CNS drugs最新文献

Background and objectives: Over the last decade, significant advancements have been made in status epilepticus (SE) management, influenced by landmark trials such as ESETT and RAMPART. The objectives of this study were to explore the evolution of drug treatments for patients with SE, to investigate its association with outcomes and mortality, and to evaluate differences in treatment patterns between adults and children for a potential shift in medication trends due to the above mentioned trials.

Methods: The medical records of patients with SE treated at University Hospital Frankfurt between 2012 and 2021 were evaluated for medication trends and outcomes. Children and adults were analyzed separately and jointly.

Results: This study included 1151 SE episodes in 1021 patients (mean age = 53.3 ± 28.3 years; 52.5 % female [n = 533]). The overall percentage of patients with SE treated prehospital was stable over the last decade. More than half (53.6 %) of children were treated prehospital, compared with less than one-third (26.7 %) of adults. Prehospital midazolam use increased over time, while diazepam use decreased. Lorazepam was the most commonly used benzodiazepine in hospitals in 2012-2013, used in 40.8 % of all episodes. However, its use declined to 27.2 % in 2020-2021, while midazolam use increased to 44.0 %. While the use of older antiseizure medications (ASMs) such as phenobarbital (p = 0.02), phenytoin (p < 0.001), and valproate (p < 0.001) decreased, the use of newer ASMs such as levetiracetam and lacosamide significantly increased (p < 0.001). Propofol and continuous midazolam infusion remained the most used third-line therapy drugs. Overall mortality was 16.5 % at discharge and 18.9 % at 30 days. Mortality rates did not change between 2012 and 2021.

Conclusion: Midazolam has become the preferred benzodiazepine in pre- and in-hospital settings, both in children and adults. The same applies to the increased use of levetiracetam and lacosamide over time in children and adults, while phenobarbital, phenytoin, and valproate use decreased. Continuous midazolam infusion and propofol remain the most frequently used anesthetic drugs. Mortality and outcome remain stable despite changes in medication patterns.

Solriamfetol (SUNOSI^®) is an oral selective dopamine and norepinephrine reuptake inhibitor approved in the EU and the USA for improving wakefulness in adults with excessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnoea (OSA). In phase III studies, 12 weeks' therapy with solriamfetol within the recommended dosage range for narcolepsy (75 mg or 150 mg once daily) or OSA (37.5 mg, 75 mg or 150 mg once daily) provided early and sustained reductions in excessive sleepiness and improvements in wakefulness relative to placebo. These effects were generally sustained through 52 weeks. The drug's effectiveness in adults with EDS associated with narcolepsy is supported by results from real-world studies. Solriamfetol demonstrated a consistent safety and tolerability profile across clinical studies, with commonly reported adverse reactions generally occurring within 2 weeks of treatment initiation and mostly resolving within 2 weeks. Thus, solriamfetol represents a useful treatment option for adults with EDS associated with narcolepsy or OSA.

Background and objectives: Medical cannabis use is increasing in Australia and other jurisdictions, yet little is known about the effects of medical cannabis on cognitive function. Findings from studies of non-medical ('recreational') cannabis may not be applicable to patients using prescribed medical cannabis to manage a health condition.

Methods: In this semi-naturalistic, open-label trial, patients with various health conditions attended a single laboratory session in which they self-administered a standard dose of prescribed medical cannabis as per instructions on the pharmacy label. We assessed cognitive performance using the Cambridge Neuropsychological Test Automated Battery (CANTAB) and Druid application (app) prior to and following (CANTAB: + 3 h; Druid: + 3 and 5.5 h) medical cannabis self-administration. We also assessed subjective drug effects prior to and following (1, 2 and 4 h) medical cannabis self-administration using a range of 0-10 cm visual analogue scales ('stoned', 'sedated', 'relaxed', 'comfortable', 'anxious' and 'confident'). Data were analyzed using linear fixed-effect models.

Results: Participants (N = 40; 22 females) were prescribed a range of products including orally administered oils (n = 23) and flower for vaporization (n = 17). Participants had a mean (standard deviation [SD]) age of 41.38 (12.66) years and had been using medical cannabis for a mean (SD) of 10.18 (8.73) months. Chronic non-cancer pain was the most common indication for medical cannabis use (n = 20), followed by sleep disorder (n = 18) and anxiety (n = 11). The mean (SD) delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) dose administered by participants was 9.61 (8.52) mg/9.15 (10.11) mg among those using an oil, and 37.00 (24.53) mg/0.38 (1.58) mg among those who vaporized flower, respectively. Participants' performance improved over time on the CANTAB Multitasking Test and Rapid Visual Information Processing test (both p-values <0.001). All other changes in cognitive performance measures over time were non-significant (p > 0.05). Vaporization of flower was associated with significantly stronger subjective feelings of 'stoned' and 'sedated' relative to oils (both p < 0.001).

Conclusions: These findings suggest that prescribed medical cannabis may have minimal acute impact on cognitive function among patients with chronic health conditions, although larger and controlled trials are needed.

Background: A significant proportion of adults with major depressive disorder (MDD) do not respond to treatments which are currently used in clinical practice such as first-generation monoamine-based antidepressants.

Objectives: The objective of this systematic review was to assess the efficacy, safety, and mechanisms of action of AXS-05, a combination of the NMDA-receptor antagonist dextromethorphan with bupropion, in adults with MDD.

Methods: We searched PubMed, Embase, Google Scholar, and ClinicalTrials.gov for current studies reporting on efficacy and/or safety of AXS-05 in patients with MDD. The search terms included: "AXS-05" OR "dextromethorphan and bupropion" AND "depression". Studies from database inception to January 2023 were evaluated. Risk of bias was assessed using the Cochrane Risk of Bias tool.

Results: The search yielded 54 studies of which 5 were included. All studies had low risk of bias. Depression severity, measured with the Montgomery-Åsberg Depression Rating Scale (MADRS) significantly decreased as early as 1-week post-treatment from baseline when compared to a placebo-controlled group (LS mean difference 2.2; 95% CI 0.6-3.9; p = 0.007) and at 2 weeks compared to an active control group (LS mean difference 4.7; 95% CI 0.6-8.8; p = 0.024). Treatment efficacy could be maintained for up to 12 months with mean MADRS score reduction of 23 points from baseline. Clinical remission and response rates also improved at week 1 and were maintained for 12 months. The treatment was well-tolerated, with some transient adverse events reported.

Conclusion: Current evidence suggests that the combination of dextromethorphan and bupropion is a well-tolerated, rapid-acting treatment option for adults with MDD. Initial success with AXS-05 supports the mechanistic role of glutamatergeric and sigma 1 signaling in the pathophysiology of MDD.

Background and objective: Status epilepticus in poststroke epilepsy is a challenging condition because of multiple vascular comorbidities and the advanced age of patients. Data on third-generation antiseizure medication (ASM) in this condition are limited. The aim of this study was to evaluate the efficacy of third-generation ASMs in the second- or third-line therapy of benzodiazepine-refractory status epilepticus in poststroke epilepsy following acute ischemic stroke.

Methods: Data on the effectiveness of third-generation ASMs in patients with status epilepticus in poststroke epilepsy were gathered from two German Stroke Registries and the Mainz Epilepsy Registry. We included only cases with epilepsy remote to the ischemic event. No patients with acute symptomatic seizures were included. The following third-generation ASMs were included: brivaracetam, lacosamide, eslicarbazepine, perampanel, topiramate, and zonisamide. The assessment of effectiveness was based on seizure freedom within 48 h since the start of therapy with the respective ASM. Seizure freedom was evaluated both clinically (clinical evaluation at least three times per day) and by daily electroencephalogram records.

Results: Of the 138 patients aged 70.8 ± 8.1 years with benzodiazepine-refractory status epilepticus in ischemic poststroke epilepsy, 33 (23.9%) were treated with lacosamide, 24 (17.4%) with brivaracetam, 23 (16.7%) with eslicarbazepine, 21 (15.2%) with perampanel, 20 (14.5%) with topiramate, and 17 (12.3%) with zonisamide. Seizure freedom within 48 h was achieved in 66.7% of patients with lacosamide, 65.2% with eslicarbazepine, 38.1% with perampanel, 37.5% with brivaracetam, 35.0% with topiramate, and 35.3% with zonisamide (p < 0.05 for comparison of lacosamide or eslicarbazepine to other ASMs).

Conclusions: Based on these data, lacosamide and eslicarbazepine might be more favorable in the treatment of refractory status epilepticus in poststroke epilepsy, when administered as second- or third-line ASMs before anesthesia. Because of the fact that these ASMs share the same mechanism of action (slow inactivation of sodium channels), our findings could motivate further research on the role that this pharmaceutical mechanism of action has in the treatment of poststroke epilepsy.

Clinical trial registration: This study was registered at ClinicalTrials.gov (NCT05267405).

Background: The question of whether multiple sclerosis requires life-long disease-modifying treatments (DMTs) remains unanswered. Some studies suggest that older patients with stable disease may safely discontinue their DMTs, yet comprehensive evidence-based data are scarce and real-world studies have provided mixed results.

Objective: The aim of this study was to assess the rate of disease reactivation and associated risk factors after discontinuation of DMTs in patients with multiple sclerosis.

Methods: We searched scientific databases (PubMed/MEDLINE, Scopus and Google Scholar) to identify real-world studies published until 31 July, 2023 that reported the number of patients who experienced relapses and/or disability accrual (outcomes of interest) following a therapy discontinuation longer than 12 months. Magnetic resonance activity and treatment re-start after DMT discontinuation were also considered as additional outcomes. We excluded studies where therapy discontinuation was explicitly related to an unintended or planned pregnancy or preceded a treatment switch. We ran random-effects meta-analyses, subgroup analyses and meta-regression models to provide pooled estimates of post-discontinuation relapse and disability events, and to identify their potential moderators (predictors).

Results: After an independent screening, 22 articles met the eligibility criteria, yielding a pooled sample size of 2942 patients followed for 1-7 years after discontinuation (11,689 patient-years). The pooled rates for relapse and disability events were 6.7 and 5.8 per 100 patient-years, respectively. However, available data did not allow us to disentangle isolated disability accrual from relapse-associated worsening. Studies including older patients (β = -0.65, p = 0.006), patients with a longer exposure to DMTs (β = -2.22, p = 0.001) and patients with a longer period of disease stability (β = -2.74, p = 0.002) showed a lower risk of relapse events. According to meta-regression equations, the risk of relapse events after DMT discontinuation became negligible (arbitrarily set at < 1% per year) at approximately 60 years of age, and after either 10 years of DMT exposure, or 8 years of disease stability. Additional analyses showed pooled rates for magnetic resonance imaging activity and re-start events of 16.7 and 17.5 per 100 patient-years, respectively.

Conclusions: Based on our quantitative synthesis of real-world data, in the absence of definitive answers from clinical trials, DMT discontinuation appears feasible with a high degree of certainty in selected patients. While our findings are robust regarding relapse events, future efforts are warranted to determine if DMT discontinuation is associated with isolated disability accrual.