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.

Schizophrenia is a complex psychiatric disorder, with cognitive impairment representing a critical unmet medical need. Current treatments primarily address positive symptoms, failing to effectively improve cognitive function and negative symptoms. This narrative review examines the current landscape of novel schizophrenia therapeutics following the discontinuation of iclepertin development, critically evaluates the most promising current candidates, and identifies priority research areas for future drug development. A comprehensive literature review was conducted covering developments from 2020 to 2025, with emphasis on Phase II and Phase III clinical data for novel mechanisms beyond traditional dopamine D₂ receptor antagonism. The landscape has been dramatically reshaped by two pivotal developments: the U.S. Food and Drug Administration (FDA) approval of xanomeline/trospium (KarXT, Cobenfy^®) in September 2024 as the first nondopaminergic antipsychotic, and the failure of iclepertin in Phase III trials in January 2025. The most compelling therapeutic approaches continue to be serotonin-dopamine activity modulators (brilaroxazine) and emerging M₄ selective agonists (NBI-1117568). Moreover, recent evidence suggests a more cautious outlook for TAAR1 agonists, with systematic analyses revealing significant placebo response challenges in recent trials. While iclepertin's discontinuation represents a significant setback for GlyT1 inhibition strategies, the approval of KarXT and advancing pipeline candidates offer potential for therapeutic advances. Critical challenges include escalating placebo responses that compromise trial assay sensitivity, underscoring the need for improved patient stratification, refined trial methodology, and outcome measures that accurately capture real-world benefit.

Background and aims: Evidence directly comparing ocrelizumab (OCR) and ofatumumab (OFA) after sphingosine-1-phosphate receptor modulators (S1PRMs) withdrawal is limited, even though this transition period carries an increased risk of disease reactivation and the two anti-CD20 agents differ in molecular properties that may influence post-S1PRM outcomes. We compared effectiveness, safety, and tolerability of OFA versus OCR in relapsing-remitting multiple sclerosis (RRMS) after S1PRM therapy.

Methods: We retrospectively analyzed adult (> 18 years) patients with RRMS from 23 Italian centers who switched from S1PRMs to OCR or OFA (October 2016 to July 2024). Clinical outcomes included annualized relapse rate (ARR), cumulative relapse incidence, confirmed disability progression (CDP), progression independent of relapse activity (PIRA), confirmed disability improvement (CDI), and variation in the expanded disability status scale score (ΔEDSS) from baseline to last follow-up. Magnetic resonance imaging (MRI) outcomes included time to overall MRI activity, new/enlarging T2 lesions, and new T1 Gd-enhancing lesions. Persistence on anti-CD20 and safety were also assessed. We applied inverse probability of treatment weighting (IPTW) to balance baseline covariates, and used Cox, Andersen-Gill, and regression models, further adjusted for variables with residual imbalance, to compare outcomes.

Results: We included 225 subjects (mean age 43.3 ± 10.6 years; OCR = 131, OFA = 94), with a median follow-up of 33 months. After IPTW, groups were well balanced. Compared with OCR, OFA was associated with lower ARR (adjusted relative risk [aRR] 0.22, 95% CI 0.06-0.86, p = 0.030) and relapse hazard (adjusted hazard ratio [aHR] 0.21, 95% CI 0.05-0.83, p = 0.026). When restricting washout to ≤ 10 weeks and applying spline-based Andersen-Gill models, results remained consistent, with OFA showing a lower relapse risk than OCR across short-to-intermediate washout intervals. CDP hazard was lower (aHR 0.38, 95% CI 0.15-0.94, p = 0.038), while PIRA and CDI did not differ. ΔEDSS favored OFA (adjusted mean difference [aMD] - 0.26, 95% CI - 0.51 to - 0.02, p = 0.046). OFA showed a lower hazard of overall MRI activity (aHR 0.41, 95% CI 0.19-0.92, p = 0.030), with similar risk for new T1 Gd+ lesions. A sensitivity analysis restricted to patients who switched to OFA or OCR during the same availability window yielded results consistent with the primary analysis. Treatment persistence was shorter on OFA, but absolute discontinuation rates were low in both groups. Severe AEs were rare and did not differ.

Conclusions: In S1PRM-exposed RRMS, OFA was associated with reduced relapse risk, disability accumulation, EDSS worsening, and MRI activity compared with OCR, with overall good tolerability and safety.

Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune disorder affecting the central nervous system, often misdiagnosed as multiple sclerosis. The identification of aquaporin-4-IgG (AQP4-IgG) has improved diagnostic precision and enabled targeted therapies. Given the unique regional challenges in healthcare delivery across the Middle East and North Africa (MENA) region, the Middle East and North Africa Committee for Treatment and Research in Multiple Sclerosis (MENACTRIMS) convened an expert panel to develop evidence-based, region-specific consensus recommendations for diagnosis and management. These guidelines endorse the 2015 International Panel for NMO Diagnosis (IPND) criteria, emphasizing AQP4-IgG testing via cell-based assays. Differential diagnosis should consider multiple sclerosis, myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and acute disseminated encephalomyelitis (ADEM). For acute treatment: initiate high-dose intravenous methylprednisolone promptly and use plasma exchange early for severe or steroid-refractory attacks. For long-term immunotherapy, monoclonal antibodies (rituximab, inebilizumab, eculizumab, ravulizumab, satralizumab, or tocilizumab) are recommended according to availability and patient factors; conventional immunosuppressants remain alternatives when biologics are inaccessible. Guidance is provided for pediatric patients and for pregnancy and breastfeeding, including planning after ≥ 12 months of disease stability and early postpartum treatment resumption. These MENACTRIMS guidelines aim to improve NMOSD outcomes across the region by promoting accurate diagnosis and timely, effective therapy.

Multiple sclerosis (MS) is a chronic, immune-mediated disorder that predominantly affects women, with an average age of onset between 20 and 50 years. As a result of the early age of onset and increasing life expectancies of women, owing to improvements in disease-modifying treatments (DMTs), recommendations regarding disease and symptom management may vary depending on their life stage and should be tailored to the individual. In addition, in recent years, new data regarding the management of MS from the preconception to postpartum period has led to evolving recommendations from both neuroimmunologists and national drug agencies alike. Similarly, an aging MS population has led to questions regarding the effect of menopause on MS and guidance regarding DMTs as patients age. The purpose of this review is to provide an up-to-date, comprehensive summary of the clinical course and management of the disease and commonly experienced symptoms during puberty, preconception and pregnancy, postpartum, menopause, and life after menopause.

Background: Baclofen is a γ-aminobutyric acid type B receptor agonist primarily used for spasticity. It is increasingly prescribed orally at high off-label doses for conditions such as alcohol use disorder, raising concerns regarding severe toxicity and withdrawal syndromes. This systematic review comprehensively characterizes the clinical presentations, management strategies, and outcomes associated with oral baclofen toxicity and withdrawal.

Methods: MEDLINE, Embase, and CENTRAL databases were searched from inception through October 2024. Eligible studies included clinical trials, observational studies, case series, and case reports describing oral baclofen toxicity or withdrawal in humans. Excluded were studies on intrathecal baclofen, non-human or preclinical data, gray literature, and reports lacking sufficient clinical data. Three reviewers independently performed study screening, data extraction, and quality assessments. The Joanna Briggs Institute Critical Appraisal Checklists for case reports, case series, and observational studies were used to evaluate methodological quality and risk of bias across included studies. Discrepancies were resolved by consensus among reviewers, with senior author verification when needed. Outcome measures included clinical presentation, management strategies, need for intensive care or mechanical ventilation, length of hospital stay, recovery status, and mortality. Because of study heterogeneity, data were synthesized narratively without a formal certainty assessment.

Results: Sixty-six case reports (44 toxicity cases from 38 case reports, 34 withdrawal cases from 28 case reports) and 18 retrospective studies (n = 1540) were included (total n = 1618 individuals). Baclofen toxicity commonly presented with central nervous system depression (68%), seizures (36%), and respiratory depression (21%), particularly at doses ≥ 300 mg. Management predominantly involved supportive measures, including mechanical ventilation in approximately 54.5% of cases. Full clinical recovery occurred in 97.7% of cases. In retrospective cohorts, mortality was generally low (~ 0-4%), with most patients recovering following supportive management. Baclofen withdrawal commonly manifested with severe psychiatric disturbances (up to 20.6%), delirium, agitation, and autonomic instability, typically emerging within 1-4 days after abrupt discontinuation. Rapid baclofen reinitiation consistently resolved withdrawal symptoms.

Conclusions: Baclofen toxicity and withdrawal can become severe or life threatening, underscoring the need for prompt recognition and careful medical management. Clinicians should exercise caution when prescribing baclofen, particularly at higher doses (≥ 300 mg/day). Prospective studies and standardized clinical guidelines are needed to enhance patient safety and optimize outcomes. PROSPERO number CRD420251155708.