CNS drugs最新文献

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.

Background and objectives: The rising prescription rates and opioid-related harms in France highlight the need for local data. Evaluating this association may help identify vulnerable subgroups and guide safer prescribing practices. This study aimed to assess the association between opioid analgesic dispensation and the risk of suicide attempt in the French population. Secondary objectives included evaluation of a dose-response relationship and examination of the potential additive effects of co-prescriptions with benzodiazepines or gabapentinoids.

Methods: We conducted a nationwide, population-based case-crossover study using data from the French National Health Insurance Database (Système National des Données de Santé, SNDS), covering 98.8% of the French population. Adults aged 18 years or older who were hospitalized for a first suicide attempt between 1 January 2013 and 31 December 2020, and who had received at least one opioid analgesic dispensation in the preceding year (excluding buprenorphine and methadone) were included. Opioid analgesic exposure during the 84 days before the attempt was compared with three earlier 84-day control periods.

Results: Among 158,400 patients (mean age 47.0 years; 64.0% women), opioid analgesic dispensation was associated with a higher risk of suicide attempt (odds ratio [OR] = 1.26; 95% confidence interval 1.25-1.28). The risk was greater for strong opioid analgesics (OR = 1.73) and higher morphine-equivalent doses. Co-prescription with benzodiazepines or gabapentinoids further increased risk.

Conclusions: Opioid analgesic use, especially at higher doses or in combination with benzodiazepines or gabapentinoids, was associated with an increased risk of suicide attempt. Clinical vigilance is warranted when prescribing these medications.

Trial registration: NCT04211077, registered 3 January 2020 (retrospectively registered).

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a cornerstone therapy for type 2 diabetes mellitus (T2DM) and heart failure, are emerging as a promising therapeutic class for the management of ischemic stroke (IS). Given that T2DM is a significant risk factor for IS, understanding the potential neuroprotective role of SGLT2i is of paramount clinical importance. This review provides a systematic and logically structured synthesis of the current evidence, beginning with foundational preclinical studies in animal models that consistently demonstrate a reduction in infarct volume and improved neurological outcomes. We then transition to the extensive clinical evidence, primarily from large-scale real-world observational studies, that has confirmed a significant reduction in stroke risk, particularly in high-risk T2DM populations. The strengths and limitations of this evidence base are critically appraised, highlighting the robustness of the findings while acknowledging the predominantly observational nature of the data and the lack of stroke-specific primary endpoints in major trials. The neuroprotective benefits of SGLT2i appear to be multifactorial; this review delves into the potential mechanisms, emphasizing a foundational, glucose-dependent pathway of ameliorating hyperglycemia-induced neurotoxicity, which is complemented by a suite of pleiotropic, glucose-independent effects, including the induction of mild ketosis, attenuation of neuroinflammation, and preservation of the neurovascular unit. Finally, we address the key clinical challenges to their application, such as the management of euglycemic ketoacidosis, and outline crucial directions for future research, underscoring the need for dedicated randomized trials.