CNS drugs最新文献

{"title":"Motor and Non-motor Complications Following Different Early Therapies in Parkinson's Disease: Longitudinal Analysis of Real-Life Clinical and Therapeutic Data from the French NS-PARK Cohort.","authors":"Aymeric Lanore, Edouard Januel, Nathalie Bertille, Margherita Fabbri, Louise-Laure Mariani, Graziella Mangone, Sara Sambin, Poornima Jayadev Menon, Melissa Tir, Matthieu Bereau, Wassilios G Meissner, Claire Thiriez, Ana Marques, Philippe Remy, Gwendoline Dupont, Elena Moro, Luc Defebvre, Jean Luc Houeto, Stéphane Thobois, Jean-Philippe Azulay, Christian Geny, Solène Frismand, Philippe Damier, Caroline Giordana, Giovanni Castelnovo, Solène Ansquer, Anne Doe De Maindreville, Sophie Drapier, David Maltête, Christine Tranchant, Olivier Rascol, Florence Tubach, Yann De Rycke, Jean-Christophe Corvol","doi":"10.1007/s40263-025-01193-5","DOIUrl":"10.1007/s40263-025-01193-5","url":null,"abstract":"<p><strong>Background: </strong>Levodopa, dopamine agonists (DA) and monoamine oxidase inhibitors (MAOI) are all approved first-line therapies for Parkinson's disease (PD), as monotherapy or in combination. Data on their use in the early management of patients with PD in real-life are lacking. Our objective was to assess the impact of early therapeutic strategies on the development of motor and neuropsychiatric complications using a nationwide PD cohort.</p><p><strong>Methods: </strong>NS-PARK is a cohort of patients with PD recruited between 2011 and 2021 from 26 expert centres for PD in France. We analysed the patients with less than 5-years disease duration and no motor complications at inclusion. We used interval censoring survival models to assess the associations between therapeutic strategies (levodopa monotherapy, levodopa alternative therapies or levodopa combinations) and motor fluctuations, dyskinesia, impulse control and related behaviours (ICRBs), apathy, psychosis/hallucination and daytime sleepiness. Analyses were adjusted for sex, age, disease duration, dopaminergic dose and disease severity.</p><p><strong>Results: </strong>We included 1722 patients (38.4% female, median age 67.7 years). At inclusion, 41% received levodopa monotherapy, 31% received levodopa alternative therapies and 28% received levodopa combinations. Compared with levodopa monotherapy, levodopa alternative therapies were associated with a lower dyskinesia risk (hazard ratio (HR) 0.48, 95% confidence interval (CI)[0.28-0.84]), but there was no significant difference in motor fluctuations. Both levodopa alternative and combinations therapies increased ICRBs risk (HR 4.06, 95% CI [2.48-6.67]; HR 5.16, 95% CI [3.00-8.86]) and decreased apathy risk (HR 0.36, 95% CI [0.26-0.49]; HR 0.52, 95% CI [0.39-0.69]). No association was found with psychosis/hallucination or daytime sleepiness.</p><p><strong>Conclusions: </strong>In this real-life cohort, our data supported an association between levodopa alternative therapies and a lower risk of dyskinesia and apathy, but a higher risk of ICRBs compared with levodopa monotherapy.</p><p><strong>Clinicaltrials: </strong></p><p><strong>Gov identifier: </strong>NCT04888364. Registered June 2021.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"879-891"},"PeriodicalIF":7.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141590","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":"Multiple Sclerosis in People of Diverse Racial and Ethnic Backgrounds: Presentation, Disease Course, and Interactions with Disease-Modifying Therapy.","authors":"Julia Li, Nandita Vas, Lilyana Amezcua, Dalia L Rotstein","doi":"10.1007/s40263-025-01205-4","DOIUrl":"10.1007/s40263-025-01205-4","url":null,"abstract":"<p><p>Multiple sclerosis (MS) affects people of all racial and ethnic backgrounds, with greatest prevalence noted in Black and white individuals living in Europe and North America. Age of MS onset seems to be earlier in Black, Latino/Hispanic, and South Asian people living with MS in North America and the United Kingdom. Additionally, Black and Latino/Hispanic people with MS in the USA are more likely to have severe initial presentations and earlier accumulation of disability compared with white people with MS. Evidence is sparse concerning how efficacy and safety of disease-modifying therapies for MS may vary with race and ethnicity, largely due to underrepresentation of racial and ethnic diversity in clinical trials. Social determinants of health such as sex, income, education, and the built environment interact with race and ethnicity to affect delays in MS diagnosis, use of therapy, and disease outcomes. In general, considering earlier disability progression, barriers to treatment access and adherence, and existing drug efficacy data, there may be even greater reason to consider early high efficacy therapy in underrepresented populations. More research and targeted interventions are needed to improve outcomes for people of diverse racial and ethnic backgrounds living with MS.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"823-842"},"PeriodicalIF":7.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658550","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":"Association Between Opioid Analgesics and Suicide Attempts: A Nationwide French Case-Crossover Study.","authors":"Bénédicte Nobile, Erika Nogue, M C Picot, Philippe Courtet, Chouki Chenaf, Nicolas Authier, Emilie Olié","doi":"10.1007/s40263-025-01221-4","DOIUrl":"https://doi.org/10.1007/s40263-025-01221-4","url":null,"abstract":"<p><strong>Background and objectives: </strong>The rising prescription rates and opioid-related harms in France highlight the need for local data. Evaluating this association may help identify vulnerable subgroups and guide safer prescribing practices. This study aimed to assess the association between opioid analgesic dispensation and the risk of suicide attempt in the French population. Secondary objectives included evaluation of a dose-response relationship and examination of the potential additive effects of co-prescriptions with benzodiazepines or gabapentinoids.</p><p><strong>Methods: </strong>We conducted a nationwide, population-based case-crossover study using data from the French National Health Insurance Database (Système National des Données de Santé, SNDS), covering 98.8% of the French population. Adults aged 18 years or older who were hospitalized for a first suicide attempt between 1 January 2013 and 31 December 2020, and who had received at least one opioid analgesic dispensation in the preceding year (excluding buprenorphine and methadone) were included. Opioid analgesic exposure during the 84 days before the attempt was compared with three earlier 84-day control periods.</p><p><strong>Results: </strong>Among 158,400 patients (mean age 47.0 years; 64.0% women), opioid analgesic dispensation was associated with a higher risk of suicide attempt (odds ratio [OR] = 1.26; 95% confidence interval 1.25-1.28). The risk was greater for strong opioid analgesics (OR = 1.73) and higher morphine-equivalent doses. Co-prescription with benzodiazepines or gabapentinoids further increased risk.</p><p><strong>Conclusions: </strong>Opioid analgesic use, especially at higher doses or in combination with benzodiazepines or gabapentinoids, was associated with an increased risk of suicide attempt. Clinical vigilance is warranted when prescribing these medications.</p><p><strong>Trial registration: </strong>NCT04211077, registered 3 January 2020 (retrospectively registered).</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945487","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":"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":"https://doi.org/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":""},"PeriodicalIF":7.4,"publicationDate":"2025-08-13","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":"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":""},"PeriodicalIF":7.4,"publicationDate":"2025-08-07","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":"https://doi.org/10.1007/s40263-025-01210-7","url":null,"abstract":"","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-08-02","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":"Peripheral Immune-Inflammatory Pathways in Major Depressive Disorder, Bipolar Disorder, and Schizophrenia: Exploring Their Potential as Treatment Targets.","authors":"Abbas F Almulla, Michael Maes","doi":"10.1007/s40263-025-01195-3","DOIUrl":"10.1007/s40263-025-01195-3","url":null,"abstract":"<p><p>Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are major mental disorders linked to substantial morbidity. Traditional monoamine-based pharmacotherapies frequently produce inadequate outcomes for many patients. The elevated levels of treatment resistance require the exploration of new pharmacological targets. Evidence indicates that peripheral immune-inflammatory dysregulation, characterized by an imbalance between immunological responses and compensatory immune-regulatory systems (IRS/CIRS), together with increased oxidative and nitrosative stress (O&NS), significantly contributes to the pathogenesis of these disorders. This review examines IRS/CIRS/O&NS pathways as new drug targets and highlights novel pharmacological trials. Antiinflammatory drugs have been repurposed as augmentation strategies for the treatment of MDD/BD and SCZ, including nonsteroidal antiinflammatory medications, such as cyclooxygenase-2 (COX-2) inhibitors; cytokine-targeting biologics, such as tumor necrosis factor-α monoclonal antibodies; and minocycline, an antibiotic that attenuates neuroinflammation. N-acetylcysteine, curcumin, and omega-3 polyunsaturated fatty acids demonstrate some efficacy as augmentation therapies in MDD, likely by diminishing IRS activation and O&NS. Strategies aimed at the gut-brain axis and gut dysbiosis, including fecal microbiota transplantation, are under investigation for their capacity to restore immunological homeostasis by improving gut barrier integrity and microbiome composition. This review examines new potential therapeutic targets arising from recent discoveries in neuro-immune interactions and oxidative stress, including particular lymphocyte surface markers, the CIRS, and intracellular network molecules in both affective and psychotic disorders. The evidence underscores the clinical importance of immune-targeted augmentation treatments in psychiatric disorders and supports the ongoing development of these novel pharmacotherapies within a precision medicine paradigm.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"739-762"},"PeriodicalIF":7.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293420","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":"Pharmacokinetics and Pharmacodynamics of Intranasal Diacetylmorphine in Heroin-Assisted Treatment for Severe Opioid Use Disorder.","authors":"Adrian Guessoum, Severin B Vogt, Maximilian Meyer, Jean Nicolas Westenberg, Benjamin Klemperer, Kenneth M Dürsteler, Matthias E Liechti, Jan Thomann, Dino Luethi, Urs Duthaler, Marc Vogel","doi":"10.1007/s40263-025-01189-1","DOIUrl":"10.1007/s40263-025-01189-1","url":null,"abstract":"<p><strong>Background: </strong>Intranasal diacetylmorphine (IN DAM) represents a promising new route of administration, which is currently under investigation as a novel treatment approach for opioid use disorder in Switzerland. This study characterized the pharmacokinetics and pharmacodynamics of therapeutically relevant intranasal doses of DAM and its metabolites in patients with severe opioid use disorder.</p><p><strong>Methods: </strong>In this prospective observational study, patients on intranasal heroin-assisted treatment (HAT) in Basel, Switzerland, self-administered their usual dose of IN DAM before receiving their daily maintenance dose. Inclusion criteria were age ≥ 18 years and current participation in IN HAT. Plasma concentrations of diacetylmorphine, 6-monoacetylmorphine (6-MAM), morphine, morphine-6-glucuronide, and morphine-3-glucuronide were measured using liquid chromatography-tandem mass spectrometry at baseline and at 2, 5, 10, 15, 20, 30, 40, 50, 60, 120, and 180 min. Acute subjective effects and cravings were assessed repeatedly using visual analog scales, withdrawal symptoms were measured using the Short Opiate Withdrawal Scale, and autonomic responses were recorded over the 3 h after IN DAM administration.</p><p><strong>Results: </strong>In total, 14 patients were included in the study. The mean self-administered IN DAM dose was 346 mg (range 190-700 mg) delivered over a mean time of 3.8 min (range 1-9 min). IN DAM elicited moderate-to-strong peak drug effects, with marked reductions in heroin craving and withdrawal symptoms. No clinically relevant respiratory depression or decrease in oxygenation saturation was observed. Subjective effects occurred rapidly within the first 2 min after the start of administration. These effects gradually increased and peaked at 30-35 min, which paralleled the rising plasma concentrations of DAM and 6-MAM, while the sustained heroin-like effects best correlated with morphine and morphine-6-glucuronide plasma concentrations. Plasma half-lives of diacetylmorphine and 6-monoacetylmorphine were longer, and time to maximal plasma concentration was later than previously reported, suggesting saturated absorption at high intranasal doses and volumes.</p><p><strong>Conclusions: </strong>IN DAM has a good safety profile and should be considered as an effective alternative for patients in HAT, offering rapid onset of effects without significant side effects. Optimization of intranasal delivery may further improve absorption and clinical utility.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"807-817"},"PeriodicalIF":7.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigational Gene Therapies for Parkinson's Disease.","authors":"Nicolas Phielipp, Claire Henchcliffe","doi":"10.1007/s40263-025-01203-6","DOIUrl":"10.1007/s40263-025-01203-6","url":null,"abstract":"<p><p>Since the publication of the first gene therapy clinical trial in Parkinson's disease (PD) in 2007, rapid advances have resulted in escalating interest in applying this technology to manipulate various cellular processes altered in PD. There is now a rich literature describing the various approaches taken, including modulating aberrant networks, restoring dopamine, and mitigating deleterious effects of known gene mutations or as a restorative therapy. Evidence has accrued supporting feasibility, safety, and tolerability of initial gene therapy approaches, as well as providing initial indications of efficacy in several cases. However, there have also been unexpected challenges, and technology is still evolving, making this an important time point to evaluate what has been learned and to place it in context to support ongoing and future efforts. In this review, we focus on the potential of gene therapy to ameliorate symptoms and modify disease progression in PD. We critically review previous clinical research, we address potential benefits and predicted limitations, and we address pipeline approaches aiming to bring a gene therapy approach to the clinic.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"725-737"},"PeriodicalIF":7.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subclinical Augmentation in Relation to Previous Dopaminergic Treatment in Patients with Restless Legs Syndrome: A Post Hoc Analysis of Two Randomized, Placebo-Controlled, Crossover Trials.","authors":"Diego Garcia-Borreguero, David Anguizola, Catalina Carvallo, Alejandro Lopez, Alba Garcia Aragón, Brian Moncada, Sergi Ferré","doi":"10.1007/s40263-025-01192-6","DOIUrl":"10.1007/s40263-025-01192-6","url":null,"abstract":"<p><strong>Background and objectives: </strong>Augmentation, a long-term complication of dopamine agonist treatment for restless legs syndrome (RLS), is preceded by a gradual loss of response. We investigated whether prior long-term dopaminergic treatment affects current and future responses to dopaminergic and non-dopaminergic drugs, which would suggest broader changes in RLS pathophysiology.</p><p><strong>Methods: </strong>We retrospectively analysed two previously published, double-blind, randomized, crossover, placebo-controlled studies with the adenosine transport inhibitor dipyridamole and the orexin receptor antagonist suvorexant. Post hoc analyses compared responses between dopaminergic (DA)-naïve and dopaminergic (DA)-treated patients with RLS. None of these patients met the diagnostic criteria for augmentation. After a 2-week washout, patients received active treatment (10-20 mg suvorexant or 200-300 mg dipyridamole) or placebo for 2 weeks, followed by crossover. Efficacy was assessed using the International RLS Rating Scale (IRLS), Clinical Global Impressions-Severity scale (CGI-S), multiple suggested immobilization test (m-SIT), periodic leg movements of sleep (PLMS) and other polysomnographic measures.</p><p><strong>Results: </strong>A total of 28 patients participated in the dipyridamole study (DA-pretreated, n = 10; DA-naïve group, n = 18), and 40 participated in the suvorexant study (DA-pretreated, n = 9; DA-naïve group, n = 31). Compared with DA-naïve patients, DA-pretreated patients responded significantly worse to both treatments on the basis of the IRLS, CGI-S, m-SIT, PLMS indices. There were no differences in sleep parameters.</p><p><strong>Conclusions: </strong>Our results suggest that previous long-term dopaminergic treatment, even before clinical augmentation is reached, induces pathophysiological changes in RLS that impair future responses to both dopaminergic and non-dopaminergic therapies. Our findings confirm previous results with gabapentin enacarbil and suggest that these changes develop well before clinical augmentation appears. Pathophysiological implications for the understanding of dopaminergic augmentation are discussed. Our results support the American Academy of Sleep Medicine (AASM) recommendation against using dopamine agonists as the initial choice for RLS treatment.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"779-793"},"PeriodicalIF":7.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224591","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}