CNS drugs最新文献

Chronic and neuropathic pain remain significant clinical challenges owing to limited efficacy and safety concerns associated with conventional analgesics, including opioids and NSAIDs. Voltage-gated sodium channels, particularly Nav1.7 and Nav1.8, have emerged as promising non-opioid targets for pain modulation, given their selective expression in peripheral nociceptors and critical roles in pain signal transmission. Recent advances in structural biology and pharmacology have enabled the development of highly selective inhibitors targeting these channels. This review explores sodium channel inhibitors currently in clinical development, with a focus on suzetrigine (VX-548), the first US Food and Drug Administration (FDA)-approved Nav1.8 inhibitor for acute pain, as well as other investigational agents such as ralfinamide, OLP-1002, LTGO-33 and HBW-004285. Despite setbacks in early candidates owing to selectivity and tolerability issues, ongoing trials demonstrate renewed optimism for a new class of analgesics that may overcome the limitations of traditional pain therapies. We discuss key pharmacological challenges observed in earlier trials including functional redundancy, species differences, and on-target side effects, and outline how emerging strategies, such as structural biology-guided design, combination therapies, and precision medicine, are paving the way for safer, more effective, nonaddictive pain treatments.

Eating disorders (EDs) are complex psychiatric conditions characterized by disruptions in eating behaviors, body image concerns, and profound medical and psychosocial consequences. Despite their significant global prevalence, coupled with high morbidity and mortality rates, pharmacological treatment options remain limited. This review synthesizes evidence from clinical drug trials conducted between 1 January 2010 and 1 January 2025, supplemented with relevant literature, to evaluate the current and emerging pharmacological landscape for EDs. A systematic search of the U.S. Clinical Trials Registry (ClinicalTrials.gov) identified 43 eligible phase I-IV clinical trials for the treatment of anorexia nervosa (n = 12), binge eating disorder (n = 27), bulimia nervosa (n = 2), and rumination disorder (n = 2). Among 24 distinct compounds studied, only 1 agent, lisdexamfetamine dimesylate, received approval from the U.S. Food and Drug Administration (FDA) for an ED during this period. Notably, few agents have demonstrated positive results in late-stage trials and remain in development for EDs as of 2025. While some emerging agents show promise, such as solriamfetol and psilocybin, there remains a significant lack of evidence-based pharmacological interventions for anorexia nervosa and a dearth of progress in pharmacotherapy for bulimia nervosa. Overall, the past 15 years have witnessed limited advancements in pharmacotherapy for EDs. There remains an urgent need for rigorous clinical trials in this area in addition to increased prioritization of ED research at the public health level to overcome longstanding barriers in the treatment of EDs.

Treatment resistance in bipolar disorder (BD) is common, and innovative treatments are needed. The opioid system is under investigation as a new target treatment of depression and BD, notably the treatment of depressive symptoms. This narrative review aims to synthesize the evidence related to opioid-receptor-modulating drugs in treating BD. The protocol was preregistered at Open Science Framework. A search of the literature databases Embase, PubMed, and PsycINFO was conducted in March 2024 for studies involving the treatment of manic or depressive symptoms of BD with an opioid-receptor-modulating drug. The studies revealed a preliminary antimanic but transient effect of intravenous naloxone and potential antimanic effects of pentazocine. Methadone showed an effect on regulating manic symptoms. The existing evidence on the effects of opioid-receptor-modulating drugs in BD is scarce, and most studies are older and based on small samples. Clinically, opioid-receptor-modulating drugs cannot be recommended or integrated into the treatment of BD. Still, well-designed, randomized controlled trials are needed to draw any firm conclusions.

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.

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).