CNS drugs最新文献

An extended-release once-daily oral capsule formulation of viloxazine (viloxazine ER; Qelbree^®), a norepinephrine reuptake inhibitor and serotonin receptor modulator, has been approved in the USA for the treatment of attention-deficit/hyperactivity disorder (ADHD) in paediatric patients and adults. This article reviews its use in adults with ADHD, with a brief overview of its pharmacological properties. In a randomized, double-blind, placebo-controlled, 6-week phase 3 trial, viloxazine ER significantly reduced the symptoms and severity of ADHD in adults, and improved executive function. Improvements were observed within 2-3 weeks and were sustained with continued treatment for over 24 months. Viloxazine ER was generally well tolerated in adults, with insomnia and headache being the most common adverse reactions. It has an acceptable safety profile, with no clinically significant cardiovascular or hepatic adverse effects. Current evidence supports viloxazine ER as a valuable addition to the therapeutic options available for adults with ADHD.

Acute ischemic stroke (AIS) remains a leading cause of mortality and long-term disability globally, with survivors at high risk of recurrent stroke, cardiovascular events, and post-stroke dementia. Statins, while widely used for their lipid-lowering effects, also possess pleiotropic properties, including anti-inflammatory, endothelial-stabilizing, and neuroprotective actions, which may offer added benefit in AIS management. This article synthesizes emerging evidence on statins' dual mechanisms of action and evaluates their role in reducing recurrence, improving survival, and mitigating cognitive decline. Key challenges limiting the full therapeutic potential of statins include interindividual variability in response and pharmacogenomic and biomarker-related resistance, inconsistencies across clinical guidelines, and limited central nervous system bioavailability. Innovations such as pharmacogenomic-guided therapy, pleiotropy-linked biomarkers, and advanced drug delivery systems (e.g., nanoparticle and intranasal formulations) may help overcome these barriers. Combination strategies with agents such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors or sodium-glucose cotransporter 2 (SGLT2) inhibitors, and targeted interventions against neuroinflammatory resistance, show promise in enhancing treatment efficacy. In doing so, we propose a shift from conventional statin use to a precision medicine paradigm that can better serve AIS survivors, especially those at risk of post-stroke dementia or those living in resource-constrained settings. While such innovations, for example, genetic testing and novel delivery methods, may not yet be feasible in all contexts, particularly low-resource environments, they represent long-term goals for equity-driven innovation. Equity in access to high-intensity statins and novel therapies remains a global priority, particularly in low- and middle-income countries. Future research should prioritize personalized, biomarker-driven approaches and inclusive clinical trials to optimize statin use across diverse AIS populations. By advancing these strategies, statins can evolve from cardiovascular agents into integral components of precision neurovascular medicine, improving long-term outcomes and quality of life for stroke survivors.

Background: TV-46000 is a long-acting subcutaneous injectable formulation of risperidone approved for treatment of schizophrenia in adults. The aim of this post hoc safety analysis of the phase 3 TV-46000 RISE (NCT03503318) and SHINE (NCT03893825) studies was to examine specific adverse events (AEs) of interest related to second-generation antipsychotic use in participants receiving TV-46000.

Methods: In RISE, participants with schizophrenia who underwent stabilization on oral risperidone were randomized to TV-46000 once monthly (q1m; dose range 50-125 mg) or once every 2 months (q2m; 100-250 mg) or placebo. In SHINE, newly recruited participants and those who completed the RISE study without relapse (rollover) received TV-46000 q1m or q2m. AEs, laboratory tests, vital signs, electrocardiogram, physical examination, and safety/tolerability assessments were recorded. This post hoc analysis evaluated specific antipsychotic-related AEs of interest and assessments related to affective, behavioral, neuromotor, endocrine, sexual/reproductive, and cardiometabolic safety and tolerability.

Results: In the two phase 3 studies, a total of 653 participants with schizophrenia were randomized to treatment, with 181 participants randomized to placebo in RISE (55 of whom were subsequently randomized to TV-46000 q1m or q2m in SHINE), 363 participants randomized to TV-46000 q1m or q2m in RISE, and 109 de novo participants randomized to TV-46000 q1m or q2m in SHINE. Among the groups in the RISE and SHINE studies, affective and behavioral AEs that occurred in ≥ 2% of participants were schizophrenia, anxiety, psychotic disorder, and depression; all occurred in ≤ 4% of participants in any group. The most common central nervous system or neuromotor AEs were headache (range, 0-6%), insomnia (< 1-6%), akathisia (< 1-4%), extrapyramidal disorder (0-4%), dizziness (0-4%), and somnolence (< 1-4%). Common metabolic-related AEs were weight increase (1-6%), increased appetite (0-3%), and hyperglycemia (0-4%). No cardiovascular AEs occurred in ≥ 2% of participants in any group. No clinically meaningful trends were observed in the results of safety assessments and AEs associated with second-generation antipsychotic use, with the exception of an increase in prolactin levels.

Conclusions: The safety profile of TV-46000 is favorable and consistent with other currently approved oral and long-acting injectable risperidone formulations.

Registration: ClinicalTrials.gov, NCT03503318, 18 April 2018; and NCT03893825; 27 March 2019.

Background and objective: Viloxazine ER (extended-release capsules; Qelbree^®) is a nonstimulant medication that has been approved by the United States Food and Drug Administration (FDA) for treatment of pediatric and adult attention-deficit/hyperactivity disorder (ADHD). This phase 3, open-label extension (OLE) trial evaluated the long-term safety and efficacy of viloxazine ER in children and adolescents with ADHD.

Methods: Participants completing the phase 2 or one of the four phase 3 double-blind, placebo-controlled clinical trials were eligible for the OLE trial. Upon entering the OLE, double-blind treatment was discontinued and participants were administered viloxazine ER 100 mg/day (children, aged 6-11 years) or 200 mg/day, (adolescents, aged 12-18 years), with dosage titration as needed over a 12-week dose-optimization period (up to 400 mg/day [children] or 600 mg/day [adolescents]). Participants then entered a maintenance period that continued through US FDA-approval (up to 72 months). Safety (primary objective) was assessed relative to OLE baseline using adverse event (AE), clinical laboratory tests, vital sign, ECG, and Columbia Suicide Severity-Rating Scale (C-SSRS) monitoring. Efficacy was assessed relative to double-blind baseline using the ADHD Rating Scale (ADHD-RS-IV/5) and the Clinical Global Impression-Improvement (CGI-I) scale. Study visits for these assessments occurred every ~ 3 months throughout maintenance treatment.

Results: Participants (N = 1100) included 646 children and 454 adolescents (66.5% male/33.5% female). Median (range) exposure to viloxazine ER in the OLE was 260 (1-1896) days, and the median modal (most frequently used) viloxazine ER doses were 300 mg/day for children and 400 mg/day for adolescents. AEs included (≥ 5% incidence) nasopharyngitis (9.7%), somnolence (9.5%), headache (8.9%), decreased appetite (6.0%), and fatigue (5.7%). AEs were mostly mild or moderate in severity (3.9% reported any severe AE); AEs led to discontinuation in 8.2% of participants. The mean ± SD changes from double-blind baseline in ADHD-RS IV/5 total score were -24.3 ± 12.0 at Month 3, -26.1 ± 11.5 at Month 12, and -22.4 ± 13.6 at participants' last OLE study visit.

Conclusions: The results of this large-scale safety trial support the long-term use of viloxazine ER as a generally well-tolerated and effective treatment option for pediatric ADHD. No new safety concerns emerged, and efficacy results suggest the potential for continued improvement over that seen during double-blind treatment.

Clinical trial registration: Clinicaltrials.gov identifier: NCT02736656.

Objective: To characterize multinational trends and patterns of opioid analgesic prescribing by sex and age.

Design, setting, and participants: We studied opioid analgesic prescribing from 2001 to 2019 with common protocol using population-based databases from eighteen countries and one special administrative region.

Main outcome measures: We measured opioid prescribing by geographical region, sex and age, estimating annual prevalent, incident, and nonincident opioid prescribing per 100 population with a 95% confidence interval (CI) and meta-analyzed the multinational and regional opioid prescribing with a random-effects model. Time trends were reported through average annual absolute changes, estimated using linear mixed models. We further explored the effect of sex and age on prevalent opioid prescribing in the multivariable analysis.

Results: Over 248 million individuals were included. Pooled multinational opioid prescribing prevalence was 9.0% amongst included countries/regions. Opioid prescribing prevalence in 2015 ranged from 2.7% in Japan to 19.7% in Iceland. Average annual absolute changes in opioid prescribing prevalence per year ranged from - 1.53% (95% CI - 2.06, - 1.00; United States Medicaid) to + 1.24% (95% CI 1.02, 1.46; South Korea). Pooled multinational incident opioid prescribing (4.9%; 95% CI 4.1, 5.9) was higher than pooled multinational nonincident opioid prescribing (3.7%; 95% CI 2.9, 4.8). The female sex and older age were associated with higher opioid prescribing. Main limitations of this study include the absence of data from study duration or individuals not covered by the data sources and the lack of information on medication adherence and indication.

Conclusions: Opioid prescribing remains unbalanced across geographical regions; however, results suggest a tendency to convergence across countries/regions. Differences in opioid prescribing by sex and age were identified.

Advances in pulmonary (PM) drug delivery through inhalation devices have enabled effective treatments for acute exacerbations of central nervous system (CNS) episodes, addressing previously unmet medical needs. While PM formulations of loxapine and levodopa are approved for agitation and off periods in Parkinson's disease (PD), respectively, there remains an unmet need for rapid-acting therapies for other acute exacerbations of neurologic disorders. In this review, the potential of PM delivery to address this gap in the management of acute CNS disorders is critically assessed, focusing on Staccato^® loxapine for agitation, Inbrija^® (levodopa) for PD, the investigational drug inhaler device Staccato^® alprazolam for epilepsy, and other investigational drug inhaler devices. PM delivery benefits from bypassing first-pass metabolism, utilizing inhalation devices to enable rapid drug delivery to the densely perfused alveolar space, arterial bloodstream, and brain. However, challenges include lung tissue sensitivity, low dose volume (compared with oral and intravenous administration), and difficulties with administration during certain acute episodes. Pharmacokinetic, efficacy, and safety data from approved or investigational PM therapies for agitation, PD, epilepsy, migraine, and insomnia present inhalation as a promising option for patients requiring acute episode management by facilitating fast absorption and onset of action and generally good tolerability. In particular, for epilepsy, on-demand medication that may be administered by patients or caregivers early at seizure onset may translate to improved patient outcomes. To enhance PM management of acute exacerbations of CNS disorders, further research and user training for optimal PM administration are required.

The aim of this article is to review the neurobiological changes associated with methamphetamine use disorder (MUD) and consider what implications they have for the development of effective pharmacotherapies. Novel pharmacotherapies are urgently needed to address the complex neurobiological changes that occur both during and after MUD. Current approaches are modelled on maintenance therapies for opioid use, particularly with the use of prescription stimulant medications to substitute for illicit methamphetamine. Existing evidence suggests that these have limited effectiveness, and enthusiasm has been dampened by concerns about the risk of toxicity. We identify an opportunity to look beyond maintenance therapies and to consider alternative models of pharmacotherapy that support the initiation and maintenance of abstinence. In doing this, we highlight the complexity of the neurobiological changes that occur both during and after cessation of methamphetamine use. We identify a need for pharmacotherapies that can address the lasting neurobiological changes from long-term methamphetamine use to improve treatment engagement and retention as well as functional recovery and to reduce relapse risk.

Background: Agitation is a common and distressing neuropsychiatric symptom in Alzheimer's disease (AD), affecting up to half of patients and contributing to faster cognitive decline and caregiver burden. Brexpiprazole, a serotonin-dopamine modulator, has been evaluated for this indication, but uncertainties remain regarding its efficacy, safety, and appropriate use in older adults.

Objective: We aimed to assess the efficacy and safety of brexpiprazole for the treatment of agitation in older adults with AD through a systematic review and meta-analysis of randomized controlled trials (RCTs).

Methods: Following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 guidelines and the Cochrane Handbook, we included RCTs comparing brexpiprazole (0.5-3 mg/day) with placebo in older adults with a clinical diagnosis of AD. Primary outcomes were agitation severity (measured using the Cohen-Mansfield Agitation Inventory [CMAI]), clinical impression (clinical global impression-severity scale [CGI-S]), neuropsychiatric symptoms (Neuropsychiatric Inventory [NPI]), and adverse events. Risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) were pooled using a random-effects model. Random-effects meta-analyses were performed using frequentist and Bayesian models in R (version 4.3.0).

Results: A total of five RCTs (N = 1770) met the inclusion criteria. Brexpiprazole was associated with a modest reduction in agitation CMAI (MD - 5.79; 95% CI - 9.55 to - 2.04; prediction interval: - 14.07 to 2.49) and improved CGI-S scores (MD - 0.23; 95% CI - 0.32 to - 0.13; prediction interval: - 0.39 to - 0.06). No significant differences were found in NPI scores. Adverse events such as extrapyramidal symptoms and daytime somnolence occurred more frequently with brexpiprazole but with wide and nonsignificant intervals. Meta-regression did not identify dose or duration as effect modifiers.

Conclusions: Brexpiprazole may offer modest short-term benefits for agitation in AD without cognitive worsening, but safety signals remain imprecise. However, prediction intervals indicate considerable uncertainty, and its use should be individualized and closely monitored. Future trials should prioritize long-term outcomes and patient-centered measures.

Registration prospero protocol number: CRD 42025646060.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting both upper and lower motor neurons. ALS is classically characterized by painless progressive weakness, causing impaired function of limbs, speech, swallowing, and respiratory function. The disease is fatal within 2-4 years, often the result of respiratory failure. The pathologic hallmark for a majority of ALS cases is aberrant cytoplasmic accumulations of the nuclear protein TAR-DNA binding protein (TDP-43). A total of 10-15% of ALS can be attributed to a single gene mutation, known as genetic or "familial" ALS, while the remainder of cases are termed nongenetic or "sporadic" although heritability has been measured in up to 37% in this population. Complex interactions between genetics, environment, and physiologic susceptibility are thought to contribute to disease. Management is primarily supportive in nature, though there are several approved treatments worldwide. This review details the mechanisms and evidence of approved disease-modifying treatments, relevant measures to track disease burden and progression used in clinical trials, and approaches to pharmacologic management of common symptoms in ALS. As there is not currently a cure for ALS, research into the complex pathophysiologic and genetic alterations contributing to disease is of great interest. This review further discusses the current understanding of genetic etiologies and altered physiology leading to disease, such as neuroinflammation, integrated stress response, aberrant proteostasis and mitochondrial dysfunction, among others. The translation of preclinical discoveries into current investigational therapeutics, novel therapeutic categories such as antisense oligonucleotides and stem cell transplantation, as well as future horizons harnessing the power of artificial intelligence in drug development and clinical trials are discussed.