CNS drugs最新文献

{"title":"Psychedelics for Alcohol Use Disorder: A Narrative Review with Candidate Mechanisms of Action.","authors":"Eric A Miller, Christy Capone, Erica Eaton, Robert M Swift, Carolina L Haass-Koffler","doi":"10.1007/s40263-025-01199-z","DOIUrl":"10.1007/s40263-025-01199-z","url":null,"abstract":"<p><p>Psychedelics have been studied since the 1950s as a potential treatment for alcohol use disorder (AUD), with over a dozen clinical trials of lysergic acid diethylamide (LSD), and several contemporary trials of psilocybin and ayahuasca for this indication. Herein, we characterize foundational studies from the 1950s to the present, with emphasis on key design factors that varied considerably between published studies. Critically, those design factors include pharmacological factors, such as presence or absence of a placebo control and the nature of the placebo (e.g., ephedrine, dextroamphetamine, diphenhydramine, or low-dose LSD), and non-pharmacological factors, such as the treatment setting and the presence or absence of psychotherapy. We found that observational studies nearly uniformly show promising results, but trials in which psychedelics were tested against placebo or standard of care control groups have been more inconsistent in both outcomes and methodologies. Given the inconsistency in published results, we review candidate mechanisms of action for psychedelics in the context of AUD. We take a biopsychosocial approach, reviewing mechanisms spanning several different hierarchical levels of analysis, including cellular neuroplasticity, cognitive neuroscience, subjective experience, and social connection. Taken together, this review highlights key findings on both the efficacy and potential mechanisms of psychedelics for the treatment of AUD, which could motivate future studies in this rapidly developing field.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"843-864"},"PeriodicalIF":7.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607673","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, Tolerability, and Pharmacokinetics of NRL-1049, a Rho-Associated Kinase Inhibitor, in Healthy Volunteers: A Phase 1, First-in-Human, Single-Ascending Dose, Randomized, Placebo-Controlled Trial.","authors":"Stuart Madden, Issam Awad, Miguel A Lopez-Toledano, Leslie Morrison, Juan Gutierrez, Leock Y Ngo, Enrique Carrazana, Adrian L Rabinowicz","doi":"10.1007/s40263-025-01198-0","DOIUrl":"10.1007/s40263-025-01198-0","url":null,"abstract":"<p><strong>Background and objectives: </strong>Cerebral cavernous malformations (CCMs) are vascular lesions of the brain that can lead to hemorrhage, focal neurologic deficits, and seizures. Rho-associated kinase (ROCK) overactivation plays a critical role in the development of CCMs, and a novel, selective ROCK2 inhibitor, NRL-1049, mitigated lesion burden and bleeding in mouse models of CCM. This study examined the safety, tolerability, and pharmacokinetics of NRL-1049 in healthy volunteers.</p><p><strong>Methods: </strong>In this first-in-human, randomized, double-blind, single-ascending dose study, participants received a single, oral dose of NRL-1049 (25, 75, 150, or 250 mg) or placebo in a fasted state (period 1). In period 2, participants received 150 mg NRL-1049 or placebo 30 min after a standardized high-fat, high-calorie meal. Blood samples for pharmacokinetic analysis were collected pre-dose and at post-dose time points from 5 min to 48 h. Treatment-emergent adverse events (TEAEs) were recorded and pharmacokinetic parameters determined, including maximum drug concentration (C_max), time to C_max (t_max), and area under the concentration-time curve (AUC) from time 0 to last quantifiable concentration (AUC_0-t) and extrapolated to infinity (AUC_0-∞).</p><p><strong>Results: </strong>Of the 24 participants in period 1 who received NRL-1049 (fasted), 9 (37.5%) experienced ≥ 1 TEAE, with 8 (33.3%) reporting ≥ 1 treatment-related TEAE. TEAEs appeared to correlate with dose, and 150 mg was the maximum tolerated dose following single-dose administration in this study. The most common TEAEs (> 5%) were dizziness (16.7%), headache (8.3%), and syncope (8.3%). In period 2 (n = 10), four (40.0%) participants who received 150 mg NRL-1049 (fed) reported ≥ 1 TEAE, and three (30.0%) reported a treatment-related TEAE. There were no reports of serious TEAEs or discontinuations due to a TEAE. NRL-1049 was rapidly absorbed in the fasted state, with median t_max ranging from 0.50 to 0.75 h. Mean C_max increased over the dose range of 25-250 mg (3.66-58.0 ng/mL). As NRL-1049 dose increased in a ratio of 1:3:6:10, mean C_max similarly increased (1:5:10:16), while AUC_0-t and AUC_0-∞ increased in a greater-than-dose proportional manner (1:5:11:25 and 1:4:10:21, respectively; P < 0.001). In the fed state (150 mg NRL-1049), mean C_max (18.5 ng/mL) was lower compared with the fasted state (34.9 ng/mL). For the active metabolite, NRL-2017, in the fasted state, median t_max was 0.88-1.63 h, and mean C_max increased over the dose range (54.2-1520 ng/mL). Mean C_max (1:6:14:28), AUC_0-t (1:4:7:14), and AUC_0-∞ (1:3:6:13) of NRL-2017 increased in a greater-than-dose proportional manner (P < 0.001). In the fed state, mean C_max was lower compared with the fasted state.</p><p><strong>Conclusions: </strong","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"865-877"},"PeriodicalIF":7.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12354486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583276","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":"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":"Plasma Protein Patterns Associated with Paliperidone Palmitate Maintenance Therapy in Schizophrenia: A Prospective Cohort Study.","authors":"Weiwei Zeng, Feiqing Liang, Xiaoying Lin, Yaoyuan Zhang, Yuanzi Zheng, Tahir Ali, HaiBin Dai","doi":"10.1007/s40263-025-01220-5","DOIUrl":"https://doi.org/10.1007/s40263-025-01220-5","url":null,"abstract":"<p><p>BACKGROUND AND OBJECTIVE: Patients with schizophrenia exhibit significant interindividual variations in their response to pharmacotherapy, adverse effects, and clinical outcomes. While once-monthly paliperidone palmitate (PP1M) injections can improve treatment adherence and continuity compared with oral formulations, suboptimal therapeutic outcomes are still observed in some patients. Although the mechanisms underlying the variability in efficacy of long-acting injectables (LAIs) remain unclear, studies suggest an association with alterations in plasma protein expression. This study aims to investigate the correlation between interindividual differences in the response to PP1M treatment and changes in plasma protein abundance using proteomic analysis.</p><p><strong>Methods: </strong>This prospective cohort study was conducted in Longgang District, Shenzhen, China. Utilizing Olink Proximity Extension Assay (PEA) proteomics technology, we analyzed plasma samples from 27 healthy controls and 28 patients with schizophrenia who were clinically indicated for and initiated on maintenance therapy with once-monthly paliperidone palmitate long-acting injection (PP1M), as assessed by their treating physicians. Plasma abundance levels of 92 proteins were measured in all patients with schizophrenia, both prior to their first PP1M administration and following at least 3 months of PP1M treatment.</p><p><strong>Results: </strong>Our findings demonstrated that maintenance therapy with PP1M for at least 3 months effectively sustained and improved clinical symptoms in clinically stable patients with schizophrenia. However, it was associated with prolactin elevation, a known effect related to paliperidone. Utilizing Olink PEA analysis, we identified 25 plasma proteins, including SNAP23, ENO2, QDPR, ANXA11, and KYAT1, that distinguished patients with schizophrenia from healthy controls. Intriguingly, K-means clustering analysis of the differentially expressed proteins (DEPs) across the three groups (healthy controls, pretreatment, and posttreatment) revealed four distinct clusters characterized by specific expression patterns: class 1 (restoration to healthy control levels), class 2 (persistent elevation), class 3 (moderate recovery), and class 4 (further reduction). Analysis of plasma DEPs before and after at least 3 months of PP1M treatment identified significantly altered proteins (ENO2, QDPR, CRKL, ANXA11, KYAT1) exhibiting the class 1 expression pattern, characterized by a progressive restoration of plasma protein abundance to levels observed in healthy controls. Furthermore, analysis of DEPs associated with PP1M-induced hyperprolactinemia (a safety outcome) revealed that patients with schizophrenia demonstrated a higher probability of developing abnormally elevated prolactin levels after at least 3 months of PP1M treatment if they exhibited baseline elevations in ANXA11 and DIABLO, coupled with reduced CLEC5A expression.</p><p><strong>Conclusions: </stron","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945498","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":"Patterns of Serum Prolactin Elevation Associated with Nine Second-Generation Antipsychotics in a Large Cohort of Patients with Schizophrenia.","authors":"Lei Zhang, Yuzhen Zheng, Jingjing Huang, Wenjuan Yu, Lihong Zhou, Luyao He, Yange Li, Hao Hu, Guanjun Li, Yifeng Shen, Jianping Zhang, Huafang Li","doi":"10.1007/s40263-025-01216-1","DOIUrl":"10.1007/s40263-025-01216-1","url":null,"abstract":"<p><strong>Background: </strong>Prolactin elevation associated with antipsychotic use significantly affects medication adherence and long-term treatment outcomes in patients with schizophrenia. The currently available data are insufficient to guide the monitoring and management of elevated prolactin levels in patients on antipsychotic medications. This study aimed to explore the patterns of prolactin level elevation associated with nine second-generation antipsychotics (SGAs) in a real-world setting and compare the associated risks.</p><p><strong>Methods: </strong>This retrospective cohort study utilized data from the inpatient electronic medical records of a large mental health center in China from 2007 to 2019. The study included patients diagnosed with schizophrenia (ICD-10 criteria) who received SGA therapy and whose serum prolactin levels were measured. Exposures were the use of nine specific SGAs (amisulpride, risperidone, paliperidone, ziprasidone, olanzapine, perospirone, quetiapine, clozapine, or aripiprazole), including polytherapy and monotherapy. The primary outcome was incident prolactin elevation in patients during hospitalization. An adjusted stratified Cox proportional hazards regression analysis was used to compare the hazard ratios (HRs) of prolactin level elevation across the nine SGAs. In addition, a dose-response analysis of these SGAs was conducted using the defined daily dose (DDD) method. Dose categories were as follows: < 0.6 DDDs/day (low dose), 0.6 to < 1.1 DDDs/day (medium dose), and ≥ 1.1 DDDs/day (high dose).</p><p><strong>Results: </strong>This study included 6489 patients with schizophrenia (mean [SD] age, 35.1 [14.2] years; 3396 males [52.3%]). Compared with the nonexposure, amisulpride (HR 2.76, 95% confidence interval [CI] 2.12-3.59), risperidone (HR 2.70, 95% CI 2.30-3.16), paliperidone (HR 1.84, 95% CI 1.37-2.46), and ziprasidone (HR 1.36, 95% CI 1.06-1.76) were associated with the highest risk of prolactin elevation. In contrast, quetiapine (HR 0.73, 95% CI 0.61-0.87), clozapine (HR 0.59, 95% CI 0.46-0.76), and aripiprazole (HR 0.30, 95% CI 0.23-0.37) were associated with the lowest risk. Amisulpride posed the highest risk among male patients, whereas risperidone posed the highest risk among female patients. Different types of dose-response associations were detected in seven SGAs.</p><p><strong>Conclusion: </strong>This cohort study, conducted in an inpatient setting, identified different risks of prolactin elevation associated with SGAs, along with their dose-response curves. Sex and age must be considered when prolactin elevation is analyzed in patients with schizophrenia who are treated with SGAs.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov identifier: NCT04002258.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882352","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}