CNS drugs最新文献

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.

Background: Safety outcomes following intravenous thrombolysis (IVT) impact overall efficacy in acute ischemic stroke (AIS), yet safety profiles of various IVT treatments remain less studied. In this study, we ranked safety profiles of various IVT treatments through a systematic review and meta-analysis of safety outcomes following IVT in AIS.

Methods: This network meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO; no. CRD42024544617). Phase 3 randomized controlled trials on IVT in AIS from Embase, Ovid Medline, and Cochrane Library were included. Primary outcomes included total serious adverse events (SAEs), symptomatic intracranial hemorrhage (sICH), and 3-month mortality.

Results: Network meta-analysis involved 21 studies for total SAEs, 21 for sICH, and 34 for mortality with no heterogeneity (I² = 0%; I² = 0%; I² = 15.86%). Compared with non-thrombolysis, alteplase 0.9 mg/kg and tenecteplase 0.25 mg/kg were associated with more SAEs (risk difference [RD] 0.03, 95% confidence interval [CI] 0.01-0.05; RD 0.04, 95% CI 0.01-0.06), sICH (RD 0.02, 95% CI 0.01-0.03; RD 0.02, 95% CI 0.01-0.03), and mortality (RD 0.01, 95% CI 0.00-0.03; RD 0.02, 95% CI 0.00-0.03). Nonimmunogenic recombinant staphylokinase (nSta) 10 mg resulted in fewer SAEs than non-thrombolysis (RD - 0.11, 95% CI - 0.21 to - 0.01), recombinant human prourokinase (rhPro-UK) 35 mg (RD - 0.12, 95% CI - 0.22 to - 0.02), alteplase 0.9 mg/kg (RD - 0.14, 95% CI - 0.23 to - 0.04), and tenecteplase 0.25 mg/kg (RD - 0.15, 95% CI - 0.24 to - 0.05) and less sICH than tenecteplase 0.25 mg/kg (RD - 0.05, 95% CI - 0.10 to 0.00). Although rhPro-UK 35 mg resulted in more sICH than non-thrombolysis (RD 0.01, 95% CI 0.00-0.02), it was associated with a lower rate of sICH compared with alteplase 0.9 mg/kg (RD - 0.01, 95% CI - 0.02 to 0.00) and tenecteplase 0.25 mg/kg (RD - 0.01, 95% CI - 0.02 to - 0.01). Compared with alteplase 0.6 mg/kg, alteplase 0.9 mg/kg and tenecteplase 0.25 mg/kg resulted in more SAEs (RD 0.04, 95% CI 0.01-0.07; RD 0.05, 95% CI 0.01-0.08) and sICH (RD 0.01, 95% CI 0.00-0.02; RD 0.02, 95% CI 0.01-0.03). When administered beyond 4.5 h with tissue window assessment, tenecteplase 0.25 mg/kg and alteplase 0.6 mg/kg were not associated with higher rates of mortality compared with non-thrombolysis.

Conclusions: Alteplase 0.6 mg/kg, rhPro-UK 35 mg, and nSta 10 mg were safer IVT options. Tenecteplase 0.25 mg/kg and alteplase 0.6 mg/kg were preferable beyond 4.5 h with tissue window assessment.