CNS drugs最新文献

{"title":"The Effects of Cenobamate and Its Dosage on Cognition: A Retrospective Longitudinal Study in 84 Individuals with Epilepsy.","authors":"Juri-Alexander Witt, Mostafa Badr, Rainer Surges, Randi von Wrede, Christoph Helmstaedter","doi":"10.1007/s40263-025-01196-2","DOIUrl":"https://doi.org/10.1007/s40263-025-01196-2","url":null,"abstract":"<p><strong>Background: </strong>Previous studies on cenobamate (CNB) have generally reported neutral to positive effects on objective cognitive performance in patients with epilepsy, but are limited to dosages up to 250 mg/day. However, a case report (Witt et al. in Neurocase 30:91-96, 2024) noted severe memory deterioration at 400 mg/day.</p><p><strong>Objective: </strong>The purpose of this study was to examine dose-dependent effects of CNB on cognition.</p><p><strong>Methods: </strong>In this retrospective longitudinal real-world study, executive functions and episodic memory were assessed in adult patients with pharmacoresistant epilepsy during CNB therapy and compared with baseline. Subgroups were stratified by daily CNB doses of ≥ 300 mg versus < 300 mg. Executive functions were assessed using the EpiTrack^®, verbal memory via the VLMT or an abbreviated version, and figural memory with the DCS-R.</p><p><strong>Results: </strong>The study included 84 patients, 24 (28.6%) of them with a CNB dose of ≥ 300 mg. With a mean CNB dose of 200.6 ± 114.3 mg (range 12.5-400.0 mg), seizure freedom was achieved in 11.9% with no significant difference between the lower and the higher dose group. Repeated measures analysis of covariance (ANCOVA) revealed a significant decline in executive functions at ≥ 300 mg (n = 84; F = 6.35, p = 0.014) compared to baseline. Changes were correlated with CNB dose (r = - 0.31, p = 0.004). Individual level analyses indicated that 50.0% of patients on higher versus 16.7% on lower CNB doses deteriorated according to reliable change indices (RCI). In a subgroup undergoing extensive memory testing, verbal retention showed a significant negative, dose-independent effect at the group level (n = 22; F = 7.95, p = 0.011), with intraindividual declines in 28.6% (≥ 300 mg) versus 13.3% (< 300 mg). Other memory parameters were unaffected.</p><p><strong>Conclusions: </strong>The results of this real-world study investigating objective cognitive performance under CNB suggest possible, partially dose-dependent negative effects of CNB on cognition. Daily CNB doses of ≥ 300 mg were associated with a significant decline in executive functions. Furthermore, a dose-independent negative effect on verbal retention was observed in a subgroup of patients undergoing extensive memory assessment. Given the limitations of retrospective audits, our findings prompt further, larger scope studies to confirm the results. However, a careful balance between seizure control at the lowest CNB dose possible and potential cognitive side effects appears advisable, which requires the implementation of cognitive monitoring in standard care where possible.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274340","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":"https://doi.org/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":""},"PeriodicalIF":7.4,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/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":""},"PeriodicalIF":7.4,"publicationDate":"2025-06-04","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}

{"title":"The Evolution of Anti-CD20 Treatment for Multiple Sclerosis: Optimization of Antibody Characteristics and Function.","authors":"Bruce A C Cree, Joseph R Berger, Benjamin Greenberg","doi":"10.1007/s40263-025-01182-8","DOIUrl":"10.1007/s40263-025-01182-8","url":null,"abstract":"<p><p>B-cell depletion with CD20-targeted agents is commonly used for treatment of multiple sclerosis (MS), other autoimmune diseases, and certain hematologic malignancies. Initial apparent success with rituximab in MS and neuromyelitis optica spurred development of the anti-CD20 monoclonal antibody (mAb) therapies ocrelizumab, ofatumumab, and ublituximab as well as the anti-CD19 mAb inebilizumab. While each are effective at targeting and depleting B cells, structural differences translate into different mechanisms of action affecting maintenance of B-cell depletion and safety and tolerability. Although the anti-CD20 mAbs differ in degree of human versus mouse sequences as well as target CD20 epitope, these properties do not appear to substantially affect activity or tolerability. In contrast, an antibody-dependent cell-mediated cytotoxicity (ADCC) versus a complement-dependent cytotoxicity mechanism of action as well as subcutaneous versus intravenous administration may provide improved tolerability. Glycoengineering of the mAbs ublituximab and inebilizumab enhances ADCC and can overcome the reduced responses to mAb-mediated B-cell depletion associated with certain genetic polymorphisms. Other strategies for therapeutic targeting of CD20, including brain shuttle antibodies (e.g., RO7121932), bispecific antibodies, chimeric antigen receptor T-cell therapies, and antibody-drug conjugates, are in active clinical development and may be future treatment approaches in MS and other B-cell-mediated autoimmune diseases.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"545-564"},"PeriodicalIF":7.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12058931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779344","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":"Opioid Analgesics: Rise and Fall of Ligand Biased Signaling and Future Perspectives in the Quest for the Holy Grail.","authors":"Émile Breault, Rebecca L Brouillette, Terence E Hébert, Philippe Sarret, Élie Besserer-Offroy","doi":"10.1007/s40263-025-01172-w","DOIUrl":"10.1007/s40263-025-01172-w","url":null,"abstract":"<p><p>Opioid analgesics have been used for more than 5000 years and remain the main pain medications prescribed today. Although morphine is considered the gold standard of pain relief, this selective µ-opioid receptor (MOP) agonist provides only moderate relief for many chronic pain conditions and produces a number of unwanted effects that can affect the patient's quality of life, prevent adherence to treatment or lead to addiction. In addition to the lack of progress in developing better analgesics, there have been no significant breakthroughs to date in combating the above-mentioned side effects. Fortunately, a better understanding of opioid pharmacology has given renewed hope for the development of better and safer pain medications. In this review, we describe how clinically approved opioids were initially characterized as biased ligands and what impact this approach might have on clinical practice. We also look at the preclinical and clinical development of biased MOP agonists, focusing on the history of oliceridine, the first specifically designed biased analgesic. In addition, we explore the discrepancies between ligands with low intrinsic efficacy and those with biased properties. Finally, we examine the rationale behind the development of biased ligands during the opioid crisis.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"565-581"},"PeriodicalIF":7.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762746","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":"Foslevodopa/Foscarbidopa: A Review in Advanced Parkinson's Disease.","authors":"Hannah A Blair","doi":"10.1007/s40263-025-01179-3","DOIUrl":"10.1007/s40263-025-01179-3","url":null,"abstract":"<p><p>Foslevodopa/foscarbidopa [PRODUODOPA^® (EU); VYALEV^™ (USA, Canada, Japan)] is a soluble formulation of levodopa and carbidopa prodrugs for 24-h continuous subcutaneous (SC) infusion. It is approved for the treatment of motor fluctuations in patients with advanced Parkinson's disease (PD). Administered via an ambulatory infusion pump, it allows for personalized dosing based on individual needs. In a randomized, double-blind, double-dummy trial, continuous SC infusion of foslevodopa/foscarbidopa provided a significant and clinically meaningful increase in hours of 'on' time without troublesome dyskinesia and a reduction in hours of 'off' time compared with oral immediate-release levodopa/carbidopa. The benefits of foslevodopa/foscarbidopa were maintained over the longer term (up to 124 weeks). Continuous SC infusion of foslevodopa/foscarbidopa was generally well tolerated, including over the longer term. However, infusion site events were common, necessitating regular monitoring, cannula replacement, infusion site rotation and aseptic techniques. Although further long-term data are required, foslevodopa/foscarbidopa represents a promising non-surgical alternative to the available device-aided therapies for patients with advanced PD whose motor fluctuations are inadequately controlled by other oral PD medications.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"621-632"},"PeriodicalIF":7.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810667","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":"Evaluation of Safety, Pharmacokinetic, and Pharmacodynamic Characteristics of a Novel Dual mGluR5/5-HT2AR Antagonist (VVZ-2471) in a Randomized, Double-Blind, First-in-Human Study.","authors":"Sungyeun Bae, HyunJoon Lee, Inkyung Song, Jina Kim, Sang Rim Lee, Sunyoung Cho, Kyung-Sang Yu, Jae-Yong Chung","doi":"10.1007/s40263-025-01181-9","DOIUrl":"https://doi.org/10.1007/s40263-025-01181-9","url":null,"abstract":"<p><strong>Background: </strong>VVZ-2471 is a dual-target compound that simultaneously inhibits both metabotropic glutamate receptor subtype 5 and serotonin receptor subtype 2A. Preclinical studies have supported VVZ-2471 as a promising candidate for opioid use disorder. This study aimed to evaluate the safety and pharmacokinetic (PK)-pharmacodynamic (PD) characteristics of VVZ-2471 capsules in healthy Korean adults.</p><p><strong>Methods: </strong>A phase I, double blind, placebo controlled, single ascending dose (SAD) and multiple ascending dose (MAD) study was conducted in healthy adult males. In the SAD study, participants received a single oral dose of VVZ-2471 ranging from 25 to 600 mg, including a satellite food-effect group receiving 200 mg. In the MAD study, participants received 200 mg once daily (QD), 200 mg twice daily, and 400 mg QD for 7 days. Plasma and urine samples were collected for the PK analyses. Safety analysis was based on adverse events, clinical laboratory tests, vital signs, physical examinations, 12-lead electrograms, oxygen saturation monitoring, and the Beck Depression Inventory-II test. The potential of VVZ-2471 for treating addiction was explored using a well-established questionnaire on smoking urges (QSU-Brief) consisting of ten items.</p><p><strong>Results: </strong>A total of 49 and 24 healthy Korean adult males completed the SAD and MAD study, respectively. The overall demographic characteristics of participants who received VVZ-2471 or placebo in the SAD and MAD studies were generally comparable. Following a single oral dose of VVZ-2471 up to 600 mg, the area under the concentration-time curve (AUC) increased proportionally with the dose. After repeated administration, the accumulation ratio of VVZ-2471 ranged from 1.4 to 2.0. In the fed state, the maximum plasma concentration and AUC of VVZ-2471 decreased to 0.78-fold and 0.61-fold, respectively, compared with the fasting state. Urinary excretion was marginal. The most common adverse events were nausea and dizziness. Among 29 smokers, participants given VVZ-2471 at 200 mg or higher had reduced smoking urges compared with the placebo.</p><p><strong>Conclusions: </strong>VVZ-2471 was well tolerated up to a single oral dose of 600 mg and a daily oral dose of 400 mg for 7 days. While preliminary, a trend of reducing smoking urges was observed in the VVZ-2471 group.</p><p><strong>Registration: </strong>Clinical Research Information Service (CRiS), Republic of Korea (a primary registry in the World Health Organization (WHO) Registry Network) identifier no. KCT000889.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":"39 6","pages":"583-595"},"PeriodicalIF":7.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968693","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":"Clozapine-Related Tachycardia: An Analysis of Incidence.","authors":"Susanna Every-Palmer, Korinne Northwood, James Tsakas, Matthew K Burrage, Dan Siskind","doi":"10.1007/s40263-025-01177-5","DOIUrl":"10.1007/s40263-025-01177-5","url":null,"abstract":"<p><strong>Background and objectives: </strong>Sinus tachycardia commonly occurs at the start of clozapine treatment, often leading to discontinuation owing to perceived adverse cardiovascular effects. However, little evidence exists on its natural course after clozapine initiation. We aimed to determine the frequency and course of clozapine-induced tachycardia over the first month of treatment and to identify possible risk factors METHODS: In this cross-sectional study, we serially monitored heart rates (HRs) and other clinical variables of psychiatric inpatients commencing clozapine over the first 28 days. HRs were plotted over time and modelled by explanatory variables, including age group, sex, body mass index (BMI), smoking status and prescribed medications for HR.</p><p><strong>Results: </strong>In total, 123 consecutive inpatients undergoing clozapine titration were assessed daily, with 2901 HR measures collected. After starting clozapine, mean HR increased from 83.7 to 99.5 beats per minute (bpm). Almost all participants (93.5%) had at least one recorded HR > 100 bpm, and 68% had three consecutive days with HR > 100 bpm (being then defined as tachycardic). At least one HR > 120 bpm was recorded in 35.8%, and 8% had persistent HRs > 120 bpm. Tachycardia occurred early during clozapine titration, with a dose response effect at lower doses, which plateaued between 150 and 350 mg daily. Tachycardia spontaneously resolved for some but 44% remained tachycardic at day 28. Female sex was associated with early tachycardia at day 14 (p = 0.008) but not at day 28, while age, smoking status, and BMI were not significantly associated with tachycardia.</p><p><strong>Conclusions: </strong>Sinus tachycardia occurred in over two thirds of participants during the first month of clozapine titration. Spontaneous resolution of tachycardia in some suggests watchful monitoring may be appropriate prior to treatment with rate-controlling agents such as β-blockers or ivabradine. Long term follow-up is required to determine the effects of sinus tachycardia on cardiovascular outcomes in patients treated with clozapine.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"597-607"},"PeriodicalIF":7.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12058960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691213","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":"Comparative Efficacy and Safety of Multiple Wake-Promoting Agents for the Treatment of Residual Sleepiness in Obstructive Sleep Apnea Despite Continuous Positive Airway Pressure: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.","authors":"Pongsakorn Tanayapong, Visasiri Tantrakul, Somprasong Liamsombut, Sukanya Siriyotha, Gareth McKay, John Attia, Ammarin Thakkinstian","doi":"10.1007/s40263-025-01175-7","DOIUrl":"10.1007/s40263-025-01175-7","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objectives: &lt;/strong&gt;Residual sleepiness can occur in adult patients with obstructive sleep apnea (OSA) despite adequate treatment with continuous positive airway pressure (CPAP). Various wake-promoting agents (WPAs) have been shown to reduce residual sleepiness in CPAP-treated patients with OSA. This systematic review and network meta-analysis aimed to compare the efficacy and safety of WPAs in this setting.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We searched MEDLINE, Scopus, and ClinicalTrials.gov up to 9 January 2025 for randomized controlled trials (RCTs) examining WPAs for treating sleepiness in patients with OSA. Included were all RCTs that explored the efficacy and/or safety of any approved WPAs (i.e., modafinil, armodafinil, solriamfetol, or pitolisant) in patients with OSA (aged &lt;math&gt;&lt;mo&gt;≥&lt;/mo&gt;&lt;/math&gt; 18 years) treated with CPAP but who are still sleepy [Epworth sleepiness scale (ESS) score ≥10]. Studies that were conducted in patients whose comorbidities cause daytime somnolence [i.e., psychiatric conditions (other than depression), other sleep disorders, medical or surgical conditions], open label extension studies, and studies published in a language other than English were excluded. The primary outcomes included ESS, maintenance of wakefulness test (MWT), and adverse events. Two authors independently assessed the risk of bias using the revised Cochrane risk-of-bias tool for randomized trials 2.0.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In total, 14 RCTs studying four WPAs (total N = 2969) including modafinil (six RCTs; 200-400 mg/day), armodafinil (four RCTs; 150-250mg/day), solriamfetol (two RCTs; 37.5-300 mg/day), and pitolisant (two RCTs; 5-40 mg/day) were included. Solriamfetol, modafinil, and armodafinil were efficacious in reducing subjective sleepiness as measured by ESS [mean difference (95% confidence interval) at &lt;math&gt;&lt;mo&gt;≤&lt;/mo&gt;&lt;/math&gt; 4 weeks: -3.84 (-5.60, -2.07), -2.44 (-3.38, -1.49), and -2.41 (-3.60, -1.21) for solriamfetol, modafinil, and armodafinil, respectively; at &gt; 4 weeks: -4.11 (-6.14, -2.08), -2.88 (-3.85, -1.91), -2.46 (-3.68, -1.24) for solriamfetol, armodafinil, and modafinil, respectively] and clinical global impression of change, as well as the objective MWT [at &lt;math&gt;&lt;mo&gt;≤&lt;/mo&gt;&lt;/math&gt; 4 weeks: 11.66 min (9.70, 13.61), 3.61 min (2.48, 4.73), and 2.52 min (1.27, 3.76) for solriamfetol, modafinil, and armodafinil, respectively; at &gt; 4 weeks: 10.34 min (4.16, 16.52) for solriamfetol]. Pitolisant showed later improvements in ESS [at &gt; 4 weeks: -2.70 (-3.66, -1.73)], with limited data on MWT. Sensitivity analyses restricted to U.S. Food and Drug Administration-approved solriamfetol dosages (37.5-150 mg/day) still showed higher efficacy, but lower anxiety risk.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Among all WPAs, solriamfetol demonstrated the highest efficacy on ESS and MWT, with the latter being significant. Modafinil demonstrated the best clinician impression, albeit not statistically significant. ","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":"39 6","pages":"527-544"},"PeriodicalIF":7.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12058958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955746","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":"Impact of Medical Comorbidities on Ketamine and Esketamine Treatment Effectiveness for Posttraumatic Stress Disorder and Depression: A Clinical Outcomes Analysis from the VA San Diego Healthcare System.","authors":"Sijia Zhang, Houtan Afshar, Peter J Colvonen, Brandon Nokes, Jason Compton, Jyoti Mishra, Andrew W Bismark, Dhakshin S Ramanathan, Miranda F Koloski","doi":"10.1007/s40263-025-01180-w","DOIUrl":"https://doi.org/10.1007/s40263-025-01180-w","url":null,"abstract":"<p><strong>Background: </strong>Ketamine and esketamine are increasingly used to manage treatment-resistant depression and have also been shown to reduce symptoms of posttraumatic stress disorder (PTSD). Little is known about how common comorbidities in the veteran population, such as traumatic brain injury (TBI) or obstructive sleep apnea (OSA), may influence ketamine and esketamine treatment outcomes.</p><p><strong>Methods: </strong>In this retrospective study, we analyzed clinical outcomes from Veterans Affairs (VA) San Diego Healthcare System's ketamine program to assess the relationship between ketamine or esketamine treatment and changes in depression and PTSD symptoms, while also examining how common medical comorbidities influence treatment outcomes. We specifically examined whether a patient's history of TBI or OSA would affect ketamine or esketamine treatment outcomes. Linear mixed-effects models were used to examine how TBI and OSA history interacted with ketamine/esketamine treatment to change PTSD Checklist for DSM-5 (PCL-5) and Patient Health Questionnaire-9 (PHQ-9) scores.</p><p><strong>Results: </strong>This study included 119 veterans who received eight sessions of ketamine or esketamine treatment at the San Diego VA Medical Center. Using linear effects modeling, we found that repeated ketamine or esketamine sessions were significantly correlated with reductions in both depression (p < 0.005) and PTSD (p < 0.05) symptom scores. However, in veterans with comorbid TBI (n = 38) and severe OSA (n = 9), depression symptoms did not improve over the course of ketamine or esketamine treatment, suggesting this subgroup may require alternative treatments or OSA treatment prior to starting ketamine or esketamine treatment.</p><p><strong>Conclusions: </strong>Ketamine and esketamine treatment did not improve symptoms of depression in veterans with comorbid TBI and severe OSA. Thus, our findings generally support ketamine and esketamine as effective interventions for depression and PTSD, while emphasizing the consideration of comorbidities such as OSA and TBI.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":"39 6","pages":"609-619"},"PeriodicalIF":7.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983268","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}