CNS drugs最新文献

Seletracetam (SEL) is a second-generation racetam derivative of the benchmark antiseizure medication (ASM) levetiracetam, discovered in a drug discovery program conducted by UCB Pharma in the early 2000s to optimize binding to synaptic vesicle glycoprotein 2A (SV2A), the main target of levetiracetam. SEL (administered orally) reached phase IIa clinical trials, but its further development was stopped, and its patent expired in 2021. In preclinical studies, SEL showed very potent seizure suppression in several acquired and genetic epilepsy models, with high CNS tolerability. Phase I human studies indicated rapid and extensive oral absorption (> 90% bioavailability), linear pharmacokinetics, and an elimination half-life of about 8 h, with mostly mild to moderate CNS adverse events. Several phase IIa trials found SEL to be effective and to have a good safety profile in patients with photosensitive epilepsy and drug-resistant focal epilepsy. A unique aspect of SEL is its high potency and water solubility that-unlike any other non-benzodiazepine (non-BDZ) ASMs-allows it to be formulated at therapeutic doses in a very low liquid volume suitable for intranasal administration and potential use in acute seizure rescue therapy. The US-based company PrevEp, Inc. (Bethesda, MD) filed a new US patent application in 2024, followed by a worldwide Patent Cooperation Treaty (PCT) application in 2025 on intranasal and orobuccal SEL formulations and new medical uses as the first potential non-BDZ rescue treatment of acute repetitive seizures and rapid epileptic seizure termination (REST). The clinical development of this novel formulation is derisked by the favorable oral SEL administration phase I and phase IIa clinical data. SEL offers several important advantages for rescue treatment in comparison with BZDs. It is only moderately sedative even at the highest doses tested orally, does not cause respiratory depression, and has no addictive potential. Thus, SEL has the potential to become the first non-BDZ acute rescue therapy. Because SEL has never been approved for use in humans, it is a new chemical entity (NCE). In this review, we describe the pharmacology of SEL, its clinical profile after oral administration, and the development of the new intranasal formulation, including first-in-human data.

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.

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 objectives: Glaucoma is one of the leading causes of irreversible blindness worldwide and is increasingly recognized as a potential adverse effect of various pharmacological agents. It has been suggested that psychotropic medications influence glaucoma risk, but findings across studies have remained inconsistent. We aimed to clarify the association between psychotropic drug use and glaucoma through a Bayesian meta-analysis.

Methods: We conducted a systematic literature search up to December 2024. Studies that examined the relationship between psychotropic medications and glaucoma or intraocular pressure (IOP), and reported odds ratios (ORs), relative risks (RRs), or mean differences, were eligible. Bayesian random-effects models were applied using informative priors based on existing evidence for specific compounds. Estimates were reported as pooled ORs and Hedges' g with corresponding 95% credible intervals (CrIs).

Results: A total of 22 observational studies, including 293,228 users of psychotropic medications, met the inclusion criteria. Selective serotonin reuptake inhibitors (SSRIs) were associated with a modestly reduced risk of open-angle glaucoma (OR = 0.832, 95% CrI: 0.753-0.921) and a small but consistent reduction in IOP (Hedges' g = -0.332, 95% CrI: -0.487 to -0.179). Although tricyclic antidepressants were expected to have a direct causative effect, results did not show a significant association with glaucoma risk (OR = 1.466, 95% CrI: 0.700-3.338). Benzodiazepines were associated with a significantly increased risk of glaucoma (OR = 1.550, 95% CrI: 1.436-1.674), with consistent effects across both short- and long-acting compounds. Topiramate demonstrated a strong association with acute angle-closure glaucoma (OR = 3.930, 95% CrI: 1.784-11.465), in accordance with its known mechanism of inducing anterior displacement of the lens-iris diaphragm. Studies on methylphenidate, limited to pediatric populations, suggested a modest but non-significant reduction in IOP compared with untreated individuals. Evidence on antipsychotics was inconsistent, precluding any quantitative synthesis.

Conclusions: While some drug classes (e.g., benzodiazepines, topiramate) show a strong association with glaucoma, results for other compounds must be taken judiciously. The high level of heterogeneity, and the presence of special populations suggest caution when moving to real-life scenarios. Nonetheless, our results highlight the importance of ophthalmologic monitoring in patients prescribed with psychiatric drugs (e.g., benzodiazepines or topiramate), at risk for angle closure.

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.

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.

Acute ischemic stroke (AIS) poses a substantial risk of permanent disability and death globally, with neuroinflammation being a key driver of secondary brain damage post-stroke. Proprotein convertase subtilisin/kexin type 9 (PCSK9), beyond its well-accepted role in cholesterol metabolism through low-density lipoprotein receptor (LDLR) degradation, has emerged as an important mediator of neuroinflammation, making it an attractive new therapeutic target. This has sparked broader discussions about the potential pleiotropic effects of PCSK9 inhibitors on brain function. Proprotein convertase subtilisin/kexin type 9 mediates inflammation post-ischemia directly and indirectly by disrupting mTOR pathways. This stimulates signaling cascades associated with inflammation. For example, the nuclear factor-κB (NF-κB), toll-like receptor 4 (TLR4), and mitogen-activated protein kinase (MAPK) pathways in microglia activation. It also brings about reaction in astrocytes and increases the release of cytokines like interleukin-1β, interleukin-6, and tumor necrosis factor-α. Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein E receptor 2 (ApoER2) present on neurons cells, leading to further inflammatory effects. Proprotein convertase subtilisin/kexin type 9 indirectly increases lipoprotein(a) [Lp(a)], which promotes inflammation through the Lp(a)-TLR4 axis and induces endothelial dysfunction. Monoclonal antibodies (evolocumab, alirocumab) and small interfering RNA (siRNA) agents (inclisiran) are examples of PCSK9 inhibitors. According to preclinical studies, these inhibitors can mitigate neuroinflammation by blocking the M1 polarization of microglia and downregulating key pro-inflammatory factors while preserving the blood-brain barrier (BBB). They also inhibit neuronal apoptosis via the Bcl-2/Bax-caspase cascade and reduce the aggregation of β-amyloid (Aβ). Evidently, the findings from cardiac ischemia-reperfusion models show that pretreatment with PCSK9 inhibitors is effective with optimal neuroprotection. Recent clinical data support these mechanisms: PCSK9 inhibitors not only lower LDL-C and Lp(a) but also reduce systemic inflammatory markers (e.g., high-sensitivity C-reactive protein [hs-CRP], interleukin-6). Early adjunctive use of evolocumab in AIS is associated with reduced early neurological deterioration, highlighting that its effects extend beyond lipid lowering to modulating immune pathways in both the central and peripheral systems. As a promising multitarget therapeutic strategy for AIS, PCSK9 inhibitors target the interconnected pathways of lipid metabolism and neuroinflammation. Future studies should address critical challenges such as defining the optimal therapeutic time window, improving BBB penetrability, and refining patient stratification to translate their neuroprotective effects into clinical benefits for stroke patients.