CNS drugs最新文献

Parkinson's disease (PD) is a common neurodegenerative movement disorder that currently has no disease-modifying therapies. Over the past two decades, there has been a substantial acceleration in the knowledge of how genetics underlies PD risk. This has given rise to pathological protein targets that can be therapeutically targeted. In particular, there is compelling evidence for developing therapeutic strategies targeting alpha-synuclein, leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GCase). These proteins are implicated in lysosomal function and may contribute to the accumulation of the hallmark pathological forms of alpha-synuclein that define PD. This review highlights current progress on PD therapies targeting these proteins as they attempt to make their way through the clinical trial pipeline, with unique and distinctive approaches being used for each target. Progress is being made in both immunotherapy and small molecule approaches to reduce aggregated forms of alpha-synuclein in the brain, with the aim to stop the propagation of disease. Pathogenic mutations in LRRK2 result in overactivation of the enzyme's catalytic kinase activity, and consequently kinase inhibitors that aim to reduce LRRK2 activity are in late phase clinical trials. In contrast, PD-associated mutations in GCase generally result in impaired lysosomal GCase activity, and thus small molecule chaperones and allosteric activators of GCase are in advanced development and clinical trials. Although these approaches seem to be generally tolerated by participants in phase I studies, challenges remain in progressing these promising therapies through phase II and beyond.

Background and objectives: The Argatroban Plus Recombinant Tissue-Type Plasminogen Activator for Acute Ischemic Stroke (ARAIS) trial did not show the benefit of argatroban as an adjunct in patients with acute ischemic stroke who received intravenous alteplase. This post hoc exploratory analysis aimed to determine whether the circadian rhythm can affect the efficacy of argatroban as an adjunct in this population.

Methods: From the per-protocol population of the ARAIS trial, patients were divided into 2 groups based on the beginning time of intravenous thrombolysis: daytime (06:00-17:59) and nighttime (18:00-05:59) groups. Each group was divided into argatroban plus alteplase and alteplase alone groups. The primary outcome was excellent functional outcome, defined as a modified Rankin Scale (mRS) score of 0 to 1 at 90 days. The safety outcome was symptomatic intracerebral hemorrhage (sICH).

Results: Among 692 patients from the per-protocol analysis, 489 were in the daytime group, and 203 in the nighttime group. In the daytime group, the proportion of patients with an excellent functional outcome was 60.5% (144/238) in the argatroban plus alteplase group versus 66.9% (168/251) in the alteplase-alone group, respectively, without significant difference between two groups (adjusted odds ratio [aOR] = 1.19; 95% CI 0.80-1.78; p = 0.40). In the nighttime group, argatroban plus alteplase was significantly associated with higher proportion of excellent functional outcome compared with alteplase alone (75.9% vs 60.3%; aOR = 0.47; 95% CI 0.24-0.93; p = 0.03). An interaction effect was found between intervention (argatroban plus alteplase or alteplase only) by different treatment period on primary outcome (P for interaction = 0.02). For safety outcomes, no significant differences in sICH rates were observed between treatment groups within either time stratum.

Conclusion: This is the first report that suggested a potential association between argatroban and a higher rate of excellent functional outcome in patients with acute ischemic stroke who received intravenous alteplase during the nighttime. This finding requires further validation in future studies.

Trial registration: ClinicalTrials.gov Identifier: NCT03740958.

Background and objective: Individuals with attention-deficit/hyperactivity disorder, their families and clinicians may report worsening symptoms despite compliant use of medication, suggesting potential tolerance, but evidence remains conflicting. Some studies have also suggested tachyphylaxis, or acute tolerance, though research is limited. We conducted the first systematic review of empirical studies focussing on tolerance/tachyphylaxis to attention-deficit/hyperactivity disorder medication to clarify their potential clinical relevance.

Methods: As registered on PROSPERO (CRD42024594759), we searched PubMed, OVID (including PsychInfo and MEDLINE) and Web of Knowledge up to 1 September, 2024, and assessed the risk of bias using National Institutes of Health quality assessment tools.

Results: The identified 17 studies were either interventional or observational, and varied greatly in design and duration. Four investigated tachyphylaxis, nine tolerance to the subjective and behavioural effects, and four tolerance to cardiovascular effects. We found preliminary evidence of tachyphylaxis to the affective or behavioural effects of stimulants, as well as tolerance to the subjective effects of d-amphetamine, such as drug liking and excitation, in neurotypical volunteers in the short term. Conversely, there was little or no evidence for tolerance to the therapeutic or cardiovascular effects of attention-deficit/hyperactivity disorder medication in clinical settings in the longer term. Quality was rated as low in most studies because of small sample sizes and methodological limitations.

Conclusions: Overall, these results do not support the hypothesis that tolerance commonly develops to the therapeutic effects of attention-deficit/hyperactivity disorder medication, although robustly designed longitudinal studies are needed to provide more conclusive evidence. Clinicians may consider other potential explanations for reduced therapeutic effects over time, including natural fluctuations of symptoms, limited compliance, life events and co-occurrent mental health conditions.

Early reocclusion is a significant contributor to early neurological deterioration and adverse outcomes in patients with acute ischemic stroke treated with intravenous thrombolysis (IVT) therapy. Although current guidelines recommend delaying antithrombotic therapy until 24 h after IVT to reduce hemorrhagic risks, the persistently high incidence of reocclusion has prompted the exploration of earlier antithrombotic strategies. Despite theoretical benefits, extensive research has not consistently demonstrated the efficacy of early antithrombotic interventions. Nevertheless, a recent randomized controlled trial encouragingly demonstrated that ultra-early intravenous administration of the antiplatelet agent tirofiban after IVT was effective at improving functional outcomes in non-cardioembolic stroke patients with a low risk of hemorrhage. However, the considerable heterogeneity in both antithrombotic regimens and patient populations across existing studies has obscured the identification of beneficial candidates and intervention protocols for early post-thrombolysis antithrombotic therapy. We synthesizes the current evidence regarding patient selection, drug choice, and optimal timing for early antithrombotic therapy, to explore potential improvements in post-IVT antithrombotic management, emphasizing the critical need to balance the prevention of ischemic progression with the risk of hemorrhagic transformation.

Background and objectives: Spinocerebellar ataxia type 3 (SCA3) is one of the most common dominantly inherited ataxias worldwide. Despite research advances, no approved disease-modifying treatment exists, and management focuses on symptom alleviation and functional capacity maximization. Symptomatic treatment guidelines are scarce, leaving decisions to physicians' discretion. The lack of studies on SCA3 symptom management hinders therapy standardization. The aim of this study was to investigate medication-usage patterns among SCA3 mutation carriers and controls included in the multicentric European Spinocerebellar Ataxia Type-3/Machado-Joseph Disease Initiative (ESMI) cohort.

Methods: We conducted a retrospective cross-sectional analysis of the medication taken by ESMI participants enrolled in the study between 2016 and 2023. Medication being used at the most recent follow-up visit available was categorized according to the Anatomical Therapeutic Chemical system. Comparisons between groups were performed using nonparametric tests for continuous variables and Fisher's exact test for categorical variables. In addition, a retrospective longitudinal analysis was conducted to study the impact of medication subclasses on disease progression, using linear mixed-effects models adjusted for relevant covariates.

Results: A total of 474 participants were included, comprising 344 SCA3 mutation carriers and 130 controls. Compared with controls, SCA3 subjects took more vitamins, mineral supplements, muscle relaxants, and medications targeting the nervous system. Psychoanaleptics and vitamins were introduced early in the disease course, whereas most other subclasses were initiated in mid-to-late stages, coinciding with the onset of neurological symptoms. Substantial disparities in medication usage were observed across the study centers. None of the medication subclasses commonly used by patients with SCA3 showed a significant impact on disease progression.

Conclusions: This is the first study to explore medication usage patterns in SCA3 mutation carriers. Our study provides a comprehensive overview of the medications administered in SCA3 and underscores the importance of collaborative efforts toward achieving standardized clinical practices in the management of this disease.

Bipolar disorder affects approximately 40 million individuals worldwide, with depression being the most prominent phase of the illness. Owing to limited treatment options, bipolar depression remains a major public health concern, often causing significant functional impairment and increased suicide risk. Current therapies frequently lack rapid effectiveness, highlighting the need for novel approaches. Psilocybin, a psychedelic compound receiving growing interest for its potential rapid antidepressant effects, is under investigation in clinical trials combined with psychotherapy. Early studies in bipolar II disorder (n = 19) show encouraging results, but evidence is still limited, and important safety concerns such as affective switching and pharmacokinetic interactions persist. Additional challenges include regulatory restrictions, infrastructure demands, and uncertainties about the role of the psychedelic experience, especially given possible interference by common bipolar medications. Cautious, rigorous research is essential to determine psilocybin's safety, efficacy, and practical application in bipolar depression, particularly for bipolar I disorder and long-term outcomes.

In Japan, the use of clozapine is strictly regulated compared with other countries. Only Novartis Pharma completely controls marketing and package inserts, with no generic drugs available. Countless requirements should be met, including that clozapine can only be prescribed by hospitals and psychiatrists registered with the Clozaril Patient Monitoring Service, hospitalization is mandatory when starting clozapine treatment, patients cannot be discharged or stay overnight outside the hospital for 3 weeks, and hospitalization for 18 weeks is recommended in principle. Blood monitoring standards are also strict. Under these circumstances, the Japanese clozapine package insert describes a titration protocol to 200 mg/day in 3 weeks, and our study has reported a high frequency of inflammatory adverse events in patients who followed this protocol. This narrative review summarizes the evidence regarding the relationship between clozapine titration speeds and inflammatory adverse events in Japanese individuals. Although several guidelines for preventing clozapine-induced inflammation are available, few studies have investigated whether the recommended titration protocols reduce the risk of inflammatory adverse events. In Japanese patients, clinicians encounter the challenge of identifying clozapine-poor metabolizers in advance, making it difficult to determine which patients would benefit from a slower titration protocol. In this article, we provided specific titration strategies to reduce inflammatory adverse events on the basis of evidence from studies in Japanese people. First, we provide an overview of the characteristics of clozapine-induced inflammation, particularly focusing on its properties as a continuum. We also propose a hypothesis regarding the immunological mechanisms by which clozapine causes inflammation on the basis of observed phenomena. Next, we summarize the risk factors for clozapine-induced inflammation. We then summarize the evidence of clozapine-induced inflammation in Japanese individuals and emphasize the importance of slower titration in this population to prevent inflammatory adverse effects. In the latter part, we propose a methodology for personalized titration in Japanese people, which involves measuring clozapine blood levels on day 8 to estimate individual clozapine metabolism capacity and adjusting the titration speed accordingly. Finally, we discuss how slower titration helps determine the minimum therapeutic dose while monitoring patients for side effects of clozapine. We hope that they may guide psychiatrists and pharmacists on clozapine titration speed and adjustment methodology, promoting the broader use of clozapine with fewer adverse events.