CNS drugs最新文献

{"title":"Viloxazine Extended-Release Capsules in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: Results of a Long-Term, Phase 3, Open-Label Extension Trial.","authors":"Robert L Findling, Alain Katic, Michael Liebowitz, James Waxmonsky, Nicholas Fry, Peibing Qin, Ilmiya Yarullina, Zulane Maldonado-Cruz, V Rose Lieberman, Jonathan Rubin","doi":"10.1007/s40263-025-01209-0","DOIUrl":"10.1007/s40263-025-01209-0","url":null,"abstract":"<p><strong>Background and objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Clinical trial registration: </strong>Clinicaltrials.gov identifier: NCT02736656.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"1157-1172"},"PeriodicalIF":7.4,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144834314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety Outcomes with the Long-Acting Subcutaneous Antipsychotic TV-46000 in Schizophrenia: A Post Hoc Analysis of Behavioral, Neuromotor, Endocrine, and Cardiometabolic Outcomes from Two Phase 3 Studies.","authors":"Christoph U Correll, Helena Knebel, Eran Harary, Roy Eshet, Orna Tohami, Mark Suett, Nir Sharon, Kelli R Franzenburg, John M Kane","doi":"10.1007/s40263-025-01197-1","DOIUrl":"10.1007/s40263-025-01197-1","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>The safety profile of TV-46000 is favorable and consistent with other currently approved oral and long-acting injectable risperidone formulations.</p><p><strong>Registration: </strong>ClinicalTrials.gov, NCT03503318, 18 April 2018; and NCT03893825; 27 March 2019.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"1139-1156"},"PeriodicalIF":7.4,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Statins in Acute Ischemic Stroke: Mechanisms, Resistance, and Precision Strategies for Neurovascular and Cognitive Protection.","authors":"Muskaan Gupta, Ivica Smokovski, Dimitrios G Chatzis, Kevin J Spring, Man Mohan Mehndiratta, Roy G Beran, Sonu M M Bhaskar","doi":"10.1007/s40263-025-01222-3","DOIUrl":"10.1007/s40263-025-01222-3","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"1083-1107"},"PeriodicalIF":7.4,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145023009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"International Trends in Opioid Prescribing by Age and Sex from 2001 to 2019: An Observational Study Using Population-Based Databases from 18 Countries and One Special Administrative Region.","authors":"Adrienne Y L Chan, Shahram Bahmanyar, Kebede Beyene, Greta Bushnell, Bruce Carleton, Amy Hai Yan Chan, Sharon Cook, Stephen Crystal, Kari Furu, Svetla Gadzhanova, Patricia García Poza, Rosa Gini, Sabrina Giometto, Jeff Harrison, Ulrike Haug, Christine Hsu, Harpa Lind Hjördísar Jónsdóttir, Joe Kai, Øystein Karlstad, Ju Hwan Kim, Kiyoshi Kubota, Edward Chia-Cheng Lai, Hyesung Lee, Wallis C Y Lau, Kathy H Li, Ersilia Lucenteforte, Géric Maura, Anke Neumann, Virginia Pate, Anton Pottegård, Nadeem Qureshi, Lotte Rasmussen, Johan Reutfors, Elizabeth E Roughead, Leena Saastamoinen, Tsugumichi Sato, Oliver Scholle, C C M Schuiling-Veninga, Chin-Yao Shen, Ju-Young Shin, Til Stürmer, Katja Taxis, Marco Tuccori, Stephen Weng, Kirstie H T W Wong, Helga Zoega, Kenneth K C Man, Ian C K Wong","doi":"10.1007/s40263-025-01215-2","DOIUrl":"10.1007/s40263-025-01215-2","url":null,"abstract":"<p><strong>Objective: </strong>To characterize multinational trends and patterns of opioid analgesic prescribing by sex and age.</p><p><strong>Design, setting, and participants: </strong>We studied opioid analgesic prescribing from 2001 to 2019 with common protocol using population-based databases from eighteen countries and one special administrative region.</p><p><strong>Main outcome measures: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"1173-1185"},"PeriodicalIF":7.4,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Opportunities for and Challenges of Pulmonary Drug Delivery in the Management of Acute Exacerbations of CNS Disorders.","authors":"Kamil Detyniecki, Adam Strzelczyk, Robert Roebling, Cedric Laloyaux, Hugues Chanteux, James C Cloyd","doi":"10.1007/s40263-025-01213-4","DOIUrl":"10.1007/s40263-025-01213-4","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"1109-1138"},"PeriodicalIF":7.4,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144798373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictors of Esketamine Response in Treatment-Resistant Depression: The Role of Temperament and Cumulative Treatment Resistance.","authors":"Riccardo Guglielmo, Margherita Marino, Elisa Briasco, Elisa Cavanna, Alberto Inuggi, Francesca Schiavon, Gabriele Giacomini, Daniela Malagamba, Andrea Escelsior, Giovanni Martinotti, Mario Amore, Gianluca Serafini","doi":"10.1007/s40263-025-01210-7","DOIUrl":"10.1007/s40263-025-01210-7","url":null,"abstract":"","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"1187-1191"},"PeriodicalIF":7.4,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brexpiprazole for the Treatment of Agitation in Older Adults with Alzheimer's Disease: A Systematic Review, Bayesian Meta-analysis, and Meta-regression.","authors":"Anderson Matheus Pereira da Silva, Luciano Falcão, Ocilio Ribeiro Gonçalves, Filipe Virgilio Ribeiro, Pedro Lucas Machado Magalhães, Mariana Lee Han, Paweł Łajczak, Mariana Letícia de Bastos Maximiano, Henrique Cal, Eryvelton de Souza Franco, Maria Bernadete de Sousa Maia","doi":"10.1007/s40263-025-01219-y","DOIUrl":"10.1007/s40263-025-01219-y","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>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).</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Registration prospero protocol number: </strong>CRD 42025646060.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"1071-1082"},"PeriodicalIF":7.4,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methamphetamine Pharmacotherapy: A Need to Re-focus on the Complex Neurobiological Changes that Occur Both During and After Methamphetamine Use Disorder.","authors":"Rebecca McKetin, Jee Hyun Kim, Alyna Turner, Michael Berk","doi":"10.1007/s40263-025-01214-3","DOIUrl":"10.1007/s40263-025-01214-3","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"1061-1070"},"PeriodicalIF":7.4,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Atogepant on Sleep Quality and Sleep-Related Adverse Events in Adult Patients with Migraine: A Prospective Observational 12-Week Study.","authors":"Luigi Francesco Iannone, Alberto Boccalini, Flavia Lo Castro, Daria Brovia, Marina Romozzi, Fabrizio Vernieri, Claudia Altamura, Simona Guérzoni","doi":"10.1007/s40263-025-01235-y","DOIUrl":"https://doi.org/10.1007/s40263-025-01235-y","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Migraine is often associated with impaired sleep quality, including insomnia, fragmented sleep, and circadian rhythm disturbances. These factors can exacerbate migraine severity and chronification. Calcitonin gene-related peptide (CGRP), a key player in migraine pathophysiology, also influences sleep regulation. While CGRP monoclonal antibodies have shown mixed effects on sleep, no study to date has evaluated the impact of gepants on sleep quality. This study assessed whether atogepant, recently approved for migraine prevention, affects sleep quality and sleep-related adverse events in real-world settings.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We conducted a prospective, observational, open-label, single-center study. All received atogepant 60 mg/day up to 12 weeks. Adults (≥ 18 years) with migraine (with/without aura or chronic migraine) experiencing ≥ 4 monthly migraine days were enrolled. Inclusion required ≥ 1 month of headache diaries and stable preventive or sleep treatments for ≥ 3 months. Patients were accepted regardless of prior preventive failures. Exclusion criteria were unstable treatments, recent sleep-impacting disease, and pregnancy. Sleep quality was assessed using five validated questionnaires (Pittsburgh Sleep Quality Index [PSQI], Athens Insomnia Scale [AIS], Bergen, Epworth Sleepiness Scale [ESS], Insomnia Severity Index [ISI]) at baseline and at follow-up. Migraine frequency, disability (Migraine Disability Assessment [MIDAS], Headache Impact Test [HIT-6]), allodynia (Allodynia Symptom Checklist [ASC-12]), acute medication use, and adverse events (AEs) were also recorded. Pre-post differences were assessed with Wilcoxon and McNemar's tests, while linear mixed-effects models were applied to evaluate the impact of clinical factors (response status, psychiatric comorbidities, prior anti-CGRP failures) on PSQI outcomes, with model fit estimated via REML and pseudo-R&lt;sup&gt;2&lt;/sup&gt;.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The study population included 43 participants (93.0% female, mean age of 51.6 [IQR 48.4-54.8] years, mean age at disease onset of 18.9 [16.0-21.7] years); 30 (69.8%) participants had chronic migraine, and among them, 23 (76.7%) had a concomitant diagnosis of medication overuse headache. Atogepant significantly improved sleep quality with PSQI scores decreased from 9.6 to 8.2 (p = 0.002) and improvements in AIS (p = 0.014) and Bergen scores (p = 0.046). Sleep duration was the only PSQI subdomain with a statistically significant change. No differences were found in ESS or ISI scores. Notably, no patients reported sleep-related AEs such as somnolence, nightmares, or vivid dreams. Psychiatric comorbidities were associated with poorer baseline sleep but did not influence the magnitude of improvement. Prior anti-CGRP failure predicted a lesser sleep benefit. Finally, migraine burden improved across all evaluated migraine-related variables. Only two patients discontinued treatment.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusi","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145274012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ethnicity-Based Personalized Clozapine Titration Strategies for Prevention of Clozapine-Induced Inflammation: Recommendations Based on Evidence from the Japanese Population.","authors":"Yuki Kikuchi, Bunichiro Onodera, Hiroshi Komatsu, Hiroaki Tomita","doi":"10.1007/s40263-025-01236-x","DOIUrl":"https://doi.org/10.1007/s40263-025-01236-x","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145250171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}