data from epilepsy patients prescribed antiseizure medication (ASM) between January 2016 and December 2021. Patients were grouped according to their line of treatment (1st, 2nd, 3rd and 4th +) during the recruitment period. Demographic and clinical characteristics, comorbidities and concomitant medications were analyzed during the baseline period (6 months before starting treatment line); antiepileptic treatments, concomitant medications, HRU and associated costs were analyzed during follow-up. RESULTS: The study included 5006 patients. Treatment duration decreased as treatment lines progressed (mean ± SD progression time: 523.2 ± 279.1 days from 1st to 2nd line, 351.6 ± 194.4 days from 2nd to 3rd line; 272.7 ± 139.3 days from 3rd to 4th + line). Significant HRU differences were found with subsequent treatment lines, including an increase in hospital admissions and patients on sick leave. Mean (95% CI) adjusted total costs per patient were €2974/year (2773-3175) in the 1st line and €5735/year (5043-6428) in the 4th + line. There was an increase in adjusted direct and total costs with subsequent treatment lines; the mean difference in total costs between cohorts was €2761 (p < 0.001). The highest direct costs were associated with epilepsy medication, days at the hospital and specialist visits. CONCLUSION: Our data revealed a progressive increase in the use of resources and associated costs across subsequent epilepsy treatment lines.

Number needed to treat and associated cost analysis of cenobamate versus third-generation anti-seizure medications for the treatment of focal-onset seizures in patients with drug-resistant epilepsy in Spain.

INTRODUCTION: Epilepsy is a serious neurological disease, ranking high in the top causes of disability. The main goal of its treatment is to achieve seizure freedom without intolerable adverse effects. However, approximately 40% of patients suffer from Drug-Resistant Epilepsy (DRE) despite the availability of the latest options called third-generation Anti-Seizure Medications(ASMs). Cenobamate is the first ASM approved in Spain for the adjunctive treatment of Focal-Onset Seizures (FOS) in adult patients with DRE. The introduction of a new drug increases the number of therapeutic options available, making it important to compare it with existing alternatives in terms of clinical benefit and efficiency. PURPOSE: This study aimed to compare the clinical benefit, in terms of the Number Needed to Treat (NNT), and the efficiency, in terms of Cost per NNT (CNT), associated with cenobamate versus third-generation ASMs used in Spain for the adjunctive treatment of FOS in patients with DRE. METHODS: The Number Needed to Treat data was calculated based on the ≥50% responder rate and seizure freedom endpoints (defined as the percentage of patients achieving 50% and 100% reduction in seizure frequency, respectively), obtained from pivotal clinical trials performed with cenobamate, brivaracetam, perampanel, lacosamide, and eslicarbazepine acetate. The NNT was established as the inverse of the treatment responder rate minus the placebo responder rate and was calculated based on the minimum, mid-range Daily Defined Dose (DDD), and maximum doses studied in the pivotal clinical trials of each ASM. CNT was calculated by multiplying the annual treatment cost by NNT values for each treatment option. RESULTS: In terms of NNT, cenobamate was the ASM associated with the lowest values at all doses for both ≥50% responder rate and seizure freedom compared with the alternatives. In terms of CNT, for ≥50% responder rate, cenobamate was the ASM associated with the lowest CNT values at DDD and lacosamide and eslicarbazepine acetate at the minimum and maximum dose, respectively. For seizure freedom, cenobamate was associated with the lowest CNT value at DDD and the maximum dose and lacosamide at the minimum dose. CONCLUSIONS: Cenobamate could represent the most effective ASM in all doses studied compared to the third-generation ASMs and the most efficient option at DDD for both ≥50% responder rate and seizure freedom. This study could represent an important contribution towards informed decision-making regarding the selection of the most appropriate therapy for FOS in adult patients with DRE from a clinical and economical perspective in Spain.

The GSK-3-inhibitor VP2.51 produces antidepressant effects associated with adult hippocampal neurogenesis.

Glycogen synthase kinase 3 (GSK-3) is a constitutively active kinase that has been implicated in the mechanism of action of mood stabilizers. According to the neurogenic hypothesis of depression, newborn neurons in the adult dentate gyrus are required for the antidepressant effects of certain agents. We demonstrate that administration of the GSK-3 inhibitor VP2.51 (2.5 mg/kg ip, for 3.5 weeks) increases cell proliferation (pH3+ cells), as well as the short- and long-term survival of newborn neurons (assessed by the 24 h survival of BrdU+ and DCX+ neurons), while significantly increasing the commitment of cells to the granule neuron lineage (Prox1 immunoreactivity). In parallel, VP2.51 induces a net antidepressant effect, as judged by the decrease in the immobility time in the forced swim test of naïve mice (non-stressed mice), as well as a therapeutic effect on previously stressed mice (Porsolt-induced stress). Interestingly, the morphological changes were found prominently in the ventral region of the hippocampus. We found that these effects are neurogenesis dependent by combining the antimitotic temozolomide (50 mg/kg ip) with the drug. Importantly VP2.51 did not provoke changes in weight or in a battery of behavioral tests (learning/memory and activity tests). As the effects of VP2.51 were concomitant with the increase in ß-catenin expression and a shift towards the inactive form of GSK-3, we suggest that VP2.51 has therapeutic benefits following stress, and it may be a preventive treatment in situations where a potential depressive state and/or loss of memory is associated with diminished neurogenesis, through selective GSK3-beta inhibition.

Insulin Regulates Astrocytic Glucose Handling Through Cooperation With IGF-I.

Brain activity requires a flux of glucose to active regions to sustain increased metabolic demands. Insulin, the main regulator of glucose handling in the body, has been traditionally considered not to intervene in this process. However, we now report that insulin modulates brain glucose metabolism by acting on astrocytes in concert with IGF-I. The cooperation of insulin and IGF-I is needed to recover neuronal activity after hypoglycemia. Analysis of underlying mechanisms show that the combined action of IGF-I and insulin synergistically stimulates a mitogen-activated protein kinase/protein kinase D pathway resulting in translocation of GLUT1 to the cell membrane through multiple protein-protein interactions involving the scaffolding protein GAIP-interacting protein C terminus and the GTPase RAC1. Our observations identify insulin-like peptides as physiological modulators of brain glucose handling, providing further support to consider the brain as a target organ in diabetes.

The relationship between behavior acquisition and persistence abilities: Involvement of adult hippocampal neurogenesis.

The influence of the learning process on the persistence of the newly acquired behavior is relevant both for our knowledge of the learning/memory mechanisms and for the educational policy. However, it is unclear whether during an operant conditioning process with a continuous reinforcement paradigm, individual differences in acquisition are also associated to differences in persistence of the acquired behavior. In parallel, adult neurogenesis has been implicated in spatial learning and memory, but the specific role of the immature neurons born in the adult brain is not well known for this process. We have addressed both questions by analyzing the relationship between water maze task acquisition scores, the persistence of the acquired behavior, and the size of the different subpopulations of immature neurons in the adult murine hippocampus. We have found that task acquisition and persistence rates were negatively correlated: the faster the animals find the water maze platform at the end of acquisition stage, the less they persist in searching for it at the learned position in a subsequent non-reinforced trial; accordingly, the correlation in the number of some new neurons' subpopulations and the acquisition rate is negative while with persistence in acquired behavior is positive. These findings reveal an unexpected relationship between the efficiency to learn a task and the persistence of the new behavior after a non-reinforcement paradigm, and suggest that the immature neurons might be involved in different roles in acquisition and persistence/extinction of a learning task. © 2016 Wiley Periodicals, Inc.

The growth factors cascade and the dendrito-/synapto-genesis versus cell survival in adult hippocampal neurogenesis: the chicken or the egg.

The decision between cellular survival and death is governed by a balance between proapoptotic versus antiapoptotic signaling cascades. Growth factors are key actors, playing two main roles both at developmental and adult stages: a supporting antiapoptotic role through diverse actions converging in the mitochondria, and a promoter role of cell maturation and plasticity through dendritogenesis and synaptogenesis, especially relevant for the adult hippocampal neurogenesis, a case of development during adulthood. Here, both parallel roles mutually feed forward each other (the success in avoiding apoptosis lets the cell to grow and differentiate, which in turn lets the cell to reach new targets and form new synapses accessing new sources of growth factors to support cell survival) in a circular cause and consequence, or a "the chicken or the egg" dilemma. While identifying the first case of this dilemma makes no sense, one possible outcome might have biological relevance: the decision between survival and death in the adult hippocampal neurogenesis is mainly concentrated at a specific time window, and recent data suggest some divergences between the survival and the maturational promoter effect of growth factors. This review summarizes these evidences suggesting how growth factors might contribute to the live-or-die decision of adult-born immature granule neurons through influencing the maturation of the young neuron by means of its connectivity into a mature functional circuit.