CNS drugs最新文献

Background and objectives: Anti-calcitonin gene-related peptide (CGRP) therapies have significantly improved migraine prevention, but the long-term impact of discontinuation remains unclear. This systematic review and meta-analysis aimed to evaluate clinical outcomes following the cessation of anti-CGRP therapy.

Methods: PubMed, Embase, and Cochrane databases were searched up to September 2024 for randomized or observational studies reporting post-discontinuation effects in patients with episodic or chronic migraine who had been preventively treated with anti-CGRP monoclonal antibodies or gepants. The primary outcome was the mean change in monthly migraine days from baseline to post-discontinuation. Secondary outcomes included acute headache medication use, the mean change in migraine frequency from active therapy to treatment cessation, and ≥ 50% responder rates. Heterogeneity was assessed with prediction intervals (PIs) for binary outcomes and I² statistics for continuous data. Random-effects models pooled mean differences (MDs) and risk ratios (RRs), with subgroup analyses based on follow-up duration, study design, and individuals with chronic migraine.

Results: Eight studies (n = 1012) evaluating anti-CGRP monoclonal antibodies interruption were included. No studies on gepant cessation were found. Monthly migraine days decreased significantly post-discontinuation compared with baseline (MD -3.78; 95% CI -4.89, -2.67; I² = 57%; p < 0.05), with reductions of - 5.70 days at 1 month and - 3.62 days at 3 months. Patients with chronic migraine showed sustained reductions (MD - 6.54; 95% CI - 8.64, - 4.43; I² = 68%; p < 0.05) in the days per month with migraine between cessation and pre-treatment periods. Monthly acute headache medication days declined from baseline (MD - 1.74; 95% CI - 2.84, - 0.64; I² = 0%; p < 0.05). Monthly migraine days increased at 3 months after discontinuation compared with just before discontinuation (MD 4.43; 95% CI 2.61, 6.25; I² = 86%; p < 0.05), with monthly acute headache drug usage rising by 3.22 days. Responder rates of ≥ 50% declined (RR 0.42; 95% CI 0.33, 0.53; PI 0.17, 1.03; p < 0.05).

Conclusions: Migraine burden worsened after discontinuation of anti-CGRP targeting therapies but remained lower than pretreatment levels. Further research is needed to explore disease-modifying potential and optimal discontinuation strategies. PROSPERO registration number CRD42024595771.

Background and objectives: Excessive daytime sleepiness (EDS) is a prominent symptom of obstructive sleep apnea (OSA), negatively affecting patients' quality of life. The objective of this study was to assess the efficacy and safety of solriamfetol in patients with OSA with EDS from China.

Methods: This multicenter, randomized, double-blind, placebo-controlled phase 3 trial compared solriamfetol (75/150 mg once daily) with placebo for 12 weeks. Adults diagnosed with OSA, mean Maintenance of Wakefulness Test (MWT) sleep latency < 30 min, and Epworth Sleepiness Scale (ESS) score ≥ 10 were included. Patients with disorders causing EDS other than OSA were excluded. Co-primary endpoints were change from baseline to week 12 in MWT mean sleep latency and ESS score; a key secondary endpoint was improvement on Patient Global Impression of Change (PGI-C), assessed on a seven-point scale. MWT was performed at baseline and at weeks 2, 5, and 12, whereas the ESS and PGI-C were evaluated at weeks 2, 5, 8, and 12. Safety and tolerability were assessed on the basis of treatment-emergent adverse events (TEAEs), laboratory tests, vital signs, 24-h ambulatory blood pressure monitoring, 12-lead electrocardiogram, and physical examination. Statistical analyses of co-primary endpoints were performed on the full analysis set (FAS) using a mixed model for repeated measures (MMRM). Safety analyses were performed on the safety population. A hierarchical testing sequence was used to control multiplicity.

Results: Of the 204 patients randomized (1:1) into placebo and solriamfetol groups, 192 completed the study (96 in each group). Co-primary endpoints were met, with significantly increased mean MWT sleep latency (P < 0.0001) and decreased ESS score (P = 0.0017) in the solriamfetol group (MWT, n = 95; ESS, n = 97) versus placebo (MWT, n = 95; ESS, n = 96) at week 12. Higher proportion of participants receiving solriamfetol (n = 90; 89.1%) reported improvement in PGI-C versus placebo (n = 77; 77.0%; P = 0.0221). At least one TEAE was reported in solriamfetol (n = 84; 82.4%) and placebo (n = 67; 65.7%) groups. The occurrence of serious TEAEs was low, with one incidence in both groups. Most frequently reported TEAEs in solriamfetol group included upper respiratory tract infection, dizziness, hyperuricemia, hypertension, hyperlipidemia, hypertriglyceridemia, and increased blood creatine phosphokinase. Most TEAEs were of mild/moderate severity and did not lead to study treatment discontinuation.

Conclusions: Solriamfetol demonstrated substantial efficacy and acceptable safety in Chinese patients with OSA with EDS, reinforcing its role as a viable treatment option.

Trial registration: ClinicalTrials.gov: NCT06103825.

Background: Although recurrent ischemic stroke (IS) is associated with higher rates of mortality and comorbidities as well as an increased economic burden than the first attack, the choice of first-line antihypertensive agent for secondary prevention remains controversial. This study examined the efficacy of various antihypertensive agents for the secondary prevention of recurrent ischemic stroke in a real-world context.

Methods: Using the National Health Insurance Research Database, patients with first acute IS from 1 January 2000 to 31 December 2020 were enrolled. Using propensity score-based probability of treatment weighting, all participants were divided into other antihypertensive drugs (OHTND), angiotensin-converting-enzyme-inhibitors/angiotensin II-receptor-blockers (ACEI/ARB), and calcium-channel-blockers (CCB) cohorts. Primary outcome was difference in risk of recurrent IS, and secondary outcomes were all-cause mortality, stroke-related death, and major adverse cardiac and cerebrovascular events (MACCEs). Cox proportional hazards models were used to estimate the adjusted hazard ratio and 95% confidence intervals.

Results: Compared with the OHTND cohort, individuals in the ACEI/ARB and CCB cohorts had a 14% (p < 0.001) and 15% (p < 0.001) lower risk of recurrent IS, respectively. Individuals in the CCB cohort had a 37% (p = 0.006) higher risk of acute myocardial infarction compared with the OHTND cohort. Compared with ACEI users, ARB users experienced a 22% lower risk of recurrent IS, while ARB users had a 46% lower risk of stroke-related death.

Conclusions: The use of ACEI/ARB following acute IS was associated with a lower risk of recurrent IS. Our results not only corresponded to pre-existing randomized controlled trials (RCTs) but also addressed the knowledge gap regarding the choice of first-line antihypertensive agents following acute IS.

Both pediatric and adult patients can develop low-grade glioma (World Health Organization [WHO] grade 2), a type of primary brain tumor that can impact neurologic function and limit one's ability to thrive and survive. Traditionally, the treatment of low-grade gliomas mirrored recommendations for patients with higher-grade gliomas, such as glioblastoma. The diagnosis and categorization of primary brain tumors, including low-grade gliomas, were transformed in 2021 with an update of the World Health Organization classification system for pediatric and adult diffuse gliomas. In the pediatric population, there is recognition that a majority of low-grade gliomas have alterations in the mitogen-activated protein kinase (MAPK) pathway (BRAF mutations and rearrangements and other alterations in genes in this pathway); whereas in the adult population, mutations in isocitrate dehydrogenase (IDH), a key enzyme of the Krebs cycle, define diffuse low-grade glioma, namely oligodendroglioma and astrocytoma. Parallel to the advancements in diagnosis and tumor classification, the treatment has advanced to develop targeted therapies for patients with diffuse low-grade glioma. This review will highlight the molecular and genetic underpinnings of these tumors and how targeted therapeutic strategies led to the US Food and Drug Administration's approvals of combination therapy with dabrafenib and trametinib for pediatric patients with BRAF V600E mutant low-grade glioma; tovorafenib, a pan-RAF inhibitor, for pediatric BRAF mutant glioma; and vorasidenib, an inhibitor of mutant IDH1/2 enzymes, for patients with mutant IDH low-grade glioma. Integration of these targeted therapies into currently accepted treatment paradigms remains to be fully understood, along with the long-term impact on patient quality of life and prognosis.

Ketamine, an anaesthetic and sedative drug, has emerged as a promising therapeutic option for the management of chronic refractory pain, but is used off-label in this indication and known for its psychomimetic side-effects. The primary objective of this manuscript is to synthesize the current evidence on ketamine efficacy and safety for chronic refractory pain. Furthermore, it aims to identify critical knowledge gaps and propose a framework for its rational and safe clinical application. This narrative review analyses key findings from randomised and non-randomised clinical trials investigating ketamine's use in chronic pain conditions. It also examines existing clinical guidelines and expert consensus statements to reach a comprehensive clinical perspective. Current evidence demonstrates that ketamine can provide significant short-term analgesia, especially in neuropathic pain, and is fairly well-tolerated in patients with severe refractory pain. However, long-term data on efficacy, cognitive impact, addiction risk and optimal dosing are severely lacking. The intravenous route remains the most studied, while alternatives are still underexplored. Ketamine is not a first-line treatment for pain and must be prescribed and supervised by trained specialists within a structured standard of care. Its future role in pain management hinges on collaborative translational research to define optimal administration routes, establish phenotyping strategies (on the basis of pain type, comorbidities and comedication), and conduct long-term studies assessing mood, quality of life and cognitive function to ensure both efficacy and safety.

Background: Individuals with schizophrenia and comorbid substance use disorder (SUD) often experience poor treatment adherence, leading to worse clinical outcomes. However, high-quality evidence from randomized trials on the preferred mode of antipsychotic treatment in this population remains limited.

Aims: The aim was to examine whether long-acting injectable (LAI) antipsychotic treatment reduces the risk of all-cause discontinuation (ACD) compared with oral antipsychotics in individuals with early phase schizophrenia and comorbid SUD.

Methods: This study was a secondary analysis of the European Long-Acting Antipsychotics in Schizophrenia Trial (EULAST), a multisite, randomized, open-label trial conducted across multiple European healthcare settings. A total of 471 individuals with early phase schizophrenia were included in this secondary analysis, stratified by presence (n = 143) or absence (n = 328) of comorbid SUD. The observation period lasted 18 months. Participants were randomly assigned to second-generation LAI or oral second-generation antipsychotic treatment. The primary outcome was ACD, an indirect measure of treatment efficacy, defined as discontinuation of the initially assigned treatment for any reason. Hazard ratios (HRs) were estimated using Cox proportional hazards regression models, adjusted for relevant covariates.

Results: Among 143 individuals with schizophrenia and SUD, LAI treatment was associated with a 36% lower risk of ACD compared with oral antipsychotics (adjusted HR = 0.641; 95% CI, 0.438-0.938; P = 0.022). Kaplan-Meier curves showed longer median time to ACD for LAI treatment (158 days) versus oral antipsychotics (97 days). By contrast, among the 328 individuals without SUD, LAI treatment did not significantly reduce ACD risk (P = 0.282). Crude HRs were also assessed, replicating the adjusted hazard findings.

Conclusions: LAI antipsychotics significantly delayed treatment discontinuation compared with oral antipsychotics in participants with early phase schizophrenia and comorbid SUD but not in those without SUD. While these findings provide robust evidence supporting the use of LAIs in people with schizophrenia and comorbid SUD, future studies are needed to more precisely quantify the potential clinical benefits and tolerability of LAIs in this high-risk population. EULAST was registered at ClinicalTrials.gov (NCT02146547).

Cerebral aspergillosis is a well-recognized and particularly severe manifestation of invasive aspergillosis, primarily affecting immunocompromised individuals. The condition is associated with high morbidity and mortality, largely due to diagnostic challenges and limited treatment options. This review examines the epidemiology, risk factors, and diagnostic issues before focusing on drug treatment, including the pharmacokinetics and pharmacodynamics of antifungal agents in the central nervous system. Resistance to current antifungal therapies is also discussed, along with future research directions.

Background: Prolactin elevation associated with antipsychotic use significantly affects medication adherence and long-term treatment outcomes in patients with schizophrenia. The currently available data are insufficient to guide the monitoring and management of elevated prolactin levels in patients on antipsychotic medications. This study aimed to explore the patterns of prolactin level elevation associated with nine second-generation antipsychotics (SGAs) in a real-world setting and compare the associated risks.

Methods: This retrospective cohort study utilized data from the inpatient electronic medical records of a large mental health center in China from 2007 to 2019. The study included patients diagnosed with schizophrenia (ICD-10 criteria) who received SGA therapy and whose serum prolactin levels were measured. Exposures were the use of nine specific SGAs (amisulpride, risperidone, paliperidone, ziprasidone, olanzapine, perospirone, quetiapine, clozapine, or aripiprazole), including polytherapy and monotherapy. The primary outcome was incident prolactin elevation in patients during hospitalization. An adjusted stratified Cox proportional hazards regression analysis was used to compare the hazard ratios (HRs) of prolactin level elevation across the nine SGAs. In addition, a dose-response analysis of these SGAs was conducted using the defined daily dose (DDD) method. Dose categories were as follows: < 0.6 DDDs/day (low dose), 0.6 to < 1.1 DDDs/day (medium dose), and ≥ 1.1 DDDs/day (high dose).

Results: This study included 6489 patients with schizophrenia (mean [SD] age, 35.1 [14.2] years; 3396 males [52.3%]). Compared with the nonexposure, amisulpride (HR 2.76, 95% confidence interval [CI] 2.12-3.59), risperidone (HR 2.70, 95% CI 2.30-3.16), paliperidone (HR 1.84, 95% CI 1.37-2.46), and ziprasidone (HR 1.36, 95% CI 1.06-1.76) were associated with the highest risk of prolactin elevation. In contrast, quetiapine (HR 0.73, 95% CI 0.61-0.87), clozapine (HR 0.59, 95% CI 0.46-0.76), and aripiprazole (HR 0.30, 95% CI 0.23-0.37) were associated with the lowest risk. Amisulpride posed the highest risk among male patients, whereas risperidone posed the highest risk among female patients. Different types of dose-response associations were detected in seven SGAs.

Conclusion: This cohort study, conducted in an inpatient setting, identified different risks of prolactin elevation associated with SGAs, along with their dose-response curves. Sex and age must be considered when prolactin elevation is analyzed in patients with schizophrenia who are treated with SGAs.

Trial registration: ClinicalTrials.gov identifier: NCT04002258.

Alzheimer's disease (AD) and Parkinson's disease (PD) are chronic neurodegenerative disorders with few effective drug treatments available. An underrated element of these diseases is that glucose uptake and energy utilization is much reduced in neurons. In the brains of patients, signaling of insulin, insulin-like growth factor 1, and other growth factors is downregulated early on. This leads to reduced glucose utilization and impaired mitochondrial function. In an attempt to compensate for the loss, other pathways are upregulated, e.g., the increased use of ketones produced from fatty acids by astrocytes that are shuttled to neurons. In addition, amino acids are increasingly used to generate energy. Despite this, neurons generate less and less energy over time, leading to impaired synaptic activity, reduced cell repair, mitogenesis, autophagy, the accumulation of misfolded proteins, and finally, to cell death. At the same time, the chronic inflammation response in the brain that is part of these diseases continues to damage neurons. Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are peptide hormones and growth factors that have shown neuroprotective effects in animal studies and in clinical trials. GLP-1 and GIP receptor agonists were able to reduce inflammation while normalizing growth factor signaling and energy utilization in the brain. Insulin signaling was improved and energy utilization, glucose uptake, mitogenesis, and mitochondrial functionality was brought back to physiological levels. In addition, the chronic inflammation response and the levels of proinflammatory cytokines in the brain were much reduced. Clinical trials testing GLP-1 receptor agonists in patients with AD or PD have been conducted and have shown first successes, serving as proof of concept that activating GLP-1 receptor is a sensible strategy to treat AD/PD. A phase II study testing liraglutide in patients with AD showed first improvements, and two phase II trials testing exendin-4 (exenatide, Bydureon^®) or lixisenatide showed improvements in patients with PD. A recent phase III trial testing exendin-4 did not show an improvement, which may be linked to the lack of insulin desensitization in the study participants. Semaglutide (Rybelsus^®; Wegovy^®; Ozempic^®) is currently in two phase III trials for AD. Current drugs that are on the market have a long half-life in the blood and do not readily cross the blood-brain barrier (BBB). Newer dual GLP-1/GIP receptor agonists have been developed that can more easily cross the BBB and that show improved protection in animal models of AD and PD. Therefore, GLP-1 and GIP receptor agonists that can cross the BBB show promise as treatments for chronic neurodegenerative disorders.